Phytopharmaceuticals in cancer chemoprevention. Bagchi D, Preuss HG, eds. Boca Raton, FL: CRC Press, 2004 Oct; :29-39
Introduction: Mankind has sought out and worked with metals for millennia. The earliest known metalwork dates to approximately 5000 B.C. Metals are ubiquitous in modem society. They form the structures of our buildings and our automobiles, and they are vital components of our computers and appliances. Many chemical reactions, including those used to manufacture products ranging from foods to drugs, are catalyzed by metals. Metals, including iron, chromium, and cobalt, are essential components of our diet. Not all exposures to metal are benign, however. For example, various forms of the metalloid arsenic have been used for centuries as a poison. Exposure to specific forms of metal, especially in the workplace, where workers may be exposed to high concentrations for many hours per day, has been linked to cancers of the lung, skin, and other organs. Because metals do not biodegrade, the level of environmental metal exposure tends to increase over time in areas where they are utilized. Archaeological data indicate that humans today possess levels of skeletal lead and cadmium many times higher than those found in ancient humans. The purpose of this chapter is to discuss metals and metalloids that have been identified as carcinogens in humans via epidemiological studies. Special emphasis will be given to the free-radical and molecular mechanisms by which metals may induce or promote cancer. Metals are defined as elements that have an unoccupied space in their outer valence shell, possess a positive charge in solution, and are good conductors of electricity. Metalloids are defined less stringently than metals. They are semiconductor elements that mayor may not display metal characteristics, depending on chemical conditions. The metalloid of greatest interest to cancer research is arsenic. The majority of elements in the periodic chart (96 of 113) can be classified as either metals or metalloids. Of these, only seven have been positively associated with human cancer. The complex chemistry of metals defies simple categorization with respect to carcinogenesis. Even metals recognized as carcinogens vary greatly with respect to carcinogenic potential, which is often a function of oxidation state. For example, exposure to chromium (VI) increases cancer risk, whereas chromium (III) exposure does not. It is, therefore, more correct to refer to specific metal forms (metal salts versus pure metals, for example) or oxidation states than to categorize any single metal as carcinogenic. Conclusions: Mankind has used metals for millennia. but the relation between metals and cancer has only been known for over a century. Only in the past three decades have the tools been available to analyze the molecular and cellular effects of metals on cancer, and only very recently has it been possible to examine the role of free radicals in normal and disease states. Because of their ability to produce free radicals, transition metals provide a unique means by which to study not only metal-related diseases, but the effects of free radicals on DNA damage, intracellular signaling, and cell-to-cell communication. With the completion of the human genome project and the use of novel technologies such as genomics and proteomics, it will soon be possible to examine the global effects of free radicals on genes and their expression.