28.1: Zinc (24c.1)

In an adult 70kg male there is approximately 1.5–2.5g of zinc, of which over 80% is found in the skeletal muscle and bone. Much smaller amounts are present in the liver, gastro­intestinal tract, skin, kidney, lung, prostate, and other organs, as shown in (Table 24c.1).

Table 24c.1 Zinc content of major organs and tissues in adult (70 kg) man. Adapted from Iyengar (1998).

Tissue	Zn conc. (mg/kg wet wt)	Total content (mg)	Percent of total body zinc
Skeletal muscle Skeleton —Bone —Marrow —Periarticular tissue —Cartilage Liver Lung Skin Whole blood Kidney Brain Teeth Hair Spleen Lymph nodes Gastrointestinal tract Prostate Other organs/tissues Total	50 90 20 11 34 40 40 15 6 50 10 250 200 20 14 15 100 Variable	1400 450 60 11 30 72 40 39 33 15 14 11.5 4 3.6 3.5 1.8 1.6 50 2240	63 20 3 < 1 1 3 2 2 1 1 1 1 < 1 < 1 < 1 < 1 < 1 2 100

Unlike other trace elements such as iron and copper, or minerals such as calcium, there are no large, sequestered, readily mobilizable stores of zinc that can be rapidly released in response to variations in dietary intakes of zinc. Instead, there is a small pool of rapidly exchangeable zinc which is located in bone, liver, pancreas, kidney, spleen and plasma and accounts for about 10% of whole-body zinc (King et al., 2000). This pool turns over com­pletely about five times each day to provide zinc for zinc-dependent meta­bolic functions throughout the body. It is the loss of a critical but small amount of zinc from this pool that leads to the biochemical and clinical signs of zinc defi­ciency (King, 2018). Bone may also provide a passive reserve of zinc, especially during growth, so that when dietary zinc intakes are low, less of the zinc released during normal bone turnover, is re-deposited in the skeleton (Zhou et al., 1993). There is also some evidence that hepatic zinc, bound to metallo­thionein and accrued during gestation, can also be mobilized during early infancy to supple­ment the infant’s needs for zinc (Zlotkin and Cherian, 1988; Coni et al., 1996).

24c.1.1 Functions of zinc at the cellular level

At the cellular level, zinc has three major meta­bolic functions — catalytic, structural, and regulatory (King and Cousins, 2014). More than 300 metallo­enzymes require zinc as a catalyst for function or regulation. During zinc defi­ciency, their activity is decreased, although their structure does not change, and with the addition of zinc, enzyme activity is restored. Zinc metallo­enzymes are involved in nucleic acid meta­bolism and cellular proliferation, differ­entiation, and growth; examples are listed in (Table 24c.2).

So far, no consistent changes in the activity of any zinc metallo­enzymes have been linked with signs and symptoms of zinc defi­ciency in experimental zinc depletion-repletion studies in humans (King et al., 2015).

Table 24c.2: Selected zinc metallo­enzymes.

Zinc metalloenzymes
Alcohol dehydrogenase
Alkaline phosphatase
Carbonic anhydrase
Carboxypeptidase
Deoxynucleotidyl transferase
DNA polymerase
Glutamic acid dehydrogenase
Malic acid dehydrogenase
Nucleoside phosphorylase
RNA polymerase
Tyrosine kinase
Zinc-copper superoxide dismutase

Zinc also plays an essential structural role in the folding of some proteins and a lack of zinc results in protein misfolding and the loss of function. A finger-like structure, known as a zinc finger motif, stabilizes the structure of a variety of proteins, including those involved in cellular differ­entiation or proliferation, signal trans­duction, cellular adhesion, or trans­cription. Zinc fingers use cysteine and histidine to form a tetrahedral Zn²⁺ coordination com­plex. The extent to which the intake of dietary zinc affects the function of zinc finger proteins is unclear. Zinc also maintains the structure of certain enzymes, notably the antioxidant enzyme, copper-zinc superoxide dismutase (Cu,Zn‑SOD) (King, 2011).

