Safety Issues Regarding the Use of Vitamin Supplements ADRIANNE BENDICH Human Nutrition Research Hoffmann-La Roche In c . Nutley, New Jersey 071 10
INTRODUCTION The safety of vitamins used to be simply stated: all water-soluble vitamins are safe at any level of intake and all fat-soluble vitamins are toxic, especially when intakes are above 10 times the recommended intake levels.' This review examines the data, mainly from well-controlled, clinical trials, that indicate that not all watersoluble vitamins are safe at any level of intake. Likewise, not all fat-soluble vitamins are toxic at or above 10 times the recommended levels of intake.
SAFETY OF THE UNITED STATES RDA LEVEL OF VITAMIN A FOUND IN MULTIVITAMIN SUPPLEMENTS The current U.S. RDA levels for each of 12 vitamins were established in 1973? and have been the standard for vitamin levels in multivitamin supplements for almost 20 years for adults and children four or more years of age (TABLEI ) . Two issues have recently arisen concerning the safety of the U.S. RDA level of vitamin A (5,000 IU) in multivitamin supplements: first, the safety of the level of vitamin A in multivitamin supplements for women of childbearing potential and, second, the purported association of elevated liver enzyme levels in elderly consuming multivitamins.
SAFETY OF THE LEVEL OF VITAMIN A IN MULTIVITAMIN SUPPLEMENTS FOR WOMEN OF CHILDBEARING POTENTIAL The concern about the potential teratogenicity of the U.S. RDA level of vitamin A found in multivitamin supplements is based on an extrapolation from the literature linking extremely high doses of vitamin A with birth defects in laboratory animals. Additionally, the known teratogenicity of a metabolite of vitamin A, 13cis retinoic acid, a prescription drug used to treat cystic acne, has increased the concern about the possible human teratogenicity of vitamin A. Since 1965, there have been five published individual cases of birth defects associated with vitamin A intakes at or above 25,000 IU per day (reviewed in refs. 3 and 4 ) . None of the reports includes a matched control population. The 5 case reports and 12 unpublished accounts were reviewed by Rosa et al.' Of the five published cases, two involve the consumption of 150,000 IU of vitamin A and one concerns the accidental swallowing of an oily liquid that Rosa et al. estimate contained 500,000 IU of vitamin A. 300
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Another case involves the consumption of 40,000 IU of vitamin A as well as 600,000 IU of vitamin D during the early weeks of pregnancy. It would be difficult to establish the potential teratogenicity of vitamin A at 40,000 IU separate from that of 600,000 1U of vitamin D (the U.S. RDA of vitamin D for pregnant women is 400 IU/day). The fifth case involved the consumption of cod liver oil supplements purportedly at a level of 25,000 IU of vitamin A per day during the first trimester and 50,000 IU per day for the remainder of the pregnancy. Cod liver oil has many constituents, including vitamin D, and may contain heavy metals such as mercury and cadmium, all of which have been implicated in causing birth defects. The U.S. RDA for vitamin A for pregnant women is 8000 IU per day. This level is based on the essentiality of vitamin A for normal embryonic growth, as well as the safety of this level of intake throughout pregnancy. The 8000 IU per day level is in accord with the International Vitamin A Consultative Group,6which set an upper limit of 10,000IU per day of vitamin A consumption during pregnancy.
U.S. RDA Levels of the Vitamins (Adults and Children Four or More Years of Age)"
TABLE 1.
Vitamin Mandatory vitamin A vitamin E vitamin C folic acid thiamine riboflavin niacin vitamin Bh vitamin BLz Optional vitamin D biotin oantothenic acid
U . S . RDA
IU IU mg Pg mg
5000 30 60 400 1.5 1.7 20 2 6
mg mg Pg
400 300
Pg
10
mg
IU me
'' Federal Register, 38 FR 20708 and 20730, August 2, 1973.
The Teratology Society, in its position paper on safe levels of vitamin A use during pregnancy,' suggested a maximum daily dose of 8000 IU. Recently, Werler ~t u I . , ~in a retrospective, case-control study, examined the potential association of vitamin A intake and risk of birth defects. There were 26.58 cases of malformations and 2609 controls. The prevalence of daily vitamin A supplementation was 0.6% for cases and 0.3% for controls. There was no statistically significant association of daily vitamin A supplementation and increased risk of birth defects. Approximately 50% of cases and controls used multivitamin supplements (including prenatals) by the third month of pregnancy. The authors conclude that there was no risk of birth defects associated with the use of multivitamin supplements and/or prenatals containing vitamin A. Several epidemiological studies have shown a significantly decreased risk of neural tube birth defects (NTD) in women who have taken multivitamin supplements during the periconceptional period (usually 1-3 months before conception
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and up to three months after conception). Additionally, intervention trials have shown that a recurrence of pregnancies with this serious birth defect is three times lower in women who were given a multivitamin supplement containing approximately the U.S. RDA level of vitamin A, as well as other vitamins, including folk acid. Research points to a critical role of folk acid in preventing NTD; however, the U.S. RDA level of vitamin A usually present in standard multivitamin supplements was not associated with any increase in the risk of this or any other birth defect.’These data, along with the studies reviewed in recent paper^,^,^ point to the safety of the U.S. RDA level of vitamin A for women of childbearing potential.
SAFETY OF THE LEVEL OF VITAMIN A IN MULTIVITAMIN SUPPLEMqNTS FOR THE ELDERLY Vitamin A is stored in the liver, and the levels increase with increasing age.’ The liver is the primary organ involved in the regulation of circulating levels of vitamin A through its production of retinol-binding protein (RBP). Under normal circumstances, vitamin A circulates in the blood bound to RBP. In cases of hypervitaminosis A, there may be insufficient RBP to bind all of the circulating vitamin A; the consequences include significantly higher circulating levels of free retinol and retinyl ester^.^'^ Krasinski et a/.’’ examined the serum retinyl ester levels and serum levels of several liver enzymes in a cross-sectional epidemiological study of a healthy elderly population. Supplemental vitamin A intakes were approximately 5000- 10,000 IU per day. Of the 562 elderly, 5 had an elevation in one liver enzyme level and 2 had an elevation in two liver enzymes. There was a modest elevation in serum retinyl ester levels in the 5 subjects, which the authors noted was 10-fold lower than the level associated with hypervitaminosis A. Based upon this limited data, the authors suggested “elderly people should limit their intake of supplemental vitamin A particularly over the long term.” In contrast to their initial report, the same group analyzed data from a more comprehensive, prospective longitudinal study that examined vitamin A parameters in healthy elderly over a five-year time span. The study involved 284 women; the mean daily supplement intake was approximately 5000 IU (range 1250-25,000 IU). Serum retinyl ester levels and serum liver enzyme levels did not differ between the nonsupplemented and supplemented groups.” A second prospective, five-year longitudinal study of 116 healthy adults over 64 years of age examined the effects of vitamin A supplementation as part of a multivitamin supplementation program.’* Nonsupplement users had not used supplements for at least the preceding 5 years, whereas supplement users had taken them for at least 5 years. Serum retinyl ester levels were significantly correlated with supplemental vitamin A intake; however, they were approximately 10-fold lower than the level associated with toxicity. Moreover, serum retinyl ester levels did not increase over time in the supplement users. No evidence of liver toxicity, as defined by elevated liver enzymes, was seen regardless of the amount of vitamin A supplementation and even after years of vitamin A supplement use. The data from the two prospective, longitudinal studies of vitamin A supplementation in elderly populations show a consistent lack of adverse effects, includ-
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ing effects on liver function, in those using vitamin A supplements at U.S. RDA levels (TABLE2). In a recent paper concerning the use of vitamidmineral supplements by the U.S. population, Subar and Block13 conclude that vitamidmineral supplementation “appears not to pose a significant health risk for most of the population.”
