Chapter 23: Toxic Effects of Metals

What is a Metal?

What defines a “metal” is not always obvious and the differences between metallic and nonmetallic elements may be subtle (Vouk, 1986). Metals are typically defined by physical properties of the element in the solid state, but can vary widely with the metallic element. General metal properties include high reflectivity (luster), high electrical conductivity, high thermal conductivity, and mechanical ductility and strength. A characteristic of metals of toxicological importance is that they may often react in biological systems by losing one or more electrons to form cations (Vouk, 1986). In the periodic table, within a group there is often a gradual transition from nonmetallic to metallic properties going from lighter to heavier atoms (eg, Group IVa transitions from carbon to lead). Metals often exhibit variable oxidation states. Various names are applied to subsets of metallic elements including alkali metals (eg, lithium and sodium), the alkaline earth metals (eg, beryllium and magnesium), the transition (or “heavy”) metals (eg, cadmium), and the metalloids (eg, arsenic and antimony), the latter of which show characteristics of metals and nonmetals.

Over 75% of the elements in the periodic table are regarded as metals and several are considered metalloids. This chapter discusses metals, and certain metal complexes or molecules, that have been reported to produce significant toxicity in humans. The discussion includes major toxic metals (eg, lead, cadmium), essential metals (eg, zinc, copper), medicinal metals (eg, platinum, bismuth), and minor toxic metals including metals of technological significance (eg, indium, uranium). This chapter will also discuss toxic metalloids (eg, arsenic, antimony) and certain nonmetallic elemental toxicants (eg, selenium, fluoride). An overview of toxic effects of metals is shown in Fig. 23-1.

Metals as Toxicants

It cannot be stressed enough that the use of metals has been critical to the progress and success of human civilization. It is difficult to imagine an advanced civilization without extensive use of metals and metal compounds. However, metals are unique among pollutant toxicants in that they are all naturally occurring and, in many cases, are already ubiquitous to some level within the human environment. Thus, regardless of how safely metals are used in industrial processes or consumer endpoint products, some level of human exposure is inevitable. Furthermore, life evolved in the presence of metals and organisms have been forced to deal with these potentially toxic, yet omnipresent, elements. Perhaps in response to, or at the very least fortuitously, many metals have become essential to various biological processes. With essentiality there is intentional bioaccumulation that involves safe transport and storage. Nonetheless, even essential metals can be toxic with increasing exposure, as they overwhelm biological systems and bind to unwanted sites. It is repeatedly seen that the nonessential toxicant metals mimic essential metals and thereby gain access to, and potentially disrupt, key cellular functions. This can also account for bioaccumulation of toxic metals without known biological function.

Metals differ from other toxic substances because, as elements, they are neither created nor destroyed by human endeavors. What human industry and civilization generally do accomplish is to concentrate metals in the biosphere. The anthropogenic contribution to the levels of metals in air, water, soil, and food is well recognized (Beijer and Jernelov, 1986). Human use of metals can also alter the chemical form or speciation of an element and thereby impact toxic potential. With a few very notable exceptions, most metals are only sparingly recycled once used. These factors combine together and tend to make metals persistent in the human environment, often resulting in protracted exposures.

Due to their very early use, metals are one of the oldest toxicants known to humans. For instance, human use of lead probably started prior to 2000 bc, when abundant supplies were obtained from ores as a by-product of smelting silver. The first description of abdominal colic in a man who extracted metals is credited to Hippocrates in 370 bc. Arsenic and mercury are discussed by Theophrastus of Erebus (370–287 bc), and Pliny the Elder (ad 23–79). Arsenic was used early on for decoration in Egyptian tombs and as a “secret poison,” whereas mercury assumed almost a mystical stature in early science and was a large focus of alchemy. However, most of the use of the metals has occurred since the onset of the industrial revolution. In this regard, many of the metals of toxicological concern today were only relatively recently discovered. For instance, cadmium was first recognized in the early 1800s, and it was much later before the metal was widely used. The toxicological importance of some of the rarer or lesser used metals has increased with new applications, such as chemotherapy and microelectronics, or other emerging technologies.

Historically, metal toxicology usually concerned acute or overt, high-dose effects, such as abdominal colic from lead or the bloody diarrhea and uropenia after mercury exposures. Due to advances in our understanding of toxic potential of metals, and the accompanying improvements in industrial hygiene and stricter environmental standards, acute high-dose effects of metals are now very uncommon in the Western world. Metal toxicology has shifted focus to more subtle, chronic, low-dose effects, in which cause-and-effect relationships may not be immediately clear. These might include a level of effect that causes a change in an important, but highly complex index of an affected individual’s performance, such as lower than expected IQs due to childhood lead exposure. Other important chronic toxic effects include carcinogenesis, and several metals have emerged as human carcinogens (Straif et al., 2009). In humans, defining the responsible agent for such toxicological effects can often be difficult, particularly when the endpoint disease may have a complex etiology caused by a number of different chemicals or even combinations of chemicals. In addition, humans are never exposed to only a single metal, but rather to complex mixtures. Rodent or cellular/molecular models are helpful but the metals as a class of toxicants clearly present many challenges in toxicological research.

The elemental nature of metals impacts their biotransformation and toxicity, as detoxication by destructive metabolism to subcomponents of lesser toxicity cannot occur with these atomic species. In essence, beyond elemental species metals are nonbiodegradable. This level of indestructibility combined with the bioaccumulation that can often occur contributes to the high concern for metals as toxicants. Most elemental metals tend to form ionic bonds. However, biological conjugation to form organometallic compounds can occur for various metals (Dopp et al., 2004; Drobna et al., 2010), particularly with metalloids, such as arsenic, that show mixed carbonaceous and metallic qualities. The redox capacity of a given metal or metallic compound should also be considered as part of its metabolism. The metabolism of metals is intricate and subtle but directly impacts toxic potential.

Movement of Metals in the Environment

Metals are redistributed naturally in the environment by both geologic and biological cycles. Rainwater dissolves rocks and ores and transports materials, including metals, to rivers and underground water (eg, arsenic), depositing and stripping materials from adjacent soil and eventually transporting these substances to the ocean to be precipitated as sediment or taken up into forming rainwater to be relocated elsewhere. Biological cycles moving metals include biomagnification by plants and animals resulting in incorporation into food cycles. In comparison, human activity often intentionally shortens the residence time of metals in ore deposits, and can result in the formation of new, non-naturally occurring metallic compounds. For instance, cadmium distribution mainly comes from human activities. Human industry greatly enhances metal distribution in the global environment by discharge to soil, water, and air, as exemplified by the 200-fold increase in lead content of Greenland ice since the onset of the industrial revolution. Mercury undergoes global cycling with elevated levels being found far from points of discharge, as, for example, with mercury in the Arctic Ocean. Mercury also undergoes biomethylation and biomagnification by aquatic organisms (see Fig. 23-5).

Increased distribution of metals and metal compounds in the environment, especially through anthropogenic activities, raises increasing concern for ecotoxicological effects. Reports of metal intoxication are common in plants, aquatic organisms, invertebrates, fish, sea mammals, birds, and domestic animals. The ecotoxicity of various metals is discussed under each individual section. Mercury poisoning from consumption of fish containing high levels of methylmercury and cadmium poisoning from consumption of rice grown in soils contaminated with cadmium from industrial discharges are examples of human consequences from environmental pollution.

Not all human toxicity occurs from metals deposited in the biosphere by human activity. For example, chronic arsenic poisoning from high levels of naturally occurring inorganic arsenic in drinking water is a major health issue in many parts of the world. Endemic intoxication from excess fluoride, selenium, or thallium can all occur from natural high environmental levels.

Chemical Mechanisms of Metal Toxicology

The precise chemical basis of metal toxicology is inadequately understood but a uniform mechanism for all toxic metals is implausible because of the great variation in chemical properties and toxic end points. Chemically, metals in their ionic form can be very reactive and can interact with biological systems in a large variety of ways. In this regard, a cell presents numerous potential metal-binding ligands. For instance, metals such as cadmium and mercury readily attach to sulfur in proteins as a preferred bioligand. Such adventitious binding is an important chemical mechanism by which exogenous metals exert toxic effects that can result in steric rearrangement that impairs the function of biomolecules (Kasprzak, 2002). An example would be the inhibition of enzyme activity by metal interaction at sites other than the active center, such as the inhibition of heme synthesis enzymes by lead. The inhibition of biologically critical enzymes is an important molecular mechanism of metal toxicology.

The metals can show more specific forms of chemical attack through mimicry. In this regard the toxic metals may act as mimics of essential metals, binding to physiological sites that normally are reserved for an essential element. Owing to their rich chemistry, essential metals control, or are involved in, a variety of key metabolic and signaling functions (Kasprzak, 2002; Cousins et al., 2006). Through mimicry, the toxic metals may gain access to, and potentially disrupt, a variety of important or even critical metal-mediated cellular functions. For example, mimicry for, and replacement of, zinc is a mechanism of toxicity for cadmium, copper, and nickel. Thallium mimics potassium and manganese mimics iron as a critical factor in their toxicity. Mimicry of arsenate and vanadate for phosphate allows for cellular transport of these toxic elements, whereas selenate, molybdate, and chromate mimic sulfate and can compete for sulfate carriers and in chemical sulfation reactions (Bridges and Zalpus, 2005). Organometallic compounds can also act as mimics of biological chemicals, as, for example, with methylmercury, which is transported by amino acid or organic anion transporters (Bridges and Zalpus, 2005). Indeed, molecular or ionic mimicry at the level of transport is often a key event in metal toxicity.

Another key chemical reaction in metal toxicology is metal-mediated oxidative damage. Many metals can directly act as catalytic centers for redox reactions with molecular oxygen or other endogenous oxidants, producing oxidative modification of biomolecules such as proteins or DNA. This may be a key step in the carcinogenicity of certain metals (Kasprzak, 2002). Besides oxygen-based radicals, carbon- and sulfur-based radicals may also occur. Nickel and chromium are two examples of metals that act, at least in part, by generation of reactive oxygen species (ROS) or other reactive intermediates (Kasprzak, 2002). Alternatively, metals may displace redox active essential elements from their normal cellular ligands, which, in turn, may result in oxidative cellular damage. For instance, cadmium, which is not redox active, may well cause oxidative stress through the release of endogenous iron, an element with high redox activity (Valko et al., 2006).

Metals in their ionic form can be very reactive and form DNA and protein adducts in biological systems. For example, once hexavalent chromium enters the cell it is reduced by various intracellular reductants to give reactive trivalent chromium species that form DNA adducts or DNA–protein cross-links, events likely to be important in chromium genotoxicity (Zhitkovich, 2005). Metals can also induce an array of aberrant gene expression, which, in turn, produces adverse effects. For example, nickel can induce the expression of Cap43/NDRG1, under the control of the hypoxia-inducible transcription factor (HIF-1), which is thought to play a key role in nickel carcinogenesis (Costa et al., 2005). An array of aberrant hepatic gene expressions occurs in adult mice after in utero arsenic exposure, which could be an important molecular event in arsenic hepatocarcinogenesis (Liu et al., 2006).

Factors Impacting Metal Toxicity

The standard factors that impact the toxic potential of all chemicals apply to the metals as well. Exposure-related factors include dose, route of exposure, duration, and frequency of exposure. Because metals can be quite reactive, the portal of entry is often initially the organ most affected, as with the lung after inhalation.

Host-based factors that can impact metal toxicity include age at exposure, gender, and capacity for biotransformation. For instance, it is quite clear that younger subjects are often more sensitive to metal intoxication, as, for example, with the neurotoxicity of lead in children. The major pathway of exposure to many toxic metals in children is food, and children consume more calories per pound of body weight than adults. Moreover, children have higher gastrointestinal absorption of metals, particularly lead. The rapid growth and proliferation in the perinate represent opportunities for toxic effects, including potentially carcinogenesis, of metallic agents, and several metals (eg, arsenic, nickel, lead, and chromium) are transplacental carcinogens in rodents. Fetal-stage toxicity of metals is well documented, as with methylmercury, and many metals are teratogenic. For many inorganics there is no impediment to transplacental transport, as with lead or arsenic, and human fetal blood lead levels (BLL) are similar to maternal levels. Elderly persons are also believed to be generally more susceptible to metal toxicity than younger adults. Recognition of factors that influence toxicity of a metal is important in determining risk, particularly in susceptible subpopulations.

Chemical-related factors directly impact the toxic potential of metals. This would include the precise metal compound and its valence state or speciation. For instance, methylmercury is a potent neurotoxin, whereas the inorganic mercurials primarily attack the kidney. Similarly, the oxidation state of chromium can differentiate the essential (naturally occurring trivalent chromium) from toxic species (hexavalent chromium).

Lifestyle factors such as smoking or alcohol ingestion may have direct or indirect impacts on the level of metal intoxication. For instance, cigarette smoke by itself contains many toxic metals, such as cadmium, and it is thought that smoking will double the lifetime burden of cadmium in nonoccupationally exposed individuals. Other components of cigarette smoke may also influence pulmonary effects, as, for instance, with metals that are lung carcinogens. Alcohol ingestion may influence toxicity by altering diet, reducing essential mineral intake, and altering hepatic iron deposition. The composition of the diet can significantly alter gastrointestinal absorption of various dietary metals.

The essentiality of metals has direct bearing on the toxic potential of a metal. Any “free” ionic metal would be potentially toxic due to reactive potential. The need to accumulate essential metals dictates the evolution of systems for the safe transport, storage, and utilization as well as, within limits, elimination of excess. For example, metallothionein (MT) is a metal-binding protein that may function in the homeostatic control of zinc (Cousins et al., 2006), and may represent a storage or transport form of this metal. Such factors imply that a threshold would exist for toxicity due to essential metal exposure. In this regard, the essential metallic elements would be expected to show a “U”-shaped dose–response curve in that, at very low exposure levels, toxic adverse effects would occur from deficiency, but at high exposure levels toxicity also occurs. The nonessential toxic metals can mimic essential elements and disrupt homeostasis, as with cadmium which will potentially displace zinc to bind to zinc-dependent transcription factors and enzymes (Waalkes, 2003).

Adaptive mechanisms can be critical to the toxic effects of metals, and organisms have a variety of ways in which they can adapt to otherwise toxic metal insults. Typically, adaptation is acquired after the first few exposures and can be long-lasting or transient after exposure ceases. Adaptation can be at the level of uptake or excretion, or, with some metals, through long-term storage in a toxicologically inert form. For instance, it appears enhanced arsenic efflux is involved in acquired tolerance to the metalloid on the cellular level (Liu et al., 2001). Conversely, intentional sequestration of toxic metals is another adaptive tactic and examples of such long-term storage include lead inclusion bodies, which form in various organs and contain protein-immobilized lead in a distinct cellular aggresome. These bodies are thought to be protective by limiting the level of free, and therefore toxic, lead within the cell, and the inability to form such bodies clearly increases the chronic toxic effects of lead, including carcinogenesis (Waalkes et al., 2004). Similarly, cadmium exposure causes the overexpression of MT that will sequester cadmium and reduce its toxicity as an adaptive mechanism (Klaassen and Liu, 1998). Metal exposure can also induce a cascade of molecular/genetic responses that may, in turn, reduce toxicity, such as with metal-induced oxidative stress responses (Valko et al., 2006). It is clear that acquired metal adaptation, although allowing immediate cellular survival, may in fact be a potential contributing factor in long-term toxicity (Waalkes et al., 2000). For instance, acquired self-tolerance to cadmium- or arsenic-induced apoptosis may actually contribute to eventual carcinogenesis by allowing survival of damaged cells that would otherwise have been eliminated (Hart et al., 2001; Pi et al., 2005).

Biomarkers of Metal Exposure

Biomarkers of exposure, toxicity, and susceptibility are important in assessing the level of concern with metal intoxication. Exposure biomarkers, such as concentrations in blood or urine, have long been used with metals. Techniques in molecular toxicology have greatly expanded the possibilities for biomarkers. Thus, in the case of chromium, DNA–protein complexes may serve as a biomarker of both exposure and carcinogenic potential. The capacity for expression of genes that potentially play protective roles against metal toxicity, as, for example, with MT and heme oxygenase, shows promise as markers of both effect and susceptibility. The use of such biomarkers may well allow identification of particularly sensitive subpopulations.

Estimates of the relationship of exposure level to toxic effects for a particular metal are in many ways a measure of the dose–response relationships discussed in great detail earlier in this book. The dose of a metal is a multidimensional concept and is a function of time as well as concentration. The most toxicologically relevant definition of dose is the amount of active metal within cells of target organs. The active form is often presumed to be the free metal, but it is technically difficult or impossible to precisely determine.

A critical indicator of retention of a metal is its biological half-life, or the time it takes for the body or organ to excrete half of an accumulated amount. The biological half-life varies according to the metal as well as the organ or tissue. For example, the biological half-lives of cadmium in kidney and lead in bone are 20 to 30 years, whereas for some metals, such as arsenic or lithium, they are only a few hours to days. For many metals, more than one half-life is needed to fully describe the retention. The half-life of lead in blood is only a few weeks, as compared with the much longer half-life in bone. After inhalation of mercury vapor, at least two half-lives describe the retention in brain, one on the order of a few weeks and the other measured in years. Continued metal exposure clearly complicates retention kinetics.

Blood, urine, and hair are the most accessible tissues for measuring metal exposure. Results from single measurements may reflect recent exposure or long-term or past exposure, depending on retention time in the particular tissue. Blood and urine concentrations usually, but not always, are reflective of more recent exposures and correlate with acute adverse effects. An exception is urinary cadmium, which may reflect kidney damage related to a renal cadmium accumulation over several decades. Hair can be useful in assessing variations in exposure to metals over the period of its growth. Analyses can be performed on segments of the hair, so that metal content of the newest growth can be compared with past exposures. Hair levels of mercury have been found to be a reliable measure of exposure to methylmercury. For most other metals, however, hair is not a reliable tissue for measuring exposure because of metal deposits from external contamination that complicate analysis.

Molecular Responses to Metal Exposure

Exposure to elevated levels of nonessential and essential metals can induce intracellular damage. This damage includes oxidative stress, which can lead to lipid peroxidation, protein denaturation, DNA damage, and organelle dysfunction. In addition, metals can disrupt the biological function/activity of proteins by either directly binding to the protein or displacing metals within metalloproteins. The ability of metals to affect gene expression is well documented. However, the role of metal-induced changes in gene expression in the etiology of human disease has only recently begun to be elucidated. Modern genomic technologies have identified hundreds to thousands of genes whose levels of expression are affected following exposure to essential and nonessential metals. Gene expression can change as a direct response to metal exposure, or to metal-induced intracellular stress, such as oxidative stress, DNA damage, or protein denaturation. The intended consequence of metal activation of gene expression is to protect the organism from metal-induced damage. Metal exposure is associated with increased expression of genes that encode proteins that: (1) remove the metal from the cell via chelation or increased export; (2) reduce the level of oxidative stress; and (3) repair the metal-induced intracellular damage. However, the inappropriate activation of gene expression following metal exposure can be a contributing factor to a variety of human pathologies (Waisberg et al., 2003).

Bioinformatic analyses of the genomic data have identified dozens of transcription factors and cognate intracellular signal transduction pathways that are activated in response to a variety of metals. Several of the more frequently identified transcription factors and signaling pathways include mitogen-activated protein kinase (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), heat shock factor protein 1 (HFS-1), hypoxia-inducible factor-1α and -2α (HIF-1α, -2α), phosphoinositide 3′-kinase (PI3K)/Akt signaling cascade, and metal regulatory transcription factor 1 (MTF-1). Although these transcription factors and signaling pathways affect the expression of proteins that protect the cell from metal toxicity, they do not exclusively control the expression of defense and repair proteins. For example, MAPKs phosphorylate and activate a collection of transcription factors to regulate gene expression. The MAPKs are part of a regulatory network that controls multiple cellular processes including cell growth, differentiation, cell survival, and the stress response (Pearson et al., 2001). Thus, any metal that activates the MAPK signaling cascade can produce unintentional effects on these basic cellular processes. It has been proposed that the activation of MAPK pathways by metals contributes to metal-induced apoptosis (Waisberg et al., 2003).

Many metal-responsive signaling pathways and the cognate transcription factors have been identified. However, the mechanisms by which metals initially activate these pathways have not been completely resolved. Metals can affect the steady-state levels of intracellular second messengers such as calcium, cAMP, cGMP, nitric oxide, and phospholipids. Cadmium and zinc affect cAMP and cGMP levels by inhibiting the cyclic nucleotide phosphodiesterase responsible for the degradation of the cyclic nucleotide (Merali et al., 1975; Watjen et al., 2001). ROS can activate redox-sensitive transcription factors such as NF-κB, AP-1, and p53 (Valko et al., 2005). It should be noted that a single metal can affect multiple signaling pathways, transcription factors, and second messengers. Likewise, the activity of a single transcription factor can be influenced by a variety of metals. For example the activity of NF-κB is affected by copper, arsenic, vanadium, chromium, cadmium, mercury, lead, or any other metal that can induce intracellular oxidative stress (Chen and Shi, 2002; Korashy and El-Kadi, 2008; Thevenod, 2009).

In addition to affecting gene expression via transcription factors, metals can induce epigenetic changes. Epigenetic changes include posttranslational modification of histones and methylation of DNA to convert cytosine to 5-methylcytosine (Esteller, 2009). The ability of nickel, cadmium, arsenic, and chromium to induce cancer has been linked to metal-inducible epigenetic changes (Arita and Costa, 2009).

Metal-Binding Proteins and Metal Transporters

Protein binding of metals is a critical aspect of essential and toxic metal metabolism (Zalpus and Koropatnick, 2000). Many different types of proteins play roles in the disposition of metals in the body. Nonspecific binding to proteins such as serum albumin or hemoglobin acts in metal transport and tissue distribution. Metals vary in their preferred site of proteinaceous binding, and can attack a variety of amino acid residues. For instance, cysteine sulfurs are preferred by cadmium and mercury, and these residues are commonly involved with overall protein structure, while copper and nickel prefer histidine imidazole. In addition, proteins with specific metal-binding properties play special roles in the trafficking of specific essential metals, and toxic metals may interact with these proteins through mimicry. Metal-binding proteins are an important emerging issue in the physiology and toxicology of metals and only a few examples are highlighted here.