Over 3% of all identified human genes contain zinc finger proteins that regulate gene expression by acting as trans­cription factors. Gene expression may also regulate the effects of zinc defi­ciency on lipid peroxidation, immune function, apoptosis, and neuronal function(King et al., 2015). Zinc is also involved in cell signaling through the metal response element-binding trans­cription factor 1 (MTF1). Whether MTF1 regulates genes negatively or positively appears to depend on the cellular zinc status. Zinc may also have a direct regulatory role controlling numerous cell-signaling pathways by modulating kinase and phosphorylase activities. For more details of the meta­bolic functions of zinc at the cellular level, see King and Cousins (2014).

Zinc-dependent cellular functions are coordinated by one or more of twenty four zinc trans­porters. Two classes of zinc trans­porters exist: ZIP proteins and ZnT proteins. It is the up- or down-regulation of these trans­porter genes in response to zinc intake that helps to maintain cellular zinc homeo­stasis. The ZnT proteins (n=10) generally trans­port zinc ions out of the cytosol, whereas ZIP (SLC 39) proteins (n=14) import the ions from the cellular com­partments or the extra­cellular space into the cytosol. Individual ZIP and ZnT trans­porters are located in specific cell types. For example, ZIP‑14 appears to be involved in the uptake of zinc by the liver in response to acute inflam­mation and infection, whereas ZnT3 is found in the synaptic vesicles of some types of neurons, and ZnT8 in the secretory granules of β‑pancreatic cells (King et al., 2015). However, the role of many of the twenty four zinc trans­porters and how their expression is altered to maintain cellular zinc homeo­stasis remains uncertain (King and Cousins, 2014).

24c.1.2 Physiological functions of zinc

Multiple physio­logical functions are affected by zinc defi­ciency due to the ubiquitous involve­ment of zinc in cellular meta­bolism. A modest deprivation in zinc intake over the long-term results in detectable changes in growth, immune function, and possibly neuro­behavioural function. Other signs of marginal zinc defi­ciency include poor appetite and impaired taste acuity (hypogeusia).

Impaired growth in zinc defi­ciency arises from the role of zinc in DNA trans­cription and gene expression, signal trans­duction pathways, and endocrine function (e.g., insulin-like growth factor); these effects are summarized in Figure 24c.1.

Figure 24c.1. Effects of zinc deficiency on metabolic processes associated with growth. Redrawn from MacDonald RS (2000).

Of the growth indices, height‑ or length-for‑age is considered the best functional bioindicator associated with the risk of zinc defi­ciency in popu­lations. Increased linear growth is the primary response to increased zinc intake, with an associated gain in weight. (de Benoist et al., 2007).

Zinc is also required for the synthesis and functions of immune regulatory proteins and for the maintenance of normal immune function. Consequently, zinc defi­ciency causes immune dysfunction. Both barrier function and cellular com­ponents of the innate immune responses (i.e., macrophage and neutrophil function) are com­promised as well as the acquired immune system, with the largest effect being on reducing CD4 T cell function (King et al., 2015). The decline in innate immunity with zinc defi­c­iency promotes systemic inflam­mation, charac­terized by elevated levels of proinflam­matory cytokines. Supplementation with zinc has been associated with decreased inflam­matory responses in children with zinc defi­ciency(Sandstead et al., 2008). With a reduced resistance to infection, the rate and duration of infections increases. Zinc defi­ciency also increases oxidative stress and DNA damage which, in turn, play a role in promoting the inflam­matory process (Wong and Ho, 2012). For more details of zinc and immune function, see Raiten et al. (2015).

