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The skin and eyes remain in constant exposure to the surrounding environment and are subject to accidental, occupational, and biological risks at all times, Normal development, homeostasis, and repair following injury depend upon appropriate levels of calcium, zinc, magnesium, copper, iron, and minute amounts of other trace metals. Both tissues exist in a permanent state of dynamic equilibrium with the environment whereby cells lost through natural wear and tear are replaced through genetically regulated mitotic patterns. Normal functional requirements of the constituent tissues depend on critical balances between trace metals, metal ion gradients, and specific carrier proteins which are modulated by upregulation of growth factors, cytokines, hormones, and subcellular regulators acting by autocrine, paracrine, and endocrine mechanisms. Metal ion gradients in epidermal tissues serve critical functions in basal cell proliferation, post-mitotic migration, and functional differentiation in normal homeostasis and in repair following injury. Toxic mechanisms reflect imbalances in trace metals or interaction between xenobiotic and trace metals through competitive binding key carrier proteins and metabolic pathways leading to trace metal imbalances and functional impairment. Alternatively, toxic injuries result through direct cytotoxic action of metal ions on cell membranes, intercellular communication, RNA and DNA damage, and mutagenic change. Arsenic is the only primary carcinogen in the skin following ingestion or topical exposure; beryllium, aluminum, and zirconium are a cause of granuloma. Aluminum as a cause for breast cancer is equivocal. Metal toxicities in the eye result from direct accidental or occupational exposure and systemic uptake of neurotoxic metals and their action on the retina and optic nerve. Calcium, zinc, magnesium, and iron are essential trace elements in eye development and physiology but silver, gold, lead, and mercury are absorbed through optic membranes or from the circulation to accumulate in the vitreous leading to local or systemic action. Lead, mercury, cadmium, aluminum, and other xenobiotic metals are implicated in structural and physiological damage in the mammalian eye. Thallium shows an affinity for melanin.

The purpose of this review is to provide a reader with a brief account of current results and views in the area of genotoxicity of metal ions, with a special attention to underlying chemical mechanisms. The text is divided into six sections. Following a general introduction in Section 1, Section 2 describes main molecular mechanisms of formation of genotoxic lesions: hydrolysis, alkylation, and radical reactions of nucleobases and the phosphosugar DNA backbone. The basics of cellular repair of DNA lesions are also shortly presented. This section serves as a background source for Sections 3, 4, and 5. Section 3 covers the main mechanisms of metal ion genotoxicity, followed by Section 4, which describes genotoxicity of individual metals; i.e., of the confirmed carcinogens As, Be, Cd, Cr, and Ni, as well as of the suspected carcinogens Co, Cu, Fe, Pb, Pt, and 238U (also known as depleted uranium). The genotoxicity of exposures to metal mixtures is also discussed. Section 5 provides a critical overview of methodologies used for studying mutagenicity and carcinogenicity of metals; the final Section 6 summarizes the current state and future perspectives of research in genotoxic mechanisms of metal ions.

Several individual metals including aluminum, arsenic, cadmium, lead, manganese, and mercury were demonstrated to affect the neurological system. Metals are ubiquitous in the environment. Environmental and occupational exposure to one metal is likely to be accompanied by exposure to other metals, as well. It is, therefore, expected that interactions or "joint toxic actions" may occur in populations exposed to mixtures of metals or to mixtures of metals with other chemicals. Some metals seem to have a protective role against neurotoxicity of other metals, yet other interactions may result in increased neurotoxicity. For example, zinc and copper provided a protective role in cases of lead-induced neurotoxicity. In contrast, arsenic and lead co-exposure resulted in synergistic effects. Similarly, information is available in the current literature on interactions of metals with some organic chemicals such as ethanol, polychlorinated biphenyls, and pesticides. In depth understanding of the toxicity and the mechanism of action (including toxicokinetics and toxicodynamics) of individual chemicals is important for predicting the outcomes of interactions in mixtures. Therefore, plausible mechanisms of action are also described.

This chapter provides a succinct summary of the nephrotoxic effects of a number of metals/metalloids on an individual or mixture basis. There is a discussion of routes of exposure, mechanisms of uptake by renal cells and the potential impact of nanomaterials on these processes. An emphasis is placed on the toxicity of these metals/ metalloids to individual cell types in the kidney and the application of biomarkers for the early detection of kidney cell injury prior to the onset of an overt clinical state such as end-stage renal disease. The issue of interactions between nephrotoxic metals in mixture exposures is discussed in relation to the application of molecular biomarkers for early detection of renal cell injury.

Certain heavy metals have been reported to seriously affect the immune system potentially resulting in a broad range of harmful health effects. Reported alterations in immune cell function include a variety of affected mechanisms. Thereby, depending on the particular metal, its concentration, route and duration of exposure, and biologic availability, the net outcome may be either immunosuppression or stimulation of immune cell activity. Since the key importance of the immune system is protection of the host against pathogenic agents, an impaired immune competence inevitably increases the susceptibility to invading pathogens. However, being aware that the immune system represents a sensitively regulated network of different cells, tissues, and soluble mediators it has to be stated that any form of dys-regulation may result in adverse health effects with overstimulation being as harmful as inhibition of functional activity. Chronic-inflammatory reactions, cancer development, hypersensitivity, allergic and autoimmune diseases are known consequences of persisting overstimulation. All these manifestations were already found to be related with heavy metal exposure.

Metals have been in the environment during the entire evolution of man and the use of metals is key to human civilization. None-the-less, several very toxic species are included in the metallic elements and compounds either widely used by man and/or widely found in the human environment. This includes the five metallic agents considered human carcinogens, namely arsenic and arsenic compounds, beryllium and beryllium compounds, cadmium and cadmium compounds, chromium(VI) compounds, and nickel compounds, all of which are proven carcinogens in laboratory animals as well. There is significant human exposure to these carcinogenic inorganics, either occupationally, through the environment, or both. Inhalation is typical in the workplace while inhalation or ingestion occurs from environmental sources. Human metallic carcinogens frequently cause tumors at the portal of entry and lung cancers are the most common tumor after inhalation. Agent-specific tumors occur as well, like urinary bladder tumors after arsenic exposure, which are due to biokinetics or mechanisms that are specific to arsenic. Even in their simplest elemental form, metals are not inert, and they have biological activity. However, it should be kept in mind that these inorganic carcinogens, when in the atomic form, cannot be broken down into less toxic subunits, and this, in part, is why they are so important as environmental human carcinogens. This chapter focuses on the metallic agents that are known human carcinogens.