The MTs are an important class of intracellular metal-binding proteins that function in essential metal homeostasis and metal detoxication (Carpene et al., 2007). They are small (6000 Da), soluble, and rich in internally oriented thiol ligands. These thiol ligands provide the basis for high-affinity binding of several essential and toxic metals including zinc, cadmium, copper, and mercury. The MTs are highly inducible by a variety of metals or other stimulants including oxidative stress, heat shock, and exposure to chemotherapeutic agents. MTs clearly play an important role in metal toxicity, as illustrated in the discussion of cadmium below.

Transferrin is a glycoprotein that binds most of the ferric iron in plasma and helps transport iron across cell membranes. The protein also transports aluminum and manganese. Ferritin is primarily a storage protein for iron. It has been suggested that transferrin may serve as a general metal detoxicant protein, since it binds a variety of toxic metals including cadmium, zinc, beryllium, and aluminum.

Ceruloplasmin is a copper-containing glycoprotein oxidase in plasma that converts ferrous iron to ferric iron, which then binds to transferrin. This protein also stimulates iron uptake by a transferrin-independent mechanism.

In all cells there are mechanisms for metal ion homeostasis that frequently involve a balance between uptake and efflux systems. A large number of membrane-bound metal transport proteins have been discovered that transport metals across cell membranes and organelles inside the cells. Metal transporters are important for cellular resistance to metals or metalloids (Rosen, 2002). For instance, enhanced efflux via multidrug resistance protein pumps is involved in acquired tolerance to arsenic (Liu et al., 2001), while decreased influx via reduced calcium G-type channels is involved in acquired tolerance to cadmium (Leslie et al., 2006). Over 10 zinc transporters and four Zip family proteins are involved in cellular zinc transport, trafficking, and signaling (Cousins et al., 2006). The importance of metal transporters in human diseases is well illustrated by Menkes disease and Wilson disease, which are caused by genetic mutations in the copper-transport protein gene ATP7A, resulting in copper deficiency (Menkes), or ATP7B, resulting in copper overload (Wilson) (see Fig. 23-7).

Metal chaperones are a class of proteins and small molecules that move metals within cells. These molecules prevent the metal ions from roaming freely in a reactive form within the cytoplasm. They are also responsible for delivering metals into metalloproteins. Copper and manganese chaperones have been extensively studied; however, chaperones of other metals (iron, zinc, molybdenum) have been reported in microbial systems and may exist in humans (Culotta, 2006).

Pharmacology of Metals

Metals and metal compounds have a long and rich history of pharmacological use. Metallic agents, largely because of their potential toxicity, have been often used in chemotherapeutic settings. For instance, mercury was used in the treatment of syphilis as early as the 16th century. Similarly, Ehrlich’s magic bullet (arsphenamine) was an organoarsenical. Today, many metallic chemicals remain valuable pharmacological tools in the treatment of human disease, as exemplified by the highly effective use of platinum compounds in cancer chemotherapy. In addition, inorganic arsenic has returned as a very effective chemotherapeutic and agent of choice against certain hematologic cancers. Other examples of medicinal metals used today include aluminum (antacids and buffered analgesics), bismuth (peptic ulcer), lithium (mania and bipolar disorders), and gold (arthritis). Metallic compounds find their way into a variety of pharmacological preparations as active or inactive ingredients. Traditional Chinese medicines, usually complex mixtures, can be made with toxic metals, such as mercury, as intentional ingredients (Liu et al., 2008).

Treatment of metal poisoning is sometimes used to prevent, or even attempt to reverse, toxicity. The therapeutic strategy is to give metal chelators that will complex the metal and enhance its excretion (Klaassen, 2006). Most chelators are not specific and will interact with a number of metals, eliminating more than the metal of concern. In addition, the vast array of biological metal ligands is a formidable barrier to chelator efficacy as is the chelator’s water/fat solubility (Klaassen, 2006). Metal chelation therapy should be considered a secondary alternative to toxic metal exposure reduction or even prevention. Chelator therapy can be used for many different metals including lead, mercury, iron, and arsenic. For detailed discussion on the pharmacology of chelation therapy, see Klaassen (2006).

Arsenic

Arsenic (As) is a toxic and carcinogenic metalloid. The word arsenic is from the Persian word Zarnikh, as translated to the Greek arsenikon, meaning “yellow orpiment.” Arsenic has been known and used since ancient times as the poison of kings and the king of poisons. The element was first isolated in about 1250. Arsenicals have been used since ancient times as drugs and even today are very effective against acute promyelocytic leukemia (Sanz and Lo-Coco, 2011). Arsenic exists in the trivalent and pentavalent forms and is widely distributed in nature. The most common inorganic trivalent arsenic compounds are arsenic trioxide and sodium arsenite, while common pentavalent inorganic compounds are sodium arsenate, arsenic pentoxide, and arsenic acid. Important organoarsenicals include arsanilic acid, arsenosugars, and several methylated forms produced as a consequence of inorganic arsenic biotransformation in various organisms, including humans. Arsine (AsH₃) is an important gaseous arsenical.

Occupational exposure to arsenic occurs in the manufacture of pesticides, herbicides, and other agricultural products. Exposure to arsenic fumes and dusts may occur in smelting industries (ATSDR, 2005a; IARC, 2011a). Environmental arsenic exposure mainly occurs from arsenic-contaminated drinking water, which can be very high depending on the subsurface geology (IARC, 2011a). Arsenic in drinking water is generally from natural sources. Although most US drinking water contains arsenic at levels lower than 5 μg/L (ppb), it has been estimated that about 25 million people in Bangladesh alone drink water with arsenic levels above 50 ppb (IARC, 2004). Food, especially seafood, may contribute significantly to daily arsenic intake. Arsenic in seafood is largely in an organic form called arsenobetaine that is much less toxic than the inorganic forms (ATSDR, 2005a).

Toxicokinetics

Inorganic arsenic is well absorbed (80%–90%) from the gastrointestinal tract, distributed throughout the body, often metabolized by methylation, and then excreted primarily in urine (NRC, 2001; IARC, 2011a; Drobna et al., 2010). Arsenic compounds of low solubility (eg, arsenic trioxide, arsenic selenide, lead arsenide, and gallium arsenide) are absorbed less efficiently after oral exposure. Skin is a potential route of exposure to arsenic, and systemic toxicity has been reported in persons having dermal contact with solutions of inorganic arsenic (Hostynek et al., 1993), but the relevance of this to today’s exposure paradigms is limited. Airborne arsenic is largely trivalent arsenic oxide. Deposition in airways and absorption of arsenicals from lungs is dependent on particle size and chemical form. Excretion of absorbed arsenic is mainly via the urine. The whole-body biological half-life of ingested arsenic is about 10 hours, and 50% to 80% is excreted over three days. The biological half-life of methylated arsenicals is in the range of 30 hours. Arsenic has a predilection for skin and is excreted by desquamation of skin and in sweat, particularly during periods of profuse sweating. It also concentrates in forming fingernails and hair. Arsenic exposure produces characteristic transverse white bands across fingernails (Mees’ line), which appear about six weeks after the onset of symptoms of arsenic toxicity. Arsenic in the fingernails and hair has been used as a biomarker for exposure, including both current and past exposures, while urinary arsenic is a good indicator for current exposure.

Methylation of inorganic arsenic species is no longer considered as a detoxication process, as recent work has identified the highly toxic trivalent methylated arsenicals (Drobna et al., 2010). Some animal species even lack arsenic methylation capacity, perhaps as an adaptation mechanism. Fig. 23-2 illustrates the biotransformation of arsenic. Arsenate (As⁵⁺) is rapidly reduced to arsenite (As³⁺) by arsenate reductase (presumably purine nucleoside phosphorylase). Arsenite is then sequentially methylated to form monomethylarsonic acid and dimethylarsinic acid (DMA⁵⁺) by arsenic methyltransferase (AS3MT) or arsenite methyltransferase using S-adenosylmethionine (SAM) as a methyl group donor. The intermediate metabolites, monomethylarsonous acid and dimethylarsinous acid (DMA³⁺), are generated during this process, and these trivalent methylated arsenicals are now thought to be more toxic than even the inorganic arsenic species (Aposhian and Aposhian, 2006; Thomas et al., 2007; Drobna et al., 2010). In humans, urinary arsenicals are composed of 10% to 30% inorganic arsenicals, 10% to 20% MMA, and 55% to 76% DMA (NRC, 2001; IARC, 2011a). However, large variations in arsenic methylation occur due to factors such as age and sex. Genetic polymorphisms impacting arsenic metabolism do exist (eg, Engström et al., 2011) and the role of these in disease states is now being defined. Arsenic metabolism also changes through the course of pregnancy, reflected in higher urinary excretion of DMA and lower urinary levels of inorganic arsenic and MMA, which may have toxicological impact on the developing fetus (Hopenhayn et al., 2003).

Toxicity

Acute Poisoning

Ingestion of large doses (70–180 mg) of inorganic arsenic can be fatal. Symptoms of acute intoxication include fever, anorexia, hepatomegaly, melanosis, cardiac arrhythmia, and, in fatal cases, terminal cardiac failure. Acute arsenic ingestion can damage mucous membranes of the gastrointestinal tract, causing irritation, vesicle formation, and even sloughing. Sensory loss in the peripheral nervous system is the most common neurological effect, appearing at one to two weeks after large doses and consisting of Wallerian degeneration of axons, a condition that is reversible if exposure is stopped. Anemia and leucopenia, particularly granulocytopenia, occur a few days following high-dose arsenic exposure and are reversible. Intravenous arsenic infusion at clinical doses in the treatment of acute promyelocytic leukemia may be significantly or even fatally toxic in susceptible patients, and a few sudden deaths have been reported (Westervelt et al., 2001). Acute exposure to a single high dose can produce encephalopathy, with signs and symptoms of headache, lethargy, mental confusion, hallucination, seizures, and even coma (ATSDR, 2005a).

Arsine gas, generated by electrolytic or metallic reduction of arsenic in nonferrous metal production, is a potent hemolytic agent, producing acute symptoms of nausea, vomiting, shortness of breath, and headache accompanying the hemolytic reaction. Exposure to arsine is fatal in up to 25% of the reported human cases and may be accompanied by hemoglobinuria, renal failure, jaundice, and anemia in nonfatal cases when exposure persists (ATSDR, 2005a).

Chronic Toxicity

The skin is a major target organ in chronic inorganic arsenic exposure. In humans, chronic exposure to arsenic induces a series of characteristic changes in skin epithelium. Diffuse or spotted hyperpigmentation and, alternatively, hypopigmentation can first appear between six months and three years with chronic exposure to inorganic arsenic. Palmar-plantar hyperkeratosis usually follows the initial appearance of arsenic-induced pigmentation changes within a period of years (NRC, 2001; IARC, 2011a). Skin cancer is common with protracted high-level arsenical exposure (see below).

Liver injury, characteristic of long-term or chronic arsenic exposure, manifests itself initially as jaundice, abdominal pain, and hepatomegaly (NRC, 2001; Mazumder, 2005). Liver injury may progress to cirrhosis and ascites, even to hepatocellular carcinoma (Liu and Waalkes, 2008; Straif et al., 2009; IARC, 2011a).

Repeated exposure to low levels of inorganic arsenic can produce peripheral neuropathy. This neuropathy usually begins with sensory changes, such as numbness in the hands and feet, but later may develop into a painful “pins and needles” sensation. Both sensory and motor nerves can be affected, and muscle tenderness often develops, followed by weakness, progressing from proximal to distal muscle groups. Histological examination reveals a dying-back axonopathy with demyelination, and effects are dose-related (ATSDR, 2005a).

An association between ingestion of inorganic arsenic in drinking water and cardiovascular disease has been shown (NRC, 2001; Chen et al., 2005; Navas-Acien et al., 2005). Peripheral vascular disease has been observed in persons with chronic exposure to inorganic arsenic in the drinking water in Taiwan. It is manifested by acrocyanosis and Raynaud’s phenomenon and may progress to endarteritis and gangrene of the lower extremities (black foot disease). Arsenic-induced vascular effects have been reported in Chile, Mexico, India, and China, but these effects do not compare in magnitude or severity with black foot disease in Taiwanese populations, indicating other environmental or dietary factors may be involved (Yu et al., 2002). Atherosclerotic models have been developed in mice with arsenic exposure (Srivastava et al., 2009). Studies have shown an association between high arsenic exposure in Taiwan and Bangladesh and an increased risk of diabetes mellitus (Navas-Acien et al., 2006; Tseng, 2008).

Immunotoxic effects of arsenic have been suggested (ATSDR, 2005a). The hematologic consequences of chronic exposure to arsenic may include interference with heme synthesis, with an increase in urinary porphyrin excretion, which has been proposed as a biomarker for arsenic exposure (Ng et al., 2005).

Mechanisms of Toxicity

The trivalent compounds of arsenic are thiol-reactive, and thereby inhibit enzymes or alter proteins by reacting with proteinaceous thiol groups. Pentavalent arsenate is an uncoupler of mitochondrial oxidative phosphorylation, by a mechanism likely related to competitive substitution (mimicry) of arsenate for inorganic phosphate in the formation of adenosine triphosphate. Arsine gas is formed by the reaction of hydrogen with arsenic, and is a potent hemolytic agent (NRC, 2001).

In addition to these basic modes of action, several mechanisms have been proposed for arsenic toxicity and carcinogenicity. Arsenic and its metabolites have been shown to produce oxidants and oxidative DNA damage, alteration in DNA methylation status and genomic instability, impaired DNA damage repair, and enhanced cell proliferation (NRC, 2001; Rossman, 2003). It appears that arsenic methylation is required for oxidative DNA damage by inorganic arsenic, but cells can still acquire a malignant phenotype without such metabolism (Kojima et al., 2009). This indicates multiple mechanisms may be at play in carcinogenesis. Unlike many carcinogens, arsenic is not a mutagen in bacteria and acts weakly in mammalian cells, but can induce chromosomal abnormalities, aneuploidy, and micronuclei formation. Arsenic can also act as a comutagen and/or cocarcinogen (Rossman, 2003; Chen et al., 2005). These mechanisms are not mutually exclusive and multiple mechanisms likely account for arsenic toxicity and carcinogenesis (Kojima et al., 2009). Some mechanisms, however, may be organ specific. There is emerging evidence that arsenic can impact target tissue stem cells in various ways to facilitate oncogenic change (Tokar et al., 2011).

Carcinogenicity

The carcinogenic potential of arsenic was recognized over 110 years ago by Hutchinson (see IARC, 2011a), who observed an unusual number of skin cancers occurring in patients treated for various diseases with medicinal arsenicals. IARC (2011a) and NTP (2011a) have long classified arsenic as a known human carcinogen, most associated with various tumors including those of the skin, lung, and urinary bladder, and possibly kidney, liver, and prostate (Straif et al., 2009; IARC, 2011a).

Arsenic-induced skin cancers include basal cell carcinomas and squamous cell carcinomas, both arising in areas of arsenic-induced hyperkeratosis. The basal cell cancers are usually only locally invasive, but squamous cell carcinomas may have distant metastases. In humans, the skin cancers often, but not exclusively, occur on areas of the body not exposed to sunlight (eg, on palms of hands and soles of feet). They also often occur as multiple primary malignant lesions. Animal models have shown that arsenic acts as a rodent skin tumor copromoter with 12-O-teradecanoyl phorbol-13-acetate in v-Ha-ras mutant Tg.AC mice (Germolec et al., 1998) or as a cocarcinogen with UV irradiation in hairless mice (Rossman et al., 2004).

The association of internal tumors in humans with arsenic exposure is well recognized (NRC, 2001; Straif et al., 2009; IARC, 2011a; NTP, 2011a). This includes arsenic-induced tumors of the human urinary bladder, and lung, and potentially the liver, kidney, and prostate (Straif et al., 2009; IARC, 2011a). In rats, the methylated arsenic species, DMA⁵⁺, is a urinary bladder tumor carcinogen and promoter and produces urothelial cytotoxicity and proliferative regeneration with continuous exposure (see Tokar et al., 2010a for review). It has been suggested that the relevance of this finding to inorganic arsenic carcinogenesis must be extrapolated cautiously, because it requires a high dose of DMA to produce these regenerative changes in rats (NRC, 2001).

In contrast to most other human carcinogens, it has been difficult to confirm the carcinogenicity of inorganic arsenic in experimental animals (Tokar et al., 2010a). Recently, a transplacental arsenic carcinogenesis model has been established in mice. Short-term exposure of the pregnant rodents from gestation days eight to 18, a period of general sensitivity to chemical carcinogenesis, produces tumors in various tissues in the offspring as adults (Tokar et al., 2010a, 2011), including sites identified in humans, such as liver and lung (Straif et al., 2009; IARC, 2011a). Prenatal exposure to arsenic in mice can also enhance the sensitivity to tumor development induced by exposure to other agents after birth, and can enhance skin and bladder cancer formation (Tokar et al., 2010a, 2011), again important human target sites of arsenic carcinogenesis (Straif et al., 2009; IARC, 2011a). Data are emerging indicating that humans exposed during early developmental periods to inorganic arsenic show a predilection toward cancer development in later life (Smith et al., 2006; Tokar et al., 2011), indicating that the developmental life stage appears to be hypersensitive to arsenic carcinogenesis in rodents and humans (Tokar et al., 2011).

Treatment

For acute arsenic poisoning, treatment is symptomatic, with particular attention to fluid volume replacement and support of blood pressure. The oral chelator penicillamine or succimer (2,3-dimercaptosuccinic acid [DMSA]) is effective in removing arsenic from the body. Dimercaptopropanesulfonic acid (DMPS) has also been used for acute arsenic poisoning with fewer side effects (Aposhian and Aposhain, 2006). However, for chronic poisoning, chelator therapy has not proven effective in relieving symptoms (Rahman et al., 2001; Liu et al., 2002) except for a limited preliminary trial with DMPS (Mazumder, 2005). The best strategy for preventing chronic arsenic poisoning is by reducing exposure.

Beryllium

Beryllium (Be), an alkaline earth metal, was discovered in 1798. The name beryllium comes from the Greek beryllos, a term used for the mineral beryl. Beryllium compounds are divalent. Beryllium alloys are used in automobiles, computers, sports equipment, and dental bridges. Pure beryllium metal is used in nuclear weapons, aircraft, x-ray machines, and mirrors. Human exposure to beryllium and its compounds occurs primarily in beryllium manufacturing, fabricating, or reclaiming industries. Individuals may also be exposed to beryllium from implanted dental prostheses. The general population is exposed to trace amounts of beryllium through the air, food, and water, as well as from cigarette smoke (WHO, 1990a,b; ATSDR, 2002).

Toxicokinetics

The primary route of exposure to beryllium compounds is through the lungs. After being deposited in the lung, beryllium is slowly absorbed into the blood. In patients accidentally exposed to beryllium dust, serum beryllium levels peak about 10 days after exposure with a biological half-life of two to eight weeks (ATSDR, 2002). Gastrointestinal and dermal absorption of beryllium is low (<1%), but incidental oral exposure to soluble beryllium compounds or exposure through damaged skin may significantly contribute to total body burden (Deubner et al., 2001). Most of the beryllium circulating in the blood is bound to serum proteins, such as prealbumins and globulins. A significant part of the inhaled beryllium is stored in the bone and lungs. More soluble beryllium compounds are distributed to the liver, lymph nodes, spleen, heart, muscle, skin, and kidney. Elimination of absorbed beryllium occurs mainly in the urine and only to a minor degree in the feces. Because of the long residence time of beryllium in the skeleton and lungs, its biological half-life is over one year (ATSDR, 2002; WHO, 1990a,b).

Toxicity

Skin Effects

Exposure to soluble beryllium compounds may result in conjunctivitis and papulovesicular dermatitis of the skin, which is likely an inflammatory response to the beryllium. Beryllium exposure may also cause a delayed-type hypersensitivity reaction in the skin, which is a cell-mediated immune response. If insoluble beryllium-containing materials become embedded under the skin, a chronic granulomatous lesion develops, which may be necrotizing and ulcerative. Skin is a route of beryllium exposure and sensitization, and the beryllium sulfate skin test and the beryllium lymphocyte proliferation test have been used to identify beryllium-sensitive individuals (Fontenot et al., 2002; Tinkle et al., 2003). Beryllium fluoride patch test may in itself be sensitizing, which has been replaced by the use of 1% beryllium sulfate (ATSDR, 2002; Fontenot et al., 2002).

Acute Chemical Pneumonitis

Inhalation of beryllium can cause a fulminating inflammatory reaction of the entire respiratory tract, involving the nasal passages, pharynx, tracheobronchial airways, and the alveoli. In the most severe cases, it produces acute fulminating pneumonitis. This occurs almost immediately following inhalation of aerosols of soluble beryllium compounds, particularly the fluoride, during the ore extraction process. Fatalities have occurred, although recovery is generally complete after a period of several weeks or even months.

Chronic Granulomatous Disease

Berylliosis, or chronic beryllium disease (CBD), was first described among fluorescent lamp workers exposed to insoluble beryllium compounds, particularly beryllium oxide. Granulomatous inflammation of the lung, along with dyspnea on exertion, cough, chest pain, weight loss, fatigue, and general weakness, is the most typical feature. Impaired lung function and hypertrophy of the right heart are also common. Chest x-rays show miliary mottling. Histologically, the alveoli contain small interstitial granulomas resembling those seen in sarcoidosis. In severe cases CBD may be accompanied by cyanosis and hypertrophic osteoarthropathy (WHO, 1990a,b; ATSDR, 2002). Beryllium sensitization following initial exposure can progress to CBD (Newman et al., 2005). As the lesions progress, interstitial fibrosis increases, with loss of functioning alveoli, impairment of effective air-capillary gas exchange, and increasing respiratory dysfunction. CBD involves an antigen-stimulated, cell-mediated immune response. Human leukocyte antigen, T cells, and proinflammatory cytokines (TNF-α and IL-6) are believed to be involved in the pathogenesis of CBD (Fontenot et al., 2002; Day et al., 2006).