SAFETY OF SINGLE-ENTITY SUPPLEMENTS ABOVE U.S. RDA LEVELS: WATER-SOLUBLE VITAMINS Vitamin B, Doses of vitamin B, over 100 times the U.S. RDA of 2 mg/day have been used in the treatment of certain conditions, without reports of adverse effects. Reports of neuropathy, however, associated with prolonged use of very high doses of the vitamin appeared in the literature. A review of the safety of vitamin B,, published in 1986,14concluded that doses of less than 500 mg/day were safe over a period as long as 6 years. An update of this review, published in 1990,15examined the dose/ duration relationship that resulted in neuropathy. The data indicate that doses of vitamin B, less than 500 mg/day for up to two years were not associated with neuropathy. Daily doses above 1000 mg or a total intake of 1000 grams or more are consistently associated with neuropathy. The neuropathy is usually reversible upon cessation of supplementation. On the basis of the data, it is strongly recommended that use of supplements over 500 mg/day be avoided; if such high level dosages are required for medical reasons, it should be under the care of a physician, and neurologic testing should be incorporated into the physician-supervised treatment program.
Niacin Niacin is a general term that includes nicotinic acid and niacinamide, both of which have vitamin activity. Nicotinic acid, but not niacinamide, has been used successfully for almost 20 years to lower serum cholesterol levels.i6 Nicotinic acid at high levels lowers total and LDL-cholesterol and triglyceride levels and raises HDL-cholesterol levels. Long-term use has been shown to decrease both coronary artery disease mortality and overall mortality in middleaged men with previous myocardial infarctions.” In 1988, the NIH expert panel on cholesterol considered nicotinic acid as one of two compounds of first choice for the treatment of primary hypercholesterolemia, with daily dosages in the range of 3-6 g/day.Ix Nicotinic acid (but not niacinamide), at doses exceeding 300 rng/day, has been associated with transient flushing of the skin, nausea, and diarrhea. Hyperuricemia, abnormal liver enzyme levels, hyperglycemia, and certain gastrointestinal side effects are often seen in doses exceeding 2.5 g/day.18-20The use of high-level, time-release, or sustained-release formulations of nicotinic acid has been associated with a greater severity of liver damage than equivalent concentrations of the non-time release form^.^'-*^ The data indicate that the long-term use of high doses of nicotinic acid is associated with hepatic side effects, which can be significantly exacerbated when a time-release formulation is used. It is therefore strongly recommended that time-
Yes no Yes
5-year longitudinal 5-year longitudinal
Increased Above Non-users
Cross-sectional
Study Type
no no
no
Hypervitaminosis A Range
Retinyl Esters
yes (51562) no no
Increased with Time
of the U.S. RDA Level of Vitamin A in Multivitamin Supplements in the Elderly
Krasinski'" el a/. (affectedkotal) Johnson" er a/. Stauber" et al.
TABLE 2. Safety
yes (51562) no no
Liver Enzymes Elevated
P
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release forms of nicotinic acid be avoided and that liver function be monitored routinely in individuals using high doses of nicotinic acid, who should in any case be under the supervision of a physician. Vitamin C
Single supplements of vitamin C are the most commonly available singleentity vitamin supplements in the United States.25Likewise, single supplements of vitamin C are the most widely used by the American The most widely available concentration of vitamin C in single-entity supplements is 500 mgitablet. Therefore, total daily intakes of approximately 10 times the U.S. RDA of vitamin C (60 mgj are quite common in the U.S. adult population. Several excellent reviews of the safety of vitamin C have been published recently; all concur that vitamin C is safe at very high levels of intake for prolonged periods of In addition, adverse effects have not been reported in eight recently published placebo-controlled, double-blind studies with dosages of vitaFive other clinical studies, min C up to 10,000mg/day taken for several using dosages up to 5000 mg/day for more than three years also reported no side effect^.^^-^* Thus, in all of the well-controlled, clinical trials reviewed to date, using daily intakes that in some instances exceed 100 times the U.S. RDA of vitamin C, no side effects have been reported.
SAFETY OF SINGLE-ENTITY SUPPLEMENTS ABOVE U.S. RDA LEVELS: FAT-SOLUBLE VITAMINS Vitamin A
It is well-recognized that very high doses of vitamin A (approximately 500,000 IU, 100 times the U.S. RDA) can have acute, reversible side effects. Moreover, chronic ingestion of doses exceeding 50,000 IU, in some instances, have been associated with headache, nausea, and other side effects in a d ~ l t s .As ~ ,discussed ~ above, there appears to be no potential human teratogenicity associated with supplemental vitamin A intakes at the recommended levels of 5000 IU for women of childbearing potential and 8000 IU for pregnant women. Vitamin E
A comprehensive review in 1988 of the literature concerning the safety of vitamin E resulted in the conclusion that vitamin E is safe at levels of intake up to approximately 3000 mg for prolonged periods of time.43 Individuals taking anticoagulants should be advised to avoid high doses of vitamin E (over 4000 IU) because vitamin E can act synergistically with this class of drugs. Since 1988, two placebo-controlled, double-blind studies specifically evaluated such vitamin E safety issues as thyroid hormone levels, which had previously been reported to decrease with supplementation; serum creatinine levels, which were sporadically reported to increase with supplementation; and serum lipid levels, which have been reported to increase, remain the same, or decrease with supplementation.
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Lack of Effect of Supplementation with 800 IU of Vitamin E for 30 Days in Subjects Over 60 Years4, TABLE 3.
Hepatic function: liver enzymes bilirubin serum albumin
Renal function: urinary creatinine serum creatinine creatinine clearance
Hematological: total and CBC RBC count platelets hemoglobin hematocrit
Thyroid function: T3 and T4 uptake T,/T4 ratio free thyroxin
Meydani et al. ,44 in a carefully controlled, double-blind study, gave healthy adults over 60 years of age either 800 IU of vitamin E or a placebo for 30 days. All subjects were housed in a metabolic ward throughout the study period so that diets were completely matched for nutrient intakes. Hepatic function, as determined by serum albumin, liver enzymes (SGPT, SGOT, LDH, and alkaline phosphatase), and total (including conjugated and unconjugated) bilirubin were unaffected by vitamin E supplementation, as shown by the fact that values in the supplemented group did not differ from those seen in the placebo group. Hematological analyses included total and individual white blood cell counts, red blood cell and platelet counts, hemaglobin, and hematocrit, none of which was affected by vitamin E. Renal function, as measured by urinary and serum creatinine, creatinine clearance, and BUN levels, was unchanged by vitamin E. Thyroid function, as reflected by T3 and T, uptakes and ratio, as well as free thyroxin were also unchanged (TABLE3). Two important changes were seen: a significant decrease in serum lipid peroxides and a significant increase in serum zinc values in the vitamin E-supplemented group. There were also improvements in clinically relevant immunological parameters in the supplemented group. Kitagawa and M i r ~ ogave ~ ~ 14 college students 900 IU of vitamin E for 12 weeks and gave 5 students matched placebos in a single-blind study. There were no changes in serum liver enzymes (SGOT, SGPT); white blood cell, red blood cell, and platelet counts; hemoglobin level: creatinine phosphokinase level; or BUN in either group during the study. Serum thyroid hormone levels (T3, T,, and TSH) were also unchanged. Bleeding times, as measured by percentage prothrombin time, partial thrombin time, hepatoplastin test, and PIVKA-I1 (protein induced by vitamin K absence or antagonist) were unaffected by vitamin E supplementation. Serum indices of cholesterol, phospholipids, triglycerides, and total lipids were similar in the placebo and supplemented groups and were unchanged following vitamin E supplementation. Using a questionnaire, it was shown that there were no differences between the placebo and vitamin E-supplemented groups in reports of muscle weakness, gastrointestinal discomfort, headache, hypertension, or visual changes. In addition to the two studies reviewed in detail, 27 clinical studies published since 1986, in which approximately 10 times the U.S. RDA level of vitamin E (30 IU) or higher had been administered, have been compiled.46Moreover, no cases of hypertension associated with intakes of high doses of vitamin E have been reported in any of the more than 50 clinical studies reviewed. The conclusions of this analysis confirm those reached in 1988; specifically, studies using doses of
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307
vitamin E ranging from 200-2400 IU, administered for periods up to 4.5 years, reported no adverse effects.
