Reconsidering the Tolerable Upper Levels of Zinc Intake among Infants and Young Children: A Systematic Review of the Available Evidence

Abstract

Safe upper levels (UL) of zinc intake for children were established based on either (1) limited data from just one study among children or (2) extrapolations from studies in adults. Resulting ULs are less than amounts of zinc consumed by children in many studies that reported benefits of zinc interventions, and usual dietary zinc intakes often exceed the UL, with no apparent adverse effects. Therefore, existing ULs may be too low. We conducted a systematic bibliographic review of studies among preadolescent children, in which (1) additional zinc was provided vs. no additional zinc provided, and (2) the effect of zinc on serum or plasma copper, ceruloplasmin, ferritin, transferrin receptor, lipids, or hemoglobin or erythrocyte super-oxide dismutase were assessed. We extracted data from 44 relevant studies with 141 comparisons. Meta-analyses found no significant overall effect of providing additional zinc, except for a significant negative effect on ferritin (p = 0.001), albeit not consistent in relation to the zinc dose. Interpretation is complicated by the significant heterogeneity of results and uncertainties regarding the physiological and clinical significance of outcomes. Current zinc ULs should be reassessed and potentially revised using data now available for preadolescent children and considering challenges regarding interpretation of results.

Keywords: review; upper-intake levels; zinc; zinc fortification; zinc nutrient reference values (NRVs); zinc supplementation.

Figure 1

Flow of study identification, screening, and inclusion.

Figure 2

Effect of additional zinc intervention on plasma or serum copper concentrations among children. Figure 2 legend: The amount of additional zinc provided in the zinc groups are shown, along with the first author and year of publication. The intervention groups are indicated, as follows. Zn-s: Zinc supplement, Zn+ Fe-s: Zinc Plus Iron supplement, Zn + Fe + Cu-s: Zinc plus iron plus copper supplement, Fe + Cu-s: Iron plus copper supplement, Zn + B2-s: Zinc plus vitamin B12 supplement, B2-s: vitamin B2 supplement, Zn + Fe + B2: zinc plus iron plus vitamin B2 supplement; Zn-f: zinc fortified, P-s: placebo supplement, P-f: Placebo fortified, Fe-f: iron fortified, Fe-s: iron supplement, Zn-H-Dose-f: Zinc high dose fortified, Zn-L-Dose-f: zinc low dose fortified. Green dots represent the means for each plot.

Figure 3

Effect of additional zinc intervention on plasma or serum ferritin concentrations among children: (a) with no additional iron, (b) with additional iron. Figure 3 legend: The amount of additional zinc provided in the zinc groups are shown, along with the first author and year of publication. The intervention groups are indicated, as follows. Zn-s: Zinc supplement; Zn+ Fe-s: Zinc plus iron supplement; Zn + Fe + Cu-s: Zinc plus iron plus copper supplement; Fe + Cu-s: Iron plus copper supplement; Zn + B2-s: Zinc plus vitamin B12 supplement; B2-s: Vitamin B2 supplement; Zn + Fe + B2-s: Zinc plus iron plus vitamin B2 supplement; P-s: Placebo supplement; Fe-f: Iron fortified; Fe-s: Iron supplement; no-s: No supplement; Zn + BCaro-s: zinc plus beta carotene supplement; BCaro-s: Beta carotene supplement; Zn + MV-s: Zinc plus multivitamin supplement; MV-s: Multivitamin supplement; Zn + VC-s: Zinc plus vitamin C supplement; VC-s: Vitamin C supplement; Zn + Fe-f: Zinc plus iron fortified; Fe-f: Iron fortified; Zn-s + Fe-f: Zinc supplement plus iron fortified; P-s + Fe-f: Placebo supplement plus iron fortified; Zn + Fe + FA-s: Zinc plus iron plus folic acid supplement; Fe + FA-s: Iron plus folic acid supplement; Zn in MNP: Micronutrient powder with zinc plus iron; MNP with no Zn: Micronutrient powder with no zinc plus iron; Zn + MN: Zinc plus micronutrient supplement; Zn + Fe + VC-s: Zinc plus iron plus vitamin C supplement. NOTE: placebo (P) concentration reported in Lind 2003 publication updated by Dr. Lind (personal communication).

Figure 4

Effect of additional zinc intervention on whole blood hemoglobin concentrations: (a) with no additional iron, (b) with additional iron. Figure 4 legend: The amount of additional zinc provided in the zinc groups are shown, along with the first author and year of publication. The intervention groups are indicated, as follows. Zn-s: Zinc supplement; Zn+ Fe-s: Zinc plus iron supplement; Zn + Fe + Cu-s: Zinc plus iron plus copper supplement; Fe + Cu-s: Iron plus copper supplement; Zn + B2-s: Zinc plus vitamin B12 supplement; B2-s: Vitamin B2 supplement; Zn + Fe + B2-s: Zinc plus iron plus vitamin B2 supplement; Zn-f: Zinc fortified; P-s: Placebo supplement; P-f: Placebo fortified; Fe-f: Iron fortified; Fe-s: Iron supplement; Zn-H-Dose-f: Zinc high dose fortified; Zn-L-Dose-f: Zinc low dose fortified; Zn-H-f: Zinc high fortified; Zn-L-f: Zinc low fortified; no-s: No supplement; Zn + BCaro-s: zinc plus beta carotene supplement; BCaro-s: Beta carotene supplement; Zn + MV-s: Zinc plus multivitamin supplement; MV-s: Multivitamin supplement; Zn + VA-s: Zinc plus vitamin A supplement; VA-s: Vitamin A supplement; Zn + VC-s: Zinc plus vitamin C supplement; VC-s: Vitamin C supplement; Zn + Fe-f: Zinc plus iron fortified; Fe-f: Iron fortified; Zn-s + Fe-f: Zinc supplement plus iron fortified; P-s + Fe-f: Placebo supplement plus iron fortified; SQ-LNS:Zn: Small quantity Lipid Nutrient supplement with zinc; SQ-LNS: No Zn: Small quantity Lipid Nutrient supplement with no zinc; Zn + Fe + FA-s: Zinc plus iron plus folic acid supplement; Fe + FA-s: Iron plus folic acid supplement; Zn in MNP: Micronutrient powder with zinc plus iron; MNP with no Zn: Micronutrient powder with no zinc plus iron; Zn + MN: Zinc plus micronutrient supplement; Zn + Fe + VC-s: Zinc plus iron plus vitamin C supplement.