The mechanism whereby zinc influences neuro­behavioral functioning is not well established. In the central nervous system, zinc is concen­trated in the presynaptic vesicles of zinc-containing neurons, which are found primarily in the forebrain and connect with other cerebral cortices and limbic structures. During synaptic events, zinc is released and passes into postsynaptic neurons, serving as neuro­trans­mitters. Zinc defi­ciency may interfere with these processes and thus com­promise neuro­behavioral functioning, especially during times of rapid growth and development, such as infancy, when demands for zinc are high (Black, 2003). Meta-analysis, however, has failed to show a significant overall effect of zinc intake on biomarkers of cognitive function in children, although the number of available studies in this review was small (n=6) (Warthon-Medina et al., 2015). There is some evidence that zinc defi­ciency may also be related to anxiety and depression. Possible mechanisms that warrant investigation include the involve­ment of zinc in the uptake of the neuro­trans­mitter serotonin (5‑HT) in the brain (Levenson, 2006). More research is also needed to clarify the mechanisms by which zinc affects taste acuity (Aliani et al, 2013). Some investigations suggest that reduced taste acuity may be linked with reductions in certain zinc metallo­proteins that act as olfactory receptors (King and Cousins, 2014).

24c.1.3 Absorption and meta­bolism of zinc

Zinc is mainly absorbed in the upper part of the small intestine by two mechanisms: a saturable, carrier-mediated process and, secondly, by a non-mediated, or passive process. Two families of zinc trans­porters control the trans­port of zinc on the enterocyte membrane and account for the saturable com­ponent. Once zinc is absorbed into the enterocyte, movement of zinc within the cell is influenced by metallo­thionein and the trans­porter ZnT7. Export of zinc from the intestinal epithelial cells into the portal vein is controlled by the ZnT1 trans­porter. About 30%–40% of the zinc in portal blood is exchanged with the liver, the main organ involved in zinc meta­bolism. From the liver, zinc is released into the systemic circulation for delivery to peripheral tissues bound mainly to albumin and α2‑macroglobulin (King and Cousins, 2014). Almost no zinc circulates in an unbound state.

Absorption of zinc by a nonsaturable or passive mechanism only occurs at high intestinal luminal zinc concen­trations generated through consumption of pharmacologic doses of zinc (King and Cousins, 2014). At such high doses (i.e., > 20mg/d Zn), fractional absorp­tion of zinc via the passive mechanism is very low, suggesting that a dose of supple­mental zinc above 20mg will have a limited influence on zinc nutrition (Tran et al., 2004).

Zinc homeo­stasis in the body is tightly controlled over a wide range of zinc intakes. This is achieved primarily by adjusting zinc excretion through the gastro­intestinal tract. Losses of zinc via the gastro­intestinal tract com­prise both unabsorbed dietary zinc and endogenous fecal zinc. The sources of endogenous fecal zinc are uncertain but probably include secretions from pancreatic and intestinal mucosal cells. When zinc intakes are very low, there is a decrease in zinc secretion into the intestinal lumen, and endogenous fecal zinc declines. With increasing zinc intakes, endogenous fecal zinc losses increase to maintain homeo­stasis. If the adult zinc intake is extremely low (e.g., < 2mg/day), then the reductions in losses of endogenous fecal zinc may be insufficient to re-establish zinc homeo­stasis. In these circumstances, additional meta­bolic adjustments occur to mobilize zinc from the small, exchangeable pool located in liver, pancreas, kidney, spleen, and possibly bone, to maintain zinc-dependent functions (King, 2011).

Unlike iron, absorp­tion of zinc does not change in response to alterations in whole-body zinc homeo­stasis or status. Instead, zinc absorp­tion is influenced by current zinc intake, not the past or long-term zinc intakes, or status (Chung et al., 2008; King, 2010). Figure 24c.2.

Figure 24c.2 Effect of dietary zinc on fractional (FZA) and total zinc absorption (TAZ}. Redrawn from King (2010).

Absorption of zinc can be measured / defi­ned in two ways: (1) the fraction (or percent) of zinc ingested that is absorbed (Fractional Zinc Absorption or FZA), deter­mined by the dividing the amount absorbed by the amount digested, and (2) the total quantity of absorbed zinc (TAZ) over the whole day. The fraction of zinc absorbed depends on the bioavailability of the ingested zinc, whereas the total quantity absorbed is dependent mainly on the amount of zinc consumed and the bioavailability of the zinc in the diet. Intake of dietary zinc affects fractional zinc absorp­tion and the total quantity of absorbed zinc differ­ently. With increasing zinc intakes, the total amount of absorbed zinc increases while the percent absorbed declines (King, 2010, Figure 24c.2). These adjustments in the efficiency of zinc absorp­tion with changes in zinc intake are controlled by the up-regulation and down-regulation of zinc trans­porters and possibly other proteins involved in the trans­port of zinc (King and Cousins, 2014; King et al., 2015).