Beta-Carotene Beta-carotene, at dosages exceeding 180 mg/day, has been used successfully in individuals with genetically inherited photosensitivities. Individuals using these high levels of beta-carotene chronically for therapeutic reasons have not developed abnormally high levels of serum vitamin A. In addition, normal volunteers given 180 mg/day of beta-carotene for 10 weeks had no evidence of hypervitaminosis A.47 Hypercarotenemia, or high serum levels of carotene, may occur when individuals take supplements containing 30 mg or more of beta-carotene for extended periods of time. In addition, individuals may develop yellow palms and soles, a condition technically known as hypercarotenodermia. This condition can be clearly differentiated from jaundice because the whites of the eyes (sclera) are yellow in those individuals with jaundice and are not yellow in those with hypercarotenodermiaS4’The skin coloration is reversible on cessation or reduction of intake. M e y ~ k e n sin, ~an~ editorial, cited a preliminary in which administration of beta-carotene supplements, either 15, 30, 45, or 60 mg for 9 months, was associated with a 40% decrease in serum vitamin E levels. The preliminary study provides no information concerning the statistical significance of the data in each supplement The findings of this preliminary study have not been corroborated in any other - ~ ~ beta-carotene published report. Specifically, in five separate s t u d i e ~ ~ Ousing supplements ranging from 30-300 mg taken daily for up to four years, there has been no finding of significant changes in serum vitamin E levels (TABLE4). Moreover, serum vitamin K levels were also found to be unaffected by betacarotene supplementation at 15, 30, or 60 mg for 6 months. Clotting times, as well as prothrombin coagulant activity, were monitored monthly and were also unaffected by beta-carotene supplementation.55 Average dietary intake of beta-carotene in the United States is approximately 1-2 mg/day. Diets recommended by the National Cancer Institute and the USDA contain approximately 5-6 mg/day of beta-carotene. Currently there is no recommended daily intake level of beta-carotene separate from its provitamin A activity.
TABLE 4. Beta-Carotene Supplementation: No Significant Effect on Serum
Vitamin E Levels
Reference Ringer et al.’” Mobarhan ef a[.” Greenberg et d.’* Richards et ul.” Willie et a/.’4
No. 10
8 913 20 14
Beta-Carotene Dose (mg)/duration (days) 300128 I20128 501365 501 1460 40142 301112
Serum Vitamin E (mg/dL) Before After 0.8 1.04 I .55 1.55 1.30 0.95
0.9 1.03 1.55 1.41 1S O 0.85
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CONCLUSIONS Regarding the issue of the safety of the level of vitamin A found in multivitamin supplements, the data indicate that the U.S. RDA level of 5000 IU is safe for all population groups, including women of childbearing potential and the elderly. The U.S. RDA level of vitamin A in prenatal vitamins is also safe. Data from clinical studies using single-entity supplements point to the fallacy in assuming that all fat-soluble vitamins are toxic above 10 times the U.S. RDA and that all water-soluble vitamins are safe at any level of intake. Specifically, very high doses of certain water-soluble vitamins, vitamin B, and niacin, are associated with clinically relevant adverse effects. By contrast, very high doses of the fat-soluble vitamin E or beta-carotene are not associated with clinically relevant adverse effects. Thus, each vitamin has its own safety profile, which must he clearly communicated to health professionals, as well as the lay public. Dissemination of accurate, scientifically based vitamin safety information can result in the prevention of avoidable adverse effects.
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35. BUCCA,C., G. ROLLA,A. OLIVA& J . C. FARINA. 1990. Effect of vitaminC on histamine bronchial responsiveness of patients with allergic rhinitis. Ann. Allergy 65: 31 1314. & E . E . GLOVER.1991. Blood pressure 36. OsILEsi, 0. D., L. TROUT,J. 0. OGUNWOLE and plasma lipids during ascorbic acid supplementation in borderline hypertensive and normotensive adults. Nutr. Res. 11: 405-412. 37. MCKEOWN-EYSSEN, G.,C . HOLLOWAY,V. JAZMAJI, E. BRIGHT-SEE,P. DION & W. R. BRUCE.1988. A randomized trial of vitamins C and E in the prevention of recurrence of colorectal polyps. Cancer Res. 4 8 4701-4705. 38. L.ux, B. & P. MAY. 1983. Long-term observation of young cystinuric patients under ascorbic acid therapy. Urol. lnt. 3 8 91-94. & A. A. FAUSER. 1988. Treatment ofidiopathic thrombo39. BROX,A. G., K. HOWSON-JAN cytopenic purpura with ascorbate. Br. J. Haematol. 7 0 341-344. 1990. Ascorbate for the treat40. VERHOEF,G. E. G., S. BOONEN& M. A. BOOGAERTS. ment of refractory idiopathic thrombocytopenic purpura. Br. J. Haematol. 74: 234. B. & P. BIERLING. 1990.Treatment ofchronicautoimmune thrombocytopenic 41. GODEAU, purpura with ascorbate. Br. J. Haematol. 75: 289-290. 42. MELETHIL, S . W., D. MASON& C.-J. CHANG.1986. Dose-dependent absorption and excretion of vitamin C in humans. Int. J. Pharmacol. 31: 83-89. A. B. & L. J . MACHLIN. 1988. Safety of oral intake of vitamin E. Am. J. 43. BENDICH, Clin. Nutr. 48: 612-619. 44. MEYDANI, S . N., M. P. BARKLUND, S . L I ~ M. , MEYDANI, R. A. MILLER,J. G. & J. B. BLUMBERG. 1990. Vitamin E suppleCANNON, F. D. MORROW, R. ROCKLIN mentation enhances cell-mediated immunity in healthy elderly subjects. Am. J. Clin. Nutr. 52: 557-563. 45. KITAGAWA, M. & M. MINO. 1989. Effects of elevated d-Alpha (RRR)-tocopherol dosage in man. J. Nutr. Sci. Vitaminol. 35: 133-142. 46. BENDICH, A. & L. J. MACHLIN. 1992. The safety of oral intakes of vitamin E: Data from clinical studies from 1986 to 1991. I n Vitamin E in Health and Disease. L . Packer & J. Fuchs, Eds.: 411-416. Marcel Dekker, Inc. New York. A. 1988. The safety of beta-carotene. Nutr. Cancer 11: 207-214. 47. BENDICH, F. L. 1990. Coming of age-the chemoprevention of cancer. N. Engl. J. 48. MEYSKENS, Med. 323: 825-827. & S. M. SAYER. 1990. 49. Xu, M. J . , Y . M. PENG,Y . L I U ,D. S. ALBERTS,P. M. PLEZIA Effect of chronic oral administration of beta-carotene on plasma alpha-tocopherol concentrations in normal subjects. Proc. Am. Assoc. Cancer Res. 31: 126. T. V., M. J. DELOOF,G. E. WINTERROWD, 50. RINGER, S. F. FRANCOM, S. K. GAYLOR, J . A. RYAN,M. E. SANDERS & G. S. HUGHES.1991. Beta-carotene’s effects on serum lipoproteins and immunologic indices in humans. Am. J. Clin. Nutr. 53: 688-694. 