Perilla Seed Oil

Overview

Perilla, or shiso (also called beefsteak), is a popular vegetable in Asia that looks like a large-leafed basil. It’s seed oil is used in a variety of foods in Asia, as well, and so it has a long track record of safety in humans. In Asia it is also used as a traditional treatment for lung health and coughs, cold and flu. Perilla seed oil is high in omega-3 fatty acids, especially alpha-linolenic acid, and these have been well tested as anti-inflammatory compounds that are useful for a variety of inflammatory conditions. The omega-3 fatty acids are known to reduce a the production of many allergic mediators when supplemented to the diet. In addition to the essential fatty acids in Perilla, there are also several pharmacologically active phenolic compounds, such as rosmarinic acid, apigenin, luteolin, chrysoleriol, quercetin, and catechin (Ueda et al., 2002; Takeda et al., 2002; Nakazawa et al., 2003; Makino et al., 2003).

Comments

Few human studies yet exist on the therapeutic value of Perilla seed oil, but there are many on some of its chemical constituents, such as the omega-3 fatty acids, and rosmarinic acid. Due to its long use in foods, its interesting mixture of phenolic compounds, promising animal studies, and low cost, it may be an excellent alternative to fish oil supplementation.

Scientific Support

Asthma and Allergies

Perilla seed oil, as a source of alpha-linolenic acid, was tested in asthma patients for the clinical features that accompanied leukotriene inhibition, including its effect on ventilatory parameters and lipid metabolism. The participants were divided into two groups. Group A were those who showed significantly suppressed leucocyte generation of leukotriene C4 (LTC4) by 4 weeks of Perilla seed supplementation. Group B were those who did not show leukotriene inhibition, but rather a significant increase in production after the same treatment. Analysis of the ventilatory clinical features and lipid metabolism between the groups prior to supplementation showed significant differences between groups, and these groups responded differently to Perilla seed oil supplementation. It was concluded that supplementation of Perilla seed oil is able to suppress generation of LTC4 in certain asthma patients, and that its ability to do so is related to clinical features such as respiratory function and lipid metabolism (Okamoto et al., 2000b).

Okamoto et al. (2000a) studied the effects of Perilla seed oil on bronchial asthma compared to the effects of corn oil on pulmonary function and the generation of leukotriene B4 (LTB4) and C4 (LTC4) by leucocytes. Perilla seed oil is rich in the omega-3 fatty acids, whereas corn oil is rich in omega-6 fatty acids. The groups were divided into 7 subjects each, and supplementation of the respective oil proceeded for 4 weeks. Significant differences in pulmonary function and leukotriene production were found between groups, and it was concluded that Perilla seed oil is beneficial for the treatment of asthma due to the suppression of LTB4 and LTC4 generation by leucocytes, and improvement in pulmonary function.

In a small study involving 5 asthma patients, supplementation with Perilla seed oil was reported to be helpful for asthma. After two weeks of supplementation, asthma symptoms, and morning and evening mean and peak flow rates (PFR) were improved significantly. Additionally, the generation of leukotrienes B-4 and C-4 by leukocytes were significantly reduced with supplementation (Kozo et al., 1997).

Cardiovascular Health

The effect of the long-term intake of an omega-3 fatty acid source, Perilla oil (PO), was compared to that of an omega-6 source, soybean oil (SO), on the risk factors of coronary heart disease and serum levels of fatty acids. Twenty elderly Japanese subjects were given SO for at least 6 months as a baseline period, then put on a PO diet for 10 months as the intervention period, and later returned to the SO diet as the washout period. The change in omega-6 to omega 3 ratio between the treatments, was 4:1 for the SO and 1:1 for the PO. At 3 months into the treatment period with PO, the alpha-linolenic acid in the serum increased from 0.8 to 1.6%, and the EPA and DHA increased from 2.5 to 3.6% and 5.3 to 6.4% respectively after 10 months of treatment, and returned to baseline in the washout period. The concentration of the oxidized LDL did not change significantly. It was concluded that in elderly subjects the levels of ALA, EPA and DHA could be increased significantly through dietary change without any adverse effects (Esaki et al., 1999).