In addition to the amount of the dietary zinc intake, the food sources of zinc may also affect zinc absorp­tion. The dietary factor with the greatest effect on zinc absorp­tion is phytic acid (myoino­sitol hexakis­phos­phoric acid (InsP6) and its associated magnesium, potassium, and calcium salts — termed phytates. Phytic acid and its salts are found in high concen­trations in unrefined cereals, legumes, nuts and oil seeds. Phytate binds zinc in the intestinal lumen and forms an insoluble com­plex that cannot be digested or absorbed by humans because of the absence of the intestinal enzyme phytase (Iqbal et al., 1994). This inhibitory effect on zinc absorp­tion can be sub­stantial. If the habitual diet is rich in phytate, adults cannot adapt to increase zinc absorp­tion (Hunt et al., 2008) or to enhance reabsorp­tion of endogenous zinc (Hambidge et al., 2010). Whether phytate has an inhibitory effect on zinc absorp­tion in young children is uncertain. Miller et al. (2015) failed to detect a negative effect of phytate on zinc absorp­tion in their isotope studies of infants and young children. In contrast to phytate, the effect of dietary intakes of protein, calcium, iron and organic acids on zinc absorp­tion appears limited or non-existent (IZiNCG, 2004; Miller et al., 2013).

Absorption and/or utilization of zinc may also be influenced by physio­logical, host-related, and contextual factors over and above that of dietary factors (Krebs et al., 2014), Figure 24c.3. Studies have shown an increase in zinc absorp­tion in late pregnancy and lactation, most notably when dietary zinc intake is low (Fung et al., 1997; Donangelo et al., 2005; Donangelo and King, 2012), and possibly a decline with aging (Turnlund et al., 1986).

Figure 24c.3. Conceptual diagram to illustrate determinants of zinc status, the gastro-intestinal homeostatic response, and the features associated with normal and abnormal zinc status. In the condi­tion of impaired zinc status, the thick arrows reflect bidirectional, co-existing efects between determinants and zinc deficiency. FAZ: fractional absorption of zinc; TAZ: total absorbed zinc; SRM: saturation response model; EE: environmental enteropathy; EZP: exchangeable zinc pool. From(Krebs et al., 2014).

Not surprisingly, given the dominant role of the gastro­intestinal tract in zinc homeo­stasis, malabsorp­tive disorders that alter the integrity of the mucosal cells, reduce zinc absorp­tion, although the magnitude of their effect is uncertain. An exception are patients with celiac disease in whom impairments in absorp­tion and increases in intestinal endogenous zinc losses have been quantified through stable isotope studies (Crofton et al., 1990; Tran et al., 2011). Accumulating evidence suggests that these same distur­bances in zinc absorp­tion occur in environmental enteric dysfunction (EED), a chronic inflam­matory condi­tion linked to chronic, sub­clinical exposure to fecal pathogens (Syed et al., 2016). However, again, the magnitude of the effect of EED has yet to be quantified (Manary et al., 2010; Lindenmayer et al., 2014).

24c.1.4 Zinc defi­ciency in humans

When homeo­static mechanisms fail to ensure that require­ments for zinc are met, clinical symptoms of zinc defi­ciency ensue. The first cases of dietary zinc defi­ciency in humans were described in the 1960s in male dwarfs from the Middle East (Prasad et al., 1963). Typical clinical features, which were corrected by zinc supple­mentation, included growth retardation, delayed secondary sexual maturation (hypogonadism), poor appetite, mental lethargy, and skin changes. In North America and New Zealand, overt and severe nutritional zinc defi­ciency was first recognized in hospital patients who received either parenteral nutrition or enteral feedings without zinc supple­ments (Kay and Tasman-Jones, 1975; Arakawa et al., 1976).

