Betacarotene

Abstract

Selenium is an essential trace element involved in several key metabolic activities via selenoprotems, enzymes that are essential to protect against oxidative damage and to regulate immune function. Selenium also may have other health benefits unrelated to its enzymatic functions. It may provide important health benefits to people whose oxidative stress loads are high, such as those with inflammatory or infectious diseases like rheumatoid arthritis or human immunodeficiency virus/acquired immunodeficiency syndrome, or who are at high risk for cancers, particularly prostate cancer. Some studies have generated compelling evidence that selenium is beneficial, either alone or in conjunction with other micronutrients. Additional data from large clinical trials that provide the highest level of evidence will be key to determining the benefits accrued at various selenium intake levels. When the strength of the evidence becomes sufficient, clinical health professionals will need to use dietary and clinical assessment methods to ensure that people at increased risk for cancer or inflammatory and infectious diseases can be appropriately advised about selenium intake.

(Can J Diet Prac Res 2005;66:98-102)

Résumé

Le sélénium est un oligoélément essentiel qui intervient dans plusieurs activités métaboliques clés par l'intermédiaire des sélénoprotéines, enzymes indispensables à la protection contre les lésions oxydatives et à la régulation de la fonction immunitaire. Le sélénium peut également apporter d'autres bienfaits pour la santé non liés à ses fonctions enzymatiques. Il peut être bénéfique pour les personnes dont le stress oxydatif est élevé, notamment celles qui souffrent de maladies inflammatoires ou infectieuses, telle l'arthrite rhumatoïde ou l'infection par le VIH, ou qui sont à risque élevé de cancer, entre autres de la prostate. Des études ont fourni des preuves concluantes que le sélénium est bénéfique, seul ou en combinaison avec d'autres micronutriments. Des données supplémentaires provenant de vastes essais cliniques qui fourniraient le niveau le plus élevé de preuves scientifiques seront essentielles pour déterminer les bienfaits correspondant à divers niveaux d'apport en sélénium. Lorsque les preuves seront suffisantes, les professionnels de la santé devront utiliser des méthodes d'évaluation diététique et clinique pour s'assurer que les personnes à risque élevé de cancer ou de maladies inflammatoires ou infectieuses reçoivent des conseils appropriés quant à l'apport en sélénium.

(Rev can prat rech diétét 2005;66:98-102)

INTRODUCTION

Selenium is an essential trace mineral derived from plants that extract selenium from soil. Selenium availability therefore is largely dependent upon soil conditions. Selenium-poor soils include those in volcanic regions, acid soils, and soils with high iron and aluminum content; parts of Europe, China, and New Zealand are particularly well known for selenium-deficient soils (1).

Recommended selenium intakes

In adults, the new Recommended Dietary Allowance (RDA) for selenium is 55 µg daily (2); this value is based on the amount needed to maximize glutathione peroxidase activity. The Tolerable Upper Intake Level is set at 400 µg daily (2). In Canada, dietary selenium intake reportedly ranges from 113 µg to 220 µg daily (3), which differs markedly from U.S. intake data (106 µg) in the Third National Health and Nutrition Survey, which was used as the basis for setting the RDA (2). This disparity may be partly related to differences in food composition databases or dietary assessment methods. For example, average selenium content reported in food composition tables does not reflect regional differences in soils. (Table 1 lists food sources of selenium.) Despite a lack of standardized selenium intake data, a selenium deficiency would not be expected in the Canadian population. However, recent evidence indicates that selenium intakes above those recommended to maximize selenoprotein synthesis may provide health benefits to those at risk for certain diseases.

Antioxidant and anti-inflammatory properties

Selenium acts as both an antioxidant and anti-inflammatory agent. Selenium is found in significant amounts in the liver, the spleen, and lymph nodes; hence, its role in immunity has been investigated. In 2000, Rayman (4) summarized selenium research in a major review. Selenium deficiency can impair both cell-mediated immunity and B cell function. Several epidemiological studies have shown that people with the highest selenium levels have a reduced risk of cancer incidence and mortality. Selenium deficiency also may be linked to the transition of harmless viruses to virulent ones, and may have an impact on viral disease progression. By acting as scavengers, glutathione peroxidases (selenoproteins) hinder the propagation of free radicals and reactive oxygen species, thereby diminishing the production of inflammatory prostaglandins and leukotrienes from hydroperoxide intermediates (4).

