Scientific Opinion on the substantiation of health claims related to zinc and function of the immune system (ID 291, 1757), DNA synthesis and cell division (ID 292, 1759), protection of DNA, proteins and lipids from oxidative damage (ID 294, 1758), maintenance of bone (ID 295, 1756), cognitive function (ID 296), fertility and reproduction (ID 297, 300), reproductive development (ID 298), muscle function (ID 299), metabolism of fatty acids (ID 302), maintenance of joints (ID 305), function of the heart and blood vessels (ID 306), prostate function (ID 307), thyroid function (ID 308), acid-base metabolism (ID 360), vitamin A metabolism (ID 361) and maintenance of vision (ID 361) pursuant to Article 13(1) of Regulation (EC) No 1924/2006
Słowa kluczowe:
DNA synthesis
Zinc
acid-base metabolism
blood vessels
bone
cell division
cognitive
fatty acids
fertility
health claims
heart
immune system
joints
muscle
oxidative damage
prostate
reproduction
thyroid
vision
vitamin A
2. Znaczenie oświadczenia dla zdrowia człowieka
2.1. Funkcjonowanie układu odpornościowego (ID 291, 1757)
The claimed effect is “immune system”. The Panel assumes that the target population is the general population.
The Panel considers that the normal function of the immune system is beneficial to human health.
2.2. Synteza DNA i podziały komórek (ID 292, 1759)
The claimed effect is “DNA synthesis / cell division”. The Panel assumes that the target population is the general population.
The Panel notes that DNA synthesis and cell division are crucial processes for tissue growth and development and for tissue maintenance through cell turnover.
The Panel considers that normal DNA synthesis and cell division are beneficial to human health.
2.3. Ochrona DNA, białek i lipidów przed uszkodzeniem oksydacyjnym (ID 294, 1758)
The claimed effects are “protection of body tissues and cells from oxidative damage; antioxidant activity; antioxidative properties” and “protection of body tissues and cells from oxidative damage”. The Panel assumes that the target population is the general population.
Reactive oxygen species (ROS) including several kinds of radicals are generated in biochemical processes (e.g. respiratory chain) and as a consequence of exposure to exogenous factors (e.g. radiation, pollutants). These reactive intermediates damage biologically relevant molecules such as DNA, proteins and lipids if they are not intercepted by the antioxidant network which includes free radical scavengers like antioxidant nutrients.
The Panel considers that the protection of DNA, proteins and lipids from oxidative damage is beneficial to human health.
2.4. Utrzymanie prawidłowego stanu kości (ID 295, 1756)
The claimed effect is “bone formation”. The Panel assumes that the target population is the general population.
The Panel considers that maintenance of normal bone is beneficial to human health.
2.5. Funkcje poznawcze (ID 296)
The claimed effect is “mental performance (where mental performance stands for those aspects of brain and nerve functions which determine aspects like concentration, learning, memory and reasoning, as well as resistance to stress)”. The Panel assumes that the target population is the general population.
The Panel considers that normal cognitive function is beneficial to human health.
2.6. Płodność i rozmnażanie (ID 297, 300)
The claimed effects are “normal fertility” and “reproduction in males”. The Panel assumes that the target population is female and male population at the reproductive age.
The Panel considers that normal fertility and reproduction are beneficial to human health.
2.7. Rozwój funkcji reprodukcyjnych (ID 298)
The claimed effect is “reproductive development”.
Reproductive development is related to children's development and health. The Panel notes that claims related to children's development and health are outside the scope of Article 13 of Regulation (EC) No 1924/2006.
2.8. Funkcje mięśni (ID 299)
The claimed effect is “required to maintain optimal muscle function”. The Panel assumes that the target population is the general population.
The Panel considers that normal muscle function is beneficial to human health.
2.9. Metabolizm kwasów tłuszczowych (ID 302)
The claimed effect is “essential co-factor in fatty acid metabolism that impacts upon hormonal health”. The Panel assumes that the target population is the general population.