51. MOBARHAN, S.,P. BOWEN,B. ANDERSEN, M. EVANS,M. STACEWICZ-SAPUNTZAKIS, s. SUGERMAN, P, S i M M S , D. LUCCHESI& H . FRIEDMAN. 1990. Effects of betacarotene repletion on beta-carotene absorption, lipid peroxidation, and neutrophil superoxide formation in young men. Nutr. Cancer 14: 195-206. E. R., J . A. BARON& T . A. STUKEL.1991. Letters to the editor. N. Engl. 52. GREENBERG, J. Med. 324: 924-925. C. E. J . VAN RENSBURG, A. J. VAN RENSBURG, G. A., A. J. THERON, 53. RICHARDS, C. A. VANDER MERWE,J. M. KUYL& R. ANDERSON. 1990. Investigation of the effects of oral administration of vitamin E and beta-carotene on the chemiluminescence responses and the frequency of sister chromatid exchanges in circulating leukocytes from cigarette smokers. Am. Rev. Respir. Dis. 142: 548-554. B. A. UNDERWOOD, J. 0. TAYLOR,& C. H. 54. WILLETT, w. c . , M. J. STAMPFER, HENNEKENS. 1983. Vitamins A, E, and carotene: effects of supplementation on their plasma levels. Am. J. Clin. Nutr. 38: 559-566. 55. CANFIELD, L. M., J. J. CORRIGAN, P. M. PLEZIA,M. JETER,s. SAYERS & D. s. ALBERTS.1990. Effects of chronic beta-carotene supplementation on vitamin K status in adults. Nutr. Cancer 13: 263-269.
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DISCUSSION D. GIBBS(University of Hawuii, Honolulu, H I ) : If you comment on the anticoagulant characteristics of vitamin E, you should also comment that it is commonly used as an anticoagulant and is preferred by some surgeons because it normalizes coagulation activity rather than lowering it. A. BENDICH (Hoffmann-LaRoche Inc., Nutley, N J ) : That’s an efficacy issue. I’m really talking about safety. It may not be prudent for individuals to take vitamin E at high levels on top of the use of vitamin K antagonist. That was the point that I was trying to make. (Scarborough General Hospital, Toronto, Ontario, Canuda): B. DRESSLER You said that the non-time-release niacin has been associated with normal liver enzymes as opposed to the time-release variety at certain dosage ranges. Are they equally efficacious in the treatment of hypercholesterolemia? BENDICH: Let me clarify. There are liver enzymes that can be elevated with the non-time release as well as with the time-release niacin. The only problem is that with the time-release there is an enormous increase in the potential severity of the adverse effects. Whether or not it is equally efficacious is not an issue. J. CLAUSEN (University oflioskilde, Denmark): Please comment on high doses of vitamin C and absorption of iron. I have an impression that vitamin C may cause hemochromatosis. BENDICH: We have published a review of this topic (Toxicol Lett. 51: 189, 1990). We looked at every study in which vitamin C and iron were given together. We found that vitamin C intake increases iron absorption in individuals who are iron deficient. When you have normal transferrin saturation level, however, vitamin C does not further increase iron absorption. D. H. Kooss (Loma Linda, C A ) :A few years ago it was reported that prolonged intake of over 800 IU of vitamin E induced deep vein thrombosis in a few people. Could you comment? You are probably referring to reports by Briggs et a / . that appeared BENDICH: as a letter to the editor. Neither were from placebo-controlled, double-blind studies. It’s important to weigh a few anecdotal reports such as these against the bulk of good well-controlled studies available. P. WALTER(University ($Busel, Switzerland):We have heard that vitamin K may be beneficial for calcium in our bones. Do you know anything about the safety of vitamin K? No safety problems have been associated with oral use of phylloquiBENDICH: none (K,) and menaquinone (KJ. They both appear to be quite safe at levels much higher than those recommended by the RDA. C. L. KRUMDIECK (University of Alabama at Birmingham): Is there any information on the potential effect of ascorbic acid on the absorption of aluminum or the neurotoxicity of aluminum? L. J . MACHLIN (Hoffmann-LaRoche Inc., Nutley, N J ) : A paperjust published in the Lancet reported increased urinary excretion of vitamin C or citric acid after administration of extremely high levels of aluminum hydroxide. N o toxicity was noted, and there is nothing in the literature to suggest an increase in tissue deposition or toxicity because of vitamin C. R. M. BALLANTINE (Honesdale, P A ) :There are two commonly believed points that I didn’t hear you mention. One was the connection between vitamin C and kidney stones, and the other was the relationship between vitamin E and hypertension. Can you speak about these?
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BE-NDICH: All reviews of the literature have shown no association of vitamin C intake and kidney stones. With regard to vitamin E and hypertension, in spite of diligent searching, I have not found the scientific source of this concern. SPEAKER: Concerning the origin of the papers on vitamin C and UNIDENTIFIED kidney stones, the only source that I could find in the literature was a letter to the editor in the Journal of the Arnrricmn Medical Association.
INTRODUCTION The safety of vitamins used to be simply stated: all water-soluble vitamins are safe at any level of intake and all fat-soluble vitamins are toxic, especially when intakes are above 10 times the recommended intake levels.' This review examines the data, mainly from well-controlled, clinical trials, that indicate that not all watersoluble vitamins are safe at any level of intake. Likewise, not all fat-soluble vitamins are toxic at or above 10 times the recommended levels of intake.
SAFETY OF THE UNITED STATES RDA LEVEL OF VITAMIN A FOUND IN MULTIVITAMIN SUPPLEMENTS The current U.S. RDA levels for each of 12 vitamins were established in 1973? and have been the standard for vitamin levels in multivitamin supplements for almost 20 years for adults and children four or more years of age (TABLEI ) . Two issues have recently arisen concerning the safety of the U.S. RDA level of vitamin A (5,000 IU) in multivitamin supplements: first, the safety of the level of vitamin A in multivitamin supplements for women of childbearing potential and, second, the purported association of elevated liver enzyme levels in elderly consuming multivitamins.