Carcinogenicity

A number of epidemiology studies in US beryllium workers found that death due to lung cancer was increased, along with increased incidence of respiratory diseases. The increase in lung cancers is linked to high exposure levels that occurred prior to stricter exposure regulations introduced in the 1950s. The likelihood of lung cancer was greater in workers with acute beryllium disease than in those with CBD (ATSDR, 2002; Gordon and Bowser, 2003). Beryllium has been classified as a human carcinogen (IARC, 1993; NTP, 2011b).

Experimental studies confirmed carcinogenic potential of beryllium compounds by inhalation. For example, a single, short (<48-minute) exposure to 410 to 980 mg/m³ beryllium metal aerosol induced lung tumors in rats 14 months after exposure. Chronic beryllium sulfate inhalation (13 months, 0.034 mg Be/m³) resulted in 100% lung tumor incidence in rats (Gordon and Bowser, 2003). Injection of beryllium compounds also induced osteosarcomas in rabbits (WHO, 1990a,b). Beryllium compounds are negative in bacterial mutation assays. In mammalian cells, soluble beryllium compounds show weak mutagenic potential, but can induce malignant transformation. The ability of beryllium compounds to produce chromosomal aberrations is controversial, and appears to depend on the compound, dose, and experimental conditions (Gordon and Bowser, 2003). The carcinogenic mechanism of beryllium is not yet clear. Several molecular events can occur including oncogene activation (K-ras, c-myc, c-fos, c-jun, and c-sis), and tumor suppressor gene dysregulation (p53, p16), but mutations in p53 or K-ras are not evident. Beryllium-induced lung tumors show hypermethylation of p16 leading to loss of expression, and have decreased expression of genes associated with DNA repair (Gordon and Bowser, 2003).

Cadmium

Cadmium (Cd) is a toxic transition metal that was discovered in 1817 as an impurity of “calamine” (zinc carbonate) for which it is named (from the Latin cadmia). Until recently the industrial use of cadmium was quite limited, but now it has become an important metal with many uses. About 75% of cadmium produced is used in batteries, especially nickel–cadmium batteries. Because of its noncorrosive properties, cadmium has been used in electroplating or galvanizing alloys for corrosion resistance. It is also used as a color pigment for paints and plastics, in solders, as a barrier to control nuclear fission, as a plastic stabilizer, and in some special application alloys. This metal is typically found in ores with other metals, and is commercially produced as a by-product of zinc and lead smelting, which are sources of environmental cadmium. Cadmium ranks close to lead and mercury as one of the top toxic substances (Nordberg et al., 2007; ATSDR, 2008).

Exposure

Food is the major source of cadmium for the general population. Many plants readily accumulate cadmium from soil. Both natural and anthropogenic sources of cadmium contamination occur for soil, including fallout of industrial emissions, some fertilizers, soil amendments, and use of cadmium-containing water for irrigation, all resulting in a slow but steady increase in the cadmium content in vegetables over the years (Järup et al., 1998). Shellfish accumulate relatively high levels of cadmium (1–2 mg/kg), and animal liver and kidney can have levels higher than 50 μg Cd/kg. Cereal grains such as rice and wheat, and tobacco concentrate cadmium to levels of 10 to 150 μg Cd/kg. With nearby industrial emission, air can be a significant source of direct exposure or environmental contamination. Total daily cadmium intake from all sources in North America and Europe ranges from 10 to 30 μg Cd per day. Of this about 10% or less is retained (Järup et al., 1998). Cigarette smoking is a major nonoccupational source of cadmium exposure, because of cadmium in the tobacco. Smoking is thought to roughly double the lifetime body burden of cadmium (Satarug and Moore, 2004).

Historically, levels of cadmium in the workplace have dramatically improved with the appreciation of its potential toxicity in humans, development of safety restrictions, and improved industrial hygiene. Inhalation is the dominant route of exposure in occupational settings. Airborne cadmium in the present-day workplace environment is generally 5 μg/m³ or less and occupational standards range from 2 to 50 μg/m³. Occupations potentially at risk from cadmium exposure include those involved with refining zinc and lead ores, iron production, cement manufacture, and industries involving fossil fuel combustion, all of which can release airborne cadmium. Other occupations include the manufacture of paint pigments, cadmium–nickel batteries, and electroplating (WHO, 1990a,b; ATSDR, 2008).

Toxicokinetics

Gastrointestinal absorption of cadmium is limited to 5% to 10% of a given dose. Cadmium absorption can be increased by dietary deficiencies of calcium or iron and by diets low in protein. In the general population, women have higher blood cadmium levels than men, possibly due to increased oral cadmium absorption because of relatively low iron stores in women of childbearing age. Indeed, women showing low serum ferritin levels have twice the normal rate of oral cadmium absorption (Nordberg et al., 2007). It has recently been shown that rats on an iron-deficient diet have an increased absorption of cadmium, which correlated with the upregulation of the iron transporter, DMT, which transports both iron and cadmium (Ryu et al., 2004). Absorption of cadmium after inhalation is generally greater, ranging from 10% to 60%, depending on the specific compound, site of deposition, and particle size (Nordberg et al., 2007; Prozialeck and Edwards, 2010). For instance, 50% of cadmium fumes, as generated in cigarette smoke, may be absorbed. It is thought that as much as 100% of cadmium eventually reaching the alveoli can be transferred to blood (Satarug and Moore, 2004).

Once absorbed, cadmium is very poorly excreted and only about 0.001% of the body burden is excreted per day. Both urinary and fecal excretory routes are operative (Satarug and Moore, 2004; ATSDR, 2008). Cadmium transport into cells is mediated through calcium channels (Leslie et al., 2006) and through molecular mimicry (Zalpus and Ahmad, 2003). Gastrointestinal excretion occurs through the bile as a glutathione complex. Cadmium excretion in urine increases relative to body burden (Nordberg et al., 2007; ATSDR, 2008). Cadmium is nephrotoxic, and when renal pathology is present the urinary excretion of cadmium is increased due to decreased renal absorption of filtered cadmium (Zalpus and Ahmad, 2003).

The relationship of cadmium metabolism and toxicity is shown in Fig. 23-3. Cadmium is transported in blood by binding to albumin and other higher-molecular-weight proteins. It is rapidly taken up by tissues and is primarily deposited in the liver and to a lesser extent in the kidney. In the liver, kidney, and other tissues, cadmium induces the synthesis of MT, a low-molecular-weight, high-affinity metal-binding protein (Klaassen et al., 1999). Cadmium is stored in the liver primarily as cadmium–MT. Cadmium–MT may be released from the liver and transported via blood to the kidney, where it is reabsorbed and degraded in the lysosomes of the renal tubules. This releases cadmium to induce more cadmium–MT complex or cause renal toxicity.

Blood cadmium levels in nonoccupationally exposed, nonsmokers are usually less than 1 μg/L. Cadmium does not readily cross the placenta. Breast milk is not a major source of early life exposure. About 50% to 75% of the retained cadmium is found in the liver and kidneys. The biological half-life of cadmium in humans is not known exactly, but is probably in the range of 10 to 30 years (Nordberg et al., 2007).

Toxicity

Acute, high-dose cadmium toxicity in humans is now a rare event. Acute cadmium toxicity from the ingestion of high concentrations of cadmium in the form of heavily contaminated beverages or food causes severe irritation to the gastrointestinal epithelium. Symptoms include nausea, vomiting, and abdominal pain. Inhalation of cadmium fumes or other heated cadmium-containing materials may produce acute pneumonitis with pulmonary edema. Inhalation of large doses of cadmium can be lethal for humans (ATSDR, 2008). Acute cadmium toxicity depends on solubility of cadmium compounds (ATSDR, 2008). For instance, with acute inhalation exposures, the more soluble cadmium chloride, oxide fume, and carbonate are more toxic than the relatively less soluble sulfide (Klimisch, 1993). The major long-term toxic effects of low-level cadmium exposure are renal injury, obstructive pulmonary disease, osteoporosis, and cardiovascular disease. Cancer is primarily a concern in occupationally exposed groups. The chronic toxic effects of cadmium are clearly a much greater concern than the rare acute toxic exposures.

Nephrotoxicity

Cadmium is toxic to tubular cells and glomeruli, markedly impairing renal function. Pathologically, these lesions consist of initial tubular cell necrosis and degeneration, progressing to an interstitial inflammation and fibrosis. There appears to be a critical concentration of cadmium in the renal cortex that, once exceeded, is associated with tubular dysfunction. This concentration depends on the individual, and chronic cadmium nephropathy is seen in about 10% of the population at renal concentrations of ~200 μg/g and in about 50% of the population at about 300 μg/g. Because of the potential for renal toxicity, there is considerable concern about the levels of dietary cadmium intake for the general population. In fact, it is thought that upwards of 7% of the general population may have significant cadmium-induced kidney alterations due to chronic exposure with kidney cadmium levels as low as 50 μg/g (Järup et al., 1998).

Cadmium-induced renal toxicity is reflected by proteinuria as a result of renal tubular dysfunction. The predominant proteins include β₂-microglobulin, N-acetyl-β-d-glucosaminidase (NAG), and MT, as well as retinol-binding protein, lysozyme, ribonuclease, α₁-microglobulin, and immunoglobulin light chains (Chen et al., 2006; Prozialeck and Edwards, 2010). The presence of larger proteins, such as albumin and transferrin, in the urine after occupational cadmium exposure suggests a glomerular effect as well. The pathogenesis of the glomerular lesion in cadmium nephropathy is not well understood (Prozialeck and Edwards, 2010). Urinary excretions of proteins and cadmium have been used as biomarkers for cadmium exposure.

The induction of MT by cadmium and the subsequent sequestration of cadmium as the cadmium–MT complex likely protect tissues from cadmium toxicity. However, if cadmium–MT complex is injected, it is acutely nephrotoxic (Nordberg, 2004). This led to the hypothesis that the cadmium–MT complex was responsible for chronic cadmium nephropathy. In this scenario, cadmium–MT released from the liver would be filtered by the kidney and reabsorbed in proximal tubule cells, where it is degraded releasing locally high levels of “free” cadmium (Fig. 23-3). Nephrotoxicity in normal rats following liver transplantation from cadmium-exposed rats supported this hypothesis (Chan et al., 1993). However, MT-null mice, which are unable to produce the major forms of MT, are hypersensitive to chronic cadmium nephropathy (Liu et al., 1998a), suggesting that cadmium nephropathy is not necessarily mediated through the cadmium–MT complex. Kidney pathology from a single injection of cadmium–MT also differs greatly from that induced by chronic oral inorganic cadmium exposure (Liu et al., 1998b). Inorganic cadmium can be taken into the kidney from the basolateral membrane, and is more toxic than cadmium–MT to cultured renal cells (Prozialeck et al., 1993; Liu et al., 1994; Zalpus and Ahmad, 2003). It is likely that inorganic cadmium can bind to other low-molecular-weight proteins or other complexes for renal uptake, and these complexes can contribute to chronic cadmium nephropathy (Zalpus and Ahmad, 2003).

Chronic Pulmonary Disease

Cadmium inhalation is toxic to the respiratory system in a fashion related to the dose and duration of exposure. Cadmium-induced obstructive lung disease in humans can be slow in onset, and results from chronic bronchitis, progressive fibrosis of the lower airways, and accompanying alveolar damage leading to emphysema. Pulmonary function is reduced with dyspnea, reduced vital capacity, and increased residual volume. The pathogenesis of these lung lesions is not completely understood, but can be duplicated in rodents (WHO, 1990a,b; ATSDR, 2008). The chronic effects of cadmium on the lung clearly increased the mortality of cadmium workers with high exposure.

Skeletal Effects

Occupational cadmium exposure is a well-recognized cause for renal tubular dysfunction associated with hypercalciuria, renal stone formation, osteomalacia, and osteoporosis (Kazantzis, 2004). The long-term consumption of cadmium-contaminated rice caused Itai-Itai disease, which occurred mostly in multiparous elderly women and was characterized by severe osteomalacia and osteoporosis, resulting in bone deformities and concomitant renal dysfunction. Vitamin D deficiency and perhaps other nutritional deficiencies are thought to be cofactors in Itai-Itai disease. Issues with loss of bone density, height loss, and increased bone fractures have now been reported in populations exposed to far lower levels of environmental cadmium than Itai-Itai victims (Kazantzis, 2004). Cadmium affects calcium metabolism, at least partially through renal dysfunction, and excess excretion of calcium often occurs in the urine. The skeletal changes are possibly related to a loss or decrease of calcium absorption, and interference with the actions of parathyroid hormone, disruption of collagen metabolism, and impairment of vitamin D activity (Nordberg et al., 2007), although the effects on vitamin D activity are debated (Engstrom et al., 2009). Cadmium may also act directly on bone and animal studies have shown the metal stimulates osteoclast activity, resulting in the breakdown of bone matrix. Cadmium in bone interferes with calcification and bone remodeling (Wang and Bhattacharyya, 1993). In accord with human victims of Itai-Itai, multiparity in mice enhances the osteotoxicity of cadmium (Bhattacharyya et al., 1988).

Cardiovascular Effects

Some epidemiological evidence suggests cadmium may be an etiologic agent for cardiovascular disease including hypertension, although these associations are not observed in all studies (Järup et al., 1998; Messner and Bernhard, 2010). The population-based US National Health and Nutrition Examination Survey (NHANES II) and studies in Belgium (Staessen et al., 1996) have not supported a role for cadmium in the etiology of hypertension or cardiovascular disease in humans. Animal studies indicate that cadmium may be toxic to myocardium (Kopp et al., 1982), although the relevance of these results to humans is not clear.

Neurotoxicity

There are only limited data from animals and humans that cadmium can be neurotoxic (Järup et al., 1998; ATSDR, 2008). Studies in humans have suggested a relationship between abnormal behavior and decreased intelligence in children and adults exposed to cadmium, but are typically complicated by exposure to other toxic metals. Furthermore, the blood–brain barrier severely limits cadmium access to the central nervous system, and a direct toxic effect appears to occur only with cadmium exposure prior to blood–brain barrier formation (young children), or with blood–brain barrier dysfunction under certain pathological conditions. Additionally, the choroid plexus epithelium may accumulate high levels of cadmium reducing access to other areas (Zheng, 2001). Although a special form of MT (MT-3) occurs in the brain, the role of MT in cadmium neurotoxicity is incompletely defined (Klaassen et al., 1999).

Carcinogenicity

Cadmium compounds are considered to be human carcinogens (IARC, 2011b; NTP, 2011c). In humans, occupational respiratory exposure to cadmium has been most clearly associated with lung cancer (IARC, 2011b; NTP, 2011c). Early human studies also indicated a possible link to cancer of the prostate, which has not been confirmed by more recent work (Sahmoun et al., 2005), despite evidence that the prostate can be a target of cadmium carcinogenesis in rats (Waalkes, 2003). Both the kidney and pancreas accumulate high concentrations of cadmium and exposure to cadmium may also be associated with human renal (Il’yasova and Schwartz, 2005) and pancreatic cancer (Schwartz and Reis, 2000; Kriegel et al., 2006).

Multiple rodent studies have confirmed that inhalation of various cadmium compounds will lead to lung cancer (Waalkes, 2003; IARC, 2011b; NTP, 2011c). Lung tumors can also be produced by systemic cadmium exposure in mice (Waalkes, 2003). Beyond the lung, in rodents cadmium can produce a variety of tumors, including malignant tumors at the site of repository injection (subcutaneous, etc). Compounds such as cadmium chloride, oxide, sulfate, sulfide, and cadmium powder produce local sarcomas in rodents after subcutaneous or intramuscular injections. A single injection can be effective, but multiple injections of cadmium at the same site cause more aggressive sarcomas that show a higher rate of local invasion and distant metastasis. The relevance of injection site sarcoma production to human cancer is unclear. Cadmium also induces tumors of the testes, specifically benign Leydig cell tumors, but this is likely due to a high-dose mechanism involving acute testicular necrosis, degenerative testicular atrophy, and subsequent overstimulation by luteinizing hormone, factors very likely of limited relevance in humans (Waalkes, 2003). Other studies have found that cadmium exposure can induce tumors of the pancreas, adrenals, liver, kidney, pituitary, and hematopoietic system in mice, rats, or hamsters. Cadmium can be carcinogenic in animals after inhalation or oral administration or by various injection routes (Waalkes, 2003). Emerging evidence indicates that cadmium exposure significantly increases the risk of breast and endometrial cancers (McElroy et al., 2006; Akesson et al., 2008; Gallagher et al., 2010). Various studies indicate zinc administration will generally block cadmium carcinogenesis, whereas dietary zinc deficiency can enhance the response (Waalkes, 2003; IARC, 2011b; NTP, 2011c). The mechanisms of cadmium carcinogenesis are poorly understood (Waalkes, 2003) and are generally categorized into four groups, aberrant gene expression, inhibition of DNA damage repair, inhibition of apoptosis, and induction of oxidative stress (Joseph, 2009). Cadmium appears to also work through estrogenic and nonestrogenic mechanisms in hormone-related cancers (Akesson et al., 2008; Benbrahim-Tallaa et al., 2009).

Treatment

At the present time, there is no effective clinical treatment for cadmium intoxication. In certain cases (Itai-Itai disease, osteomalacia) vitamin D is prescribed, although its effects have not been satisfactory (Nordberg et al., 2007). In experimental systems some chelators can reduce acute cadmium-induced mortality (Klaassen et al., 1984), but chelation therapy for cadmium generally results in significant adverse effects.

Chromium

Chromium (Cr) was named from the Greek word “chroma” meaning color, because of the many colorful compounds made from it. It is part of the mineral crocoite (lead chromate), and the element was first isolated in 1798. Most naturally occurring chromium is found in the trivalent state in chromite ores, which are generally refined to ferrochromium or metallic chromium for use in industrial processes. Because trivalent chromium (Cr³⁺) is an essential trace nutrient important for glucose metabolism, it will be discussed separately in the section “Essential Metals with Potential for Toxicity.”

Hexavalent chromium (Cr⁶⁺) is rarely found in nature and is formed as a by-product of various industrial processes. Most chromite ores are processed to sodium dichromate, a hexavalent chromium compound, which is used as an oxidizing agent in stainless steel production and welding, chromium plating, ferrochrome alloys and chrome pigment production, and tanning industries (Ashley et al., 2003). Hexavalent chromium is a human carcinogen and produces a variety of toxic effects (ATSDR, 2008). Chromium in ambient air originates primarily from industrial sources, particularly ferrochrome production, ore refining, and chemical processing. Chromium fallout is deposited on land and water, and, eventually, in sediments. Widespread industrial uses have increased chromium levels in the environment. The hexavalent chromium compounds are also toxic to ecosystems, and microbial and plant variants occur that adapt to high chromium levels in eco-environment (Cervantes et al., 2001). Up to 38% of drinking water supplies in California have detectable levels of hexavalent chromium, but little is known about the health effects from environmental exposures (Costa and Klein, 2006; Sedman et al., 2006). Cobalt–chromium alloy hip replacement can increase blood levels of chromium (Bhamra and Case, 2006).

Toxicokinetics

Absorption of hexavalent chromium compounds is higher (2%–10%) than that of trivalent chromium compounds (0.5%–2%). Inhaled chromium compounds are absorbed in the lung via transfer across alveolar cell membranes. Dermal absorption depends on the chemical form, vehicle, and integrity of the skin. Concentrated potassium chromate may cause chemical burns to the skin and facilitate absorption. Hexavalent chromium readily crosses cell membranes via sulfate and phosphate transporters, while trivalent chromium compounds form octahedral complexes making entry into cells difficult (ATSDR, 2008). Once in the blood, hexavalent chromium is taken up by erythrocytes, while trivalent chromium is only loosely associated with erythrocytes. Chromium compounds are distributed to all organs of the body, with high levels in liver, spleen, and kidney. Particles containing chromium can be retained in the lungs for years. Absorbed chromium is excreted primarily in urine. The half-life for excretion of potassium chromium is about 35 to 40 hours (Sedman et al., 2006; ATSDR, 2008).

Once hexavalent chromium enters cells, it is reduced intracellularly by ascorbic acid, glutathione, and/or cysteine, ultimately to trivalent chromium. It is thought that the toxicity of hexavalent chromium compounds results from damage to cellular components during this process, including the generation of free radicals and the formation of DNA adducts (Zhitkovich, 2005).

Toxicity

Toxic effects have been attributed primarily to airborne hexavalent chromium compounds in industrial settings. Hexavalent chromium is corrosive and may cause chronic ulceration and perforation of the nasal septum, as well as chronic ulceration of other skin surfaces (ATSDR, 2008). It elicits allergic contact dermatitis among previously sensitized individuals, which is a type IV allergic reaction inducing skin erythema, pruritus, edema, papule, and scars. The prevalence of chromium sensitivity is less than 1% among the general population (Proctor et al., 1998). Occupational exposure to chromium may be a cause of asthma (Bright et al., 1997). Accidental ingestion of high doses of hexavalent chromium compounds may cause acute renal failure characterized by proteinuria, hematuria, and anuria, but kidney damage from lower-level chronic exposure is equivocal (ATSDR, 2008).

Carcinogenicity

Hexavalent chromium compounds are classified as known to be human carcinogens by the National Toxicology Program (NTP, 2011d). Occupational exposure to hexavalent chromium compounds, particularly in the chrome production and pigment industries, is associated with increased risk of lung cancer and hexavalent chromium–containing compounds are considered to be human carcinogens (IARC, 1990). Hexavalent chromium compounds are genotoxic; a review of more than 700 sets of short-term genotoxicity test results with 32 chromium compounds revealed 88% of hexavalent chromium compounds were positive, as a function of solubility and bioavailability to target cells (De Flora, 2000). Trivalent chromium compounds were generally nongenotoxic, probably because trivalent chromium is not readily taken up by cells. Once hexavalent chromium enters cells, it is reduced by various intracellular reductants to create reactive chromium species. During the reduction process, various genetic lesions can be generated, including chromium–DNA adducts, DNA–protein cross-links, DNA–chromium intrastrand cross-links, DNA strand breaks, and oxidized DNA bases (O’Brien et al., 2003; Zhitkovich, 2005). Hexavalent chromium compounds are mutagenic, causing base substitutions, deletions, and transversions in bacterial systems, and hypoxanthine guanine phosphoribosyltransferase, supF mutations, etc, in mammalian mutagenesis systems (Cohen et al., 1993; O’Brien et al., 2003).