Selenium and disease outcome

Many studies have demonstrated a relationship between selenium status and various disease parameters. However, few clinical trials have been conducted to determine whether selenium intakes above the level needed to maximize glutathione peroxidase activity affect disease outcome favourably. We review recent research elucidating the role that selenium may play in enhancing immunity, protecting against selected cancer sites, and moderating infection and inflammation. Particular emphasis is given to prostate cancer, human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), and rheumatoid arthritis (RA).

SELENIUM AND HEALTH

Immunity

Selenium plays an important role in human health. Selenoprotems are involved m reproduction, thyroid activity, DNA synthesis, muscle function, and several other metabolic functions (4).

Adequate nutritional status is essential to proper immune system functioning. Opportunistic infections and an inability to resist tumour development may be observed in undernourished people whose immunity is compromised (5). Selenium has been shown to enhance the growth and activity of T lymphocytes and other immunocompetent cells (6). This finding suggests the need for studies of selenium's effects on serious viral infections such as HIV/AIDS, or diseases such as cancer, in which immune system strength can influence outcome.

Roy et al. (7) demonstrated that a daily 200µg sodium selemte supplement for eight weeks significantly augmented the T lymphocyte-mediated immune response in healthy people whose selenium stores were replete. Additional research (8) in the same subjects showed that selenium supplementation enhanced the proliferation of activated T cells, enhanced the response to antigen stimulation of lymphocytes, increased the ability of lymphocytes to become cytotoxic for tumour cell destruction by 118%, and increased natural killer-cell activity by 82%. The researchers concluded that selenium intake beyond that normally achieved in diet enhances immunity via increased expression of receptors for interleukin-2.

Because of the impact of aging on immunity and the potential for impaired nutritional status, much of the research on selenium and immunity has been conducted among the elderly. Overall, both in vitro (9) and clinical trials (10-12) have shown that a selenium supplement of at least 100 µg daily, alone or in combination with other vitamins such as vitamin E or minerals such as zinc, improves serum selenium values and immune response, particularly for natural killer cells and lymphocytes. Improved nutritional status among elderly people, whether they are institutionalized or living independently (and apparently healthy), can enhance immunity that may or may not be related to a specific nutrient.

One randomized, double-blind, placebo-controlled trial (13) demonstrated that a low-dose supplement of zinc (20 mg) and selenium (100µg) improved serological protection (p

Supplementation with micronutrients, including minerals such as selenium and zinc, could reduce morbidity from respiratory infections among the elderly. Correcting probable marginal deficiencies in elderly people could have an important impact on public health.

Cancer

In 1969, Shamberger and Frost (14) reported that regional cancer mortality rates were inversely correlated with selenium exposure, and that selenium might therefore have a protective effect against cancer in humans. Since then, the literature on selenium and cancer has grown extensively, and several important studies bear mentioning. Of particular importance are the results of the Linxian trial in China (15), which has one of the world's highest rates of esophageal cancer.

Linxian trial: Linxian Nutritional Intervention Trial data were collected from 1986 to 1991; overall, participants who received selenium, beta-carotene, and vitamin E in doses one to two times higher than the U.S. RDA had significantly lower cancer mortality rates than those who did not. However, separating the effects of selenium from those of beta-carotene and vitamin E was not possible with the Einxian study design. In further study using a stratified case-cohort sample, the researchers therefore measured serum selenium levels (1985 baseline vs. postdiagnostic values); these were associated with subsequent development of esophageal and gastric cardia cancer, but not gastric non-cardia cancer. The proportion of esophageal and gastric cardia cancer attributable to low selenium levels was 26.4% (95% CI= 14.45-38.36). The relative risk with highest to lowest quartile of serum selenium was 0.56 (95% CI=0.44-0.71) for esophageal cancer, and 0.47 (95% CI=0.33-0.65) for gastric cardia cancer. These results support other findings that selenium levels affect the incidence of some cancers (15).

