Chapter 3 - Routes of Exposure, Dose, and Toxicokinetics of Metals

Abstract

The chapter first describes the main sources of metal exposure through air, food, and water, but also points to unusual sources such as medical implants. Special attention is given to the processes of lung deposition and clearance of inhaled gases, vapors, and particulates, including ultrafine particles. In contrast to the extensive studies on the lung, the absorption of metal in the gastrointestinal tract is less well understood. A summary diagram shows the contribution of all the absorption processes to the total body burden. Since the publication of the third edition, new information has become available on the mechanisms of transport and distribution of metals in the body. In particular, it has been shown that several metals can cross cell membranes via specific carriers and ion channels intended for endogenous substrates. One well-documented example is the chromate oxyanion that is structurally similar to the sulfate anion and thereby gains entrance into the cell via the sulfate carrier. Attention is also given to the transport of ultrafine particles and nanoparticles across barrier epithelia. The fecal excretion of several metals occurs as the end result of extensive enterohepatic recirculation. In the case of certain organometallic species, gut microflora may play a critical role in converting the metal to an inorganic form, which is excreted in the feces. Renal accumulation and excretion of metals has also received considerable attention. Renal accumulation of cadmium in the form of its complex with the small molecular weight protein, metallothionein, remains one of the best-documented mechanisms. Toxicokinetic models continue to be useful in providing a quantitative description of the overall body turnover of metals. They can be useful in establishing dose-response relationships where, for example, the range of half-times of elimination of a metal can contribute to the overall variance in the dose-response relationship. In addition to the observation-based models, pharmacokinetic models can be developed based on a priori physiological and mechanistic considerations. The chapter concludes with a consideration of indicator media that best reflect the dose to the critical organ.