The Panel notes that the claimed effect, hormonal health, has not been sufficiently defined in the evidence provided.
The Panel considers that normal metabolism of fatty acids is beneficial to human health.
2.10. Utrzymanie prawidłowego stanu stawów (ID 305)
The claimed effect is “joint health”. The Panel assumes that the target population is the general population.
The Panel notes that joint health relates to maintenance or improvement of joint function.
The Panel considers that maintenance of normal joints is beneficial to human health.
2.11. Funkcjonowanie serca i naczyń krwionośnych (ID 306)
The claimed effect is “cardiovascular health”. The Panel assumes that the target population is the general population.
Cardiovascular health has not been defined in the list and is interpreted as function of the heart and blood vessels in order to allow a scientific evaluation.
The Panel considers that the normal function of the heart and blood vessels is beneficial to human health.
2.12. Funkcjonowanie prostaty (ID 307)
The claimed effect is “prostate health”. The Panel assumes that the target population is the general male population.
The Panel considers that normal prostate function is beneficial to human health.
2.13. Funkcjonowanie tarczycy (ID 308)
The claim effect is “thyroid health”. The Panel assumes that the target population is the general population.
The Panel considers that normal thyroid function is beneficial to human health.
2.14. Metabolizm kwasowo-zasadowy (ID 360)
The claimed effect is “acid-base metabolism”. The Panel assumes that the target population is the general population.
The Panel considers that normal acid-base metabolism is beneficial to human health.
2.15. Metabolizm witaminy A (ID 361)
The claimed effect is “involvement in vitamin A metabolism and process of vision”. The Panel assumes that the target population is the general population.
The Panel considers that normal metabolism of vitamin A is beneficial to human health.
2.16. Utrzymanie prawidłowego wzroku (ID 361)
The claimed effect is “involvement in vitamin A metabolism and process of vision”. The Panel assumes that the target population is the general population.
The Panel considers that maintenance of normal vision is beneficial to human health.
3. Naukowe uzasadnienia wpływu na zdrowie człowieka -
Zinc is present in all tissues. It has essential structural, regulatory or catalytic roles in many enzymes. It maintains the configuration of a number of non-enzymatic proteins such as pre-secretory granules of insulin, some mammalian gene transcription proteins and thymulin. It facilitates hormone and receptor binding at membrane and nuclear levels, and it may maintain integrity of biomembranes. Consequently zinc participates in gene expression and in the mechanisms and control of major metabolic pathways involving proteins, carbohydrates, nucleic acids and lipids (SCF, 1993; DoH, 1991). Human zinc deficiency symptoms include retarded growth, depressed immune function, skin lesions, skeletal abnormalities, impaired reproductive ability and behavioural abnormalities such as changes in mood, loss of affect and emotional lability, anorexia, dysfunction of smell and taste, irritability and depression (SCF, 2003; EVM, 2002, Cousins, 2006).
3.1. Funkcjonowanie układu odpornościowego (ID 291, 1757)
Zinc deficiency is associated with a decline in most aspects of immune function. Lymphopaenia and thymic atrophy are observed. Cell mediated and antibody mediated responses are reduced. In addition to the generalized effects of zinc on DNA synthesis, zinc deficiency appears to induce apoptosis, resulting in a loss of B-cell and T-cell precursors within the bone marrow. Thymulin is a zinc-dependent enzyme that stimulates the development of T cells within the thymus. The production of cytokines by mononuclear cells is also reduced by zinc deficiency. Adequate zinc status is necessary for natural killers cell function. Zinc deficiency renders people more susceptible to infections, while zinc supplementation in humans has shown benefit in immune responses to bacterial and viral infections (Freake, 2006; King and Cousins, 2006; IoM, 2001). Infants with acrodermatitis enteropathica, a rare inborn error with a reduced ability to absorb dietary zinc, highlight the immune functions which are dependent on zinc. These patients show impaired lymphocyte proliferation and response to mitogens, decreased/inverted CD4/CD8 ratios, impaired NK activity and cytotoxicity.