Confounding effects: Effects of one micronutrient may be confounded by effects of others. Nutrition intervention trials are difficult to design and evaluate because micronutrients often are grouped according to proposed mechanisms of action. For example, effects of retinol and zinc could be combined because of their roles in immunity, and effects of selenium, betacarotene, and vitamin E could be combined because of their antioxidant properties. Studies in progress are designed to eliminate confounding information, but have not yet generated sufficient data. Two of these studies are the Prevention of Cancer by Intervention with Selenium trial and the Selenium and Vitamin E Cancer Prevention Trial (4).

Effect on various cancers: Following Clark et al.'s (16) publication of results from their randomized, controlled trial with skin cancer patients, other researchers revisited data from several prospective studies to ascertain the relationship between selenium and cancer. Clark et al. (16) found no effect on skin cancer incidence in 1,312 patients receiving 200 µg of selenium or placebo daily for four or more years (selenium group, n = 653; placebo group, n=659). However, they did find reductions in total cancer mortality and total cancer incidence, particularly for prostate, colorectal, and lung cancers (Table 2).

In the Health Professionals Follow-Up Study (17), selenium and prostate cancer were examined in a nested case-control design. A comparison of the highest to lowest quintile of selenium (as measured m toenails because they indicate longterm selenium intake) revealed that the odds ratio for prostate cancer was 0.35 (95% CI=0.16-0.78, p for trend=0.03). Brooks et al. (18) did not observe a dose-related response for plasma selenium and prostate cancer in their case-control study, but a threshold selenium value appeared necessary to confer reduced risk. In their nested case-control study, Helzlhouer et al. (19) observed a statistically significant protective association between selenium and prostate cancer only when gamma-tocopherol levels were high. (Gamma-tocopherol is the form of vitamin E in food; alpha-tocopherol is found in supplements.)

In a lung cancer study, Knekt et al. (20) concluded that the role of selenium in protecting against cancer might be a function of the oxidative stress load (e.g., smoking and the interaction with other antioxidants such as vitamin E). In the Finnish Mobile Clinic Health Examination Survey, these researchers reported that an inverse association between selenium and lung cancer risk existed only when alpha-tocopherol levels were low (

Current and future trials: Additional intervention trials are needed to clarify the role of supplemental selenium in protecting against cancer and reducing overall incidence and mortality. In current and future trials, study design will be critical for determining the impact of selenium alone or in combination with other micronutrients. A broad assessment of the literature suggests that several micronutrients have an impact on cancer, either through antioxidant or immune functions, and micronutrient interactions will confound efforts to delineate specific roles clearly. In addition, other factors may need to be considered. For example, the effect that lycopene, found primarily in tomatoes, has on prostate cancer has provided new research directions. Unfortunately, research costs will limit the number of nutritional interventions that can be included for study.

Three issues need to be resolved before specific recommendations can be made on the benefits of selenium in protecting against certain forms of cancer:

1. The form of selenium that provides the best protection.

2. Whether there is a threshold value or a range of intakes that confers protection.

3. Whether interactions exist with other micronutrients, particularly vitamin E in its different forms.

HIV/AIDS infection

The host's nutritional status is an important consideration in the study of infectious disease. Research has linked selenium deficiency and enterovirus to Keshan disease and myocarditis outbreaks in specific regions of China (21). Selenium or trace element supplementation has been demonstrated to reduce infections among the elderly (22), critically ill patients (23), and burn and trauma victims (24,25). The relationship between plasma selenium levels and liver cancer risk after chronic hepatitis infection is unclear (26), but a continuous supplemental selenium intake (one 200-µg selenized yeast tablet daily for four years) appears to act as a chemopreventive agent in those with hepatitis B infection (27).

Two of the most important advances in our understanding of selenium's role are in the areas of viral pathology and HIV/AIDS. Beck et al. (28) first demonstrated in mice that not only does micronutrient deficiency affect viral infection severity, but selenium deficiency can promote the transition of a relatively harmless virus into a virulent one. Such an effect may help to explain the first appearance of HIV in Zaire and the appearance of new influenza strains in China; both countries have higher prevalences of selenium deficiency. Beck (29) further demonstrated that the coxsackievirus B3 mutation in selenium-deficient mice was a change in the gene itself (i.e., genotypic), rather than a change in its phenotypic expression.