Bioavailability

In a study on the bioavailability of enteric-coated (Entrox) perilla seed oil, 12 healthy volunteers were given (enteric) coated or non-coated capsules containing 6 g of a Perilla seed formulation. The Perilla seed formulation was alpha-linolenic acid (ALA)-rich and was given in a single dose followed by a 3 week washout period. There were no difference in the pharmacokinetics of the two formulations, however, the levels of plasma ALA measured within 24 hours were significantly higher for the enteric-coated treatment group (Kurowska et al., 2003).

Safety / Dosage

Although Perilla has few clinical studies in humans, and most of the feeding studies have been done in animals, there has been a long track record of use in humans as a food in Asia, and this has never been associated with safety problems. About 6 grams daily of Perilla seed oil would contribute about 3 grams of alpha-linolenic acid to the diet.

Contact dermatitis develops in about 20-50% of the long-term workers with Perilla culture, and this is thought to be due to the 1-perillaldehyde and perillalcohol content of the shiso oil (Okazaki et al., 1981).

References

1.Ezaki O, Takahashi M, Shigematsu T, Shimamura K, Kimura J, Ezaki H, Gotoh T. Long-term effects of dietary alpha-linolenic acid from perilla oil on serum fatty acids composition and on the risk factors of coronary heart disease in Japanese elderly subjects. J Nutr Sci Vitaminol (Tokyo). 1999 Dec;45(6):759-72.

2.Kozo A., Fumihiro M, Takashi M, Yasuhiro H, Satoshi Y, Hirofumi T, Yoshiro T, Takao T. A pilot study: Effects of dietary supplementation with alpha-linolenic acid-enriched perilla seed oil on bronchial asthma. Allergology International. 1997 46(3):181-185.

3.Kurowska EM, Dresser GK, Deutsch L, Vachon D, Khalil W. Bioavailability of omega-3 essential fatty acids from Perilla seed oil. Prostaglandins Leukotrienes & Essential Fatty Acids. 2003 March;68(3):207-212.

4.Makino T, Furuta Y, Wakushima H, Fujii H, Saito K, Kano Y.Anti-allergic effect of Perilla frutescens and its active constituents.Phytother Res. 2003 Mar;17(3):240-3.

5.Nakazawa T, Yasuda T, Ueda J, Ohsawa K. Antidepressant-Like Effects of Apigenin and 2,4,5-Trimethoxycinnamic Acid from Perilla frutescens in the Forced Swimming Test. Biol Pharm Bull. 2003 Apr;26(4):474-80.

6.Okamoto M, Mitsunobu F, Ashida K, Mifune T, Hosaki Y, Tsugeno H, Harada S, Tanizaki Y, Kataoka M, Niiya K, Harada M. Effects of perilla seed oil supplementation on leukotriene generation by leucocytes in patients with asthma associated with lipometabolism. Int Arch Allergy Immunol. 2000a Jun;122(2):137-42.

7.Okamoto M, Mitsunobu F, Ashida K, Mifune T, Hosaki Y, Tsugeno H, Harada S, Tanizaki Y.Effects of dietary supplementation with n-3 fatty acids compared with n-6 fatty acids on bronchial asthma. Intern Med. 2000b Feb;39(2):107-11.

8.Okazaki N, Matunaka M, Kondo M, Okamoto K. Contact Dermatitis Due to Beefsteak Plant Perilla-frutescens-var-acuta. Hifu. 1982 24(2):250-256.

9.Takeda H, Tsuji M, Miyamoto J, Matsumiya T. Rosmarinic acid and caffeic acid reduce the defensive freezing behavior of mice exposed to conditioned fear stress. Psychopharmacology (Berl). 2002 Nov;164(2):233-5.

10.Ueda H, Yamazaki C, Yamazaki M.Luteolin as an anti-inflammatory and anti-allergic constituent of Perilla frutescens. Biol Pharm Bull. 2002 Sep;25(9):1197-202.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.

Vitamin A

Overview

Vitamin A is fat-soluble vitamin that is part of a family of compounds including retinol, retinal and beta-carotene. Beta-carotene is also known as “pro-vitamin A” because it can be converted into vitamin A when additional levels are required. Food sources of vitamin A include organ meats such as liver and kidney, egg yolks, butter, cod liver oil, fortified dairy products such as milk and some margarines. For comparitive purposes, one serving (3 ounces) of beef liver contains approximately 30,000IU of vitamin A, while one cup of fortified milk contains 500IU and an egg contains 250-300IU. For beta-carotene, an average carrot provides about 20,000IU of vitamin A, while a half-cup of spinach or sweet potatoes provides approximately 7,000IU

Vitamin A is involved in myriad metabolic reactions in the body, but as a dietary supplement, the most prevalent claims are for promoting skin health, eyesight, and general immune function, with occasional claims made in the areas of “anti-aging” and “anti-cancer” effects.