Two genetic disorders are known to induce zinc defi­ciency: acrodermatitis enteropathica and sickle cell disease (King et al., 2015).

Secondary zinc defi­ciency has been documented in the presence of Crohn disease, inflam­matory bowel disease, ulcerative colitis, and malabsorp­tion syndromes. A variety of other diseases — including renal and liver diseases, diabetes, acquired immuno-defi­ciency syndrome, and alcoholism — also induce secondary zinc defi­ciency. In such cases, zinc defi­ciency may arise from either increased urinary excretion of zinc (hyper­zincuria) or excess endogenous fecal zinc losses (Aggett and Comerford, 1995).

Treatment with certain drugs has also been associated with secondary zinc defi­ciency. For example, long-term treatment with penicillamine for Wilson’s disease (Smolarek and Stremmel, 1999) diethylenetriamine pentaacetate for the treatment of iron overload in thalassemia and sickle cell anemia (King and Cousins, 2014), and the administration of chlorthiazide (used to treat edema) and glucagon (used to control blood glucose levels) (Prasad and Oberleas, 1976) have all been implicated as iatrogenic causes of zinc defi­ciency.

In some industrialized countries marginal zinc defi­ciency, charac­terized by slow physical growth, has been identified in apparently healthy infants and children (Hambidge et al., 1972a; Walravens and Hambidge, 1976; Walravens et al., 1983; Smit-Vanderkooy and Gibson, 1987; Gibson et al., 1989a). More recent double-blind preventative zinc supple­mentation studies in both industrialized and low-incom­e countries have confirmed an increasing range of other functional impairments associated with zinc defi­ciency in children, in addition to impaired growth (Brown et al., 2009). In many of these studies, abnormalities of the immune system and increased risk of some com­mon childhood infections have been reported. In settings where zinc defi­ciency is likely to be a problem, reductions in the incidence of diarrhea following preventive zinc supple­mentation have been observed, although the impact on lower respiratory infections, including pneumonia, has been less consistent (Haider and Bhutta, 2009; Brown et al., 2009; Lassi et al., 2010; Roth et al., 2010; Mayo-Wilson et al., 2014; Liu et al., 2018), and no clear effect on the incidence malaria (Brown et al., 2009; Mayo-Wilson et al., 2014). Therapeutic zinc supple­mentation has been shown to reduce the duration of acute and persistent diarrhea (Bhutta et al., 2000; Haider and Bhutta, 2009) , and is now recom­men­ded by World Health Organization to be included in diarrhea control programs (WHO/UNICF, 2004).

Reports of zinc-related neuro­behavioral abnormalities in children and/or adults include delays in child development, anorexia, dysfunction of smell and taste, irritability, mood and depression. However, studies of zinc defi­ciency or zinc supple­mentation on neuro­behavioral function, have produced inconsistent results, possibly due in part to the differ­ences in the measure­ment methods used (Warthon-Medina et al., 2015). In a meta-analysis of trials in infants and young children, for example, analysis of a small subset of randomized controlled trials (n=6) showed no significant effect of zinc on cognitive function or motor skills (Warthon-Medina et al., 2015). In contrast, results of a randomized controlled trial on Peruvian infants suggested that supple­mental zinc may support normative neuro-development in infants consuming low zinc diets (Colombo et al., 2014).

Several preventive zinc supple­mentation trials have also been conducted during pregnancy. The results have been inconsistent; only some have reported a positive effect of supple­mental zinc on pregnancy outcom­e measures. In 2007, a meta-analysis showed a 14% reduction in infants born prematurely among zinc supple­mented women, but no impact on infant birth­weight, although there was a suggestion of a positive effect on birth­weight in a subset of the women who were underweight or zinc-defi­cient (Hess and King, 2009). Two sub­sequent meta-analysis, one spanning five continents, of randomized controlled trials in which zinc supple­ments were given together with other micronutrient supple­ments, again indicated that only the effect on risk of preterm birth was significant, with no evidence of any effect on any parameter of fetal growth (low-birth­weight, birth­weight, length at birth, head circumference at birth) (Chaffee and King, 2012; Ota et al., 2015). More recently, a meta-analysis of studies of preventive zinc supple­mentation during pregnancy for three months or longer, reported no significant increase in birth­weight and no decrease in the risk of low birth­weight (Liu et al., 2018).

