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In the human studies, the effects of high or moderately high dietary zinc on several indicators known to be associated with copper status have been investigated. These indicators included plasma zinc and copper concentrations, cholesterol and lipoprotein cholesterol concentrations, and several enzyme activities (e.g. ESOD and ceruloplasmin). Effects of zinc on the latter are thought to precede changes in plasma and tissue levels of the elements, given the primary role of zinc as a component of different enzymes. In humans supplemented with zinc, plasma zinc concentration was elevated, while plasma copper concentration was not affected. In the earlier studies, Yadrick et al. (1989) and Fischer et al.(1984) reductions in ESOD activity were found upon zinc supplementation. This was thought to be associated with copper deficiency, like the reduction in ceruloplasmin activity. In the more recent studies by Davis et al. (2000) and Milne et al. (2001), however, only very small reductions in ESOD activity were observed that did not correlate with changes in copper balance. The clinical significance of this ESOD reduction is questionable, because the findings in these studies on more specific copper deprivation signs (i.e., decreased serum ceruloplasmin and platelet cytochrome c oxidase) indicate that sub-optimal intake of zinc was more effective than a moderately high intake of zinc in inducing changes associated with a decreased copper status in postmenopausal women. It might also be that the small decrease in ESOD activity with high zinc intake was not caused by an interference with copper metabolism, but was more reflective of reduced oxidative stress given the serum glutathione and erythrocyte glutathione peroxidase findings. However, one can only conclude from Daviset al. (2000) and Milne et al. (2001) that very subtle changes were induced by the different dietary treatments.

The subtle changes in clinical-biochemical parameters, as reported in the Grand Forks studies, are hardly indicative for zinc-induced perturbations of the copper homeostasis. These biochemical changes do not lead to detectable deterioration of red blood cell functioning. Therefore, these changes are also of marginal biological significance, if any. Hence, it is concluded that in women supplemented with zinc, a dose of 50 mg Zn2+/day is a NOAEL (equivalent to 0.83 mg/kg bw/day).