Comments

Retinol, is the most usable form of vitamin A, and is often referred to as “preformed” vitamin A and found in dietary supplement in various stabilized forms. Beta-carotene is a provitamin A carotenoid that is more efficiently converted into retinol than other carotenoids, but the most prudent approach to vitamin A and carotenoids supplementation may be a combined approach that delivers small supplemental amounts of preformed vitamin A along with mixed carotenoids (versus purely beta-carotene at high doses).

Scientific Support

Vitamin A is needed by all of the body’s tissues for general growth and repair processes and is especially important for bone formation, healthy skin/hair, night vision and function of the immune system. Because of these myriad functions, the health claims associated with vitamin A are numerous.

Vitamin A may help boost immune system function and resistance to infection and the clinical and laboratory evidence to support such supplement claims is quite extensive. Vitamin A supplements have been suggested for treatment and prevention of HIV infection – even though some in vitro data suggest that vitamin A may actually activate HIV (Humphrey et al. 1999, Nduati et al. 1995). Studies of vitamin A supplementation in HIV+ patients (up to a single oral dose of 300,000IU) showed no differences in any lymphocyte subset or activation marker or any change in viral load at any time during an 8-week follow up period – suggesting no benefit nor adverse effect of vitamin A supplements on immune parameters in HIV+ patients (Humphrey et al. 1999).

In elderly Italian subjects, vitamin A supplementation (800mcg/d retinol palmitate) has been shown to reduce T-cell numbers, suggesting a comprised cell-mediated immune function, (Fortes et al. 1998) while in populations of healthy men (van Poppel et al. 1993), vitamin A deficient children (Semba et al. 1992), lung cancer patients (Micksche et al. 1977), and elderly English patients (Penn at el. 1991), vitamin A (or beta-carotene) supplementation resulted in a significant increase in cell-mediated immunity, including absolute number of T cells, T4 subsets, T4 to T8 ratio, and lymphocyte proliferation responses.

Low plasma retinol concentrations indicate depleted levels of vitamin A – and occurrence that can result from an inadequate intake of vitamin A, but also from a deficiency in protein, calories, and zinc (all needed for the synthesis of retinol binding protein, which is needed for the mobilization of vitamin A from liver stores to the general circulation).

The “immune” angle for vitamin A and its derivatives follows from its role in cell differentiation and maintenance of the surface linings of eyes and respiratory, urinary, and intestinal tracts as well as skin and mucous membranes throughout the body (thwarting bacterial infection). Vitamin A is also known to have wide-ranging effects on general functioning of the immune system cells, including lymphocytes.

Safety / Dosage

Be aware that as a fat-soluble vitamin, vitamin A can be stored in the body and levels can build up over time. Possible toxicity can result with high dose supplementation (50,000 IU/day) leading to vomiting, headaches, joint pain, skin irritation, gastrointestinal distress and hair loss. Extreme caution should be exercised during pregnancy, as high dose vitamin A has been associated with teratogenic effects (birth defects). Maximum intake of 5000 IU of vitamin A is suggested during pregnancy.

Vegetarians, who do not consume eggs and dairy foods, often need greater amounts of provitamin A carotenoids to meet their need for vitamin A. Vegans may especially benefit from a daily supplement containing a blend of provitamin A carotenoids and preformed vitamin A.

The Recommended Dietary Allowance (RDA) for vitamin A is listed in units referred to as Retinol Activity Equivalanets (RAEs) to account for differences in the activities of retinol and provitamin carotenoids such as beta-carotene. On dietary supplement labels, however, the Daily Value is used for all nutrients – with the value for vitamin A set at 5,000 IU for adults – even while the RAE for vitamin A is lower – at 2330IU (700mcg RAE) for adult women and 3000IU (900mcg RAE) for adult men. Based on the most recent evidence for the long-term effects of high vitamin A intake on bone health (see below), it is prudent to keep total vitamin A intake from foods, fortification, and supplements to less than 300IU of preformed vitamin A daily. Although there is no established DV for beta carotene, a daily intake of 5-20mg would roughly approach those levels achieved by a diet high in fruits and vegetables and the Institute of medicine suggests that a daily consumption of 3-6mg of beta-carotene will maintain plasma beta-carotene levels in the range associated with a lower risk of chronic diseases.