In comparison with 15 age-matched, HFV-negative controls, 49 HIV-positive patients, none of whom smoked or had an active opportunistic infection, had lower plasma antioxidant micronutrient levels, including selenium levels, and higher lipid peroxides and breath alkanes. Allard and colleagues' (30) data indicated increased oxidative stress and an impaired antioxidant defense system in HIV-positive people. These people may reach a level of oxidative stress and impaired defense that overwhelms the immune system, resulting in a progressive worsening of the syndrome. If this is true, then optimal intakes of micronutrients such as selenium may slow the transition to a disease state.

Dworkin et al. (31) reported that HIV-positive patients' antioxidant deficiency was most likely due to increased utilization of antioxidant micronutrients to counter oxidative stress, because dietary intakes were generally adequate. Dworkin et al. (32) also demonstrated that significant correlations exist between total lymphocyte count and both plasma selenium (r=0.53, p

Subclinical malnutrition is present among HIV-positive people. Baum et al. (33) showed that plasma selenium deficiency was independently and significantly associated with HIVrelated mortality (RR= 10.8, p

Inflammation

Selenium is involved in several biochemical pathways associated with rheumatic diseases. As an antioxidant (glutathione peroxidase), selenium can hinder the propagation of free radicals, and as an anti-inflammatory agent, it can diminish inflammatory prostaglandm production and modulate the respiratory burst (4). Researchers therefore have hypothesized that selenium status may affect disease severity or progression.

The benefit of selenium supplementation in patients with RA remains to be demonstrated (36-38); however, in a prospective study, Knekt et al. (39) did find that low selenium status and low alpha-tocopherol status may predict rheumatoid factor (RF)-negative RA. Of 18,709 Finnish males and females, 122 developed RA; 34 were RF-negative. When highest to lowest selenium intakes were compared, the relative risk of developing RA was 0.16 (95% CI=0.04-0.69) in RF-negative patients. When highest to lowest selenium intakes were compared in RFpositive patients, the relative risk remained unchanged at 0.96 (95% CI=0.49-1.90). This finding suggests that selenium may prevent RA in at least a subset of patients with inflammatory disease.

The immune system inflammatory response m patients with asthma results in increased oxygen free radicals (40). Some investigators have therefore speculated that selenium supplementation may reduce the severity of the inflammatory reaction (40,41). These researchers found a relationship between selenium status and glutathione peroxidase, as well as the inflammatory response. More clinical data on rheumatic disease and selenium are needed to determine whether selenium can modify the inflammatory process.

RELEVANCE TO PRACTICE

In the studies discussed, selenium was usually administered as sodium selemte, the form found in multivitamin and mineral supplements, or as a selenium-enriched yeast substance. Both forms have good bioavailability, allowing studies to be at least somewhat comparable.

A selenium deficiency would not be expected in the general population, and the selenium RDA remains a useful tool in assessing healthy Canadians. However, modified nutrition recommendations may be needed for some at-risk groups. The evidence accumulating about the role of nutrition in chronic disease prevention is promising. Early results indicate that optimal nutrition provides health benefits, but that all risks must be properly evaluated to ensure that the benefit of supplementation does indeed outweigh any risks.

Subclinical deficiencies within certain groups are likely due to a combination of increased need and malnutrition. For example, some people's selenium status may be suboptimal if the oxidative stress load is taken into consideration. Under such circumstances, health professionals should tailor nutrition advice individually. For example, after completing a dietary and nutritional assessment, a registered dietitian might advise an HIV-positive client to take a selenium supplement.

Before practice guidelines addressing optimal nutrition and disease reduction can be developed and implemented, results from current trials must be interpreted. The strength of the evidence for selenium and prostate cancer approaches the highest level, but even so, questions remain about the wisdom of making recommendations. In fact, new evidence from the research group that completed a 1996 landmark study (16) indicates that, although other cancer risk reductions were achieved, squamous cell carcinomas and total nonmelanoma skin cancers in patients receiving 200-µg selenium supplementation increased by 25% and 17%, respectively (42). These findings are similar to those with beta-carotene supplementation among smokers, and indicate the importance of designing studies that attempt to determine appropriate micronutnent levels and elucidate mechanisms of action.

In the future, many micronutnent recommendations for healthy Canadians may differ from those for at-risk groups. This is already the case for calcium and osteoporosis; the Osteoporosis Society of Canada vitamin D recommendations are twice the Adequate Intake levels for adults (43). Dietitians will need to plan continuing education activities so that advances in nutrition and chronic disease prevention are well understood. While the future of nutrition holds great promise, giving nutrition advice will, without doubt, grow more complex.