Zinc status is sometimes com­promised in the elderly, probably because of low zinc intakes and age-related changes in physio­logical function (de Jong et al., 2001). As well, the presence of hypochlorhydria, malabsorp­tion syndromes, and the use of certain medications may have exacerbating roles (Aggett and Comerford, 1995). There are several reports of improvements in some aspects of immune function in older adults, including nursing home elderly, following zinc supple­mentation (Bogden et al., 1994; Barnett et al., 2016). Other possible zinc-related degenerative changes in the elderly that warrant further study include hypogeusia, delayed wound healing, anorexia, deterioration of glucose tolerance, and depression (Marcellini et al., 2006; Levenson, 2006; Lin et al., 2017). For example, correlations between zinc status (based on serum zinc concen­trations) and symptoms of depression have been observed in observational studies in elderly women (Marcellini et al., 2006).Improvements in patients with depression given supple­mental zinc have also been reported, especially when the supple­mental zinc is used in com­bination with antidepressant drug therapy (Ranjbar et al., 2014).

24c.1.5 Food sources and dietary intakes

There is no functional reserve or body store of zinc, as noted earlier, so an adequate regular supply of readily absorbable zinc is required. Hence, individuals consuming a usual diet low in zinc and/or with poor zinc bioavailability may be nutritionally zinc defi­cient. Food sources of readily absorbable zinc include organ meats, red meat, poultry, fish, and shellfish; oysters are one of the richest food sources of absorbable zinc. In general, the amount of zinc is higher in dark red meat than in white meat. Starchy roots, tubers, fruits, and vegetables have a low zinc content. Zinc is less readily available in whole grain cereals, nuts and legumes: their zinc content varies, depending on the zinc content of the soil or fertilizer treatment, growing location, and processing methods (e.g., milling of cereals). Loss of zinc from most foods during cooking is minimal.

Several dietary com­ponents have been investigated as potential modifiers of zinc bioavailability. A systematic review, however, concluded that for many of these potential modifiers, data were insufficient to accurately determine their impact on zinc absorp­tion (Bel-Serrat et al., 2014). A notable exception is phytic acid (myoinositol hexakisphosphoric acid (InsP6) and its associated magnesium, potassium, and calcium salts — termed “phytates” — potent inhibitors of zinc absorp­tion, as noted earlier. In general, phytic acid and its salts are found in high concen­trations in unrefined cereals, legumes, nuts and oil seeds. Concen­trations vary widely depending on the botanical variety, environmental or climatic growing condi­tions, the use of phosphate fertilizers, and the stage of maturation. The highest levels are reached at seed maturity. During some food-processing, preparation and cooking practices, such as milling / pounding, soaking, germination / malting, mixtamalization, or fermentation, phytate is dephosphorylated to the lower myo-inositol phosphate forms (IP1 to IP4) that don't inhibit zinc absorp­tion (Gibson et al., 2018).

The inhibiting effect of phytate on zinc absorp­tion follows a dose-dependent response. Hambidge and colleagues have developed a trivariant model to predict the inhibitory effect of differ­ent levels of phytate on zinc absorp­tion as a function of zinc intake (Miller et al., 2007). Development of this model led the European Food Safety Authority (EFSA) to generate dietary zinc require­ments for adults based on four levels of dietary phytate (EFSA, 2014). When daily phytate intakes in adults reach 1200mg/d, a level surpassed in some low incom­e countries with staple diets of unfermented cereals and/or legumes, the average zinc require­ment for adults, com­piled by EFSA (2014) nearly doubles (Gibson et al., 2019). Values for the phytate content of raw and processed plant-based staples are available in the FAO / INFOODS / IZiNCG Global Food Composition Database for Phytate.