Much has been made in the general media about the “osteoporosis risk” associated with higher than average vitamin A intakes. These stories are based on research studies that note the highest incidence of osteoporosis occurs in northern Europe – a population with a high vitamin A intake. What the researchers also note, and many of the media reports fail to also note, is that this northern European population also has a reduced biosynthesis of vitamin D associated with lower levels of sun exposure. More recent studies of the effect of vitamin A intake on vitamin D metabolism and bone health have suggested that a high vitamin A intake may impair the ability of vitamin D to promote intestinal calcium absorption. At very high levels of intake (retinol intake at more than 1500-3000mcg/day (2-3 times the recommended amount for adults), studies have shown a reduced bone mineral density and an increased risk of hip fracture compared to lower intakes of vitamin A (500-1250mcg/day). There does not seem to be any evidence of an association between beta-carotene intake and increased risk of osteoporosis – or between recommended intakes of preformed vitamin A and osteoporosis. The Tolerable Upper Intake Level (UL) for vitamin A is the same for men, women, and pregnant women (3000mcg RAEs, or 10,000IU).

Beta-carotene is covered in more detail as an antioxidant in the Eye Health section. Although some large clinical trials have associated beta-carotene supplements with a greater incidence of lung cancer and death in current/heavy smokers, other large studies have found no adverse effects of up to 25-50mg/day of beta-carotene in otherwise healthy subjects.

References

1.Allende LM, Corell A, Madrono A, Gongora R, Rodriguez-Gallego C, Lopez-Goyanes A, Rosal M, Arnaiz-Villena A. Retinol (vitamin A) is a cofactor in CD3-induced human T-lymphocyte activation. Immunology. 1997 Mar;90(3):388-96.

2.Daudu PA, Kelley DS, Taylor PC, Burri BJ, Wu MM. Effect of a low beta-carotene diet on the immune functions of adult women. Am J Clin Nutr. 1994 Dec;60(6):969-72.

3.Fortes C, Forastiere F, Agabiti N, Fano V, Pacifici R, Virgili F, Piras G, Guidi L, Bartoloni C, Tricerri A, Zuccaro P, Ebrahim S, Perucci CA. The effect of zinc and vitamin A supplementation on immune response in an older population. J Am Geriatr Soc. 1998 Jan;46(1):19-26.

4.Humphrey JH, Quinn T, Fine D, Lederman H, Yamini-Roodsari S, Wu LS, Moeller S, Ruff AJ. Short-term effects of large-dose vitamin A supplementation on viral load and immune response in HIV-infected women. J Acquir Immune Defic Syndr Hum Retrovirol. 1999 Jan 1;20(1):44-51.

5.Kutukculer N, Akil T, Egemen A, Kurugol Z, Aksit S, Ozmen D, Turgan N, Bayindir O, Caglayan S. Adequate immune response to tetanus toxoid and failure of vitamin A and E supplementation to enhance antibody response in healthy children. Vaccine. 2000 Jul 1;18(26):2979-84.

6.Micksche M, Cerni C, Kokron O, Titscher R, Wrba H. Stimulation of immune response in lung cancer patients by vitamin A therapy. Oncology. 1977;34(5):234-8.

7.Molina EL, Patel JA. A to Z: vitamin A and zinc, the miracle duo. Indian J Pediatr. 1996 Jul-Aug;63(4):427-31.

8.Nduati RW, John GC, Richardson BA, Overbaugh J, Welch M, Ndinya-Achola J, Moses S, Holmes K, Onyango F, Kreiss JK. Human immunodeficiency virus type 1-infected cells in breast milk: association with immunosuppression and vitamin A deficiency. J Infect Dis. 1995 Dec;172(6):1461-8.

9.Penn ND, Purkins L, Kelleher J, Heatley RV, Mascie-Taylor BH, Belfield PW. The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: a randomized controlled trial. Age Ageing. 1991 May;20(3):169-74.

10.Quadro L, Gamble MV, Vogel S, Lima AA, Piantedosi R, Moore SR, Colantuoni V, Gottesman ME, Guerrant RL, Blaner WS. Retinol and retinol-binding protein: gut integrity and circulating immunoglobulins. J Infect Dis. 2000 Sep;182 Suppl 1:S97-S102.