Acknowledgement

Milly Ryan-Harshman received a grant from Wyeth Consumer Healthcare Inc. to co-author this review.

References

1. Reilly C. Selenium in food and health. London, UK: Blackie Academic and Professional; 1996.

2. Food and Nutrition Board, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington, DC: National Academy Press; 2000.

3. Thompson JN, Erdody P, Smith DC. Selenium content of food consumed by Canadians. J Nutr 1975;105:274-7.

4. Rayman MP. The importance of selenium to human health. Lancet 2000;356:233-41.

5. Chandra RK. Nutrition and immunoregulation. Significance for host resistance to tumors and infectious diseases in humans and rodents. J Nutr 1992;122(3 Suppl):754-7.

6. Wang RD, Wang CS, Feng ZH, et al. Investigation on the effect of selenium on T lymphocyte proliferation and its mechanisms. J Tongji Med Univ 1992;12:33-8.

7. Roy M, Kiremidjian-Schumacher L, Wishe HI, et al. Supplementation with selenium and human immune cell functions. I. Effect on lymphocyte proliferation and interleukin 2 receptor expression. Biol Trace Elem Res 1994:41:103-14.

8. Kiremidjian-Schumacher L, Roy M, Wishe HI, et al. Supplementation with selenium and human immune cell functions. II. Effect on cytotoxic lymphocytes and natural killer cells. Biol Trace Elem Res 1994;41:115-27.

9. Ventura MT, Serlenga E, Tortorella C, et al. In vitro vitamin E and selenium supplementation improves neutrophil-mediated functions and monocyte chemoattractant protein-1 production in the elderly. Cytobios 1994;77:225-32.

10. Peretz A, Neve J, Desmedt ], et al. Lymphocyte response is enhanced by supplementation of elderly subjects with selenium-enriched yeast. Am J Clin Nutr 1991;53:1323-8.

11. Bunker VW, Stansfield MF, Deacon-Smith R, et al. Dietary supplementation and immunocompetence in housebound elderly subjects. Br J Biomed Sci 1994;51:128-35.

12. Ravaglia G, Forti P, Maioli F, et al. Effect of micronutrient status on natural killer cell immune function in healthy free-living subjects aged >/= 90 y. Am J Clin Nutr 2000;71:590-8.

13. Girodon F, Galan P, Monget A-L, et al. Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. Arch Intern Med 1999:159:748-54.

14. Shamberger RJ, Frost DV. Possible protective effect of selenium against human cancer. CMAJ 1969:100:682.

15. Mark SD, Qiao YL, Dawsey SM, et al. Prospective study of serum selenium levels and incident esophageal and gastric cancers. J Natl Cancer Inst 2000;92:1753-63.

16. Clark LC, Combs GF, Turnbull BW, et al. Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin: a randomized controlled trial. JAMA 1996;276:1957-63.

17. Yoshizawa K, Willett WC, Morris SJ, et al. Study of prediagnostic selenium level in toenails and the risk of advanced prostate cancer. J Natl Cancer Inst 1998;90:1219-24.

18. Brooks JD, Metier J, Chan DW, et al. Plasma selenium level before diagnosis and the risk of prostate cancer development. J Urol 2001;166:2034-8.

19. Helzlhouer KJ, Huang H-Y, Alberg AJ, et al. Association between a-tocopherol, γ-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst 2000;92:2018-23.

20. Knekt P, Marniemi J, Teppo L, et al. Is low selenium status a risk factor for lung cancer? Am J Epidemiol 1998;148:975-82.

21. Peng T, Li Y, Yang Y, et al. Characterization of enterovirus isolates from patients with heart muscle disease in a selenium-deficient area of China. J Clin Microbiol 2000;38:3538-43.

22. Johnson MA, Porter KH. Micronutrient supplementation and infection in institutionalized elders. Nutr Rev 1997;55:400-4.

23. Forceville X, Vitoux D, Gauzit R, et al. Selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients. Crit Care Med 1998;26:1478-9.