Molar ratios of phytate-to-zinc of individual foods or whole diets can be used to estimate the likely proportion of zinc absorbed. Diets with a phytate-to-zinc molar ratio of more than about 15 have poor zinc bioavailability, whereas those with ratios between 5 and 15 are said to have medium bioavailability, and those with ratios less than 5 have good bioavailability (WHO/FAO, 2004).

In the past, millimolar ratios of phytate × calcium : zinc were also used to predict zinc absorp­tion because dietary calcium was said to influence the inhibitory effect of phytate on zinc bioavailability. The use of this ratio has now been discontinued in the absence of any demonstrated effect of calcium on zinc absorp­tion from diets adequate in zinc, irrespective of whether intakes of dietary phytate were high or low (Hunt and Beiseigel, 2009). Whether calcium has an adverse effect in phytate-containing diets low in zinc is uncertain (King et al., 2015). Earlier, the amount and type of dietary protein was said to enhance zinc absorp­tion but more recent data have not confirmed this (IZiNCG, 2004; Miller et al., 2013).

A com­petitive interaction between iron and zinc may occur, depending on the form of the iron, as well as the condi­tions and levels under which both the iron and zinc are given (Lönnerdal, 2000). A decrease in zinc absorp­tion may occur when the ratio of iron to zinc is very high (i.e., > 25:1) and when the iron is administered in water and fed under fasting condi­tions. Hence, women taking high-dose prenatal iron supple­ments (60mg elemental iron/day) may require additional zinc (Caulfield et al., 1999). For example, supple­mentation with 60mg elemental iron in a multiple micronutrient supple­ment blunted the increase in serum zinc observed in Cambodian women who received the same supple­ment but with no iron (Holmes et al., 2019). However, this interaction is less apparent when the iron is provided in a com­plex food matrix (Olivares et al., 2012; Esamai et al., 2014).

In general, in omnivorous adult diets in affluent countries, meat and meat products supply the greatest amount of zinc, followed by cereals and dairy products (Briefel and Johnson, 2004; EFSA, 2014). However, interest in vegetarian diets has increased in these countries with high-phytate diets of cereals, legumes and nuts replacing meat and meat products (American Dietetic Association, 2003). Increasingly zinc fortified beverages, fortified cereals, and supple­ments are becom­ing important sources of dietary zinc, especially among young children in North America (Arsenault and Brown, 2003; Butte et al., 2010).

24c.1.6 Effects of high intakes of zinc

There are no reported cases of toxicity from excess intakes of dietary zinc, although toxicity arising from short-term exposure to very high levels of contaminant zinc (> 300ppm), from the improper storage of food or beverages in galvanized vessels, has been reported (Brown et al., 1964). Signs and symptoms include dehydration, vomiting, electrolyte imbalance, abdominal pain, nausea, lethargy, dizziness, and muscular incoordination (Fosmire, 1990).

Adverse effects of excess zinc on copper meta­bolism have been described (Prasad et al., 1978a; Fischer et al.,1984; Samman and Roberts, 1988; Yadrick et al., 1989) with a decrease in the activity of erythrocyte Cu,Zn‑SOD being the most consistent finding (Fischer et al.,1984).However, the clinical significance of a decrease in erythrocyte SOD activity is unknown.

High intakes of zinc have also been associated with reductions in serum HDL cholesterol levels in some studies (Hooper et al., 1980),. and detrimental effects on the immune system (Chandra, 1984). Hence, excessive self-supple­mentation with zinc may have an adverse effect on health, although doses of 25–35mg/day zinc in adults do not appear to pose a health hazard (Smith, 1994). In Europe the zinc content of the most com­mon single nutrient supple­ment is 30mg per capsule (range 15–50mg), and 10–15mg (range 2–20mg) for multi-nutrient supple­ments(EFSA, 2002).