11.Ravaglia G, Forti P, Maioli F, Bastagli L, Facchini A, Mariani E, Savarino L, Sassi S, Cucinotta D, Lenaz G. Effect of micronutrient status on natural killer cell immune function in healthy free-living subjects aged >/=90 y. Am J Clin Nutr. 2000 Feb;71(2):590-8.

12.Rosales FJ, Kjolhede C. A single 210-mumol oral dose of retinol does not enhance the immune response in children with measles. J Nutr. 1994 Sep;124(9):1604-14.

13.Rumore MM. Vitamin A as an immunomodulating agent. Clin Pharm. 1993 Jul;12(7):506-14.

14.Schmidt K. Antioxidant vitamins and beta-carotene: effects on immunocompetence. Am J Clin Nutr. 1991 Jan;53(1 Suppl):383S-385S.

15.Semba RD, Muhilal, Scott AL, Natadisastra G, Wirasasmita S, Mele L, Ridwan E, West KP Jr, Sommer A. Depressed immune response to tetanus in children with vitamin A deficiency. J Nutr. 1992 Jan;122(1):101-7.

16.Semba RD. The role of vitamin A and related retinoids in immune function. Nutr Rev. 1998 Jan;56(1 Pt 2):S38-48.

17.Semba RD. Vitamin A and immunity to viral, bacterial and protozoan infections. Proc Nutr Soc. 1999 Aug;58(3):719-27.

18.Semba RD. Vitamin A, immunity, and infection. Clin Infect Dis. 1994 Sep;19(3):489-99.

19.van Poppel G, Spanhaak S, Ockhuizen T. Effect of beta-carotene on immunological indexes in healthy male smokers. Am J Clin Nutr. 1993 Mar;57(3):402-7.

20.West CE, Rombout JH, van der Zijpp AJ, Sijtsma SR. Vitamin A and immune function. Proc Nutr Soc. 1991 Aug;50(2):251-62.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.

Zinc

Overview

Zinc is an essential trace mineral that functions as part of about 300 different enzymes. As such, zinc plays a role in numerous biochemical pathways and physiological processes. More than 90% of the body’s zinc is stored in the bones (30%) and muscles (60%), but zinc is also found widely distributed in small amounts in virtually all body tissues. The richest dietary sources of zinc are seafood (especially oysters), meat, fish, eggs, and poultry. Because of the varied roles of zinc in the body, claims for zinc-containing dietary supplements are numerous, including those for improved wound healing, general immune system support (including reduced severity and length of colds and upper respiratory tract infections), and support of various “male” aspects of health (supporting a healthy prostate gland, preventing benign prostatic hyperplasia, and increasing fertility via enhanced sperm production.

Comments

Zinc lozenges have become one of the most popular natural approaches to treating the common cold and the scientific evidence generally supports this use for short periods of time (1-2 weeks). Zinc lozenges appear to reduce cold symptoms such as sore throats, hoarseness and coughing – and may even be able to shorten the duration of colds by a full day or so. Like vitamin C, zinc is an essential nutrient for optimal functioning of the immune system – and they both possess significant antiviral activity when consumed at elevated levels for a short period of time. It also appears, however, that some forms of zinc lozenges may be more effective than other forms (due to the total amount of ionized zinc that the lozenge actually releases into the mouth and throat). At least one study has shown that lozenges containing zinc gluconate plus citric acid, sorbitol or mannitol may not deliver high enough levels of ionized zinc – whereas those lozenges which contained glycine (an amino acid) appeared to deliver a higher quantity of ionized zinc.

Scientific Support

Because zinc is an essential part of nearly 300 different biochemical pathways, “structure/function” claims can be made for the nutrient’s role in a wide variety of processes including digestion, wound healing, energy production, growth, cellular repair, collagen synthesis, bone strength, cognitive function, carbohydrate metabolism (glucose utilization and insulin production), and reproductive function. Even mild zinc deficiency has been associated with depressed immunity, decreased sperm count and impaired memory. Perhaps the most popular claim for zinc is for its role in immunity, where zinc delivered in lozenge form may interfere with the replication of the cold virus (rhinovirus).

Zinc deficiency is common in developing countries and in some elderly and athletic populations (Bogden et al. 1990, Bunker et al. 1994, Johnson and Porter 1997, Mahalanabis et al. 2002, Penny et al. 1999, Sazawal et al. 1998, Singh et al. 1994) and in these populations, zinc supplementation at dosages of 10-25mg/day – improves most markers of immune function and duration of illness (diarrhea and upper respiratory tract infections).

