Importance of Zinc for Human Health

Introduction

The importance of zinc for normal growth and survival of plants and animals was recognized a long time ago. Yet the existence of its deficiency in humans was doubted because of the element's ubiquitous distribution in the environment and the lack of obvious clinical signs of deficiency. Nevertheless, evidence of human deficiency began to emerge during the 1960s, when cases of zinc-responsive dwarfism and delayed sexual maturation were first reported in Egyptian adolescents (1). Since then, a number of intervention trials have been carried out to assess the impact of zinc supplementation, particularly in low-income populations who are likely to suffer from zinc deficiency (2). Results of these studies have shown that zinc supplementation increases growth among stunted children and reduces the prevalence of common childhood infections. These studies are briefly reviewed in this document, which is presented in three parts:

• Part 1 provides background information on zinc metabolism and dietary requirements
• Part 2 highlights the consequences and causes of zinc deficiency
• and Part 3 reviews the methods to estimate the risk of zinc deficiency in populations and strategies for improving zinc status.

Part 1

Biological Functions of Zinc

Zinc is the most ubiquitous of all trace elements involved in human metabolism. More than one hundred specific enzymes require zinc for their catalytic function (3). If zinc is removed from the catalytic site, activity is lost; replacement of zinc restores activity. Zinc participates in all major biochemical pathways and plays multiple roles in the perpetuation of genetic material, including transcription of DNA, translation of RNA, and ultimately cell division. When the supply of dietary zinc is insufficient to support these functions, biochemical abnormalities and clinical signs may develop. Studies in individuals with acrodermatitis enteropathica, a genetic disorder with zinc malabsorption resulting in severe deficiency, have provided much insight into the functional outcomes of zinc deficiency (4). These include impairments of dermal, gastrointestinal, neurologic and immunologic systems.

Zinc affects both non-specific and specific immune functions. In terms of non-specific immunity, it affects the integrity of epithelial barrier and function of neutrophils, monocytes and macrophages. With regard to specific immunity, both lymphopenia and declined lymphocyte function occur in zinc deficiency. Although most of these effects are derived from experimental animals, studies in human subjects have also shown that altered zinc status can affect immune competence. For example, elderly subjects who received supplemental zinc demonstrated improvement in delayed cutaneous hypersensitivity, number of circulating T cells and serum IgG antibody response to tetanus toxoid (5). In other studies of experimentally induced mild zinc deficiency among adults, a reduction in serum thymulin and specific subpopulations of lymphocytes occurred during zinc depletion, and these returned to normal levels following zinc repletion (6). Although specific links between altered immunity and different infections are not well understood, changes in immune functions are clinically important because decreased rates of infections have been observed following zinc supplementation in community based studies.

Zinc Metabolism

Zinc is released from food as free ions during digestion. These liberated ions may then bind to endogenously secreted ligands before their transport into the enterocytes in the duodenum and jejunum (3). Specific transport proteins may facilitate the passage of zinc across the cell membrane into the portal circulation. With high intakes, zinc is also absorbed through a passive paracellular route.

The portal system carries absorbed zinc directly to the liver, and then released into systemic circulation for delivery to other tissues. About 70% of zinc in circulation is bound to albumin, and any condition that alters serum albumin concentration can have a secondary effect on serum zinc levels. Although serum zinc represents only 0.1% of the whole body zinc, the circulating zinc turns over rapidly to meet tissue needs.

Loss of zinc through gastrointestinal tract accounts for approximately half of all zinc eliminated from the body. Considerable amount of zinc is secreted through the biliary and intestinal secretions, but most of it is reabsorbed and this process is an important point of regulation of zinc balance. Other routes of zinc excretion include the urine and surface losses (desquamated skin, hair, sweat).

Human Requirements

Since the mid 1990s, the World Health Organization/Food and Agriculture Organization/International Atomic Energy Association (WHO/FAO/IAEA) and the Food and Nutrition Board (FNB) of the Institute of Medicine (IOM) have convened expert committees to develop estimates of human zinc requirements and dietary intakes needed to satisfy these requirements (7,8). For most age groups, the committees used a factorial method to estimate the average physiological requirement, which is defined as the amount of zinc that must be absorbed to offset the amount of zinc lost from both intestinal and non-intestinal sites. In growing children and pregnant women, the amount of zinc retained in newly accrued tissues is added to the requirements, and in lactating women the zinc secreted in breast milk is added. The estimates of requirements derived by the WHO committees are based on limited studies conducted in subjects who had very low zinc intakes. The FNB/IOM reviewed a larger number of studies conducted at varying levels of intakes. The reference body weights used by the WHO are based on the NCHS growth data, while the FNB/IOM committee applied reference body weights that are suitable for the North American population. The estimates of requirements derived by the two committees are different for these reasons (Table 1). More recently, the International Zinc Nutrition Consultative Group (IZiNCG) reviewed the methods adopted by these committees and revised the estimates of zinc requirement and recommended dietary intake (9).