SAFETY OF THE LEVEL OF VITAMIN A IN MULTIVITAMIN SUPPLEMENTS FOR WOMEN OF CHILDBEARING POTENTIAL The concern about the potential teratogenicity of the U.S. RDA level of vitamin A found in multivitamin supplements is based on an extrapolation from the literature linking extremely high doses of vitamin A with birth defects in laboratory animals. Additionally, the known teratogenicity of a metabolite of vitamin A, 13cis retinoic acid, a prescription drug used to treat cystic acne, has increased the concern about the possible human teratogenicity of vitamin A. Since 1965, there have been five published individual cases of birth defects associated with vitamin A intakes at or above 25,000 IU per day (reviewed in refs. 3 and 4 ) . None of the reports includes a matched control population. The 5 case reports and 12 unpublished accounts were reviewed by Rosa et al.' Of the five published cases, two involve the consumption of 150,000 IU of vitamin A and one concerns the accidental swallowing of an oily liquid that Rosa et al. estimate contained 500,000 IU of vitamin A. 300
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301
Another case involves the consumption of 40,000 IU of vitamin A as well as 600,000 IU of vitamin D during the early weeks of pregnancy. It would be difficult to establish the potential teratogenicity of vitamin A at 40,000 IU separate from that of 600,000 1U of vitamin D (the U.S. RDA of vitamin D for pregnant women is 400 IU/day). The fifth case involved the consumption of cod liver oil supplements purportedly at a level of 25,000 IU of vitamin A per day during the first trimester and 50,000 IU per day for the remainder of the pregnancy. Cod liver oil has many constituents, including vitamin D, and may contain heavy metals such as mercury and cadmium, all of which have been implicated in causing birth defects. The U.S. RDA for vitamin A for pregnant women is 8000 IU per day. This level is based on the essentiality of vitamin A for normal embryonic growth, as well as the safety of this level of intake throughout pregnancy. The 8000 IU per day level is in accord with the International Vitamin A Consultative Group,6which set an upper limit of 10,000IU per day of vitamin A consumption during pregnancy.
U.S. RDA Levels of the Vitamins (Adults and Children Four or More Years of Age)"
TABLE 1.
Vitamin Mandatory vitamin A vitamin E vitamin C folic acid thiamine riboflavin niacin vitamin Bh vitamin BLz Optional vitamin D biotin oantothenic acid
U . S . RDA
IU IU mg Pg mg
5000 30 60 400 1.5 1.7 20 2 6
mg mg Pg
400 300
Pg
10
mg
IU me
'' Federal Register, 38 FR 20708 and 20730, August 2, 1973.
The Teratology Society, in its position paper on safe levels of vitamin A use during pregnancy,' suggested a maximum daily dose of 8000 IU. Recently, Werler ~t u I . , ~in a retrospective, case-control study, examined the potential association of vitamin A intake and risk of birth defects. There were 26.58 cases of malformations and 2609 controls. The prevalence of daily vitamin A supplementation was 0.6% for cases and 0.3% for controls. There was no statistically significant association of daily vitamin A supplementation and increased risk of birth defects. Approximately 50% of cases and controls used multivitamin supplements (including prenatals) by the third month of pregnancy. The authors conclude that there was no risk of birth defects associated with the use of multivitamin supplements and/or prenatals containing vitamin A. Several epidemiological studies have shown a significantly decreased risk of neural tube birth defects (NTD) in women who have taken multivitamin supplements during the periconceptional period (usually 1-3 months before conception
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and up to three months after conception). Additionally, intervention trials have shown that a recurrence of pregnancies with this serious birth defect is three times lower in women who were given a multivitamin supplement containing approximately the U.S. RDA level of vitamin A, as well as other vitamins, including folk acid. Research points to a critical role of folk acid in preventing NTD; however, the U.S. RDA level of vitamin A usually present in standard multivitamin supplements was not associated with any increase in the risk of this or any other birth defect.’These data, along with the studies reviewed in recent paper^,^,^ point to the safety of the U.S. RDA level of vitamin A for women of childbearing potential.
SAFETY OF THE LEVEL OF VITAMIN A IN MULTIVITAMIN SUPPLEMqNTS FOR THE ELDERLY Vitamin A is stored in the liver, and the levels increase with increasing age.’ The liver is the primary organ involved in the regulation of circulating levels of vitamin A through its production of retinol-binding protein (RBP). Under normal circumstances, vitamin A circulates in the blood bound to RBP. In cases of hypervitaminosis A, there may be insufficient RBP to bind all of the circulating vitamin A; the consequences include significantly higher circulating levels of free retinol and retinyl ester^.^'^ Krasinski et a/.’’ examined the serum retinyl ester levels and serum levels of several liver enzymes in a cross-sectional epidemiological study of a healthy elderly population. Supplemental vitamin A intakes were approximately 5000- 10,000 IU per day. Of the 562 elderly, 5 had an elevation in one liver enzyme level and 2 had an elevation in two liver enzymes. There was a modest elevation in serum retinyl ester levels in the 5 subjects, which the authors noted was 10-fold lower than the level associated with hypervitaminosis A. Based upon this limited data, the authors suggested “elderly people should limit their intake of supplemental vitamin A particularly over the long term.” In contrast to their initial report, the same group analyzed data from a more comprehensive, prospective longitudinal study that examined vitamin A parameters in healthy elderly over a five-year time span. The study involved 284 women; the mean daily supplement intake was approximately 5000 IU (range 1250-25,000 IU). Serum retinyl ester levels and serum liver enzyme levels did not differ between the nonsupplemented and supplemented groups.” A second prospective, five-year longitudinal study of 116 healthy adults over 64 years of age examined the effects of vitamin A supplementation as part of a multivitamin supplementation program.’* Nonsupplement users had not used supplements for at least the preceding 5 years, whereas supplement users had taken them for at least 5 years. Serum retinyl ester levels were significantly correlated with supplemental vitamin A intake; however, they were approximately 10-fold lower than the level associated with toxicity. Moreover, serum retinyl ester levels did not increase over time in the supplement users. No evidence of liver toxicity, as defined by elevated liver enzymes, was seen regardless of the amount of vitamin A supplementation and even after years of vitamin A supplement use. The data from the two prospective, longitudinal studies of vitamin A supplementation in elderly populations show a consistent lack of adverse effects, includ-
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303
ing effects on liver function, in those using vitamin A supplements at U.S. RDA levels (TABLE2). In a recent paper concerning the use of vitamidmineral supplements by the U.S. population, Subar and Block13 conclude that vitamidmineral supplementation “appears not to pose a significant health risk for most of the population.”
SAFETY OF SINGLE-ENTITY SUPPLEMENTS ABOVE U.S. RDA LEVELS: WATER-SOLUBLE VITAMINS Vitamin B, Doses of vitamin B, over 100 times the U.S. RDA of 2 mg/day have been used in the treatment of certain conditions, without reports of adverse effects. Reports of neuropathy, however, associated with prolonged use of very high doses of the vitamin appeared in the literature. A review of the safety of vitamin B,, published in 1986,14concluded that doses of less than 500 mg/day were safe over a period as long as 6 years. An update of this review, published in 1990,15examined the dose/ duration relationship that resulted in neuropathy. The data indicate that doses of vitamin B, less than 500 mg/day for up to two years were not associated with neuropathy. Daily doses above 1000 mg or a total intake of 1000 grams or more are consistently associated with neuropathy. The neuropathy is usually reversible upon cessation of supplementation. On the basis of the data, it is strongly recommended that use of supplements over 500 mg/day be avoided; if such high level dosages are required for medical reasons, it should be under the care of a physician, and neurologic testing should be incorporated into the physician-supervised treatment program.