The Panel concludes that a cause and effect relationship has been established between the dietary intake of zinc and the normal function of the immune system. However, the evidence provided does not establish that inadequate intake of zinc leading to impaired function of the immune system occurs in the general EU population.
3.2. Synteza DNA i podziały komórek (ID 292, 1759)
Zinc has essential structural, regulatory or catalytic roles in many enzymes. Zinc plays a role in the stabilization of genetic material and is an essential component of some enzymes that participate in the synthesis of nucleic acids. About 1% of human genome codes for zinc finger proteins that play an important regulatory function in gene expression Zinc inadequacy affects gene expression, DNA or RNA metabolism and impairs cell division (Freake, 2006; EVM, 2002; King and Cousins, 2006; IoM, 2001).
The Panel concludes that a cause and effect relationship has been established between the dietary intake of zinc and normal DNA synthesis and cell division. However, the evidence provided does not establish that inadequate intake of zinc leading to impaired DNA synthesis and cell division occurs in the general EU population.
3.3. Ochrona DNA, białek i lipidów przed uszkodzeniem oksydacyjnym (ID 294, 1758)
Zinc participates in the antioxidant defence system of the body. It can bind to thiol groups in proteins, making them less susceptible to oxidation. By displacing redox-reactive metals such as iron and copper from both proteins and lipids it can reduce the metal-induced formation of hydroxyl radicals and thus protect the macromolecules. Zinc induces the expression of metallothionein and increases the activity of catalase both of which can scavenge reactive oxygen species (ROS). Increased oxidative stress results in the release of zinc from metallothionein, presumably making it more available for other proteins. Zinc is a cofactor of the antioxidant enzyme copper/zinc-superoxide dismutase (Freake, 2006).
The Panel concludes that a cause and effect relationship has been established between the dietary intake of zinc and the protection of DNA, proteins and lipids from oxidative damage. However, the evidence provided does not establish that inadequate intake of zinc leading to impaired protection of DNA, proteins and lipids from oxidative damage occurs in the general EU population.
3.4. Utrzymanie prawidłowego stanu kości (ID 295, 1756)
Zinc is an essential cofactor for enzymes involved in synthesis of various bone matrix constituents and plays a particularly important role in the regulation of bone deposition and resorption. Zinc also plays a structural role in the bone matrix. Bone mineral is composed of hydroxyapatite crystals, which contain zinc complexed with fluoride. Zinc is required for osteoblastic activity, directly by activating aminoacyl-tRNA synthetase in osteoblastic cells and stimulating cellular protein synthesis. Zinc also promotes bone mineralization through its role as a cofactor of alkaline phosphatase (Lowe et al., 2002; Meunier et al., 2005).
Zinc deficiency results in impaired DNA synthesis and protein metabolism, which lead to negative effects on bone formation. In animals, zinc deficiency has been associated with abnormalities in bone growth, bone formation, and mineralization. Zinc concentration in bone is greatly reduced during zinc deficiency. Zinc intake has been reported to be associated with low bone mass in women. Furthermore, reduced serum or plasma zinc concentrations have also been reported in osteoporotic women (Ilich and Kerstetter, 2000; Lowe et al., 2002; Meunier, 2005).
A total of 54 references were cited for the substantiation of the claimed effect. Some studies show that serum zinc concentration could be reduced or that zinc excretion could be higher in bone disease (e.g. osteoporosis, osteopenia) (Herzberg et al., 1990; Holloway et al., 1996; Igarashi and Yamaguchi, 2001; Nishi, 1996; Sugiyama et al., 2000). Data from an observational study also suggest that low intake of zinc could be associated with an increased incidence of fracture (Elmstahl et al., 1998).
The Panel concludes that a cause and effect relationship has been established between the dietary intake of zinc and maintenance of normal bone. However, the evidence provided does not establish that intake of zinc inadequate for the maintenance of normal bone occurs in the general EU population.