The Tolerable Upper Intake Level (UL) for zinc set by the U.S. Food and Nutrition Board for adults and pregnant and lactating women > 19y, is 40mg/d, a level based on the adverse effects of high doses of supple­mental zinc (50mg Zn/d) on copper status biomarkers, notably reductions in the activity of erythrocyte Cu,Zn‑SOD. For infants the corresponding UL is 4mg, with adjustments for children based on body weight (IOM, 2001).Concern has been raised that the UL set by U.S. Food and Nutrition Board for preschool children (i.e., 7mg/day) in the US and Canada may be too low as many have dietary zinc intakes that exceed the UL due to their consumption of zinc-fortified beverages, fortified ready-to‑eat breakfast cereals, and zinc supple­ments (Arsenault and Brown, 2003; Butte et al., 2010). Sensitive biomarkers of copper status were reportedly unchanged by supple­mentation with 5, 10, or 15mg of zinc daily for four months in healthy boys in a double-blind, placebo-controlled randomized trial(Bertinato et al 2013). EFSA (2002) has set a lower level for the UL for adults and pregnant and lactating women (25mg Zn/d), although their UL for preschoolers 1–3y is the same as that of U.S. Food and Nutrition Board (i.e., 7mg/d).

24c.1.7 Biomarkers of zinc status

Zinc is classified as a type II nutrient (Golden, 1995) because it is essential for multiple meta­bolic functions, as discussed earlier. As a consequence, in zinc defi­ciency the physio­logical effects that arise are associated with a number of diverse biochemical changes, making it difficult to identify biomarkers of zinc nutrition (King, 2011). In contrast, reductions in tissue nutrient concen­trations of type I nutrients, such as iron, iodine, and vitamin A, arising from defi­cits in dietary intakes, cause a decline in one or more specific functions which can be readily identified using selected biomarkers (King, 2011).

To identify popu­lations at elevated risk of zinc defi­ciency, three indicators were recom­men­ded by WHO / UNICF / IAEA / IZiNCG: (a) prevalence of usual zinc intakes below the estimated average require­ment, (b) percentage with low plasma/serum zinc concen­trations, and (c) percentage of children aged < 5y who are stunted (i.e., HAZ < –2SD) ; (de Benoist et al., 2007), These recom­men­dations were endorsed by the BOND Expert Zinc Panel (King et al., 2015). For details see IZiNCG Technical Brief No. 1 (2007).

For each indicator, a “trigger level” is given for the prevalence considered indicative of elevated risk and of public health concern, at which level an intervention to improve popu­lation zinc status is warranted. Reference limits for plasma/serum zinc (depending on age, sex, time of day, fasting status) are available to identify popu­lations at risk of zinc defi­ciency, provided the correct protocols are followed for the collection, separation, and analysis of plasma zinc. Assessment of the functional indicator — impaired linear growth — should be made in com­bination with at least one of the other indicators in view of its poor specificity (King et al., 2015). In the future, a model com­prising key meta­bolic indicators, serum albumin, and a biomarker of inflam­mation may be developed for popu­lation zinc assessment (King, 2018).

Assessment of zinc status at the individual level is particularly difficult because serum or plasma zinc concen­trations are homeo­statically controlled and do not decline with marginal zinc intakes. Hence, serum or plasma zinc is only useful to measure zinc status in individuals with either a very low or high supply of dietary zinc. Instead, the recom­men­ded approach for individuals com­bines a medical history, dietary and clinical assessment, with plasma or serum zinc providing only supple­mentary data (King et al., 2015).

The BOND Zinc Expert Panel classified the other possible zinc biomarkers into three groups: (1) potentially useful (2) emerging biomarkers and (3) those deemed not useful. These are shown below in Box 24c.1.

Box 24c.1 Possible Zinc Biomarkers. From (King et al., 2015).

• Potential Biomarkers that show promise, but data are insufficient to establish specific cutoffs indicating zinc inadequacy in popu­lations: Hair zinc, Urinary zinc, Neurobehavioral function
• Emerging Biomarkers for which there is some theoretical basis for a relation to zinc intake or status, but testing is insufficient to confirm the relation: Nail zinc, Zinc-dependent proteins (i.e. cellular metallo­thionein, metallo­thionein and zinc-trans­porter expression), Oxidative stress and DNA integrity, Zinc kinetics , Taste acuity
• Not useful Biomarkers that do not relate consistently to zinc intake or status: Zinc-dependent enzymes, Erythrocyte and leukocyte zinc