ing state at an iron-zinc ratio of 25:1 but not at 1:1 or 2.5:1 (Sandstrom et al., 1985). When iron and zinc supplements were given with a meal, however, this effect was not observed. Other investigators have reported similar observations (Davidsson et al., 1995; Fairweather-Tait et al., 1995b; Valberg et al., 1984; Walsh et al., 1994; Yip et al., 1985). A radioisotope-labeling study by Davidsson and coworkers (1995) showed that fortifying foods such as bread, infant formula, and weaning foods with iron had no effect on zinc absorption. In general, the data indicate that large doses of supplemental iron inhibit zinc absorption if both are taken without food, but do not inhibit zinc absorption if they are consumed with food. Because there is no evidence of any clinically significant adverse effect associated with iron-zinc interactions, this effect is not used to determine a UL for iron.

Gastrointestinal Effects. High-dose iron supplements are commonly associated with constipation and other gastrointestinal (GI) effects including nausea, vomiting, and diarrhea (Blot et al., 1981; Brock et al., 1985; Coplin et al., 1991; Frykman et al., 1994; Hallberg et al., 1966c; Liguori, 1993; Lokken and Birkeland, 1979) (Table 9-18). Because GI effects are local, the frequency and severity of the effect depends on the amount of elemental iron released in the stomach (Hallberg et al., 1966c). The adverse effects of supplemental iron appear to be reduced when iron is taken with food (Brock et al., 1985). While most of the observed effects are relatively minor, some individuals have found them severe enough to stop further supplementation (Frykman et al., 1994).

A single-blinded, 8-week study by Brock et al. (1985) reported “moderate to severe” GI effects in 50 percent of subjects taking 50 mg/day of elemental iron as ferrous sulfate. This finding is supported by other better-controlled, prospective studies showing GI effects at similar doses (Coplin et al., 1991; Frykman et al., 1994; Lokken and Birkeland, 1979). These data suggest a definite causal relation between high iron intake and GI effects.

Secondary Iron Overload. Secondary iron overload occurs when the body iron stores are increased as a consequence of parenteral iron administration, repeated blood transfusions, or hematological disorders that increase the rate of iron absorption. Although the iron in patients with secondary iron overload tends to be stored initially in macrophages where it is less damaging, the typical pathological consequences of iron overload that are characteristic of hereditary hemochromatosis may eventually occur.