Niacin Niacin is a general term that includes nicotinic acid and niacinamide, both of which have vitamin activity. Nicotinic acid, but not niacinamide, has been used successfully for almost 20 years to lower serum cholesterol levels.i6 Nicotinic acid at high levels lowers total and LDL-cholesterol and triglyceride levels and raises HDL-cholesterol levels. Long-term use has been shown to decrease both coronary artery disease mortality and overall mortality in middleaged men with previous myocardial infarctions.” In 1988, the NIH expert panel on cholesterol considered nicotinic acid as one of two compounds of first choice for the treatment of primary hypercholesterolemia, with daily dosages in the range of 3-6 g/day.Ix Nicotinic acid (but not niacinamide), at doses exceeding 300 rng/day, has been associated with transient flushing of the skin, nausea, and diarrhea. Hyperuricemia, abnormal liver enzyme levels, hyperglycemia, and certain gastrointestinal side effects are often seen in doses exceeding 2.5 g/day.18-20The use of high-level, time-release, or sustained-release formulations of nicotinic acid has been associated with a greater severity of liver damage than equivalent concentrations of the non-time release form^.^'-*^ The data indicate that the long-term use of high doses of nicotinic acid is associated with hepatic side effects, which can be significantly exacerbated when a time-release formulation is used. It is therefore strongly recommended that time-
Yes no Yes
5-year longitudinal 5-year longitudinal
Increased Above Non-users
Cross-sectional
Study Type
no no
no
Hypervitaminosis A Range
Retinyl Esters
yes (51562) no no
Increased with Time
of the U.S. RDA Level of Vitamin A in Multivitamin Supplements in the Elderly
Krasinski'" el a/. (affectedkotal) Johnson" er a/. Stauber" et al.
TABLE 2. Safety
yes (51562) no no
Liver Enzymes Elevated
P
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305
release forms of nicotinic acid be avoided and that liver function be monitored routinely in individuals using high doses of nicotinic acid, who should in any case be under the supervision of a physician. Vitamin C
Single supplements of vitamin C are the most commonly available singleentity vitamin supplements in the United States.25Likewise, single supplements of vitamin C are the most widely used by the American The most widely available concentration of vitamin C in single-entity supplements is 500 mgitablet. Therefore, total daily intakes of approximately 10 times the U.S. RDA of vitamin C (60 mgj are quite common in the U.S. adult population. Several excellent reviews of the safety of vitamin C have been published recently; all concur that vitamin C is safe at very high levels of intake for prolonged periods of In addition, adverse effects have not been reported in eight recently published placebo-controlled, double-blind studies with dosages of vitaFive other clinical studies, min C up to 10,000mg/day taken for several using dosages up to 5000 mg/day for more than three years also reported no side effect^.^^-^* Thus, in all of the well-controlled, clinical trials reviewed to date, using daily intakes that in some instances exceed 100 times the U.S. RDA of vitamin C, no side effects have been reported.
SAFETY OF SINGLE-ENTITY SUPPLEMENTS ABOVE U.S. RDA LEVELS: FAT-SOLUBLE VITAMINS Vitamin A
It is well-recognized that very high doses of vitamin A (approximately 500,000 IU, 100 times the U.S. RDA) can have acute, reversible side effects. Moreover, chronic ingestion of doses exceeding 50,000 IU, in some instances, have been associated with headache, nausea, and other side effects in a d ~ l t s .As ~ ,discussed ~ above, there appears to be no potential human teratogenicity associated with supplemental vitamin A intakes at the recommended levels of 5000 IU for women of childbearing potential and 8000 IU for pregnant women. Vitamin E
A comprehensive review in 1988 of the literature concerning the safety of vitamin E resulted in the conclusion that vitamin E is safe at levels of intake up to approximately 3000 mg for prolonged periods of time.43 Individuals taking anticoagulants should be advised to avoid high doses of vitamin E (over 4000 IU) because vitamin E can act synergistically with this class of drugs. Since 1988, two placebo-controlled, double-blind studies specifically evaluated such vitamin E safety issues as thyroid hormone levels, which had previously been reported to decrease with supplementation; serum creatinine levels, which were sporadically reported to increase with supplementation; and serum lipid levels, which have been reported to increase, remain the same, or decrease with supplementation.
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ANNALS NEW YORK ACADEMY OF SCIENCES
Lack of Effect of Supplementation with 800 IU of Vitamin E for 30 Days in Subjects Over 60 Years4, TABLE 3.
Hepatic function: liver enzymes bilirubin serum albumin
Renal function: urinary creatinine serum creatinine creatinine clearance
Hematological: total and CBC RBC count platelets hemoglobin hematocrit
Thyroid function: T3 and T4 uptake T,/T4 ratio free thyroxin
Meydani et al. ,44 in a carefully controlled, double-blind study, gave healthy adults over 60 years of age either 800 IU of vitamin E or a placebo for 30 days. All subjects were housed in a metabolic ward throughout the study period so that diets were completely matched for nutrient intakes. Hepatic function, as determined by serum albumin, liver enzymes (SGPT, SGOT, LDH, and alkaline phosphatase), and total (including conjugated and unconjugated) bilirubin were unaffected by vitamin E supplementation, as shown by the fact that values in the supplemented group did not differ from those seen in the placebo group. Hematological analyses included total and individual white blood cell counts, red blood cell and platelet counts, hemaglobin, and hematocrit, none of which was affected by vitamin E. Renal function, as measured by urinary and serum creatinine, creatinine clearance, and BUN levels, was unchanged by vitamin E. Thyroid function, as reflected by T3 and T, uptakes and ratio, as well as free thyroxin were also unchanged (TABLE3). Two important changes were seen: a significant decrease in serum lipid peroxides and a significant increase in serum zinc values in the vitamin E-supplemented group. There were also improvements in clinically relevant immunological parameters in the supplemented group. Kitagawa and M i r ~ ogave ~ ~ 14 college students 900 IU of vitamin E for 12 weeks and gave 5 students matched placebos in a single-blind study. There were no changes in serum liver enzymes (SGOT, SGPT); white blood cell, red blood cell, and platelet counts; hemoglobin level: creatinine phosphokinase level; or BUN in either group during the study. Serum thyroid hormone levels (T3, T,, and TSH) were also unchanged. Bleeding times, as measured by percentage prothrombin time, partial thrombin time, hepatoplastin test, and PIVKA-I1 (protein induced by vitamin K absence or antagonist) were unaffected by vitamin E supplementation. Serum indices of cholesterol, phospholipids, triglycerides, and total lipids were similar in the placebo and supplemented groups and were unchanged following vitamin E supplementation. Using a questionnaire, it was shown that there were no differences between the placebo and vitamin E-supplemented groups in reports of muscle weakness, gastrointestinal discomfort, headache, hypertension, or visual changes. In addition to the two studies reviewed in detail, 27 clinical studies published since 1986, in which approximately 10 times the U.S. RDA level of vitamin E (30 IU) or higher had been administered, have been compiled.46Moreover, no cases of hypertension associated with intakes of high doses of vitamin E have been reported in any of the more than 50 clinical studies reviewed. The conclusions of this analysis confirm those reached in 1988; specifically, studies using doses of
BENDICH: SAFETY ISSUES
307
vitamin E ranging from 200-2400 IU, administered for periods up to 4.5 years, reported no adverse effects.