24. Berger MM, Spertini F, Shenkm A, et al. Trace element supplementation modulates pulmonary infection rates after major burns: a double-blind, placebo-controlled trial. AmJ Clin Nutr 1998;68:365-71.

25. Porter JM, Ivatury RR, Azimuddin K, et al. Antioxidant therapy in the prevention of organ dysfunction syndrome and infectious complications after trauma: early results of a prospective randomized study. Am Surg 1999;65:478-83.

26. Yu MW, Horng IS, Hsu KH, et al. Plasma selenium levels and risk of hepatocellular carcinoma among men with chronic hepatitis virus infection. Am J Epidemiol 1999;150:367-74.

27. Yu SY, Zhu YJ, Li WG. Protective role of selenium against hepatitis B virus and primary liver cancer in Qidong. Biol Trace Elem Res 1997;56:117-24.

28. Beck MA, Shi Q, Morris VC, et al. Rapid genomic evolution of a nonvirulent coxsackievirus B3 m selenium-deficient mice results in selection of identical virulent isolates. Nat Med 1995;1:433-6.

29. Beck MA. The influence of antioxidant nutrients on viral infection. Nutr Rev 1998;56:S140-6.

30. Allard JP, Aghdassi E, Chau J, et al. Oxidative stress and plasma antioxidant micronutrients in humans with HIV infection. Am J Clin Nutr 1998;67:143-7.

31. Dworkin BM, Wormser GP, Axelrod F, et al. Dietary intake in patients with AIDS, patients with AIDS-related complex and serologically positive HIV patients: correlations with nutritional status. J Parenter Enterai Nutr 1990;21:43-53.

32. Dworkin BM, Rosenthal WS, Wormser GP, et al. Abnormalities of blood selenium and glutathione peroxidase activity in patients with acquired immunodeficiency syndrome and AIDS-related complex. Biol Trace Elem Res 1988;15:167-77.

33. Baum MK, Shor-Posner G, Lai S, et al. High risk of HIV-related mortality is associated with selenium deficiency. J Acquir Immune Defic Syndr Hum Retrovirol 1997;15:370-4.

34. Hon K, Hatfield D, Malsarelli F, et al. Selenium supplementation suppresses tumor necrosis factor alpha-induced human immunodeficiency virus type 1 replication in vitro. AIDS Res Hum Retroviruses 1997;13:1325-32.

35. Baum MK, Miguez-Burbano MJ, Campa A, et al. Selenium and interleukins in persons infected with human immunodeficiency virus type 1. J Infect Dis 2000;182(Suppl 1):S69-73.

36. Peretz AM, Neve JD, Famaey JP. Selenium in rheumatic diseases. Semin Arthritis Rheum 1991;20:305-16.

37. Tarp U, Overvad K, Hansen JC, et al. Low selenium level in severe rheumatoid arthritis. Scand J Rheumatol 1985;14:97-101.

38. Tarp U, Overvad K, Thorling EB, et al. Selenium treatment in rheumatoid arthritis. Scand J Rheumatol 1985;14:364-8.

39. Knekt P, Heliovaara M, Aho K, et al. Serum selenium, serum alphatocopherol, and the risk of rheumatoid arthritis. Epidemiology 2000; 11:402-5.

40. Misso NL, Powers KA, Gillon RL, et al. Reduced platelet glutathione peroxidase activity and serum selenium concentration in atopic asthmatic patients. Clin Exp Allergy 1996;26:838-47.

41. Horvathova M, Jahnova E, Gazdik F. Effect of selenium supplementation in asthmatic subjects on the expression of endothelial cell adhesion molecules in culture. Biol Trace Elem Res 1999;69:15-26.

42. Duffield-Lillico AJ, Slate EH, Reid ME, et al. Selenium supplementation and secondary prevention of nonmelanoma skin cancer in a randomized trial. J Natl Cancer Inst 2003;95:1477-81.

43. Whiting S. The Osteoporosis Society of Canada (OSC) 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. Can J Diet Prac Res 2003;64:5.

MILLY RYAN-HARSHMAN, PhD, RD, FEAST Enterprises, Oshawa, ON; WALID ALDOORI, MB, BCh, MPA, ScD, Wyeth Consumer Healthcare Inc., Mississauga, ON

Copyright Dietitians of Canada Summer 2005
Provided by ProQuest Information and Learning Company. All rights Reserved