This chapter addresses the physiology of iron metabolism by host and pathogen, discusses the immunological data, reviews the clinical studies in humans, and draws conclusions about the benefits and risks for military personnel, particularly premenopausal women, of giving iron supplements.

Iron is a highly reactive metal able to generate oxygen free radicals that are toxic to cells. However, the aerobic nature of the earth creates a problem, because oxygen is also needed for life. Because iron can shift between the ferrous and ferric states and can readily and reversibly bind with oxygen, while containing it in a nonreactive state, iron-containing proteins have been selected as the predominant carrier of oxygen. In the environment, the problem of reactive free oxygen has been solved by converting inorganic iron to oxyhydroxide polymers, which reduces the amount of uncomplexed ferric (Fe⁺⁺⁺) in solution at biological pH to tolerable levels (< 10¹⁸ M). In the mammalian host, iron is present predominantly as protein complexes, including transport, storage, enzyme, and oxygen transporter systems, primarily as heme, iron-sulfur proteins, and ferritin intracellularly, or bound to extracellular transport glycoproteins such as transferrin in serum or lactoferrin on mucosal surfaces. Mammals have overcome the environmental restrictions and biological imperatives of bound, insoluble iron by developing an effective iron acquisition system able to compete with hydroxyl ion for ferric iron. Iron absorption, transport to and into cells, and storage are closely regulated by systems that sense the amount of available free iron and rapidly respond to maintain iron homeostasis.

This mechanism has been essential, because iron is the most abundant transition metal in humans, amounting to approximately 4 g in adult males, with about 1 g in storage forms. In young adult women, the amount of storage iron is considerably reduced to around 300 mg because of continuing iron losses during menstruation. Iron balance is tightly controlled, amounting to only 1 to 2 mg lost per day in men, but more in menstruating females, which is why iron-deficiency anemia is common among adult women.

In addition to oxygen transport, iron is essential for many physiological processes, as iron metalloproteins are able to accept electrons from various donors, to shift oxidation state, and to participate in redox reactions and hence serve in the electron transport chain in the form of cytochromes and mitochondrial iron-sulphur proteins (Griffiths, 1987). Many iron metalloproteins are enzymes, including enzymes involved in oxygen metabolism itself (catalase, peroxidase, superoxide dismutase), as well as flavoproteins such as xanthine oxidase and dehydrogenase; NADH/NADPH dehydrogenases; amino acid hydroxylases; and a key enzyme for DNA synthesis, ribonucleotide reductase.