Evidence exists to support the use of zinc lozenges in reducing the duration and severity of colds. Although concentrated zinc lozenges can help kill cold viruses in the mouth and throat, it is important to begin using them as soon as possible following the onset of cold symptoms (ideally within the first 24-48 hours). Test tube studies have shown that zinc can block the cold virus from replicating – an effect that could help the body’s natural immune defenses “get a jump” on killing the viruses. Most studies of the effect of zinc lozenges (typically zinc gluconate or zinc acetate) on the common cold have shown that subjects in the supplement group tend to have fewer “symptomatic” days (on average 2-3 fewer sick days) compared to subjects receiving a placebo (measured in terms of coughing, sore throat, nasal congestion and headache).

Occasionally, high dose zinc supplements are recommended to diabetic patients. Such patients commonly suffer from increased loss of zinc and reduced body stores of zinc. High doses of zinc have been shown to mimic the effects of insulin in reducing blood sugar and promoting wound healing. These effects, however, should be considered preliminary and high dose zinc supplements are not recommended for diabetics except on the advice of their personal physician.

Exercise performance has also been associated with adequate zinc status – especially in athletes who avoid red meat, concentrate their diets too much on carbohydrates or follow an overly restricted dietary regime. Low zinc intake (below 3mg/day) has been linked to reduced activity of a zinc-containing enzyme in red blood cells called carbonic anhydrase (which helps red blood cells transport carbon dioxide from tissues to the lungs to be exhaled). Mild to moderate zinc deficiency can lead to significant reductions in the body’s ability to take up and use oxygen, remove carbon dioxide and generate energy during high intensity exercise.

Safety / Dosage

The short-term use of zinc at therapeutic doses for cold relief (see below) is assumed to be safe and chronic supplementation with zinc at levels 2-3 times the current RDA should not be expected to pose any significant adverse side effects. However, high doses of zinc are not recommended for periods of more than two weeks due to concerns of immune system suppression, interference with copper absorption and other long-term health effects such as increased risk for heart disease. High doses of zinc (gram levels) can cause nausea, diarrhea, and vomiting.

The Daily Value for zinc is 15mg per day – a level that should be adequate for support of bone metabolism and optimal physical performance. As therapy for colds, however, higher levels are required – with levels in the range of 13-23mg (in lozenge form) taken every 2-4 hours for no more than 2 weeks. These levels appear to be quite effective for reducing duration and severity of cold symptoms compared to not taking zinc lozenges. It is also important to note that other supplements, particularly high levels of calcium and iron can decrease zinc absorption, while complexation (chelation) with various amino acids (such as glycine, histidine and aspartate) or other organic compounds (such as gluconate or picolinate) may increase zinc bioavailability. Zinc supplementation can also reduce absorption of copper (Bonham et al. 2003) and iron (Donangelo et al. 2002), but may also potentiate the effect of supplemental vitamin A on night vision and immune parameters (Christian et al. 2001).

References

1.Abbasi AA, Prasad AS, Rabbani P, DuMouchelle E. Experimental zinc deficiency in man. Effect on testicular function. J Lab Clin Med. 1980 Sep;96(3):544-50.

2.Bogden JD, Oleske JM, Lavenhar MA, Munves EM, Kemp FW, Bruening KS, Holding KJ, Denny TN, Guarino MA, Holland BK. Effects of one year of supplementation with zinc and other micronutrients on cellular immunity in the elderly. J Am Coll Nutr. 1990 Jun;9(3):214-25.

3.Bogden JD, Oleske JM, Lavenhar MA, Munves EM, Kemp FW, Bruening KS, Holding KJ, Denny TN, Guarino MA, Krieger LM, et al. Zinc and immunocompetence in elderly people: effects of zinc supplementation for 3 months. Am J Clin Nutr. 1988 Sep;48(3):655-63.

4.Bonham M, O'Connor JM, Alexander HD, Coulter J, Walsh PM, McAnena LB, Downes CS, Hannigan BM, Strain JJ. Zinc supplementation has no effect on circulating levels of peripheral blood leucocytes and lymphocyte subsets in healthy adult men. Br J Nutr. 2003 May;89(5):695-703.