Beta-Carotene Beta-carotene, at dosages exceeding 180 mg/day, has been used successfully in individuals with genetically inherited photosensitivities. Individuals using these high levels of beta-carotene chronically for therapeutic reasons have not developed abnormally high levels of serum vitamin A. In addition, normal volunteers given 180 mg/day of beta-carotene for 10 weeks had no evidence of hypervitaminosis A.47 Hypercarotenemia, or high serum levels of carotene, may occur when individuals take supplements containing 30 mg or more of beta-carotene for extended periods of time. In addition, individuals may develop yellow palms and soles, a condition technically known as hypercarotenodermia. This condition can be clearly differentiated from jaundice because the whites of the eyes (sclera) are yellow in those individuals with jaundice and are not yellow in those with hypercarotenodermiaS4’The skin coloration is reversible on cessation or reduction of intake. M e y ~ k e n sin, ~an~ editorial, cited a preliminary in which administration of beta-carotene supplements, either 15, 30, 45, or 60 mg for 9 months, was associated with a 40% decrease in serum vitamin E levels. The preliminary study provides no information concerning the statistical significance of the data in each supplement The findings of this preliminary study have not been corroborated in any other - ~ ~ beta-carotene published report. Specifically, in five separate s t u d i e ~ ~ Ousing supplements ranging from 30-300 mg taken daily for up to four years, there has been no finding of significant changes in serum vitamin E levels (TABLE4). Moreover, serum vitamin K levels were also found to be unaffected by betacarotene supplementation at 15, 30, or 60 mg for 6 months. Clotting times, as well as prothrombin coagulant activity, were monitored monthly and were also unaffected by beta-carotene supplementation.55 Average dietary intake of beta-carotene in the United States is approximately 1-2 mg/day. Diets recommended by the National Cancer Institute and the USDA contain approximately 5-6 mg/day of beta-carotene. Currently there is no recommended daily intake level of beta-carotene separate from its provitamin A activity.
TABLE 4. Beta-Carotene Supplementation: No Significant Effect on Serum
Vitamin E Levels
Reference Ringer et al.’” Mobarhan ef a[.” Greenberg et d.’* Richards et ul.” Willie et a/.’4
No. 10
8 913 20 14
Beta-Carotene Dose (mg)/duration (days) 300128 I20128 501365 501 1460 40142 301112
Serum Vitamin E (mg/dL) Before After 0.8 1.04 I .55 1.55 1.30 0.95
0.9 1.03 1.55 1.41 1S O 0.85
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ANNALS NEW YORK ACADEMY OF SCIENCES
CONCLUSIONS Regarding the issue of the safety of the level of vitamin A found in multivitamin supplements, the data indicate that the U.S. RDA level of 5000 IU is safe for all population groups, including women of childbearing potential and the elderly. The U.S. RDA level of vitamin A in prenatal vitamins is also safe. Data from clinical studies using single-entity supplements point to the fallacy in assuming that all fat-soluble vitamins are toxic above 10 times the U.S. RDA and that all water-soluble vitamins are safe at any level of intake. Specifically, very high doses of certain water-soluble vitamins, vitamin B, and niacin, are associated with clinically relevant adverse effects. By contrast, very high doses of the fat-soluble vitamin E or beta-carotene are not associated with clinically relevant adverse effects. Thus, each vitamin has its own safety profile, which must he clearly communicated to health professionals, as well as the lay public. Dissemination of accurate, scientifically based vitamin safety information can result in the prevention of avoidable adverse effects.
REFERENCES 1.
2. 3. 4.
5.
6. 7. 8.
9. 10.
II. 12.
13.
L I N D E RM. , C., Eds. 1990. Nutritional biochemistry and metabolism. 2nd edit. Elsevier Science Publishing Company, Inc. New York. Federal Register. August 2, 1973. FR 20708 and 20730. BF.NDICH, A. & L. LANGSETH.1989. Safety of vitamin A. Am. J. Clin. Nutr. 4 9 358-37 I . HATHCOCK, J . N., D. G. HATTAN, M. Y. JENKINS, J. T. MCDONALD, P. R. SUNDARESAN & V. L. WILKENING. 1990. Evaluation of vitamin A toxicity. Am. J. Clin. Nutr. 52: 183-202. ROSA, F. W., A. L. WILK & F. 0. KEI.SEY. 1986. Teratogen update: vitamin A congeners. Teratology 33: 355-364. International Vitamin A Consultative Group, Eds. 1986. The safe use of vitamin A by women during the reproductive years. International Life Sciences Institute/Nutrition Foundation. Washington, D.C. Teratology Society. 1987. Teratology society position paper: recommendations for vitamin A use during pregnancy. Teratology 35: 269-275. M., M., E. J. LAMMER, L. ROSENBERG & A. A. MITCHELL.1990. Maternal W~RLER vitamin A supplementation in relation to selected birth defects. Teratology 42: 497-503. BENDICH, A. 1991. Importance of vitamin status to pregnancy outcomes. I n Micronutrients in health and in disease prevention. A. Bendich & C. E. Butterworth, Eds.: 235-262. Marcel Dekker, Inc. New York. S. D.. R. M. RUSSELL, C. L. OTRADOVEC, J. A. SADOWSKI, S. C. HARTZ, KRASINSKI, R. A. JACOB& R. B. MCGANDY.1989. Relationship of vitamin A and vitamin E intake to fasting plasma retinol, retinol-binding protein, retinyl esters, carotene, alpha-tocopherol, and cholesterol among elderly people and yound adults: increased plasma retinyl esters among vitamin A-supplement users. Am. J . Clin. Nutr. 4 9 112-120. E. J . , E. A. KRALL,B. DAWSON-HUGHES, G. E. DALLAL & R. M. RUSSEL. JOHNSON, The effect of multivitamins containing vitamin A on serum retinyl esters and liver function tests in healthy women. In press. STAUBER, P. M., B. SHERRY, D. J. VANDERJAGT, H. N. BHAGAVAN & P. J. GARRY. 1991. A longitudinal study of the relationship between vitamin A supplementation and plasma retinol, retinyl esters, and liver enzyme activities in a healthy elderly population. Am. J. Clin. Nutr. 54: 878-883. SUBAR, A. F. & G. BLOCK.1990. Use of vitamin and mineral supplements: demo-
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14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.