Hexavalent chromium compounds also react with other cellular constituents during the intracellular reduction process. They can cause the generation of reactive oxygen radicals, inhibit protein synthesis, and arrest DNA replication. Hexavalent chromium can also cause disturbances of the p53 signaling pathway, cell cycle arrest, apoptosis, interference of DNA damage repair, and neoplastic transformation. All these effects could well play an integrated role in chromium carcinogenesis (O’Brien et al., 2003; Costa and Klein, 2006).

Inhaled chromium compounds can penetrate many tissues in the body, and thus have the potential to cause cancer at sites other than the lung. Accumulating evidence indicates an association between cancers of the bone, prostate, hematopoietic system, stomach, kidney, and urinary bladder and hexachromium chromium exposure (Costa, 1997). Furthermore, exposure of hexavalent chromium compounds through the drinking water enhances UV-induced skin cancer in hairless mouse model (Costa and Klein, 2006). An association of hexavalent chromium in the drinking water with stomach cancer has also been reported (Sedman et al., 2006).

Lead

Lead (Pb) has been used by humans for at least 7000 years, because it is easy to extract and work with and widespread. It is highly malleable and ductile as well as easy to smelt. In the early Bronze Age, lead was used with antimony and arsenic. Lead’s elemental symbol, Pb, is an abbreviation of its Latin name plumbum. Lead in lead compounds primarily exists in the divalent form. Metallic lead (Pb⁰) is resistant to corrosion and can combine other metals to form various alloys. Organolead compounds are dominated by Pb⁴⁺. Inorganic lead compounds are used as pigments in paints, dyes, and ceramic glazes. Organolead compounds were once widely used as gasoline additives. Lead alloys are used in batteries, shields from radiation, water pipes, and ammunition. Environmental lead comes mainly from human activity and is listed as a top toxic substance (ATSDR, 2005b). The phasing out of leaded gasoline and the removal of lead from paint, solder, and water supply pipes have significantly lowered BLL in the general population. Lead exposure in children remains a major health concern. Lead is not biodegradable and ecotoxicity of lead remains a concern. For instance, the leaded fish sinkers or pellets lost in the bottom of lakes and river banks can be mistaken for stone and ingested by birds causing adverse effects including death (De Francisco et al., 2003).

Exposure

Lead-containing paint in older housing is a primary source of lead exposure in children (Levin et al., 2008). Major environmental sources of lead for infants and toddlers up to four years of age is hand-to-mouth transfer of lead-containing paint chips or dust from floors of older housing (Manton et al., 2000; Levin et al., 2008). Lead in household dust can also come from outside of the home and may be related to lead in neighborhood soil (von Lindren et al., 2003). A major route of exposure for the general population is from food and water. Dietary intake of lead has decreased dramatically in recent years, and for infants, toddlers, and young children is <5 μg per day (Manton et al., 2005). A review by the EPA in 2004 found lead levels in 71% of the water systems in the United States showed <5 μg Pb/L (ppb). Only 3.6% exceeded the action level of 15 ppb. Lead in urban air is generally higher than that in rural air. Air lead in rural areas of eastern United States is typically 6 to 10 ng/m³ (ATSDR, 2005b).

Other potential sources of lead exposure are recreational shooting, hand-loading ammunition, soldering, jewelry making, pottery making, gunsmithing, glass polishing, painting, and stained glass crafting. Workplace exposure is gradually being reduced. Herbal medicines could be potential sources of lead exposure (Levin et al., 2008). Certain Ayurvedic herbal products were found to be contaminated with lead ranging up to 37 mg/g and over 55 cases of lead poisoning have been related to the ingestion of herbal medicines (Patrick, 2006).

BLL are commonly used for monitoring human exposure to lead. The uses of other biomarkers for lead exposure have been critically reviewed (Barbosa et al., 2005).

Toxicokinetics

Adults absorb 5% to 15% of ingested lead and usually retain less than 5% of what is absorbed. Children absorb 42% of ingested lead with 32% retention (Ziegler et al., 1978). Lead absorption can be enhanced by low dietary zinc, manganese, iron, and calcium (Mahaffey, 1985; Wu et al., 2011), especially in children (Mahaffey, 1985). Airborne lead is a minor component of exposure. Lead absorption by the lungs depends on the form (vapor vs particle), particle size, and concentration. About 90% of lead particles in ambient air that are inhaled are small enough to be retained. Absorption of retained lead through alveoli is relatively efficient.

Lead in blood is primarily (~99%) in erythrocytes bound to hemoglobin; only 1% of circulating lead in serum is available for tissue distribution (ATSDR, 2005b). Lead is initially distributed to soft tissues such as kidney and liver, and then redistributed to skeleton and hair. The half-life of lead in blood is about 30 days. The fraction of lead in bone increases with age from 70% of body burden in childhood to as much as 95% in adulthood, with a half-life of about 20 years. Lead released from bones may contribute up to 50% of the lead in blood, and can be a significant source of endogenous exposure. Bone lead release may be important in adults with accumulated exposure and in women due to bone resorption during pregnancy, lactation, and menopause, and from osteoporosis (Silbergeld et al., 1993; Gulson et al., 2003). Lead crosses the placenta, so that cord blood generally correlates with maternal BLL but is often slightly lower. Lead accumulation in fetal tissues, including brain, is proportional to maternal BLL (Goyer, 1996).

The major route of excretion of absorbed lead is the kidney. Renal excretion of lead is usually through glomerular filtrate with some renal tubular resorption. Fecal excretion via biliary tract accounts for one-third of total excretion of absorbed lead (ATSDR, 2005b).

Physiological-based pharmacokinetic (PBPK) models have been developed for lead risk assessment. The O’Flaherty model is a model for children and adults. The integrated exposure uptake (IEUBK) model was developed by EPA for predicting BLL in children. The Leggett model allows simulation of lifetime exposures and can be used to predict blood lead in both children and adults (ATSDR, 2005b).

Toxicity

Lead can induce a wide range of adverse effects in humans depending on the dose and duration of exposure. The toxic effects range from inhibition of enzymes to the production of severe pathology or death (Goyer, 1990). Children are most sensitive to effects in the central nervous system, while in adults, peripheral neuropathy, chronic nephropathy, and hypertension are concerns. Other target tissues include the gastrointestinal, immune, skeletal, and reproductive systems. Effects on heme biosynthesis provide a sensitive biochemical indicator even in the absence of other detectable effects.

Neurological, Neurobehavioral, and Developmental Effects in Children

Clinically overt lead encephalopathy may occur in children with high exposure to lead, probably at BLL of 70 μg/dL or higher. Symptoms of lead encephalopathy begin with lethargy, vomiting, irritability, loss of appetite, and dizziness, progressing to obvious ataxia, and a reduced level of consciousness, which may progress to coma and death. The pathological findings at autopsy are severe edema of the brain due to extravasations of fluid from capillaries in the brain. This is accompanied by the loss of neuronal cells and an increase in glial cells. Recovery is often accompanied by sequelae including epilepsy, mental retardation, and, in some cases, optic neuropathy and blindness (Goyer, 1990; Bellinger, 2005; ATSDR, 2005b; Laraque and Trasande, 2005).

The most sensitive indicators of adverse neurological outcomes are psychomotor tests or mental development indices, and broad measures of IQ. Most studies report a 2- to 4-point IQ deficit for each μg/dL increase in BLL within the range of 5 to 35 μg/dL. The Centers for Disease Control and Prevention set the goal of eliminating ≥10 μg/dL BLL in children by 2010 (CDC, 2005). However, effects of lead on IQ may occur below this level (Bellinger, 2005; Murata et al., 2009). Recent studies found that deficits in cognitive and academic skills could occur with BLL <5.0 μg/dL (Lamphear et al., 2000). A study of a cohort of children from pregnancy to 10 years of age found that lead exposure around 28 weeks of gestation is a critical period for later child intellectual development, and lead’s effect on IQ occurs with first few micrograms of BLL (Schnaas et al., 2006). Some now consider no level of lead exposure to be “safe” in childhood with regard to neurodevelopment (Bellinger, 2008).

Lead can affect the brain by multiple mechanisms (Goyer, 1996; ATSDR, 2005b). It may act as a surrogate for calcium and/or disrupt calcium homeostasis. The stimulation of protein kinase C may result in alteration of blood–brain barrier and inhibition of cholinergic modulation of glutamate-related synaptic transmissions. Lead affects virtually every neurotransmitter system in the brain, including glutamatergic, dopaminergic, and cholinergic systems. All these systems play a critical role in synaptic plasticity and cellular mechanisms for cognitive function, learning, and memory.

Neurotoxic Effects in Adults

Adults with occupational exposure may demonstrate abnormalities in a number of measures in neurobehavior with cumulative exposures resulting from BLL > 40 μg/dL (Lindgren et al., 1996). Peripheral neuropathy is a classic manifestation of lead toxicity in adults. More than a half-century ago, foot drop and wrist-drop characterized the house painter and other workers with excessive occupational exposure to lead but are rare today. Peripheral neuropathy is characterized by segmental demyelination and possibly axonal degeneration. Motor nerve dysfunction, assessed clinically by electrophysiological measurement of nerve conduction velocities, occurred with BLL as low as 40 μg/dL (Goyer, 1990).

Hematologic Effects

Lead has multiple hematologic effects, ranging from increased urinary porphyrins, coproporphyrins, δ-aminolevulinic acid (ALA), and zinc protoporphyrin to anemia. The heme biosynthesis pathway and the sites of lead interference are shown in Fig. 23-4. The most sensitive effects of lead are the inhibition of δ-aminolevulinic acid dehydratase (ALAD) and ferrochelatase. ALAD catalyzes the condensation of two units of ALA to form phorphobilinogen (PBG). Inhibition of ALAD results in accumulation of ALA. Ferrochelatase catalyzes the insertion of iron into the protoporphyrin ring to form heme. Inhibition of ferrochelatase results in accumulation of protophorphyrin IX, which takes the place of heme in the hemoglobin molecule and, as the erythrocytes containing protoporphyrin IX circulate, zinc is chelated at the site usually occupied by iron. Erythrocytes containing zinc protoporphyrin are intensely fluorescent and may be used to diagnose lead exposure. Feeding lead to experimental animals also raises heme oxygenase activity, resulting in increases in bilirubin formation. Anemia only occurs in very marked cases of lead toxicity, and is microcytic and hypochromic, as in iron deficiency. The changes in ALAD in peripheral blood and excretion of ALA in urine correlate with BLL and serve as early biochemical indices of lead exposure (ATSDR, 2005b).

Genetic polymorphisms have been identified for alleles of the ALAD gene that may affect the toxicokinetics of lead. However, no firm evidence exists for an association between ALAD genotype and susceptibility to lead toxicity at background exposures, and, thus, population testing for ALAD polymorphism is not justified (Kelada et al., 2001).

Renal Toxicity

Acute lead nephrotoxicity consists of proximal tubular dysfunction and can be reversed by treatment with chelating agents. Chronic lead nephrotoxicity consists of interstitial fibrosis and progressive nephron loss, azotemia, and renal failure (Goyer, 1989). A characteristic microscopic change is the presence of intranuclear inclusion bodies. By light microscopy the inclusions are dense, homogeneous, and eosinophilic with hematoxylin and eosin staining. The bodies are composed of a lead–protein complex. The protein is acidic and contains large amounts of aspartic and glutamic acids with little cystine. The inclusion bodies are a form of aggresome accumulating large amounts of lead in a relatively inert, nontoxic state. MT-null mice cannot form inclusion bodies following lead treatment and are hypersensitive to lead-induced nephropathy and carcinogenesis, suggesting that lead inclusion body formation requires MT as a participant (Qu et al., 2002; Waalkes et al., 2004). In fact, MT is found on the outer surface of lead inclusion bodies, indicating that it may transport the metal to the forming inclusion (Waalkes et al., 2004). Lead nephrotoxicity impairs the renal synthesis of heme-containing enzymes in the kidney, such as heme-containing hydroxylase involved in vitamin D metabolism causing bone effects (ATSDR, 2005b). Hyperuricemia with gout occurs more frequently in the presence of lead nephropathy (Batuman, 1993). Lead nephropathy can be a cause of hypertension (Gonick and Behari, 2002).

Effects on Cardiovascular System

There is evidence of a causal relationship between lead exposure and hypertension (Gonick and Behari, 2002; ATSDR, 2005b; Navas-Acien et al., 2007). Analysis of data from the NHANES II for the US population, including BLL and blood pressure measurements in a general population (5803 people aged 12–74), found a correlation between BLL at relatively low levels and blood pressure (Harlan, 1988). An epidemiology reappraisal using meta-analysis of 58,518 subjects from both the general population and occupationally exposed groups from 1980 to 2001 suggested a weak, but significant association between BLL and blood pressure (Nawrot et al., 2002). Elevated blood pressure is more pronounced in middle age than at young age (ATSDR, 2005b). A systematic review of human data indicates a causal relationship between lead and hypertension (Navas-Acien et al., 2007).

A review of chronic lead exposure on blood pressure in experimental animals indicated that at lower doses, lead consistently produced hypertension effects, whereas at higher doses results are inconsistent (Victery, 1988). The pathogenesis of lead-induced hypertension is multifactorial including: (1) inactivation of endogenous nitric oxide and cGMP, possibly through lead-induced ROS; (2) changes in the rennin–angiotensin–aldosterone system, and increases in sympathetic activity, important humoral components of hypertension; (3) alterations in calcium-activated functions of vascular smooth muscle cells including contractility by decreasing Na⁺/K⁺-ATPase activity and stimulation of the Na⁺/Ca²⁺ exchange pump; and (4) a possible rise in endothelin and thromboxane (Gonick and Behari, 2002; Vaziri and Sica, 2004).

Immunotoxicity

The developing immune system is sensitive to toxic effects of lead (Dietert et al., 2004). A hallmark of lead-induced immunotoxicity is a pronounced shift in the balance in T helper cell function toward Th2 responses at the expense of Th1 functions, resulting in elevated IgE levels. Increased IgE levels and inflammatory cytokines were found in lead-exposed neonatal rodents, and there is an association between BLL and elevated IgE levels in children (Karmaus et al., 2005; Luebke et al., 2006). Thus, lead immunotoxicity might be a risk factor for childhood asthma (Dietert et al., 2004). In experimental animals, lead has been shown to target macrophages and T cells, especially CD4⁺ T cells. In occupational exposure, lead-associated changes include altered T-cell subpopulations, reduced immunoglobulin levels, and reduced polymorphonuclear leukocyte chemotactic activity (Dietert et al., 2004; Luebke et al., 2006).

Bone Effects

Lead has an extremely long half-life in bone, accounting for over 90% of the body lead in adults. It can affect bone by interfering with metabolic and homeostatic mechanisms including parathyroid hormone, calcitonin, vitamin D, and other hormones that influence calcium metabolism. Lead substitutes for calcium in bone (Pounds et al., 1991). It is known to affect osteoblasts, osteoclasts, and chondrocytes and has been associated with osteoporosis and delays in fracture repair (Carmouche et al., 2005). In children exposed to lead, a higher bone mineral density (BMD) was observed. This may be due to accelerated bone maturation through inhibition of parathyroid hormone–related peptide, may ultimately result in lower peak BMD in young adulthood, and might predispose subjects to osteoporosis later in life (Campbell et al., 2004). A positive association between lead exposure and dental caries in children has been shown in a number of studies. Lead is deposited in teeth, inhibits mineralization of enamel and dentine, and affects metabolism of the cells in the dental pulp (ATSDR, 2005b). Lead in bone is recognized as a potential source for exposure to other tissues when bone is mobilized, as during pregnancy (Silbergeld, 1991).

Other Effects

Lead colic is a major gastrointestinal symptom of severe lead poisoning, and is characterized by abdominal pain, nausea, vomiting, constipation, and cramps (ATSDR, 2005b). It is rarely seen today.

Lead-induced gametotoxic effects have been demonstrated in both male and female animals (Goyer, 1990). There is also evidence that lead may disrupt the hypothalamic–pituitary–gonadal axis. An increase in the maternal BLL may also contribute to premature birth and reduced birth weight (ATSDR, 2005b).

Carcinogenicity

The association of lead exposure with increased human cancer risk was strengthened by recent studies (ATSDR, 2005c), and inorganic lead compounds were recently reclassified as probably carcinogenic to humans while organic lead compounds were considered not classifiable as to human carcinogenicity (IARC, 2006). A study of a cohort of 20,700 workers coexposed to lead and engine exhaust found a 1.4-fold increase in the overall cancer incidence and a 1.8-fold increase in lung cancer among those who ever had elevated BLL (Anttila et al., 1995). Another epidemiological study of 27,060 brain cancer cases and 108,240 controls who died of nonmalignant disease in the United States from 1984 to 1992 provides evidence for a potential link between occupational exposure to lead and brain cancer (Cocco et al., 1998). A meta-analysis of published data on cancer incidence among workers in various industries with lead exposure indicates a significant excess of cancer deaths from stomach cancer, lung cancer, and bladder cancer (Fu and Boffetta, 1995). Analysis of eight principal studies with well-documented lead exposures suggests associations of lead exposure with increased lung and stomach cancers (Steenland and Boffetta, 2000). However, workers were not exposed to lead alone, and exposures to other potential carcinogens such as arsenic, cadmium, and engine exhausts could confound these interpretations. Lead does not appear to be directly genotoxic in vivo or in vitro, and lead may interact with other toxicants to facilitate chemical carcinogenesis (Silbergeld, 2003).

Lead is a nephrocarcinogen in adult rodents (Waalkes et al., 1995, 2004; IARC, 2006). Lead-induced renal tumors also occur after perinatal exposure in the absence of the extensive chronic nephropathy (Waalkes et al., 1995). MT-null mice, which do not form lead inclusion bodies, are hypersensitive to lead-induced proliferative lesions of the kidney (Waalkes et al., 2004) and develop testicular teratomas (Tokar et al., 2010b) compared with similarly exposed wild-type mice.

Several mechanisms have been proposed for lead-induced carcinogenesis, including regenerative repair, inhibition of DNA synthesis or repair, generation of ROS with oxidative damage to DNA, substitution of lead for zinc in transcriptional regulators, interaction with DNA-binding proteins, and aberrant gene expression (Silbergeld et al., 2000; Qu et al., 2002; Silbergeld, 2003).

Treatment

Chelation therapy is warranted in workmen with BLL >60 μg/dL. For children, criteria have been established (Laraque and Trasande, 2005) that may serve as guidelines to assist in evaluating the individual case with potential health effects. The oral chelating agent DMSA (also called succimer) has advantages over EDTA in that it can be given orally and is effective in temporarily reducing BLL. However, DMSA neither improves long-term BLL in children nor reduces brain lead levels beyond the cessation of lead exposure alone (Cremin et al., 1999; O’Connor and Rich, 1999). A recent study shows that DMSA lowered BLL in children, but had no detectable benefit on learning and behavior (Dietert et al., 2004). Chelation therapy is nonetheless still recommended for children (Warniment et al., 2010). Treatment of organic lead poisoning is symptomatic.

Mercury

Mercury (Hg) was named after the Greco-Roman god known for swift flight. Also called quicksilver, metallic mercury is in liquid state at room temperature. The symbol Hg was derived from the Latinized Greek hydrargyrum, meaning “water” and “silver.” Mercury was known in ancient times from approximately 1500 bc. By 500 bc mercury was used to make amalgams with other metals. Mercury vapor (Hg⁰) is much more hazardous than the liquid form. Mercury binds to other elements (such as chlorine, sulfur, or oxygen) to form inorganic mercurous (Hg¹⁺) or mercuric (Hg²⁺) salts. This metal can form a number of stable organometallic compounds by attaching to one or two carbon atoms. Methylmercury (CH₃Hg⁺, or MeHg) is the toxicologically most important organic form (ATSDR, 1999a,b). Mercurial compounds have characteristic toxicokinetics and health effects that depend on oxidation state and associated organic species.

Global Cycling and Ecotoxicology

Mercury exemplifies movement of metals in the environment (Fig. 23-5). Atmospheric mercury, in the form of mercury vapor (Hg⁰), is derived from natural degassing of the earth’s crust and through volcanic eruptions as well as from evaporation from oceans and soils. Anthropogenic sources are estimated to contribute two-thirds of the total atmospheric mercury (Lindberg et al., 2007). These contributions include emissions from metal mining and smelting (mercury, gold, copper, and zinc), coal combustion, municipal incinerators, and chloralkali industries. Mercury vapor is a chemically stable monatomic gas and its residence time in atmosphere is about one year. Thus, mercury is globally distributed even from point resources. Eventually it is oxidized to a water-soluble inorganic form (Hg²⁺), and returned to the earth’s surface in rainwater. The metal may then be reduced back to mercury vapor and returned to the atmosphere, or it may be methylated by microorganisms present in sediments of bodies of fresh and ocean water. This natural biomethylation reaction produces methylmercury (MeHg). Methylmercury enters the aquatic food chain starting with plankton, then herbivorous fish, and finally ascending to carnivorous fish and sea mammals. On the top of the food chain, tissue mercury can rise to levels 1800 to 80,000 times higher than levels in the surrounding water. This biomethylation and bioconcentration result in human exposure to methylmercury through consumption of fish (Clarkson, 2002; Risher et al., 2002). Organomercurial compounds are generally more toxic than inorganic mercury to aquatic organisms, aquatic invertebrates, fish, plants, and birds. Organisms in the larval stages are generally more sensitive to toxic effects of mercury (Boening, 2000).

Exposure

Dietary Exposure

Consumption of fish is the major route of exposure to methylmercury. Unlike the case of polychlorinated biphenyls, which are also deposited in fat, cooking the fish does not lower the methylmercury content. Inorganic mercury compounds are also found in food. The source of inorganic mercurial is unknown but the amounts ingested are far below known toxic levels. Mercury in the atmosphere and in drinking water is generally so low that they do not constitute an important source of exposure to the general population (ATSDR, 1999a,b; Clarkson, 2002).

