Medicinal Inorganic Chemistry: Continuum of Dose versus Response—From Deficiency through Optimal Intake to Toxicity

Metal-ion essentiality is not a static concept. Over the course of the last several decades, essentiality has been redefined to broaden the definition beyond “necessary to support human life” to include “having a defined biochemical function.” The main effect of this redefinition has been to restrain the addition of additional ultratrace elements, present in the human body, but not clearly required in a specific amount in the daily nutrient intake, to the ever-expanding list of known essential elements. Essential metal ions are associated not only with recognizable deficiency symptoms under conditions of inadequate intake but also with existing homeostatic mechanisms that regulate absorption, distribution, storage, and excretion of the metal-ion in vivo. The Bertrand diagram is a schematic representation of the range of essential metal-ion intake consistent with optimal nutrient intake, bounded on the lower intake range by deficiency symptoms and on the upper intake end, by increasingly severe toxicity symptoms. The continuum of dose versus response includes both tails of this spectrum for all essential metal ions. Not all metal ions are the same: each has an appropriate “window of optimal intake” whose width and concentration ranges vary widely from one metal ion to the other. Keywords: essential element; Bertrand diagram; optimal intake; reference dose; body burden; iron; zinc; copper; manganese; endogenous ligands