5.Brun JF, Dieu-Cambrezy C, Charpiat A, Fons C, Fedou C, Micallef JP, Fussellier M, Bardet L, Orsetti A. Serum zinc in highly trained adolescent gymnasts. Biol Trace Elem Res. 1995 Jan-Mar;47(1-3):273-8.

6.Bunker VW, Stansfield MF, Deacon-Smith R, Marzil RA, Hounslow A, Clayton BE. Dietary supplementation and immunocompetence in housebound elderly subjects. Br J Biomed Sci. 1994 Jun;51(2):128-35.

7.Christian P, Khatry SK, Yamini S, Stallings R, LeClerq SC, Shrestha SR, Pradhan EK, West KP Jr. Zinc supplementation might potentiate the effect of vitamin A in restoring night vision in pregnant Nepalese women. Am J Clin Nutr. 2001 Jun;73(6):1045-51.

8.Couzy F, Lafargue P, Guezennec CY. Zinc metabolism in the athlete: influence of training, nutrition and other factors. Int J Sports Med. 1990 Aug;11(4):263-6.

9.Donangelo CM, Woodhouse LR, King SM, Viteri FE, King JC. Supplemental zinc lowers measures of iron status in young women with low iron reserves. J Nutr. 2002 Jul;132(7):1860-4.

10.Hunt CD, Johnson PE, Herbel J, Mullen LK. Effects of dietary zinc depletion on seminal volume and zinc loss, serum testosterone concentrations, and sperm morphology in young men. Am J Clin Nutr. 1992 Jul;56(1):148-57.

11.Johnson MA, Porter KH. Micronutrient supplementation and infection in institutionalized elders. Nutr Rev. 1997 Nov;55(11 Pt 1):400-4.

12.Lukaski HC. Magnesium, zinc, and chromium nutriture and physical activity. Am J Clin Nutr. 2000 Aug;72(2 Suppl):585S-93S.

13.Mahalanabis D, Chowdhury A, Jana S, Bhattacharya MK, Chakrabarti MK, Wahed MA, Khaled MA. Zinc supplementation as adjunct therapy in children with measles accompanied by pneumonia: a double-blind, randomized controlled trial. Am J Clin Nutr. 2002 Sep;76(3):604-7.

14.Nishi Y. Anemia and zinc deficiency in the athlete. J Am Coll Nutr. 1996 Aug;15(4):323-4.

15.Penny ME, Peerson JM, Marin RM, Duran A, Lanata CF, Lonnerdal B, Black RE, Brown KH. Randomized, community-based trial of the effect of zinc supplementation, with and without other micronutrients, on the duration of persistent childhood diarrhea in Lima, Peru. J Pediatr. 1999 Aug;135(2 Pt 1):208-17.

16.Peretz A, Neve J, Jeghers O, Pelen F. Zinc distribution in blood components, inflammatory status, and clinical indexes of disease activity during zinc supplementation in inflammatory rheumatic diseases. Am J Clin Nutr. 1993 May;57(5):690-4.

17.Sazawal S, Black RE, Bhan MK, Jalla S, Sinha A, Bhandari N. Efficacy of zinc supplementation in reducing the incidence and prevalence of acute diarrhea--a community-based, double-blind, controlled trial. Am J Clin Nutr. 1997 Aug;66(2):413-8.

18.Sazawal S, Black RE, Jalla S, Mazumdar S, Sinha A, Bhan MK. Zinc supplementation reduces the incidence of acute lower respiratory infections in infants and preschool children: a double-blind, controlled trial. Pediatrics. 1998 Jul;102(1 Pt 1):1-5.

19.Sazawal S, Jalla S, Mazumder S, Sinha A, Black RE, Bhan MK. Effect of zinc supplementation on cell-mediated immunity and lymphocyte subsets in preschool children. Indian Pediatr. 1997 Jul;34(7):589-97.

20.Singh A, Failla ML, Deuster PA. Exercise-induced changes in immune function: effects of zinc supplementation. J Appl Physiol. 1994 Jun;76(6):2298-303.

21.Smith JC, Makdani D, Hegar A, Rao D, Douglass LW. Vitamin A and zinc supplementation of preschool children. J Am Coll Nutr. 1999 Jun;18(3):213-22.

EDITOR'S NOTE: This monograph can be found in The Health Professional's Guide to Dietary Supplements (Lippincott, Williams & Wilkins) by Shawn M. Talbott, PhD and Kerry Hughes, MS.