Occupational Exposure

Inhalation of mercury vapor can occur from the working environment, as in the chloralkali industry, where mercury is used as a cathode in the electrolysis of brine. Occupational exposure may also occur during manufacture of a variety of scientific instruments and electrical control devices, and in dentistry where mercury amalgams are used in tooth restoration. In the processing of and extraction of gold, especially in developing countries, large quantities of metallic mercury are used to form an amalgam with gold. The amalgam is then heated to drive off the mercury, resulting in a substantial atmospheric release (ATSDR, 1999a,b; Eisler, 2003).

Medicinal Exposure

Mercury was an important constituent of drugs for centuries and was used as an ingredient in diuretics, antiseptics, skin ointments, and laxatives. These uses have largely been replaced by safer drugs. Thimerosal contains the ethylmercury radical attached to the sulfur group of thiosalicylate (49.6% mercury by weight as ethylmercury), and has been used as a preservative in many vaccines since 1930s, although its use in children’s vaccines was discontinued in 2001 over concerns that children may be exposed to excessive levels of mercury. The use of mercury amalgam in dental restoration releases mercury vapor in the oral cavity and can result in increased mercury body burden. Although the potential health effects of amalgams have been fiercely debated (Clarkson and Magos, 2006; Mutter et al., 2007), the amounts are low compared with occupational exposure (Clarkson et al., 2003).

Accidental Exposure

Fatal mercury poisonings come mainly from accidental exposure. Elemental mercury spills can occur in many ways, such as from broken elemental mercury containers, medicinal devices, barometers, and melting tooth amalgam fillings to recover silver. Inhalation of large amount of mercury vapor can be deadly (Baughman, 2006). Oral ingestion of large amounts of inorganic mercury chloride has also been lethal in suicide cases (ATSDR, 1999a,b). A well-known organomercurial poisoning episode was from consumption of fish contaminated with methylmercury from industrial waste in Minamata, Japan. Consumption of grains and rice treated with methylmercury or ethylmercury as fungicides to prevent plant root diseases in Iraq and China also led to a significant number of poisonings (Clarkson, 2002; Risher et al., 2002). Contact with even a small amount of dimethylmercury (CH₃CH₃Hg) can penetrate laboratory gloves resulting in rapid transdermal absorption, delayed cerebella damage, and death (Nierenberg et al., 1998).

Toxicokinetics

Mercury Vapor

Mercury vapor is readily absorbed (about 80%) in the lungs, rapidly diffuses across alveolar membranes into the blood, and distributes to all tissues in the body due to its high lipid solubility. Once the vapor has entered cells, it is oxidized to divalent inorganic mercury by tissue and erythrocyte catalase. A significant portion of mercury vapor crosses the blood–brain barrier and placenta before it is oxidized by erythrocytes, and thus shows more neurotoxicity and developmental toxicity compared with administration of inorganic mercury salts that cross membranes less rapidly. After mercury vapor undergoes oxidation, its deposition resembles inorganic mercury. Approximately 10% of mercury vapor is exhaled within a week of exposure, and that converted to inorganic mercury is excreted mainly in urine and feces, with a half-life of one to two months (Clarkson et al., 2003; ATSDR, 1999a,b). Liquid metallic mercury, such as that swallowed from a broken thermometer, is only poorly absorbed by the gastrointestinal tract (0.01%), is not biologically reactive, and is generally thought to be of little or no toxicological consequence.

Inorganic Mercury

Inorganic mercury is poorly absorbed from the gastrointestinal tract. Absorption ranges 7% to 15% of ingested dose, depending on the inorganic compound. A small portion of absorbed inorganic mercury is formed by reduction in tissues and exhaled as mercury vapor. The highest concentration of inorganic mercury is found in kidney, a major target. Renal uptake of mercury salts occurs through two routes: from luminal membranes in renal proximal tubule in the form of the cysteine S-conjugates (Cys-S-Hg-S-Cys) or from the basolateral membrane through organic anion transporters (Bridges and Zalpus, 2005). Inorganic mercury salts do not readily pass blood–brain barrier or placenta and are mainly excreted in urine and feces, with a half-life of about two months.

Methylmercury

Methylmercury is well absorbed from the gastrointestinal tract. About 95% of methylmercury ingested from fish is absorbed. It is distributed to all tissues in about 30 hours. About 10% of absorbed methylmercury is distributed to the brain and 5% remains in blood. The concentration in erythrocytes is 20 times that in plasma. Methylmercury is bound to thiol-containing molecules such as cysteine (CH₃Hg-S-Cys), which mimic methionine to cross the blood–brain barrier and placenta through the neutral amino acid carrier. Methylmercury readily accumulates in hair, and although concentrations are proportional to that in blood, they are about 250-fold higher. Thus, hair mercury is often used as an indicator of exposure. Methylmercury undergoes extensive enterohepatic recycling, which can be interrupted to enhance fecal excretion. Methylmercury is slowly metabolized to inorganic mercury by microflora in intestine (about 1% of the body burden per day). In contrast to inorganic mercury, 90% of the methylmercury is eliminated from the body in the feces, and less than 10% is in the urine, with a half-life of 45 to 70 days (Clarkson, 2002; Risher et al., 2002; Bridges and Zalpus, 2005).

The disposition of ethylmercury is similar to methylmercury. The major differences include that the conversion to inorganic mercury in body is much faster for ethylmercury, which can result in renal injury. The mercury levels in brain are lower for ethylmercury than those for methylmercury. The half-life for ethylmercury is only 15% to 20% of that for methylmercury (Clarkson et al., 2003).

Toxicity

Mercury Vapor

Inhalation of mercury vapor at extremely high concentrations may produce an acute, corrosive bronchitis and interstitial pneumonitis and, if not fatal, may be associated with central nervous system effects such as tremor or increased excitability. With chronic exposure to mercury vapor, the major effects are on the central nervous system. Early signs are nonspecific, and this condition has been termed the asthenic-vegetative syndrome or micromercurialism. Identification of the syndrome requires neurasthenic symptoms and three or more of the following clinical findings: tremor, enlargement of the thyroid, increased uptake of radioiodine in the thyroid, labile pulse, tachycardia, dermographism, gingivitis, hematologic changes, or increased excretion of mercury in urine. The triad of tremors, gingivitis, and erethism (memory loss, increased excitability, insomnia, depression, and shyness) has been recognized historically as the major manifestation of mercury poisoning from inhalation of mercury vapor. Sporadic instances of proteinuria and even nephrotic syndrome may occur in persons with exposure to mercury vapor, particularly with chronic occupational exposure. The pathogenesis is probably immunologically similar to that occurring after exposure to inorganic mercury (Clarkson, 2002; ATSDR, 1999a,b). Mercury vapor release from amalgam is in general too low to cause significant toxicity (Clarkson et al., 2003; Factor-Litvak et al., 2003; Horsted-Bindslev, 2004).

Inorganic Mercury

Kidney is the major target organ for inorganic mercury (ATSDR, 1999a,b). Although a high dose of mercuric chloride is directly toxic to renal tubular cells, chronic low-dose exposure to mercury salts may induce an immunologic glomerular disease (Bigazzi, 1999). Exposed persons may develop proteinuria that is reversible after they are removed from exposure. Experimental studies have shown that the pathogenesis has two phases including an early phase characterized by an anti–basement membrane glomerulonephritis, followed by a superimposed immune complex glomerulonephritis with transiently raised concentrations of circulating immune complexes (Henry et al., 1988). The pathogenesis of the nephropathy in humans appears similar, although antigens have not been characterized. In humans, the early glomerular nephritis may progress to interstitial immune complex nephritis (Pelletier and Druet, 1995; Bigazzi, 1999).

Methylmercury

The major human health effect from exposure to methylmercury is neurotoxicity. Clinical manifestations of neurotoxicity include paresthesia (a numbness and tingling sensation around the mouth, lips) and ataxia, manifested as a clumsy, stumbling gait, and difficulty in swallowing and articulating words. Other signs include neurasthenia (a generalized sensation of weakness), vision and hearing loss, and spasticity and tremor. These may finally progress to coma and death. Neuropathological observations have shown that the cortex of the cerebrum and cerebellum are selectively involved with focal necrosis of neurons, lysis and phagocytosis, and replacement by glial cells. These changes are most prominent in the deeper fissures (sulci), as in the visual cortex and insula. The overall acute effect is cerebral edema, but with prolonged destruction of gray matter and subsequent gliosis, cerebral atrophy results (Takeuchi, 1977). A study of the Iraq epidemic of methylmercury exposure (Bakir et al., 1973) has provided dose–response estimates of the body burden of mercury required for the onset and frequency of symptoms (Fig. 23-6).

Mechanism of Toxicity

High-affinity binding of divalent mercury to sulfhydryl groups of proteins in the cells is an important mechanism for producing nonspecific cell injury or even cell death. A number of general mechanisms of toxicity have been observed after mercury exposures. Although mercury does not participate in Fenton-like reactions, oxidative stress plays a significant role in mercury toxicity. Reduced glutathione levels and antioxidant enzymes have been reported in mice exposed to methylmercury (Stringari et al., 2008; Franco et al., 2009). Genes associated with oxidative stress have been found to be upregulated by inorganic mercury exposure using microarray studies in yeast and human cells (Kawata et al., 2007; Jin et al., 2008). In vitro exposures to inorganic or methylmercury also affected the MAPK signaling pathway (Kim et al., 2002; Hao et al., 2009). Methylmercury has also been shown to disrupt microtubules in neurites and in neonatal mice (Ferraro et al., 2009; Fukushima et al., 2009). Both inorganic and methylmercury damage mitochondria and disrupt intracellular calcium homeostasis (Freitas et al., 1996; Konigsberg et al., 2001; Cambier et al., 2009).

Sensitive Subpopulations

Early life stages are particularly vulnerable to mercury intoxication (Counter and Buchanan, 2004). In Minamata, Japan, pregnant women who consumed fish contaminated with methylmercury manifested mild or minimal symptoms, but gave birth to infants with severe developmental disabilities, raising initial concerns for mercury as a developmental toxicant. Methylmercury crosses the placenta and reaches the fetus, and is concentrated to a level in fetal brain at least five to seven times that of maternal blood (Clarkson, 2002). Prenatal methylmercury exposure at high levels can induce widespread damage to the fetal brain. However, the observed effects from low-level exposures are inconsistent (Counter and Buchanan, 2004; Davidson et al., 2004). In the Seychelles Children Development Study, a group with significant methylmercury exposure from a diet predominantly of fish was studied for adverse developmental effects. These children were examined six times over 11 years using extensive batteries of age-appropriate developmental end points, but no convincing associations were found except for delayed walking (Davidson et al., 2006). The National Research Council reviewed the epidemiological studies relating in utero methylmercury exposure and fetal neurological development. It concluded that the current EPA reference dose (RfD) for methylmercury of 0.1 μg/kg per day or 5.8 μg/L cord blood is scientifically justifiable for protection of human health (NRC, 2000). The RfD is equivalent to 12 ppm methylmercury in maternal hair.

The safety of thimerosal (ethylmercury) used in childhood vaccines has also received extensive attention. A recent review indicates that thimerosal is safe at the doses used in vaccines, except for a potential for local hypersensitivity (Clarkson et al., 2003). However, some infants may be exposed to cumulative levels of mercury during the first six months of life that may exceed EPA recommendations (Ball et al., 2001). Steps have been rapidly taken to remove thimerosal from vaccines in the United States by switching to single-dose vials that do not require preservatives. Nonetheless, the World Health Organization concluded that it is safe to continue using thimerosal in vaccines, which is important for developing countries where it is essential to use multidose vials (Clarkson et al., 2003).

Although the use of mercury amalgam in children can contribute to mercury exposure, the level of exposure is too low to cause significant toxicological effects (DeRouen et al., 2006).

Acrodynia has occurred in children chronically exposed to inorganic mercury compounds in teething powder and diaper disinfectants, as well as to organomercurials. It is characterized by pink hands and feet (also called pink disease). These subjects are photophobic and suffer from joint pains (Clarkson, 2002).

Treatment

Therapy for mercury poisoning should be directed toward lowering the concentration of mercury at the critical organ or site of injury. For the most severe cases, particularly with acute renal failure, hemodialysis may be the first measure, along with administration of chelating agents for mercury, such as cysteine, EDTA, BAL, or penicillamine. Caution should be taken to avoid inappropriate use of chelating agents in putative mercury poisoning patients (Risher and Amler, 2005).

Chelation therapy is not very helpful for alkyl mercury exposure. Biliary excretion and reabsorption by the intestine can be interrupted by oral administration of a nonabsorbable thiol resin, which can bind mercury and enhance fecal excretion (Clarkson, 2002).

Nickel

Nickel (Ni) has been in use since ancient times. However, because the ores of nickel were easily mistaken for ores of silver, a more complete understanding of nickel and its specific use came with more contemporary times. In 1751, nickel was first isolated from the ore kupfernickel (niccolite) from which it derives its name. Nickel is used in various metal alloys, including stainless steels, in electroplating, batteries, pigments, catalysts, and ceramics. Major properties of nickel alloys include strength, corrosion resistance, and good thermal and electrical conductivity. Occupational exposure to nickel occurs by inhalation of nickel-containing aerosols, dusts, or fumes, or dermal contact in workers engaged in nickel production (mining, milling, refinery, etc) and nickel-using operations (melting, electroplating, welding, nickel–cadmium batteries, etc) (ATSDR, 2005c; NTP, 2011e). Nickel, like many other metals, is ubiquitous in nature, and the general population is exposed to low levels of nickel in air, cigarette smoke, water, and food. These exposures are generally too low to be of real toxicological concern (Kasprzak et al., 2003). Nickel has various oxidation states but the 2+ oxidation state is the most prevalent form in biosystems. The major soluble nickel compounds are nickel acetate, nickel chloride, nickel sulfate, and nickel nitrate. The important water-insoluble nickel compounds include nickel sulfide, nickel subsulfide, nickel oxide, nickel carbonyl, and nickel carbonate (ATSDR, 2005c).

Toxicokinetics

Inhalation of nickel is the most important route toxicologically. Inhaled nickel particles are deposited in the respiratory tract and, as with all inhaled particles, the site of deposition depends on the particle size. Large particles (5–30 μm) deposit in the nasopharyngeal area via impaction, smaller particles (1–5 μm) enter the trachea and bronchiolar region by sedimentation, and particles smaller than 1 μm enter the alveolar space. About 25% to 35% of the inhaled nickel that is retained in the lungs is absorbed into the blood. The insoluble nickel particles can be taken up into cells by phagocytosis. When applied or in contact with skin, the rate of absorption depends on the rate of penetration into the epidermis, which differs for different chemical forms of nickel. In humans, about 27% of a single oral dose of nickel in drinking water is absorbed, depending on the compound, whereas only about 1% is absorbed when nickel is given with food. Intestinal nickel absorption occurs through calcium or iron channels, or by the divalent metal transport protein-1 (ATSDR, 2005c).

The main transport proteins of nickel in blood are albumin, histidine, and α₂-microglobulin. Nickelplasmin and MT also can bind and transport nickel. Following inhalation exposure, nickel is distributed to the lungs, skin, kidneys, liver, pituitary, and adrenals. The half-life of nickel is one to three days for nickel sulfate, five days for nickel subsulfide, and more than 100 days for nickel oxide (ATSDR, 2005c). Absorbed nickel is excreted into urine. Urinary nickel correlates closely with exposure to airborne levels of insoluble nickel compounds. Thus, urinary nickel may serve as a suitable measure of current nickel exposure.

The marked differences in carcinogenic activities of various nickel compounds may be due to differences in delivery of nickel ion to specific cells and subcellular target molecules. For example, injection of animals with crystalline nickel subsulfide or crystalline nickel sulfide results in a high incidence of tumors at the site of injection sites, although tumors are generally not observed in animals similarly injected with soluble nickel sulfate (IARC, 1990). The crystalline nickel particles can be actively phagocytized and apparently deliver larger quantities of nickel ions into the nucleus of local cells compared with water-soluble nickel compounds that diffuse away from the site (Kasprzak et al., 2003; Costa et al., 2005). Several water-soluble nickel compounds can, however, produce local malignant tumors when repeatedly injected into the peritoneal cavity of rats, suggesting repeated exposures to the target cells may be required (IARC, 1990).

Essentiality of nickel in higher organisms is questionable, although nickel may be nutritionally essential for some plants, bacteria, and invertebrates. Nickel deficiency syndromes have not been reported in humans and nickel-dependent enzymes or cofactors are unknown (Denkhaus and Salnikow, 2002).

Toxicity

Contact Dermatitis

Nickel-induced contact dermatitis is the most common adverse health effect from nickel exposure and is found in 10% to 20% of the general population. It can result from exposure to airborne nickel, liquid nickel solutions, or prolonged skin contact with metal items containing nickel, such as coins and jewelry. Nickel sensitization usually arises from prolonged contact with nickel or exposure to a large dose of nickel. The resulting dermatitis is an inflammatory reaction mediated by type IV delayed hypersensitivity (ATSDR, 2005c).

Nickel Carbonyl Poisoning

Metallic nickel combines with carbon monoxide to form nickel carbonyl (Ni[CO]₄), which decomposes to nickel and carbon monoxide on heating to 200°C (the Mond process). This reaction provides a convenient and efficient method for nickel refining. However, nickel carbonyl is extremely toxic, and can cause acute toxicity. Intoxication begins with headache, nausea, vomiting, and epigastric or chest pain, followed by cough, hyperpnea, cyanosis, gastrointestinal symptoms, and weakness. The symptoms may be accompanied by fever and leukocytosis. The more severe cases can progress to pneumonia, respiratory failure, and eventually to cerebral edema and death.

Carcinogenicity

Nickel is a respiratory tract carcinogen in nickel-refining industry workers (IARC, 1990; Straif et al., 2009; NTP, 2011e). Risks are highest for lung and nasal cancers among workers heavily exposed to nickel. Because the refining of nickel in some plants that were studied involved the formation of nickel carbonyl, it was believed for a time that nickel carbonyl was the principal carcinogen. However, multiple additional epidemiological studies of workers in other refineries suggest that the source of the increased risk is the mixture of nickel compounds (IARC, 1990; Straif et al., 2009; NTP, 2011e). Studies often involve a complex mixture of the metal and several of its compounds making separate carcinogenic assessment challenging (Straif et al., 2009; NTP, 2011e). Nickel sulfate and combinations of nickel sulfides and oxides encountered in nickel refining are considered to cause human cancer (IARC, 1990; NTP, 2011e). Human studies have also shown a strong association between primary exposure to water-soluble nickel compounds in the nickel-refinery industry and elevated cancer risk (Grimsrud and Andersen, 2010; NTP, 2011e). Nonetheless, controversy remains about the role of soluble nickel compounds in human cancer causation based on a biokinetic hypothesis that they are unable to deliver sufficient nickel to critical local targets because they are soluble (Goodman et al., 2011). Metallic nickel is considered reasonably anticipated to be a human carcinogen based on multiple positive rodent studies (NTP, 2011e).

Studies with rats and some with mice have shown that inhaled or intratracheal instilled nickel subsulfide or nickel oxide produces lung tumors, including carcinoma, in a dose-related fashion and causes adrenal gland tumors (IARC, 1990; NTP, 2011e). Injection of various nickel compounds (generally water insoluble) at various sites (subcutaneous, intramuscular, intrarenal, etc) causes local tumors (primarily sarcomas) in laboratory animals often in a dose-related fashion (IARC, 1990; NTP, 2011e). The relevance of routes to human exposure situations is debatable, but such data are used to assess carcinogenic potential. Nickel monoxides, hydroxides, and crystalline sulfides are also considered to be carcinogenic in animals based on studies finding injection site tumors and/or lung tumors after intratracheal instillations (IARC, 1990; NTP, 2011e). Metallic nickel produces injection site tumors and lung tumors after intratracheal instillation (IARC, 1990; NTP, 2011e). Rodent carcinogenesis studies of soluble nickel compounds have also yielded positive results in rodents (Kasprzak et al., 2003). For instance, water-soluble nickel acetate is a complete transplacental carcinogen for the rat pituitary and initiator of kidney tumors in the rat (Diwan et al., 1992). The water-soluble nickel compounds, nickel chloride, nickel sulfate, and nickel acetate, produced local mesotheliomas or sarcomas when given by repeated intraperitoneal injection to rats (IARC, 1990), suggesting repeated exposure to soluble salts is required (IARC, 1990). In two strain A mouse studies, multiple intraperitoneal injections of nickel acetate increased lung adenocarcinoma incidence (one study) and lung tumor multiplicity (both studies; IARC, 1990). However, many rodent studies using soluble nickel compounds have been negative (Sivulka, 2005).

Mechanism for Nickel Carcinogenesis

The carcinogenicity of nickel is thought to be due to the generation of ionic nickel in target cells at sites that are key for carcinogenesis (NTP, 2011e). This has allowed consideration of these compounds as a single group (Straif et al., 2009; NTP, 2011e). Ionic nickel is thought to be the active and genotoxic form of the metal, and there is no reason to suspect that the mechanisms by which nickel causes cancer in experimental animals would differ from humans (NTP, 2011e).

Carcinogenic nickel particles that are phagocytized and deliver large quantities of nickel ions into the nucleus are generally not mutagenic but are clastogenic (Costa et al., 2005). In this way insoluble nickel compounds can produce specific chromosomal damage, notable in the heterochromatic long arm of the X chromosome that suffers regional decondensation, frequent deletions, and other aberrations (Costa et al., 2005). Nickel compounds also produce chromosomal abnormalities such as sister chromatid exchange, especially in hetrochromatin, micronuclei formation in human lymphocytes, microsatellite mutations in human lung cancer cells, and mutations in renal cells (Kasprzak et al., 2003). Many studies in vitro and in vivo indicate a variety of soluble and insoluble forms of nickel cause genetic damage, including DNA damage, cell transformation, and DNA repair disruption (NTP, 2011e). The redox activity of nickel may produce ROS that could attack DNA directly (NTP, 2011e).