3.5. Funkcje poznawcze (ID 296)
A total of 27 references were cited for the substantiation of the claimed effect. One of these, Maylor et al. (2006), studied the effects of zinc supplementation on cognitive function in healthy middle-aged and older adults. The study was a randomised double-blind placebo-controlled design (n=387) with healthy adults between 55 and 87 years. Zinc supplementation (0, 15 or 30 mg/day) were administered for 6 months. The Automated Neuropsychological Test Battery was performed at 0, 3 and 6 months. Younger adults (<70 years) performed significantly better on all tests than older adults (>70 years), and performance improved with practice on some measures. For two out of eight dependent variables, there were significant interactions indicating a beneficial effect (at 3 months only) of both 15 and 30 mg/day on one measure of spatial working memory and a detrimental effect of 15 mg/day on one measure of attention.
Evidence for improved cognitive function among school-aged children has been derived from studies of urban and rural children in China. In the rural population of children, the positive effect of zinc on cognitive function was dependent on the provision of other supplemental micronutrients, while in the urban group, supplemental zinc had a positive effect that was independent of the provision of other micronutrients (Hotz, 2006).
In the central nervous system zinc has a role as a neurosecretory product or cofactor, and is highly concentrated in the synaptic vesicles of specific neurons, called zinc containing neurons. Zinc-containing neurons are a subset of glutamatergic neurons (Frederickson, 2000).
The Panel concludes that a cause and effect relationship has been established between the dietary intake of zinc and normal cognitive function. However, the evidence provided does not establish that inadequate intake of zinc leading to impaired cognitive function occurs in the general EU population.
3.6. Płodność i rozmnażanie (ID 297, 300)
Zinc plays a role in reproduction in males and females. Spermatogenesis is a zinc dependent process and seminal fluid is particularly rich in zinc. An important class of “zinc finger” transcription factors is the steroid/thyroid receptor superfamily, which is responsible for mediating the biological response to a wide range of hormonal and metabolic signals. Low dietary zinc status has been associated with low circulating concentrations of several hormones including testosterone. The original description of zinc deficiency in humans included lack of pubertal development (IoM, 2001; Freake, 2006).
The Panel concludes that a cause and effect relationship has been established between the dietary intake of zinc and normal fertility and reproduction. However, the evidence provided does not establish that inadequate intake of zinc leading to impaired fertility and reproduction occurs in the general EU population.
3.7. Funkcje mięśni (ID 299)
A total of six references were cited for the substantiation of the claimed effect. Four studies dealt with outcomes unrelated to the claimed effect such as serum testosterone levels and blood rheology during exercise and physical performance. The Panel notes, that these references did not provide any scientific data that could be used to substantiate the claimed effect.
In one double-blind cross over study with 16 women the effect of zinc on muscle strength and endurance, followed by zinc supplementation (135 mg/day for 14 days) was assessed using isometric and isokinetic tests of the knee extensor and flexor muscle groups . After zinc treatment, a significant increase in isometric endurance but not in dynamic endurance was observed (Krotkiewski et al., 1982). The Panel notes the small size of the study and the lack of information on the overall nutritional status of intervention and control groups. The Panel also notes that the dose administered in this study is above the established upper intake level of 25 mg/day for zinc.
In a zinc repletion depletion study with eight men, the effect of zinc on isokinetic peak force and total work capacity was assessed. The peak force of the muscle groups tested was not affected by acute zinc depletion, but total work capacity for the knee extensor muscles and shoulder extensor and flexor muscles significantly declined (Van Loan et al., 1999).The Panel notes the small size of the study.
The Panel concludes that a cause and effect relationship has not been established between the dietary intake of zinc and normal muscle function.
3.8. Metabolizm kwasów tłuszczowych (ID 302)
Zinc is necessary for the conversion of linoleic acid to gamma-linolenic acid and the mobilization of dihomogammalinolenic acid for the synthesis of series-1 prostaglandins (IoM 2001, Freake HC, 2006).
The Panel concludes that a cause and effect relationship has been established between the dietary intake of zinc and normal metabolism of fatty acids. However, the evidence provided does not establish that inadequate intake of zinc leading to impaired fatty acid metabolism occurs in the general EU population.