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35. BUCCA,C., G. ROLLA,A. OLIVA& J . C. FARINA. 1990. Effect of vitaminC on histamine bronchial responsiveness of patients with allergic rhinitis. Ann. Allergy 65: 31 1314. & E . E . GLOVER.1991. Blood pressure 36. OsILEsi, 0. D., L. TROUT,J. 0. OGUNWOLE and plasma lipids during ascorbic acid supplementation in borderline hypertensive and normotensive adults. Nutr. Res. 11: 405-412. 37. MCKEOWN-EYSSEN, G.,C . HOLLOWAY,V. JAZMAJI, E. BRIGHT-SEE,P. DION & W. R. BRUCE.1988. A randomized trial of vitamins C and E in the prevention of recurrence of colorectal polyps. Cancer Res. 4 8 4701-4705. 38. L.ux, B. & P. MAY. 1983. Long-term observation of young cystinuric patients under ascorbic acid therapy. Urol. lnt. 3 8 91-94. & A. A. FAUSER. 1988. Treatment ofidiopathic thrombo39. BROX,A. G., K. HOWSON-JAN cytopenic purpura with ascorbate. Br. J. Haematol. 7 0 341-344. 1990. Ascorbate for the treat40. VERHOEF,G. E. G., S. BOONEN& M. A. BOOGAERTS. ment of refractory idiopathic thrombocytopenic purpura. Br. J. Haematol. 74: 234. B. & P. BIERLING. 1990.Treatment ofchronicautoimmune thrombocytopenic 41. GODEAU, purpura with ascorbate. Br. J. Haematol. 75: 289-290. 42. MELETHIL, S . W., D. MASON& C.-J. CHANG.1986. Dose-dependent absorption and excretion of vitamin C in humans. Int. J. Pharmacol. 31: 83-89. A. B. & L. J . MACHLIN. 1988. Safety of oral intake of vitamin E. Am. J. 43. BENDICH, Clin. Nutr. 48: 612-619. 44. MEYDANI, S . N., M. P. BARKLUND, S . L I ~ M. , MEYDANI, R. A. MILLER,J. G. & J. B. BLUMBERG. 1990. Vitamin E suppleCANNON, F. D. MORROW, R. ROCKLIN mentation enhances cell-mediated immunity in healthy elderly subjects. Am. J. Clin. Nutr. 52: 557-563. 45. KITAGAWA, M. & M. MINO. 1989. Effects of elevated d-Alpha (RRR)-tocopherol dosage in man. J. Nutr. Sci. Vitaminol. 35: 133-142. 46. BENDICH, A. & L. J. MACHLIN. 1992. The safety of oral intakes of vitamin E: Data from clinical studies from 1986 to 1991. I n Vitamin E in Health and Disease. L . Packer & J. Fuchs, Eds.: 411-416. Marcel Dekker, Inc. New York. A. 1988. The safety of beta-carotene. Nutr. Cancer 11: 207-214. 47. BENDICH, F. L. 1990. Coming of age-the chemoprevention of cancer. N. Engl. J. 48. MEYSKENS, Med. 323: 825-827. & S. M. SAYER. 1990. 49. Xu, M. J . , Y . M. PENG,Y . L I U ,D. S. ALBERTS,P. M. PLEZIA Effect of chronic oral administration of beta-carotene on plasma alpha-tocopherol concentrations in normal subjects. Proc. Am. Assoc. Cancer Res. 31: 126. T. V., M. J. DELOOF,G. E. WINTERROWD, 50. RINGER, S. F. FRANCOM, S. K. GAYLOR, J . A. RYAN,M. E. SANDERS & G. S. HUGHES.1991. Beta-carotene’s effects on serum lipoproteins and immunologic indices in humans. Am. J. Clin. Nutr. 53: 688-694. 51. MOBARHAN, S.,P. BOWEN,B. ANDERSEN, M. EVANS,M. STACEWICZ-SAPUNTZAKIS, s. SUGERMAN, P, S i M M S , D. LUCCHESI& H . FRIEDMAN. 1990. Effects of betacarotene repletion on beta-carotene absorption, lipid peroxidation, and neutrophil superoxide formation in young men. Nutr. Cancer 14: 195-206. E. R., J . A. BARON& T . A. STUKEL.1991. Letters to the editor. N. Engl. 52. GREENBERG, J. Med. 324: 924-925. C. E. J . VAN RENSBURG, A. J. VAN RENSBURG, G. A., A. J. THERON, 53. RICHARDS, C. A. VANDER MERWE,J. M. KUYL& R. ANDERSON. 1990. Investigation of the effects of oral administration of vitamin E and beta-carotene on the chemiluminescence responses and the frequency of sister chromatid exchanges in circulating leukocytes from cigarette smokers. Am. Rev. Respir. Dis. 142: 548-554. B. A. UNDERWOOD, J. 0. TAYLOR,& C. H. 54. WILLETT, w. c . , M. J. STAMPFER, HENNEKENS. 1983. Vitamins A, E, and carotene: effects of supplementation on their plasma levels. Am. J. Clin. Nutr. 38: 559-566. 55. CANFIELD, L. M., J. J. CORRIGAN, P. M. PLEZIA,M. JETER,s. SAYERS & D. s. ALBERTS.1990. Effects of chronic beta-carotene supplementation on vitamin K status in adults. Nutr. Cancer 13: 263-269.
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DISCUSSION D. GIBBS(University of Hawuii, Honolulu, H I ) : If you comment on the anticoagulant characteristics of vitamin E, you should also comment that it is commonly used as an anticoagulant and is preferred by some surgeons because it normalizes coagulation activity rather than lowering it. A. BENDICH (Hoffmann-LaRoche Inc., Nutley, N J ) : That’s an efficacy issue. I’m really talking about safety. It may not be prudent for individuals to take vitamin E at high levels on top of the use of vitamin K antagonist. That was the point that I was trying to make. (Scarborough General Hospital, Toronto, Ontario, Canuda): B. DRESSLER You said that the non-time-release niacin has been associated with normal liver enzymes as opposed to the time-release variety at certain dosage ranges. Are they equally efficacious in the treatment of hypercholesterolemia? BENDICH: Let me clarify. There are liver enzymes that can be elevated with the non-time release as well as with the time-release niacin. The only problem is that with the time-release there is an enormous increase in the potential severity of the adverse effects. Whether or not it is equally efficacious is not an issue. J. CLAUSEN (University oflioskilde, Denmark): Please comment on high doses of vitamin C and absorption of iron. I have an impression that vitamin C may cause hemochromatosis. BENDICH: We have published a review of this topic (Toxicol Lett. 51: 189, 1990). We looked at every study in which vitamin C and iron were given together. We found that vitamin C intake increases iron absorption in individuals who are iron deficient. When you have normal transferrin saturation level, however, vitamin C does not further increase iron absorption. D. H. Kooss (Loma Linda, C A ) :A few years ago it was reported that prolonged intake of over 800 IU of vitamin E induced deep vein thrombosis in a few people. Could you comment? You are probably referring to reports by Briggs et a / . that appeared BENDICH: as a letter to the editor. Neither were from placebo-controlled, double-blind studies. It’s important to weigh a few anecdotal reports such as these against the bulk of good well-controlled studies available. P. WALTER(University ($Busel, Switzerland):We have heard that vitamin K may be beneficial for calcium in our bones. Do you know anything about the safety of vitamin K? No safety problems have been associated with oral use of phylloquiBENDICH: none (K,) and menaquinone (KJ. They both appear to be quite safe at levels much higher than those recommended by the RDA. C. L. KRUMDIECK (University of Alabama at Birmingham): Is there any information on the potential effect of ascorbic acid on the absorption of aluminum or the neurotoxicity of aluminum? L. J . MACHLIN (Hoffmann-LaRoche Inc., Nutley, N J ) : A paperjust published in the Lancet reported increased urinary excretion of vitamin C or citric acid after administration of extremely high levels of aluminum hydroxide. N o toxicity was noted, and there is nothing in the literature to suggest an increase in tissue deposition or toxicity because of vitamin C. R. M. BALLANTINE (Honesdale, P A ) :There are two commonly believed points that I didn’t hear you mention. One was the connection between vitamin C and kidney stones, and the other was the relationship between vitamin E and hypertension. Can you speak about these?
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BE-NDICH: All reviews of the literature have shown no association of vitamin C intake and kidney stones. With regard to vitamin E and hypertension, in spite of diligent searching, I have not found the scientific source of this concern. SPEAKER: Concerning the origin of the papers on vitamin C and UNIDENTIFIED kidney stones, the only source that I could find in the literature was a letter to the editor in the Journal of the Arnrricmn Medical Association.