Epigenetic Effects

A broad spectrum of epigenetic effects occurs with nickel and includes alterations in gene expression resulting from perturbed DNA methylation and posttranslational histone modification (Arita and Costa, 2009). A notable nickel-inducible gene is Cap43/NDRG1, under the control of the HIF-1. During tumor development, HIF-1 facilitates angiogenesis and regulates numerous genes including glucose transport and glycolysis, which are essential for tumor growth. A correlation of overexpression of Cap43 with the neoplastic state of the cells was noted (Costa et al., 2005). Another nickel-induced gene amplification is the Ect2 gene. The Ect2 protein is overexpressed in nickel-transformed cells, which can cause microtubule disassembly and cytokinesis, and may contribute to morphological changes in cells (Clemens et al., 2005). Nickel produces low, but measurable ROS in cells and depletes cellular glutathione. Oxidative DNA damage, oxidative protein damage, and lipid peroxidation, as well as inhibition of DNA repair enzymes, can be observed following nickel exposure (Kasprzak et al., 2003; Valko et al., 2005).

Treatment of Nickel Toxicity

Sodium diethylcarbodithioate (DDTC) is the preferred drug for nickel treatment. Disulfiram, another nickel-chelating agent, has been used in nickel dermatitis and in nickel carbonyl poisoning. Other chelating agents, such as d-penicillamine and DMPS, provide some degree of protection from clinical effects (Blanusa et al., 2005).

Cobalt

Cobalt (Co) is a relatively rare, ferromagnetic transition metal first isolated in the 1730s. The name cobalt comes from the German word kobalt, which is derived from kobold meaning “goblin,” a name applied by miners of the time to cobalt ore, which was thought to be worthless and poisonous. Cobalt is usually not mined alone and tends to be produced primarily as a by-product of copper and nickel mining. It is useful in various alloys, where it provides corrosion and wear resistance, and in cemented carbides (“hard” metals). It is used in permanent magnets, as a paint or varnish dryer, in catalysts, and in production of pigments (ATSDR, 2004a).

Toxicokinetics

The toxicokinetics and possible adverse health effects of inorganic cobalt compounds have been reviewed (De Boeck et al., 2003; ATSDR, 2004a; Lison, 2007). Cobalt absorption depends on the compound. Less than 5% of an oral dose of cobalt oxide is absorbed, whereas about 30% of an oral dose of cobalt chloride is absorbed in rodents. Oral absorption of cobalt varies widely in humans, and it is estimated to be between 5% and 45%. Increasing doses of cobalt results in a decreasing proportional absorption, so increased cobalt levels tend not to cause significant accumulation. Absorption of inhaled cobalt compounds appears to be relatively effective in humans and animals. About 80% of absorbed cobalt is excreted in urine, and about 15% is excreted in feces. The liver, kidneys, adrenals, and thyroid have relatively high concentrations. The normal levels in human urine and blood are <2.0 and 0.2 to 0.5 μg/L, respectively. Cobalt in blood is largely associated with red blood cells.

Essentiality

Cobalt is an essential nutrient, in small amounts, to mammals, including humans. The essential form of cobalt is cobalamin, a cobalt-containing tetrapyrrolic ring and critical component of vitamin B₁₂. Vitamin B₁₂ is required for the production of red blood cells and in the prevention of pernicious anemia. Insufficient natural levels of cobalt in the diet of sheep and cattle result in cobalt deficiency disease, characterized by anemia and loss of weight or retarded growth. If other requirements for cobalt exist, they are not well defined (Herbert, 1996).

Toxicity

Occupational inhalation of cobalt-containing dust in industrial settings may cause respiratory irritation at air concentrations between 0.002 and 0.01 mg/m³. Higher concentrations may be a cause of “hard metal” pneumoconiosis, a progressive form of pulmonary interstitial fibrosis. This disease is observed in workers exposed to cobalt–tungsten carbide but not observed with exposure to cobalt alone (ATSDR, 2004a; NTP, 2011f). Occupational dermal exposure is sometimes associated with an allergic dermatitis.

Cobalt can be erythropoietic when excessive amounts are ingested by most mammals, including humans. Chronic oral administration of high levels of cobalt for the treatment of anemia can cause goiter, and epidemiological studies suggest that the incidence of goiter is higher in regions containing increased levels of cobalt in water and soil. The goitrogenic effect has been elicited by the oral administration of 3 to 4 mg/kg to children in the course of treatment of sickle cell anemia. Intravenous exposure to cobalt can cause increased blood pressure, slowed respiration, tinnitus, and deafness due to nerve damage. Cardiomyopathy with signs of congestive heart failure has been associated with excessive cobalt intake (>10 mg per day), particularly from drinking beer to which cobalt was added as a foaming agent. Autopsy findings in such cases have found a 10-fold increase in the cardiac levels of cobalt. In animals, myocardial degeneration can be produced by cobalt injection. In rats cobalt injection will produce hyperglycemia due to pancreatic β-cell damage (Lison, 2007).

Based on experimental studies in animals, cobalt sulfate has been classified as reasonably anticipated to be carcinogenic in humans (NTP, 2011f). In rodents, inhalation of cobalt sulfate induces lung tumors, including carcinoma, in rats and mice (Bucher et al., 1999). Repository injections or implantation of various cobalt compounds can produce local sarcomas in rodents (IARC, 1991). Incidence of adrenal gland tumors was also increased in female rats expose to cobalt sulfate (NTP, 2011f). The mechanisms by which cobalt produces cancer are not fully defined but potentially include inhibition of DNA repair and formation of DNA-damaging ROS, and through alterations of important cellular functions by replacing other essential metal ions (ATSDR, 2004a; NTP, 2011f).

Cobalt–tungsten carbide powders and hard metals are reasonably anticipated to be human carcinogens based on limited evidence of carcinogenicity from human studies and supporting evidence from studies on mechanisms of carcinogenesis (NTP, 2011f). No studies examining the carcinogenicity of cobalt–tungsten carbide powders or hard metals in animals have been identified. Potential carcinogenic mechanisms include the release of cobalt ions, increased production of ROS with resultant oxidative stress response, and by causing cytotoxicity, genotoxicity, inflammation, and apoptosis (NTP, 2011f).

Copper

Copper (Cu) has been used for many centuries. By 2000 bc, “bronze” or copper–tin alloys were in wide use in Europe. In Roman times, copper became known as cerium because so much of it was mined in Cyprus, and eventually Anglicized into copper. Copper is an essential element widely distributed in nature. Food, beverages, and drinking water are major sources of exposure in the general population. The Recommended Dietary Allowance (RDA) of copper varies according to age, and pregnancy and lactation. Daily intake of copper in adults is 0.9 mg per day, in children between 0.2 and 0.9 mg per day, and in pregnant or lactating women 1.0 to 1.3 mg per day (IOM and Food and Nutrition Board, 2001). The average daily intake of copper from food is ~1.2 to 1.7 mg per day (Chambers et al., 2010).

Copper exposure in industry is primarily from inhaled particulates in mining or metal fumes in smelting operations, welding, or related activities. In the general population, exposure to elevated levels of copper can occur via metal leaching from copper plumbing or copper lined cookware (ATSDR, 2004b). Excess copper in the water represents a significant risk factor to the aquatic environment, producing endocrine disruption and other toxic effects in fish (Handy, 2003).

Toxicokinetics

Approximately 55% to 75% of an oral dose of copper is absorbed from the gastrointestinal tract, primarily in the duodenum. Intestinal copper absorption can be reduced by zinc, iron, molybdate, and fructose (IOM and Food and Nutrition Board, 2001). Following intestinal absorption, copper is transported into the serum where it binds to a series of copper-binding proteins and small peptides, such as albumin, and amino acids. Although all tissues and cells contain copper, the primary sites for copper storage include the liver, which accounts for >80% of the stored copper, and brain. Within the cell, a majority of copper is complexed by glutathione, MT, and cytosolic copper chaperons, which work in conjunction with copper-ATPases to maintain copper homeostasis (Harris, 2000; Mercer, 2001). The remainder of copper is complexed by copper-containing proteins, where the metal serves as a cofactor in enzymatic reactions (Stern, 2010). The amount of copper in the body is maintained at homeostatic levels mainly through control of excretion, although copper binding to hepatic MT may act as a form of intracellular storage. In mammals, the major route of excretion for excess copper is via the feces, with very little copper excreted into the urine. The bile is the major route of excretion from the liver. Bile secretion, enterohepatic recirculation, and intestinal reabsorption all help to maintain copper homeostasis.

Essentiality

Copper is an essential component of several metalloenzymes, including type A oxidases and type B monoamine oxidases. Of the type B oxidases, cytochrome c oxidase is probably the most important because it catalyzes a key reaction in energy metabolism, and inherited mutational defects can result in severe pathology in humans (Hamza and Gitlin, 2002). Of the type A oxidases, lysyl oxidase plays a major role in the formation and repair of extracellular matrix by oxidizing lysine residues in elastin and collagen, thereby initiating the covalent cross-linkage (Kagan and Li, 2003). Copper/zinc superoxide dismutase (SOD) is present in most cells, particularly of the brain, thyroid, liver, lung, and blood, and helps protect from oxygen toxicity by reducing superoxide radicals to hydrogen peroxide (Valko et al., 2005).

Copper deficiency is uncommon in humans, but can occur as a result of malnutrition, overdose of molybdenum, or excessive consumption of zinc (Maret and Standstead, 2006). Copper deficiency manifests clinically by hypochromic, microcytic anemia that is refractory to iron supplementation and predisposes to infection. More recently, a series of case reports has implicated acquired copper deficiency in the etiology of adult-onset progressive myeloneuropathy and in the development of severe blood disorders including myelodysplastic syndrome (Kumar et al., 2005; Goodman et al., 2009). This deficiency is sometimes accompanied by bone abnormalities. Less frequent manifestations are hypopigmentation of the hair and hypotonia. Biomarkers of copper deficiency include low serum and urine copper levels, ceruloplasmin concentration, and copper-dependent enzyme activities (IOM and Food and Nutrition Board, 2001).

Toxicity

The upper safe limit for daily copper consumption is estimated to be 10 mg Cu per day. The most commonly reported adverse health effects of excess oral copper intake are gastrointestinal distress. Nausea, vomiting, and abdominal pain have been reported shortly after drinking solutions of copper sulfate or beverages stored in containers that readily release copper (Pizarro et al., 1999). Ingestion of drinking water with >3 mg Cu/L will produce gastrointestinal symptoms. Ingestion of large amounts of copper salts, most frequently copper sulfate, may produce hepatic necrosis and death. Animal and human epidemiological studies have not found any relation between copper exposure and cancer (ATSDR, 2004b).

Hereditary Disease of Copper Metabolism

Menkes Disease

This is a rare sex-linked genetic defect in copper metabolism resulting in copper deficiency in male infants. It is characterized by peculiar hair, failure to thrive, severe mental retardation, neurological impairment, connective tissue dysfunction, and death usually by three to five years of age. The majority of the pathologies associated with Menkes disease can be linked to deficiencies in copper-containing proteins (Tümer and Møller, 2010). Bones are osteoporotic with flared metaphases of the long bones and bones of the skull. There is extensive degeneration of the cerebral cortex and of white matter. The gene responsible for Menkes disease, ATP7A, belongs to the family of ATPases and is a copper transporter (Fig. 23-7). Deficiency in this copper transporter in Menkes disease blocks copper transportation across the basolateral membrane of intestinal cells into the portal circulation, resulting in accumulation of copper in the enterocytes and systemic copper deficiency in the body. The transport of copper to the brain is also blocked, causing severe neurological abnormalities. Animal models for copper deficiency support the importance of adequate copper intake during embryogenesis and early development (Shim and Harris, 2003). Supplementation with copper-histidine has been shown to delay disease progression of the disease and successfully increase life span (Kodama et al., 2011).

Wilson Disease

This is an autosomal recessive genetic disorder of copper metabolism characterized by the excessive accumulation of copper in liver, brain, kidneys, and cornea (Huster, 2010). Serum ceruloplasmin is low and serum copper not bound to ceruloplasmin is elevated. Urinary excretion of copper is high. Clinical abnormalities of the nervous system, liver, kidneys, and cornea are related to copper accumulation. Patients with Wilson disease have impaired biliary excretion of copper, which is believed to be the fundamental cause of the hepatic copper overload. Wilson disease is associated with hepatic diseases ranging from mild hepatitis to acute liver failure. There is also an increased incidence of hepatocarcinoma in patents with Wilson disease (Wang et al., 2002). Neurological symptoms associated with Wilson disease include dystonia, tremor, dysarthria, and psychiatric disturbances. Genetic studies have identified the defect in copper transport as mutations of the Wilson disease locus (WND) on chromosome 13, encoding P-type ATPase (ATP7B) (Huster, 2010). There appear to be several polymorphisms of the defect, which may explain the clinical variability in the disorder. Diagnosis may be suspected with elevated serum copper but must be confirmed by liver biopsy and elevated liver copper (normally 15-55 μg/g vs >250 μg/g in Wilson disease).

Hereditary Aceruloplasminemia

This is the autosomal recessive genetic disorder of copper-binding protein ceruloplasmin, associated with the iron overload syndrome. Clinical signs and symptoms, which result from iron overload in the brain, include mental confusion, memory loss, dementia, cerebellar ataxia, altered motor function, retinal degeneration, and diabetes (Xu et al., 2004). Ceruloplasmin-null mice accumulate iron predominantly in organs of reticuloendothelial system. In these mice, hematologic indices and serum iron are abnormal by 10 weeks of age, with profound iron overload in the spleen and liver. Hepatic copper deposition is also approximately doubled in these mice. However, neurodegeneration and diabetes are not observed in these mice (Shim and Harris, 2003).

Indian Childhood Cirrhosis (ICC)

This is a disorder occurring in young children characterized by jaundice due to an insidious and progressive liver disease. Two distinguishing features are a widespread brown orcein staining (indicating copper) and intralobular hepatic fibrosis progressing to portal cirrhosis and chronic inflammation. The etiology is not known but it is suspected that bottle feeding of milk contaminated with copper from storage in brass vessels may be important. However, epidemiological studies also suggest an autosomal recessive genetic component because of strong familial occurrence and high consanguinity among affected children (WHO, 1998a,b).

Idiopathic Copper Toxicosis or Non-Indian Childhood Cirrhosis

This is a rare disorder in children similar to ICC occurring in some Western countries. The largest series of cases are reported from the Tyrol region of Austria. This population also used copper vessels to store milk, and the incidence of the disorder has declined since replacement of the copper vessels. A number of other cases have been reported from other parts of the world, some from increased amounts of copper in the drinking water (WHO, 1998a,b).

Treatment

Treatment for Wilson disease and other diseases of copper overload includes copper chelators and supplementation with zinc salts. Clinical improvement can be achieved by chelation of copper with d-penicillamine, Trien (triethylenetetramine 2HCl), zinc acetate, and tetrathiomolybdate. The combination of tetrathiomolybdate and zinc acetate is more effective (Brewer, 2005). N-Acetylcysteine amide can cross the blood–brain barrier and was developed to help prevent neurodegenerative disorders (Cai et al., 2005).

Iron

Iron (Fe) is a highly abundant transition metal that came into use around 4000 bc. An early source of iron was from fallen meteorites and the name may derive from the Ethruscan word aisar that means “the gods.” Iron is an essential metal for erythropoiesis and a key component of hemoglobin, myoglobin, heme enzymes, metalloflavoprotein enzymes, and mitochondrial enzymes. Physiologically, iron mainly exists as the ferrous (2+) and ferric (3+) forms. Toxicological considerations are important in terms of iron deficiency, accidental acute exposures, and chronic iron overload due to idiopathic hemochromatosis or as a consequence of excess dietary iron or frequent blood transfusions (Papanikolaou and Pantopoulos, 2005; Weinberg, 2010).

Toxicokinetics

Iron metabolism is regulated by a complex series of events that maintain homeostasis, mainly involving absorption, storage, and excretion (Wang and Pantopoulos, 2011; Theil, 2011). Heme iron from meat, poultry, and fish is highly bioavailable. Nonheme iron absorption is influenced by its solubility and by other dietary factors, such as ascorbic acid which enhances uptake. Absorption involves movement of ferrous ions from the intestinal lumen into the mucosal cells via the divalent metal transporter protein 1 (DMT1) among several other transporters (Theil, 2011). The metal is then transferred from the mucosal cell to the plasma, where iron is bound to transferrin for transport and distribution. A β₁-globulin produced in the liver, transferrin, delivers iron to tissues by binding to transferrin receptor-1 on the cell membrane, followed by endocytosis. Intracellular iron homeostasis is regulated by a complex coordination of iron trafficking and iron storage involving an iron response element/iron regulatory protein system and antioxidant response elements (Wang and Pantopoulos, 2011; Theil, 2011). The human body contains ~3 to 5 g of iron. About two-thirds of body iron is in hemoglobin, 10% is in myoglobin and iron-containing enzymes, and the remainder is bound to iron storage proteins such as ferritin and hemosiderin, stored in liver and reticuloendothelial cells in the spleen and bone marrow. Iron stores serve as a reservoir to supply cellular iron needs, mainly for hemoglobin production. Erythrocyte destruction and production are responsible for most iron turnover. Hepcidin, a small peptide of liver origin, modulates iron absorption in response to erythropoiesis (Papanikolaou and Pantopoulos, 2005). The major route of excretion of iron is into the gastrointestinal tract and eventually the feces.

Essentiality and Deficiency

Iron deficiency is the most common nutritional deficiency worldwide, affecting infants, young children, and women of childbearing age and is considered a major public health issue (Theil, 2011). The critical period for iron deficiency in children is between the ages of six months and two years. The major manifestation of iron deficiency is anemia with microcytic hypochromic red blood cells. Other effects of iron deficiency include impaired psychomotor development and intellectual performance, decreased resistance to infection, adverse pregnancy outcomes, and possibly increased susceptibility to lead and cadmium toxicity. Oral ferrous sulfate is the treatment of choice for iron deficiency.

Toxicity

Acute iron poisoning from accidental ingestion of iron-containing dietary supplements is the most common cause of acute toxicity. It most often occurs in children. This type of poisoning decreased following the introduction of childproof lids on prescription medicines and vitamin supplements. Severe toxicity occurs after the ingestion of more than 0.5 g of iron or 2.5 g of ferrous sulfate. Toxicity occurs about one to six hours after ingestion. Symptoms include abdominal pain, diarrhea, and vomiting. Of particular concern are pallor or cyanosis, metabolic acidosis, liver damage, and cardiac collapse. Death may occur in severely poisoned children within 24 hours. Supportive therapy and iron chelation with deferoxamine (also known as desferrioxamine) should be used as soon as possible. Inhalation of iron oxide fumes or dust may cause pneumoconiosis in occupational settings (Doherty et al., 2004).

Chronic iron toxicity from iron overload in adults is a relatively common problem. There are three basic ways in which excessive amounts of iron can accumulate in the body. The first is hereditary hemochromatosis due to abnormal absorption of iron from the intestinal tract. Hereditary hemochromatosis is an autosomal recessive disorder attributed to mutation in the hemochromatosis gene. The second possible cause of iron overload is excess intake via the diet or from oral iron preparations. The third circumstance in which iron overload can occur is repeated blood transfusions for some form of refractory anemia and is referred to as transfusional siderosis. The pathological consequences of iron overload are similar regardless of the basis. Hemosiderosis refers to increased iron stores in the form of hemosiderin. The body iron content can increase 20 to 40 g, up to 10 times higher than normal levels. Hemochromatosis refers to excessive deposition of iron that causes organ damage, often resulting in fibrosis. Inhalation of iron oxide fumes or dust by workers in hematic mines (mainly Fe₂O₃), steel workers, and welders may produce siderosis (nonfibrotic), and in some cases silicosis (fibrotic) in the lung, with increases in total body iron (Doherty et al., 2006). Liver iron overload from hereditary hemochromatosis appears to be associated with an increased risk for hepatocellular carcinoma, as well as with other malignancies (Papanikolaou and Pantopoulos, 2005). Oxidant stress would be a presumable carcinogenic mode of action.

Increased body iron may play a role in the development of cardiovascular disease, including cardiomyopathy (Gujja et al., 2010). It is suspected that iron may produce free radical damage resulting in artherosclerosis and ischemic heart disease (Alpert, 2004). It is clear that mortality from cardiovascular disease is correlated with liver iron overload (Yuan and Li, 2003; Gujja et al., 2010). Several neurodegenerative disorders are associated with aberrant iron metabolism in the brain, such as neuroferritinopathy, aceruloplasminemia, and manganism (Aschner et al., 2005; Papanikolaou and Pantopoulos, 2005).

Treatment

Desferrioxamine is the chelator of choice for the treatment of acute iron intoxication and chronic iron overload. Iron chelators have also been proposed for the treatment of cancers with iron overload (Buss et al., 2004).

Magnesium

Magnesium (Mg) was recognized as an element in 1755. The name originates from the Greek word for a district in Thessaly called Magnesia. Magnesium is a nutritionally essential metal that plays a key role in a wide range of important fundamental cellular reactions (Herroeder et al., 2011). Nuts, cereals, seafood, and meats are good dietary sources of magnesium. The drinking water content of magnesium increases with hardness of the water. Magnesium citrate, oxide, sulfate, hydroxide, and carbonate are widely taken as antacids or cathartics. Magnesium hydroxide, or milk of magnesia, is one of the universal antidotes for poisoning. Topically, the sulfate is also used to relieve inflammation. Parenteral administration of magnesium sulfate has been used in the treatment of seizures associated with eclampsia of pregnancy and acute nephritis.

Toxicokinetics

Oral magnesium is absorbed mainly in the small intestine. The colon also absorbs some magnesium. Calcium and magnesium are competitive with respect to absorption, and excess calcium will partially inhibit magnesium absorption. Serum magnesium levels are remarkably constant. Magnesium is excreted into the digestive tract by the bile and in pancreatic and intestinal juices. Approximately 60% to 65% of the total body magnesium is in the bone, 27% in muscle, 6% to 7% in other organs, and only 1% is in extracellular fluid. Of the magnesium filtered by the glomeruli, about 95% is reabsorbed, an important factor in maintaining homeostasis.