Table 1. Estimated physiological requirements for absorbed zinc by age group and sex

	WHO			FNB/IOM		IZiNCG
Age	Reference Wt. (Kg)	Requirement (mg/day)	Age	Reference Wt. (Kg)	Requirement (mg/day)	Referenc Wt. (Kg)	Requirement (mg/day)
6-12 mo	9	0.84	6-12 mo	9	0.84	9	0.84
1-3 yr	12	0.83	1-3 yr	13	0.74	12	0.53
3-6 yr	17	0.97	4-8 yr	22	1.20	21	0.83
6-10 yr	25	1.12
10-12 yr	35	1.40	8-13 yr	40	2.12	38	1.53
12-15 yr	48	1.82
15-18 yr M	64	1.97	14-18 yr M	64	3.37	64	2.52
15-18 yr F	55	1.54	14-18 yr F	57	3.02	56	1.98
Pregnancy	-	2.27	Pregnancy*	-	4.1-5.0	-	2.68
Lactation	-	2.89	Lactation*	-	3.8-4.5	-	2.98

* Different stages of pregnancy/ lactation


Dietary Sources of Zinc and Bioavailability

Zinc occurs in a wide variety of foods, but is found in highest concentrations in animal sources, particularly beef, pork, poultry and fish, and in lesser amounts in eggs and dairy products. Zinc content is relatively high in nuts, legumes and whole grain cereals and is lower in fruits and vegetables.

Dietary factors can alter the proportion of zinc that is available for absorption in the intestine by as much as ten-fold. Most of the available information on the effect of specific dietary factors on zinc absorption has been derived from studies measuring absorption from single test meals. Though these data may not reflect the true proportion of zinc absorbed from meals consumed over the whole day, they are useful to identify the factors that affect zinc absorption. The dietary components that have a substantial impact on the absorption of zinc are phytate and calcium, which inhibit zinc absorption, and protein, which enhances the absorption (10). Phytate content is high in cereal grains, nuts and legumes. It is a strong chelator of minerals including zinc. Because phytate can not be digested and absorbed, minerals bound to phytate also pass through the intestines unabsorbed. The inhibitory effect of calcium may result from the formation of insoluble calcium-zinc-phytate complexes in the intestinal tract. Both the total amount and the type of protein in the diet influence zinc absorption. Increasing protein intake results in a higher absorption of zinc. Animal protein such as meat and egg protein enhances absorption of zinc, while casein may have inhibitory effect.

Dietary Reference Intakes

The two committees charged with developing dietary reference values, WHO/FAO/IAEA and FNB/IOM, estimated percent absorption of dietary zinc based on data available from absorption studies (7,8). Two types of study designs have been used to estimate dietary zinc absorption - single test meal and total-diet studies. Using data from both types of studies, the WHO committee derived the estimates of zinc absorption for different types of diets; 50% from highly refined diets, 30% from mixed refined diets and 15% from unrefined cereal diets. The FNB/IOM committee selected data from only total diet studies, which provide more valid estimates of zinc absorption. These studies, using labeled meals, are able to measure true zinc absorption by making correction for intestinal losses of endogenous zinc. But the committee used only studies conducted in American males and the diet types included mixed diets as well as semi-purified formula diets, resulting in higher estimates of absorption (40%). These types of diets do not represent typical diets consumed by most populations. The IZiNCG has recently revised the estimates of zinc absorption using studies with different types of diets, but excluded those that used formula diets. The absorption estimates with mixed refined vegetarian diets are 26% for men and 34% for women. The corresponding figures with unrefined cereal diets are 18% for men and 25% for women.

The estimates for absorption are now applied to the physiological requirements for absorbed zinc to derive average requirement and recommended dietary allowances (RDA) for zinc. Estimated average requirement (EAR) represents the mean dietary requirement, or the dietary intake level at which 50% of individuals would meet their physiological requirement. The RDA is set at two standard deviations (SD) above the EAR, considering the individual variation of requirement. At this level of intake, almost all individuals meet their requirements. The revised estimates of EAR and RDA developed by IZiNCG for the purpose of international application are presented in Table 2.

Table 2: Revised EAR and RDA for zinc (mg/day)*

Age/Sex	Reference Body Weight (kg)	Mixed/Refined vegetarian diets		Unrefined cereal based diets
		EAR	RDA	EAR	RDA
6-11 mo	9	3	4	4	5
1-3 yr	12	2	3	2	3
4-8 yr	21	3	4	4	5
9-13 yr	38	5	6	7	9
14-18 yr M	64	8	10	11	14
14-18 yr F	56	7	9	9	11
> 19 yr M	65	10	13	15	19
> 19 yr F	55	6	8	7	9
Pregnancy	-	8	10	10	13
Lactation	-	7	9	8	10

* IZiNCG, 2004

Zinc Toxicity

Individuals may be exposed to high intakes of zinc, either through supplemental zinc or by contact with environmental zinc. Overt toxicity symptoms, such as nausea, vomiting, epigastric pain, diarrhea and lethargy may occur with acute high intakes (11). Approximately 200-400 mg zinc is known to produce immediate vomiting in adults. Short-term exposure to high levels of contaminant zinc (>300 ppm) from improper storage of food or beverages in galvanized vessels has caused acute gastroenteritis.