3.9. Utrzymanie prawidłowego stanu stawów (ID 305)
A total of 23 references were cited for the substantiation of the claimed effect, including three review and background papers, one national food consumption survey and 19 human studies. The Panel considers that the review and background papers, which were very general in nature, and the national food consumption survey, did not provide any scientific data that could be used to substantiate the claimed effect. A number of human studies dealt with zinc interaction with other nutrients, zinc metabolism and homeostasis and zinc status in different age populations. These studies dealt with outcomes unrelated to the claimed effects. The Panel notes, that these references did not provide any scientific data that could be used to substantiate the claimed effect.
The human studies in the diseased population (rheumatoid arthritis, juvenile arthritis or osteoarthritis patients) show that serum concentrations of zinc are reduced in some cases. As serum zinc can be influenced by inflammatory conditions this is not an unexpected result (Dore-Duffy et al., 1990; Grennan et al., 1980; Haugen et al., 1992; Helgeland et al., 2000; Helliwell et al., 1984; Honkanen et al., 1991; Naveh et al., 1997; Zoli et al., 1998; Niedermeier and Griggs, 1971). The Panel, moreover, considers that the evidence provided does not establish that patients with rheumatoid arthritis, juvenile arthritis or osteoarthritis are representative of the general population with regard to the functional condition of the joints.
The Panel concludes that a cause and effect relationship has not been established between the dietary intake of zinc and maintenance of normal joints.
3.10. Funkcjonowanie serca i naczyń krwionośnych (ID 306)
A total of 5 references were cited for the substantiation of the claimed effect, including three narrative reviews and two human studies. The Panel considers that the reviews, which were very general in nature, did not provide any scientific data that could be used to substantiate the claimed effect.
One human study dealt with erythrocyte carbonic anhydrase activity during exercise (Lukaski, 2005) which is unrelated to the claimed effect. In one cross sectional study Singh et al. (1998) reported an association between a low dietary zinc intake, and low serum zinc concentrations, and an increased prevalence of coronary artery disease in a rural and urban Indian population. The Panel notes that limited conclusions can be drawn from this study on the claimed effect.
The Panel concludes that a cause and effect relationship has not been established between the dietary intake of zinc and normal function of the heart and blood vessels.
3.11. Funkcjonowanie prostaty (ID 307)
Prostate has high concentration of zinc. A total of 3 references were cited for the substantiation of the claimed effect. These studies dealt with outcomes such as the hypoxia-inducible-factor-1α, the anti-tumor effect of zinc in prostate cancer and the plasma zinc levels in prostate disorders, which are unrelated to the claimed effect. The Panel notes, that these references did not provide any scientific data that could be used to substantiate the claimed effect.
The Panel concludes that a cause and effect relationship has not been established between the dietary intake of zinc and normal prostate function.
3.12. Funkcjonowanie tarczycy (ID 308)
The major secretory product of the thyroid gland is thyroxine (T4), which is converted to the active thyroid hormone triiodo-L-thyronine (T3) within cells by deiodinases. T3 actions in its target tissues are initiated by binding of the hormone to specific thyroid hormone receptor proteins within the nucleus. T3 receptors are included among the nuclear zinc-binding proteins. Thus it appears that lack of zinc might impair thyroid hormone signalling by reducing the ability of the thyroid hormone receptor to bind to DNA and thereby influence target gene transcription (Freake, 2006; Freake et al., 2001).
A total of 7 references were cited for the substantiation of the claimed effect, including one opinion of a scientific body, one review paper, one human study and four in vivo studies.
In the review (Christianson, 1991) and the opinion of the scientific body (SCF 2003) the claimed effect was not stated. One in vivo study dealt with the effect of zinc deficiency on metabolic rate (Evans, 2004) which is unrelated to the claimed effect. The Panel notes that these references did not provide any scientific data that could be used to substantiate the claimed effect
In a 75 days metabolic study of low zinc intakes in six men, Wada and King (1986) reported that circulating TSH, total T4 and free T4 tended to decrease during the zinc depletion phase, returning to control concentrations after zinc repletion, but only the decrease in free T4 was considered to be significant. The Panel notes that limited conclusions can be drawn from this small study on the claimed effect.