Essentiality and Deficiency

Magnesium is a cofactor of many enzymes. In the glycolytic cycle, there are seven key enzymes that require divalent magnesium. Magnesium-containing enzymes are also involved in the citric acid cycle and in β-oxidation of fatty acids. Deficiency may occur as a complication of various disease states such as malabsorption syndromes, renal dysfunction, and endocrine disorders. Magnesium deficiency in humans causes neuromuscular irritability, frank tetany, and even convulsions. Magnesium deficiency induces an inflammatory syndrome (Mazur et al., 2007), and is a risk factor for diabetes mellitus, hypertension, hyperlipidemia, and ischemic heart diseases (Ueshima, 2005). Supplementation of magnesium, by either intravenous or oral administration, is beneficial.

Toxicity

In industrial exposures, no ill effects are produced with a twofold increase in serum magnesium, although concurrent increases occur in serum calcium. Inhaled freshly generated magnesium oxide can cause metal fume fever, similar to that caused by zinc oxide. In nonoccupationally exposed individuals, toxicity can occur when magnesium-containing drugs, usually antacids, are ingested chronically by persons with serious renal failure. The toxic effects may progress from nausea and vomiting to hypotension, electrocardiograph abnormalities, central nervous system effects, coma, and systolic cardiac arrest (Herroeder et al., 2011). Magnesium toxicity can sometimes be counteracted with calcium infusion.

Manganese

Manganese (Mn) was in use in prehistoric times. Paints that were pigmented with manganese dioxide can be traced back 17,000 years. The pure element was isolated in 1774 and named after the Latin magnes, meaning “magnet.” Manganese is an essential metal required for many metabolic and cellular functions. Manganese metalloenzymes include arginase, glutamine synthetase, phosphoenolpyruvate decarboxylase, and manganese SOD (Aschner and Aschner, 2005). Manganese is also a cofactor for a number of enzymatic reactions. It exists in many valences but the divalent cation is by far the predominant species within cells. Divalent manganese may be oxidized to the more reactive and toxic trivalent form. The major source of manganese intake is from food. Vegetables, grains, fruits, nuts, and tea are rich in manganese. Daily manganese intake ranges from 2 to 9 mg (ATSDR, 2008). The adequate intake is 2.3 and 1.8 mg per day for adult men and women, respectively (IOM, 2002).

Occupational exposures to high concentrations of manganese can occur in a number of settings, including manganese dioxide mines and smelters. Significant exposure can also occur in factories making manganese steel alloys, electrical coils, batteries, glass, and welding rods, and during production of potassium permanganate (KMnO₄). The industrial use of manganese has expanded in recent years as a ferroalloy in the iron industry and as a component of alloys used in welding (Crossgrove and Zheng, 2004).

Environmental exposures are often associated with manganese-based organometallic pesticides, maneb and mancozeb. Manganese intoxication has also been reported after ingestion of contaminated water (Crossgrove and Zheng, 2004; ATSDR, 2008). There is current interest in the toxicology of manganese-containing fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). In addition, manganese compounds, such as mangafodipir, are increasingly used as MRI enhancers in clinical imaging techniques.

Toxicokinetics

Approximately 1% to 5% of ingested manganese is normally absorbed. Interactions between manganese and iron, as well as other divalent elements, occur and impact the toxicokinetics of manganese especially following oral exposure (Roth and Garrick, 2003). Iron and manganese can compete for the same binding protein in serum (transferrin) and the same transport systems (DMT1). Inhalation of particulate manganese may result in direct transfer to brain tissue via the olfactory system (Tjalve and Henriksson, 1999). Within the plasma, manganese is largely bound to γ-globulin and albumin, with a small fraction bound to transferrin. Manganese concentrates in mitochondria, so that tissues rich in these organelles, such as pancreas, liver, kidneys, and intestines, have the highest concentrations of manganese. It readily crosses the blood–brain barrier and accumulates in specific brain regions (Crossgrove and Zheng, 2004). Manganese is eliminated in the bile and reabsorbed in the intestine. The principal route of manganese excretion is with the feces. Biliary excretion is poorly developed in neonates and exposure during this period may result in increased delivery of manganese to the brain and other tissues (Aschner and Aschner, 2005).

Essentiality and Deficiency

Manganese deficiency has been produced in many species of animals, but questions remain about whether deficiency has actually been demonstrated in humans (WHO, 1996). Deficiency in animals results in impaired growth, skeletal abnormalities, and disturbed reproductive function.

Toxicity

Chronic manganese-induced neurotoxicity (manganism) is of great concern and the brain is considered the most sensitive organ to manganese. Manganism affects the release of dopamine from dopaminergic neurons, the same neurons affected by Parkinson disease. While both conditions lead to some similar neurological effects, effects on dopaminergic neurons are not the same, also causing distinct behavioral effects (Guilarte, 2010). Neurotoxicity due to inhalation of airborne manganese ranging from 0.027 to 1 mg Mn/m³ has been reported in a number of occupational settings. Overt manganism occurs in workers exposed to aerosols containing extremely high levels of manganese (>1–5 mg Mn/m³). Neurotoxicity also occurs following ingestion of manganese-contaminated water (1.8–14 ppm; Aschner et al., 2005). Manganism is associated with elevated brain levels of manganese, primarily in those areas known to contain high concentrations of nonheme iron, such as the substantia nigra, basal ganglia, caudate–putamen, globus pallidus, and subthalamic nuclei (Aschner et al., 2007). Early manifestations of manganese neurotoxicity include headache, insomnia, memory loss, muscle cramps, and emotional instability. Initial outward symptoms progress gradually and are mainly psychiatric. As exposure continues and the disease progresses, patients may develop prolonged muscle contractions (dystonia), decreased muscle movement (hypokinesia), rigidity, hand tremor, speech disturbances, and festinating “cock-walk” gait. These signs are associated with damage to dopaminergic neurons that control muscle movement (Crossgrove and Zheng, 2004; Aschner et al., 2005). Specialized T1-weighted magnetic resonance brain imaging of manganism patients indicates high levels in the basal ganglia and especially in the globus pallidus.

Inhalation of manganese-containing dust in certain occupational settings can lead to an inflammatory response in the lung. Symptoms of lung irritation and injury may include cough, bronchitis, pneumonitis, and, occasionally, pneumonia (ATSDR, 2008). Men working in plants with high concentrations of manganese dust show an incidence of respiratory disease that is 30 times greater than normal. Manganese exposure also alters cardiovascular function in animals and humans, as evidenced by abnormal electrocardiogram and the inhibition of myocardial contraction. Manganese dilates blood vessels and induces hypotension (Jiang and Zheng, 2005). When manganese is combined with bilirubin, it produces intrahepatic cholestasis by acting on the synthesis and degradation of cholesterol and the inhibition of the transport pump Mrp2 (Akoume et al., 2004). Liver cirrhosis is a major contributing factor for hepatic encephalopathy, often associated with increased manganese levels in the brain (Mas, 2006).

Interactions between manganese and iron play a role in manganese toxicity. The coaccumulation of iron with manganese in the globus pallidus raises the concern that iron may be a contributing factor facilitating neuronal cell loss during manganese intoxication. Chronic exposure to manganese alters iron concentrations in blood and cerebrospinal fluid, presumably due to manganese–iron interaction at certain iron–sulfur-containing proteins, which regulate iron homeostasis. Manganese intoxication in monkeys causes elevated iron deposition in the globus pallidus and substantia nigra. The excess iron may produce oxidative stress via the Fenton reaction, leading to neuronal damage. Dysfunctional iron metabolism has also been seen in manganism patients. Serum parameters associated with iron metabolism, such as ferritin, transferrin, and total-iron-binding capacity, are significantly altered (Roth and Garrick, 2003; Crossgrove and Zheng, 2004). High levels of total iron and iron-associated oxidative stress, decreased ferritin, and abnormal mitochondrial complex-1 have been repeatedly reported in post-mortem samples of substantia nigra from manganism patients.

Available data indicate that inorganic manganese is not carcinogenic in humans or rodents, and negative in the Ames test, but may cause DNA damage and chromosome aberrations in vitro in mammalian cells (Gerber et al., 2002).

Molybdenum

Molybdenum (Mo) was first separated from lead and graphite in 1778. The name “molybdenum” was derived from Greek molybdos meaning “lead-like.” As an essential element, molybdenum acts as a cofactor for four enzymes in humans: sulfite oxidase, xanthine oxidase, aldehyde oxidase, and mitochondrial amidoxime reductase (Mendel and Bittner, 2006). Molybdenum exists in five oxidation states but the predominant species are Mo⁴⁺ and Mo⁶⁺. Molybdenum concentration in food varies considerably depending on the local environment. Molybdenum is added in trace amounts to fertilizers to stimulate plant growth. The human requirement for molybdenum is low and easily provided by a common US diet. The RDA for molybdenum is 45 μg per day (IOM and Food and Nutrition Board, 2001).

The most important mineral source of molybdenum is molybdenite (MoS₂). The industrial uses of this metal include the manufacture of high-temperature-resistant steel alloys for gas turbines and jet aircraft engines and in the production of catalysts, lubricants, and dyes. Ammonium tetrathiomolybdate is used as a molybdenum-donating copper chelator in treatment of Wilson disease (Brewer, 2003).

Toxicokinetics

Water-soluble molybdenum compounds are readily absorbed when ingested. In animals, gastrointestinal absorption varies between 75% and 95%. In humans, absorption of molybdenum after oral intake varies from 28% to 77% (Vyskocil and Viau, 1999). Once absorbed, molybdenum rapidly appears in blood and most tissues. The highest molybdenum concentrations are found in kidneys, liver, and bones. Very little molybdenum appears to cross the placenta. When elevated exposure is ceased, tissue concentrations quickly return to normal levels. Molybdenum metabolism is related to copper and sulfur. Exposure to molybdenum decreases intestinal absorption of copper and sulfate, and impairs the sulfation of chemicals (Boles and Klaassen, 2000). Excretion, primarily via the urine, is rapid and 36% to 90% of a dose of molybdenum is excreted in urine in experimental animals. In humans, the urinary excretion ranges from 17% to 80% of the total dose. Very little (<1%) of molybdenum excretion is via bile (Vyskocil and Viau, 1999). When consuming a low-molybdenum diet, the intestinal molybdenum absorption and tissue uptake are increased, while urinary excretion is decreased to reduce the molybdenum loss. With high dietary intake, urinary excretion can be dramatically increased to help eliminate excess molybdenum (Novotny and Turnlund, 2006).

Essentiality and Deficiency

Molybdenum deficiency has been described in various animal species and consists of disturbances in uric acid metabolism and sulfite metabolism. Molybdenum cofactor (Moco) deficiency is a pleiotropic genetic disorder characterized by the loss of the molybdenum-dependent enzymes sulfite oxidase, xanthine oxidoreductase, and aldehyde oxidase, due to mutations in the genes involved with Moco biosynthesis. This rare human genetic metabolic disorder is characterized by severe neurodegeneration resulting in early childhood death (Schwarz, 2005).

Toxicity

Molybdenum is of low toxicity. Chronic exposure to excess molybdenum in humans is characterized by high uric acid levels in serum and urine. A gout-like syndrome has been observed in inhabitants exposed to high levels of environmental molybdenum or among workers exposed to molybdenum in a copper–molybdenum plant (Vyskocil and Viau, 1999). When inhaled, both metallic molybdenum and sparingly soluble molybdenum trioxide have been reported to cause pneumoconiosis. Recent work in animal models suggests that combinations of molybdenum and copper can significantly affect male reproduction (Wirth and Mijal, 2010). Molybdenosis (teart) is a form of molybdenum poisoning that produces a disease in ruminants similar to copper deficiency (Barceloux, 1999a,b). Generally, soluble molybdenum compounds are more toxic than insoluble compounds. In many ways molybdenum toxicity resembles copper deficiency. Treatment with supplemental copper can often reverse the adverse effects of excess molybdenum (Vyskocil and Viau, 1999). Conversely, treatment of Wilson disease with molybdenum compounds is used to reduce copper burden. Molybdenum treatment may also be beneficial for angiogenesis, inflammation, and other disorders associated with excess copper (Brewer, 2003).

Selenium

Selenium (Se) was discovered in 1817, and named after the Greek word selene meaning moon. Although technically a nonmetal, certain forms have metal-like properties. Selenium is an essential element found in selenoproteins and deficiency is recognized in humans and animals (Högberg and Alexander, 2007). It is also toxic and high doses cause overt selenium poisoning (selenosis). The availability and the toxic potential of selenium compounds are related to their chemical forms and, most importantly, to solubility. Selenium occurs in nature and biological systems as selenate (Se⁶⁺), selenite (Se⁴⁺), selenide (Se²⁺), and elemental selenium (Se⁰) (Fairweather-Tait et al., 2010).

Foods are a good source of selenium. Seafood (especially shrimp), meat, milk products, and grains provide the largest amounts in the diet. Levels of selenium in river water vary depending on environmental and geologic factors. Combustion of coal and other fossil fuels are the primary sources of airborne selenium compounds. Occupational exposure comes from selenium refining operations, metal smelting, and milling operations, incineration of rubber tires, and municipal waste. Rocks and soil, plants, and tobacco are other sources of selenium exposure (Högberg and Alexander, 2007; Fairweather-Tait et al., 2010).

Toxicokinetics

Orally administered selenite, selenate, and selenomethione are readily absorbed, often greater than 80%, whereas elemental selenium and selenides are virtually insoluble and poorly absorbed. Because of their insolubility, these forms may be regarded as an inert selenium sink. Monogastric animals have higher intestinal absorption than ruminants, probably because selenite is reduced to an insoluble form in rumen. Selenium accumulates in many tissues, with the highest accumulation in the liver and kidney. It is transferred through the placenta to the fetus, and it also appears in milk. Levels in milk are dependent on dietary intake. Selenium in red blood cells is associated with glutathione peroxidase and is about three times more concentrated than in plasma. Selenium is primarily eliminated in urine and feces. In cases of acute exposure to toxic concentrations of selenium, significant amounts are eliminated in expired air, causing the characteristic “garlic breath” (Högberg and Alexander, 2007; Fairweather-Tait et al., 2010).

Selenium metabolism is well regulated in order to meet several metabolic needs (Fig. 23-8). Inorganic selenium and selenocysteine undergo stepwise reduction to the key intermediate hydrogen selenide, which is either transformed to selenophosphate for selenoprotein synthesis or excreted into breath or urine after being transformed into methylated metabolites of selenide (Högberg and Alexander, 2007; Fairweather-Tait et al., 2010). Selenophosphate is involved in the synthesis of selenocystein tRNA according to the UGA code for the selenocysteine residue. The translation of selenoprotein mRNA requires cis-acting sequences in the mRNA and transacting factors dedicated to selenocysteine incorporation (Högberg and Alexander, 2007). Selenoprotein synthesis is highly dependent on selenium availability.

Essentiality and Deficiency

Selenium is notable for its actions in antioxidant systems through involvement in over 20 selenoproteins (Högberg and Alexander, 2007; Fairweather-Tait et al., 2010). For instance, glutathione peroxidase is the selenium-dependent enzyme that reduces peroxides using glutathione, and thereby protects membrane lipids, proteins, and nucleic acids from damage by oxidants or free radicals. The enzyme thioredoxin reductase is another selenium-dependent enzyme that has an important role in body’s defense against oxidative damage. Selenoprotein P is the major plasma selenoprotein, and serves as an antioxidant in the extracellular space and transports selenium from the liver to other tissues. Selenium W is a low-molecular-weight selenoprotein and may have redox functions. Iodothreonine deiodinases are selenoproteins contributing to systemic or local thyroid hormone homeostasis. Selenium content in endocrine tissues (thyroid, adrenals, pituitary, testes, and ovary) is higher than that in many other organs. Hormones and growth factors also regulate expression of selenoproteins (Kohrle et al., 2005).

The most extensively documented deficiency of selenium in humans is Keshan disease. This is an endemic cardiomyopathy first discovered in Keshan County in China where there are very low concentrations of selenium in the soil and food. Keshan disease patients show very low plasma selenium levels. This deficiency occurs most frequently in children under 15 years of age and in women of childbearing age and is characterized by various degrees of cardiomegaly and cardiac decompensation. Deficiency of selenium also occurs in domestic animals and rodents. Selenium supplementation reduces these adverse effects (Fairweather-Tait et al., 2010).

Kashin–Beck disease is an osteoarthropathy found in areas where combined deficiency of selenium and iodine occurs with elevated exposure to mycotoxin and fulvic acids (Fairweather-Tait et al., 2010). Selenium deficiency is a major contributing factor in this disease. Other potential effects of selenium deficiency include immune dysfunction, and susceptibility to cancer or infectious/inflammatory diseases (Högberg and Alexander, 2007; Fairweather-Tait et al., 2010). Established tolerable upper intake limits of selenium in adults are 200 to 300 μg per day (Duffield-Lillico et al., 2002; Högberg and Alexander, 2007). Metabolic balance studies in adults indicate about 50 to 70 μg per day is required to maintain selenium balance and presumably to satisfy selenium requirement (Högberg and Alexander, 2007). Data indicate that daily intake less than 20 μg can cause Keshan disease.

Toxicity

Acute selenium toxicity in humans is rare. Intentional or accidental ingestion of a large dose of sodium selenate or sodium selenite can be life-threatening. Symptoms of fatal selenium intoxication include nausea and vomiting, followed by pulmonary edema and rapid cardiovascular collapse (Fairweather-Tait et al., 2010).

Chronic selenium toxicity (selenosis) can occur with environmental exposure when the intake exceeds the excretory capacity. Effects are mainly dermal and neurological including hair and fingernail loss, tooth discoloration, numbness, paralysis, and occasional hemiplegia. Selenosis occurred in several villages in China where people were exposed to very high selenium in food (Fairweather-Tait et al., 2010). Intoxication from environmental selenium has also been noted in people residing in Venezuela and South Dakota. Selenium toxicity in animals was recognized in South Dakota when the livestock that had been grazed in areas with high soil selenium developed alkali disease and blind staggers. In a study of people living in this area, poor dentition, a yellowish discoloration of the skin, skin eruptions, and diseased fingernails and toenails were found (Fairweather-Tait et al., 2010).

Plants vary in their ability to accumulate selenium. Grasses, grains, and most weeds do not accumulate selenium even when grown in high selenium areas, so that these plants add little to the selenium content of livestock feed. But there are several plant species that are classified as “selenium accumulators” and they may contain selenium at very high concentrations (100–10,000 mg/kg). These plants usually grow in nonagricultural areas and when consumed by livestock may cause selenium intoxication. Selenium has produced loss of fertility and congenital defects and is considered embryotoxic and teratogenic in animals (ATSDR, 2003a,b; Högberg and Alexander, 2007).

Selenium has various bioinorganic interactions, which may affect the toxicity of selenium or other metals. It forms insoluble complexes with various metals, as, for example, with arsenic. Selenium complexation can increase the biliary excretion of various metals. Selenium forms complexes with copper, and toxicity of either selenium or copper is influenced by the intake of the other elements. The methylation of selenium can influence other methylation reactions, and can alter arsenic metabolism and toxicity (Zeng et al., 2005). Selenium prevents the toxic effects of cadmium and can reduce the toxic effects of methylmercury. The mechanisms for these interactions are only partially understood, but their occurrence influences the determination of safe and toxic levels of selenium for the general population (WHO, 1996).

Some epidemiological data have linked low blood selenium levels and increased cancer risk in various populations (ATSDR, 2003a,b). Selenium supplementations appear to decrease human cancer rates, especially for prostate cancer (Duffield-Lillico et al., 2002; Fairweather-Tait et al., 2010). Increasing selenium content of forage crops has been shown to be beneficial in reducing cancer risk. Some experimental evidence supports a role for selenium in reduction of spontaneous tumors or tumors formed by organic carcinogens in rats and mice. On the other hand, selenium sulfide is considered reasonably anticipated to be a human carcinogen based on multiple positive rodent studies where tumors of the lung or liver were produced after exposure via stomach tube (NTP, 2011g).

Trivalent Chromium

Essentiality

Trivalent chromium (Cr³⁺) is a naturally occurring essential trace nutrient serving an important role in glucose metabolism by enhancing insulin signaling (IOM and Food and Nutrition Board, 2001). The glucose tolerance factor is a complex of trivalent chromium, nicotinic acid, and amino acids, and physiologically potentiates the action of insulin in glucose, lipid, and protein metabolism (IOM and Food and Nutrition Board, 2001). Other effects of trivalent chromium include the beneficial roles in growth, immune response, and stress. The tissue levels of chromium are reduced among diabetic individuals, but the effects of chromium supplementation in type 2 diabetes are still controversial (Cefalu and Hu, 2004). The adequate intake of chromium is now proposed as 35 and 25 μg/kg per day for men and women, respectively, which is lower than previous 50 to 200 μg per day. Chromium picolinate contains Cr³⁺ and is a top-selling nutritional supplement. It was thought to have adverse effects and perhaps the potential to cause cancer (Vincent, 2004), but an in-depth study of chronic chromium picolinate feeding has now shown no evidence of carcinogenesis in male or female mice or female rats only and equivocal evidence of a response (preputial gland tumors) in male rats (Stout et al., 2010).

Zinc

Zinc (Zn) was named from German zink meaning tin. It has been used since ancient times in alloys and medicines. An essential metal, zinc deficiency results in severe health consequences. In contrast, zinc toxicity is relatively uncommon and occurs only at very high exposure levels. Zinc is ubiquitous in the environment and is present in most foodstuffs, water, and air. The major route of zinc intake is through the diet, the contents of which vary from 5.2 to 16.2 mg Zn per day (ATSDR, 2005d). RDA for zinc in children less than three years old is 3 mg per day; this value increases to 8 mg per day for children between four and 13 years old. For men >14 years old the RDA is 11 mg per day, while for women it is 8 to 9 mg per day, which increases to 12 to 13 mg per day during pregnancy (Yates et al., 2001).

Occupational exposure to dusts and fumes of metallic zinc occurs in zinc mining and smelting. The zinc content of substances in contact with galvanized copper or plastic pipes may be high. Many countries regulate workplace levels of zinc oxide fume and dust at levels between 5 and 10 mg/m³ (WHO, 1998a,b).