Chronic overdosage of zinc, in the range of 100-300 mg zinc/day for adults may induce copper deficiency (12) and alterations in the immune response (13). Intakes as low as 50 mg supplemental zinc/day affected copper metabolism as measured by a decrease in erythrocyte copper-zinc SOD activity (14). A study in female subjects receiving 100 mg zinc/day showed a significant reduction in high density lipoprotein cholesterol levels after four weeks (15). However, these levels returned to normal after eight weeks, suggesting that this effect may be transient.

The WHO/FAO/IAEA Expert Consultation derived upper limits for zinc intakes (7). These were based on the observation that 60 mg of supplemental zinc/day resulted in adverse interactions with other nutrients, and it was considered that intakes should not exceed this amount. After accounting for a 25 percent possible variation in population intakes, the upper limit for males was set at 45 mg/day. This was extrapolated to other age/sex groups based on differences in metabolic rates.

The FNB/IOM committee also based the upper limits of zinc on studies that measured the effect of supplemental intakes on copper status, but estimated the upper tolerable limits based on the Lowest Observed Adverse Effect Level (LOAEL) and the No Observed Adverse Effect Level (NOAEL). For adults, LOAEL of 60mg zinc/day was derived from the study on copper metabolism described above (14). Considering individual variation in this response, a factor of 1.5 was used to extrapolate the LOAEL (60 mg/day) to the NOAEL (40 mg/day) for both male and female adults. For children, the upper limit was based on the results of one study in newborn infants (16). No changes in copper status were observed in infants receiving formulas with 1.8 mg or 5.8 mg zinc/L. Based on an estimated consumption of 0.78 L formula/day, the formula with 5.8 mg zinc/L was estimated to provide an average intake of 4.5 mg zinc/day, and this figure was used as the NOAEL for infants 0-6 months of age. This was rounded down to 4 mg for the upper limit. This upper limit was then extrapolated to older children based on reference body weights (Table 2).

The IZiNCG concurs with the upper limit of 40 mg zinc/day set for adults by FNB/IOM, but the upper limits proposed for young children are considered to be low. Unfortunately, there is lack of adequate data to better define the upper limits for children. It is apparent that a large proportion of US children has usual zinc intakes greater than the proposed upper limit (17). The median intake of zinc by healthy infants 2-11 months of age is 5.5 mg/day, whereas the upper limit set for this age group is 5 mg. The median zinc intake by 1-3 year old children is 6.3 mg/day and the upper limit for this age group is 7 mg. Thus many children have intakes higher than the upper limits and do not manifest any toxic signs of excessive intake of zinc.

IZiNCG reviewed the data available from two recent supplementation studies in children (18, 19). In the study conducted in India, children between 6-12 months of age received 10 mg zinc/day and those between 1-2 years of age received 20 mg/day (18). Plasma copper concentration was reported to be lower in the supplemented group as compared to placebo group. However, it is not clear what dosage level and which age group was affected. The second study was conducted in Indonesia in 6 month-old infants (19). They were given either 10 mg zinc/day or placebo for 6 months. Plasma copper concentration did not differ between the two groups at the end of the supplementation period. These results were used to set the NOAEL and derive upper limits for infants and older children (Table3).

Table 3. Upper limits or NOAEL for zinc intake by age group

	WHO			FNB/IOM		IZiBCG
Age	Reference Wt. (Kg)	Requirement (mg/day)	Age	Reference Wt. (Kg)	Requirement (mg/day)	Reference Wt. (Kg)	Requirement (mg/day)
6-12 mo	9	0.84	6-12 mo	9	0.84	9	0.84
1-3 yr	12	0.83	1-3 yr	13	0.74	12	0.53
3-6 yr	17	0.97	4-8 yr	22	1.20	21	0.83
6-10 yr	25	1.12
10-12 yr	35	1.40	9-13 yr	40	2.12	38	1.53
12-15 yr	48	1.82
15-18 yr M	55	1.54	14-18 yr M	64	3.37	64	2.52
15-18 yr F	55	1.54	14-18 yr F	57	3.02	56	1.98
Pregnancy	-	2.27	Pregnancy*	-	4.1-5.0	-	2.68
Lactation	-	2.89	Lactation*	-	3.8-4.5	-	2.98

Further prospective studies of the possible adverse effects of varying levels of supplemental zinc are urgently required to derive the upper limits for total zinc intakes among children. There are several factors to be considered in the design of such studies. These include the proportion of zinc derived from the diet and the supplements, bioavailabilty of zinc if the supplement is taken with meals, the baseline copper status and copper intake of individuals.

See Also: Zinc, Part 2 and Zinc, Part 3. 

References

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This material has been prepared by V. Reddy on behalf of the IFM's Advisory Committee on Child Health and Nutrition, January 2005.