In zinc deficient rats, reduced plasma T4 and T3 concentrations were observed (Lukaski et al., 1992; Freake et al., 2001). In zinc deficient guinea pigs, thyroid glands were smaller in size and showed histopathological changes of atrophy and degeneration in the follicles. They concluded that thyroid lesions were related to the depletion in serum T3 and T4 which was, in turn, owing to zinc deficiency (Gupta et al., 1997). The Panel considers that the evidence provided in animals does not predict an effect of zinc intake on thyroid function in humans.
The Panel concludes that the evidence provided is insufficient to establish a cause and effect relationship between the dietary intake of zinc and normal thyroid function.
3.13. Metabolizm kwasowo-zasadowy (ID 360)
Zinc has essential structural, regulatory or catalytic roles in many enzymes. Carbonic anhydrase, is a zinc metalloenzyme, where zinc is a direct participant in the catalytic function.
Blood and extracellular fluid pH are also tightly regulated by the presence of buffer systems which attenuate changes as a consequence of acid load mainly from cellular metabolism or the ingestion of acids in the diet. The principal buffer system is based on bicarbonate (HCO3-). In blood, the major product of oxidative metabolism, CO2, reacts with water in the presence of carbonic anhydrase to form carbonic acid (H2CO3) which is relatively unstable and tends to dissociate and generate H+ and HCO3-. In vivo studies have shown that dietary zinc deficiency significantly reduces red blood cell carbonic anhydrase activity (Freake, 2006; King and Cousins, 2006).
The Panel concludes that a cause and effect relationship has been established between the dietary intake of zinc and acid-base metabolism. However, the evidence provided does not establish that inadequate intake of zinc leading to impaired acid-base metabolism occurs in the general EU population.
3.14. Metabolizm witaminy A (ID 361)
Zinc participates in the absorption, mobilization, transport and metabolism of micronutrients, including vitamin A, through its involvement in protein synthesis and cellular enzyme functions (IoM, 2001). In humans, cross-sectional studies and supplementation trials have failed to establish a consistent relationship between zinc and vitamin A status. However, a positive association may exist in malnourished populations in which deficiencies of both micronutrient often coexists (IoM, 2001; Christian and West, 1998). Because zinc is required for the synthesis of retinol binding protein (RBP), zinc deficiency influences the mobilization of vitamin A from the liver and its transport into the circulation (IoM, 2001).
The Panel concludes that a cause and effect relationship has been established between the dietary intake of zinc and normal metabolism of vitamin A. However, the evidence provided does not establish that inadequate intake of zinc leading to impaired vitamin A metabolism occurs in the general EU population.
3.15. Utrzymanie prawidłowego wzroku (ID 361)
Zinc regulates the metabolic conversion of retinol to retinaldeyde (retinal) through the zinc-dependent enzyme retinol dehydrogenase. The conversion of retinol to retinal is a critical step in the visual cycle in the retina of the eye (Christian and West, 1998; Grahan, 2001). In retina and retinal pigment epithelium, there is evidence that zinc can modify photoreceptor plasma membranes, regulate the light-rhodopsin reaction, modulate synaptic transmission and serve as an antioxidant (Grahan et al., 2001; Ugarte and Osborne, 2001). A significant reduction in the synthesis of rhodopsin was reported in zinc deficient rats, which was postulated to be owing to impaired protein (opsin and alcohol dehydrogenase) synthesis (IoM, 2001). Zinc deficiency in humans has been shown to result in poor dark-adaptation, which improved after the provision of a therapeutic dose of 220 mg/day of zinc (Morrison, 1978).
The Panel concludes that a cause and effect relationship has been established between the dietary intake of zinc and maintenance of normal vision. However, the evidence provided does not establish that intake of zinc inadequate for the maintenance of normal vision occurs in the general EU population.