Toxicokinetics

The absorption of zinc from the gastrointestinal tract is homeostatistically regulated. About 20% to 30% of ingested zinc is absorbed. Zinc uptake from the intestinal lumen involves passive diffusion and a carrier-mediated process through zinc-specific transmembrane transporters such as ZnT-1. Intestinal absorption of zinc can be reduced by dietary fiber, phytates, calcium, and phosphorus, while amino acids, picolinic acid, and prostaglandin E2 can enhance zinc absorption. Once absorbed, zinc is widely distributed throughout the body. The total zinc content of the human body is in the range of 1.5 to 3 g, most of which is found in muscle (60%), bone (30%), skin/hair (8%), liver (5%), and pancreas (3%). The highest concentrations of zinc are found in prostate, pancreas, liver, and kidney. In plasma, zinc concentration is about 1 mg/L, and is bound to albumin (60%–80%), which represents the metabolically active pool of zinc. The remainder is bound to α₂-macroglobulin and transferrin. Zinc is excreted in both urine and feces. The concentration of zinc in the plasma is not a sensitive indicator of zinc status and does not reflect the dose–response relationship between zinc levels in the body and effects at various target sites. Zinc ions are involved as intercellular and intracellular messengers, and the homeostasis of zinc has to be tightly controlled. The most reliable index of zinc status is the determination of zinc balance, using a U-shaped homeostatic model to analyze the relationship between intake and excretion (WHO, 1998a,b).

Zinc is an effective inducer of MT synthesis and, when MT is saturated in intestinal cells, zinc absorption is decreased. MT is also an important storage depot for cellular zinc. Liver MT concentration is influenced by hormonal factors, including adrenocorticotropic hormone and parathyroid hormone, and various stimuli that impact zinc metabolism. The high concentration of zinc in the prostate is probably related to the rich content of zinc-containing enzyme acid phosphatase.

Essentiality and Deficiency

More than 300 catalytically active zinc metalloenzymes and 2000 zinc-dependent transcription factors exist (Ziegler and Filer, 1996; Cai et al., 2005). Zinc participates in a wide variety of metabolic processes, supports a healthy immune system, and is essential for normal growth and development during pregnancy, childhood, and adolescence. Zinc deficiency is related to poor dietary zinc intake, dietary phytate (inositol hexakisphosphate) intake, chronic illness, or over supplementation with iron or copper (Prasad, 2004). Symptoms of zinc deficiency include growth retardation, appetite loss, alopecia, diarrhea, impaired immune function, cognitive impairments, dermatitis, delayed healing of wounds, taste abnormalities, and impaired sexual function (Prasad, 2004; Cai et al., 2005; Cousins et al., 2006). Acrodermatitis enteropathica is a rare autosomal recessive disorder involving zinc deficiency that can begin to appear after weaning from breast or formula feeding. The deficiency is due to mutations in a zinc-specific transporter that is highly expressed in the intestine. The disease is characterized by periorificial and acral dermatitis, alopecia, and diarrhea (Maverakis et al., 2007). Zinc supplementation, alone or with other micronutrients, is recommended for zinc-deficient children, especially in developing countries.

Therapeutic uses of zinc include the treatment of acute diarrhea in infants with severe zinc deficiency, the treatment of common cold by its antiviral and immunomodulatory effects, therapy for Wilson disease to help reduce copper burden and to induce MT, and in the prevention of blindness in age-related macular degeneration (Prasad, 2004).

Toxicity

Acute zinc toxicity from excessive ingestion is uncommon, but gastrointestinal distress and diarrhea have been reported following ingestion of beverages standing in galvanized cans. Following inhalation of zinc oxide, and to a lesser extent other zinc compounds, the most common effect is “metal fume fever” characterized by fever, chest pain, chills, cough, dyspnea, nausea, muscle soreness, fatigue, and leukocytosis. Acute inhalation of high levels of zinc chloride as in the military use of “smoke bombs” results in more pronounced damage to the mucous membrane including interstitial edema, fibrosis, pneumonitis, bronchial mucosal edema, and ulceration. Chronic intakes of zinc (150–450 mg per day) have been associated with low copper status, altered iron function, and reduced immune function. Recently, excessive use of denture adhesive cream has been recognized as a potential source for zinc toxicity. These individuals ingest 350 to 1200 mg of zinc per day (Hedera et al., 2009). Following long-term exposure to lower doses of zinc (60 mg per day), symptoms generally result from a decreased dietary copper absorption, leading to early symptoms of copper deficiency, such as decreased erythrocyte number or decreased hematocrit (Yates et al., 2001).

Neuronal Toxicity

Zinc has dual effects in the brain. As an essential cofactor for numerous enzymes and proteins, zinc deficiency may alter activity of the antioxidant enzyme Cu–Zn SOD, resulting in excess free radicals that are damaging to cell membranes (Valko et al., 2005). A genetic abnormality of Cu–Zn SOD may be the basis of a familial form of amyotrophic lateral sclerosis (Selverstone Valentine et al., 2005). Zinc can also act as a neurotransmitter for normal brain functions (Frederickson et al., 2005; Cousins et al., 2006). It modulates the solubility of β-amyloid in the brain and protects against β-amyloid toxicity, but excess zinc may trigger neuronal death that is independent or synergistic with the toxic effect of β-amyloid (Valko et al., 2005). In contrast, excess zinc released by oxidants can act as a potent neurotoxin (Frederickson et al., 2005). Synaptically released zinc might contribute to excitotoxic brain injury, and the release of excess, toxic free zinc into the brain that occurs during excitotoxic brain injury could be a factor that sets the stage for the later development of Alzheimer disease.

Pancreatic Toxicity

Because large amounts of zinc accumulate in secretory granules of pancreatic islet β-cells, zinc released under certain conditions can affect the function or survival of islet cells and cause β-cell death. Excess dietary zinc is associated with damage to exocrine pancreas. A single, high-dose injection of zinc increases plasma α-amylase activity and can produce fibrosis and necrosis of pancreatic exocrine cells, but does not affect the islets of Langerhans cells (Cai et al., 2005).

Zinc and Carcinogenicity

Epidemiological studies of workers in electrolytic zinc and copper refining industries have not found an increased incidence of cancer associated with occupational zinc inhalation. Oral zinc supplementation does not appear to have a significant effect on cancer incidence (ATSDR, 2005d). In contrast, zinc deficiency may be associated with increased risk of cancer in humans (Prasad and Kucuk, 2002). Zinc supplementation could decrease oxidative stress and improve immune function, which may be a possible mechanism for its cancer preventive activity (Prasad and Kucuk, 2002). In experimental animals, zinc prevents cadmium-induced testicular cancer, but facilitates cadmium-induced prostate tumors (Waalkes, 2003).

Aluminum

Aluminum (Al) is the third most abundant element in the earth’s crust after oxygen and silicon. Elemental aluminum was first identified in 1827. Due to its high reactivity, aluminum is not found in the free state in nature. Chemical compounds of aluminum occur typically in the trivalent state (Al³⁺). As a hard trivalent ion, aluminum binds strongly to oxygen donor ligands such as citrate and phosphate. The chemistry of aluminum compounds is complicated by a tendency to hydrolyze and form polynuclear species, many of which are sparingly soluble (Harris et al., 1996).

Aluminum has many uses, mainly in the form of alloys, and finds use in packing, construction, transportation, electrical applications, and beverage cans. Aluminum compounds are also used as food additives. Human exposure to aluminum comes primarily from food and secondarily from drinking water. The amount of aluminum in the food supply is small compared with pharmaceutical use of aluminum in antacids and buffered analgesics (Soni et al., 2001). Occupational exposures to aluminum occur during mining and processing, as well as in aluminum welding. The levels of exposure can vary greatly according to the type of industry and hygiene conditions. Inhalation of aluminum-containing dust particles is of health concern (Sjögren et al., 2007).

Aluminum exists predominantly in forms that are innocuous to humans and most species. However, acidic conditions, such as acid rain or dry acid deposition, can dramatically increase the amount of aluminum in ecosystems, resulting in well-described destructive effects on plants, fish, and other wildlife. However, aluminum is not bioaccumulated to any significant extent except in the tea plant (Sparling and Lowe, 1996).

Toxicokinetics

Aluminum is poorly absorbed following either oral or inhalation exposure and is essentially not absorbed dermally. Inhalation of particulate aluminum may result in direct transfer to brain tissue via the olfactory system (Tjalve and Henriksson, 1999). Less than 1% of aluminum in the diet is absorbed. Absorption from the gut depends largely on pH and the presence of complexing ligands, particularly carboxylic acids, through which aluminum becomes absorbable. For example, intestinal absorption is enhanced in the presence of citrate. Biological speciation is also of major importance in distribution and excretion of aluminum in mammals (Sjögren et al., 2007). In plasma, 80% to 90% of aluminum binds to transferrin, an iron transport protein with receptors in many tissues. The transferrin pathway is also considered a mechanism for aluminum transport across the blood–brain barrier (Yokel, 2006). Lung, liver, and bone have the highest concentrations of aluminum (Sjögren et al., 2007). Aluminum is removed from blood by the kidneys and excreted in urine. In patients with impaired renal function, tissue aluminum concentrations can increase and are associated with encephalopathy and osteomalacia.

Aluminum compounds can alter absorption of other elements in the gastrointestinal tract. For instance, aluminum inhibits fluoride absorption and may decrease the absorption of calcium and iron compounds and salicylic acid, which, in turn, may affect the absorption of aluminum (Exley et al., 1996). The binding of phosphorus by aluminum in the intestinal tract can lead to phosphate depletion and, potentially, osteomalacia. Aluminum interacts with calcium in bone and kidney, resulting in aluminum osteodystrophy (Goyer, 1997). Aluminum may also alter gastrointestinal tract motility by inhibition of acetylcholine-induced contractions, which is probably why aluminum-containing antacids often cause constipation.

Toxicity

Acute aluminum toxicity is rare. Most cases of aluminum toxicity in humans are observed in patients with chronic renal failure, or in persons exposed to aluminum in the workplace, with the lung, bone, and central nervous system as major target organs. Aluminum affects similar target organs in animals and can produce developmental effects.

Lung and Bone Toxicity

Occupational exposure to aluminum dust can produce lung fibrosis in humans, but this effect is probably due to lung overload caused by excessive deposition of dust (Sjögren et al., 2007). Osteomalacia has been associated with excessive intake of aluminum-containing antacids in otherwise healthy individuals. This is assumed to be due to interference with intestinal phosphate absorption. Osteomalacia also can occur in uremic patients exposed to aluminum in the dialysis fluid. In these patients, osteomalacia may be a direct effect of aluminum on bone mineralization as bone levels are high (Soni et al., 2001).

Neurotoxicity

Aluminum is neurotoxic to experimental animals, with wide species and age variations. In susceptible animals, such as rabbits and cats, aluminum toxicity is characterized by progressive neurological impairment resulting in death associated with status epilepticus (WHO, 1997). The most prominent early pathological change is the accumulation of neurofibrillary tangles (NFTs) in large neurons, proximal axons, and dentrites of neurons of many brain regions. This is associated with loss of synapses and atrophy of the dendritic tree. Not all species show this reaction to aluminum. For instance, rats fail to develop NFTs or encephalopathy and monkeys develop NFTs only after more than a year of aluminum infusion. Impairment of cognitive and motor function and behavioral abnormalities are often observed. Whereas studies in animals have provided some insights into the mechanisms of the neurotoxicity of aluminum in experimental models, the relationship to any human disease is still uncertain.

Dialysis Dementia

This is a progressive, neurological syndrome reported in patients on long-term intermittent hemodialysis for chronic renal failure (Sjögren et al., 2007). The first symptom in these patients is a speech disorder followed by dementia, convulsions, and myoclonus. The disorder, which typically arises after three to seven years of dialysis treatment, may be due to aluminum intoxication. The aluminum content of brain, muscle, and bone increases in these patients. Sources of the excess aluminum may be from oral aluminum hydroxide commonly given to these patients or from aluminum in dialysis fluid derived from the tap water used to prepare the dialysate fluid. The high serum aluminum concentrations may be related to increased parathyroid hormone levels that are due to low blood calcium and osteodystrophy common in patients with chronic renal disease. The syndrome may be prevented by avoiding the use of aluminum-containing oral phosphate binders and by monitoring of aluminum in the dialysate.

The Chamorro people of the Marina Islands in the Western Pacific Ocean, particularly Guam and Rota, have an unusually high incidence of neurodegeneration of the Alzheimer type. Garruto et al. (1984, 1985) noted that the volcanic soils of the regions of Guam with a high incidence of amyotrophic lateral sclerosis and parkinsonism–dementia syndromes (ALS-PD) contained high concentrations of aluminum and manganese and were low in calcium and magnesium. They postulated that a low intake of calcium and magnesium induced secondary hyperparathyroidism, resulting in an increase in the deposition of calcium, aluminum, and other toxic metals, and eventually in neuronal injury and death. How and why aluminum enters the brain of these people is unclear. The incidence of these disorders dramatically decreased or disappeared during the past 60 years, possibly as the result of radical socioeconomic, ethnographic, and ecological changes brought about by the rapid westernization of Guam, rather than genetic factors (Garruto et al., 1985; Plato et al., 2003).

Alzheimer Disease

A possible relationship between aluminum and Alzheimer disease has been a matter of speculation for decades (Sjögren et al., 2007; Bondy, 2010). The basis for this relationship is the finding of increased aluminum levels in Alzheimer brains and neurofibrillary lesions in experimental animals, and the fact that aluminum is associated with various components of the pathological lesions in Alzheimer brain tissue. However, elevated aluminum levels in Alzheimer brains may be a consequence and not a cause of the disease. The reduced effectiveness of the blood–brain barrier in Alzheimer might allow more aluminum into the brain. Also, recent studies have raised the possibility that the staining methods in earlier studies may have led to aluminum contamination (Makjanic et al., 1998; Bondy, 2010). Furthermore, the NFTs seen in aluminum encephalopathy differ structurally and chemically from those in Alzheimer (WHO, 1997). Epidemiological studies examining the role of aluminum exposure in Alzheimer disease arrive at conflicting conclusions. An examination of 20 epidemiological studies concluded that there is not enough evidence to support a primary causative role of aluminum in Alzheimer disease, and aluminum does not induce Alzheimer pathology in vivo in any species, including humans (WHO, 1997). However, there is increasing evidence suggesting a link between aluminum in the brain and other neurodegenerative diseases (Kawahara, 2005; Bondy, 2010).

Treatment

Chelation therapy for aluminum, mostly in dialyzed and/or uremic patients, resembles that for iron overload, with deferoxamine and deferiprone (Blanusa et al., 2005).

Bismuth

Bismuth (Bi) is a metal with a stable valence of 3+. The name bisemutum is from German Wismuth, perhaps from the term weiβe Masse, for “white mass.” It was confused in early times with tin and lead due to its resemblance to those elements. Bismuth was shown to be distinct from lead in 1753. The solubility of most bismuth salts is low but can be affected by pH and the presence of sulfhydryl or hydroxy-containing ligands. The significance of environmental and occupational bismuth exposure is unclear. Human exposure to bismuth generally is due to medicinal use.

Trivalent insoluble bismuth salts such as bismuth subnitrate, subcarbonate, and subgallate are used for various gastrointestinal disorders including diarrhea, flatulence, constipation, cramps, and dyspepsia. Colloidal bismuth subcitrate, bismuth subsalicylate, and ranitidine bismuth citrate are widely used to treat peptic ulcer and Helicobacter pylori–associated gastritis. Outdated medicinal applications include the use of bismuth salts for treatment of syphilis, malaria, warts, stomatitis, and infections of the upper respiratory tract (Slikkerveer and de Wolff, 1996). A potential application includes the use of bismuth subnitrate to prevent cisplatin nephrotoxicity, probably due to a specific induction of renal MT (Kondo et al., 2004), although this does not appear to have been applied in practice. The use of α-particle-emitting bismuth compounds as radiotherapeutic agents and as antitumor agents shows some promise (Wild et al., 2011).

Toxicokinetics

Most bismuth compounds are insoluble and poorly absorbed from the gastrointestinal tract or when applied to the skin. The three widely used compounds, colloidal tripotassium dicitrato bismuthate, bismuth subsalicylate, and ranitidine bismuth citrate, are all poorly absorbed (<1%) (Tillman et al., 1996). The highest concentrations of bismuth are found in kidneys, and to a lesser extent in the brain, liver, and bone (Slikkerveer and de Wolff, 1996; Larsen et al., 2005). Passage of bismuth into the amniotic fluid and fetus has been demonstrated. Bismuth is cleared from the body through urine and feces (Gregus and Klaassen, 1986). Traces of bismuth can be found in milk and saliva. The elimination half-life is reported to be about 21 days, depending on bismuth compounds.

Toxicity

Bismuth-containing medications are consumed worldwide and the risk of bismuth-related toxicity in the general population is relatively low. The main target organs for bismuth toxicity are kidney, brain, and bone (Slikkerveer and de Wolff, 1996; Tillman et al., 1996; Larsen et al., 2005). Acute renal injury is related to very high doses of bismuth, or to oral intake of organic bismuth compounds such as bismuth sodium triglycocollamate or thioglycollate, particularly in children. The tubular epithelium is the primary site of toxicity, where bismuth produces degeneration of renal tubular cells and nuclear inclusion bodies composed of bismuth–protein complex analogous to those found with lead exposure (Fowler and Goyer, 1975). A large single oral dose of colloidal bismuth subcitrate damages the proximal tubes, but the damage is reversible in both humans and animals (Leussink et al., 2001).

An episode of bismuth-associated encephalopathy in France in the 1970s revealed a potential neurotoxic effect of bismuth, although it cannot be exclusively attributed to bismuth alone (Slikkerveer and de Wolff, 1996). High amounts of bismuth were found in the reticular and hypothalamic nuclei, in the oculomotor and hypoglossal nuclei, and in Purkinje cells after an eight-month exposure to bismuth. Axonal transport seems to influence the distribution of bismuth. Ultrastructurally, accumulation of bismuth was seen in lysosomes (Larsen et al., 2005).

Treatment

The most effective treatment of bismuth toxicity is to discontinue bismuth intake. Chelation therapy using dimercaprol (BAL), DMSA, and DMPS reduces the bismuth concentration in most organs (especially kidney and liver) and increase elimination of bismuth in urine. BAL was the only chelator effective in lowering brain bismuth concentrations (Slikkerveer and de Wolff, 1996).

Gallium

Gallium (Ga) has a very low melting point with the main valence state of 3+ (gallic), although the 2+ (gallous) form can also form stable gallium compounds. Gallium, stemming from Gallia meaning Gaul or France, was predicted to exist prior to being discovered in 1875 by its characteristic spectrum. Gallium is of interest because of the use of radiogallium as a diagnostic tool for the localization of bone lesions. Nonradioactive gallium nitrate has been used as an antitumor agent and in the treatment of hypercalcemia. Gallium is obtained as a by-product of copper, zinc, lead, and aluminum refining and is used in high-temperature thermometers, as a substitute for mercury in arc lamps, as a component of metal alloys, and as a seal for vacuum equipment. Gallium arsenide is a widely used semiconductor material. Gallium is the only metal other than mercury that is liquid at or near room temperature.

Toxicokinetics

Gallium salts are sparingly absorbed from the gastrointestinal tract, but accumulation in tissues can be observed after repeated administrations. The oral bioavailability is improved with gallium complexes such as gallium maltolate. Gallium accumulates mainly in bone, inflammatory lesions, and tumors, as well as in the liver, spleen, and kidney. It binds to plasma transferrin and enters cells by iron transport mechanisms. Urine is the major route of gallium excretion with lesser amounts in the feces (Fowler and Sexton, 2007; Chitambar, 2010).

Toxicity

The trivalent gallium cation biologically resembles ferric iron. It affects cellular acquisition of iron by binding to transferrin and interacts with the iron-dependent enzyme ribonucleotide reductase, resulting in decreased dNTP pools and inhibition of DNA synthesis (Chitambar, 2010). The abundance of transferrin receptors and ribonucleotide reductase renders tumor cells susceptible to the cytotoxicity of gallium. Use of bolus intravenous injection of gallium nitrate in the treatment of lymphoma and bladder cancer is limited by potential nephrotoxicity, which can be reduced by slow continuous infusion over several days (Chitambar, 2010). Gallium nitrate is an effective treatment for cancer-related hypercalcemia and diseases associated with accelerated bone loss including myeloma, bone metastasis, Paget disease, and osteoporosis. It accumulates in metabolically active regions of bone and favorably alters the mineral properties to enhance hydroxyapatite crystallization and reduce mineral solubility. Gallium inhibits osteoclastic bone resorption without poisoning the osteoclast cells, yielding a skeletal system with increased calcium and phosphate content and improved strength (Chitambar, 2010). Adverse effects may include nausea, vomiting, and anemia. Less frequent are gallium-induced neurological, pulmonary, and dermatologic effects.

Acute and chronic toxicity to lung (including alveolar and bronchioalveolar tumors), testes, and kidney is associated with exposures of gallium arsenide in animals, although the role of the individual metals in this response is unclear (Tanaka, 2004; Chitambar, 2010). There is little information regarding adverse effects of gallium compounds following occupational exposure, but renal toxicity was the primary side effect of gallium nitrate treatment in human clinical trials (Fowler and Sexton, 2007).

Gold

Gold (Au) was well known and highly valued since prehistoric times. It is widely distributed but usually in small quantities. The metal has a number of industrial uses because of its electrical and thermal conductivity. Monovalent organogold salts (eg, auranofin, aurothioglucose, gold sodium thiomalate) are used for the treatment of rheumatoid arthritis. Monovalent and trivalent coordinated gold complexes have antitumor potential (Kostova, 2006). Colloidal gold or gold nanoparticles are used to label subcellular structures for electron microscopy, carriers for drugs, and photothermal agents (Khlebtsov and Dykman, 2011).

Toxicokinetics

Gold salts are poorly absorbed from the gastrointestinal tract. The more water-soluble, therapeutic gold compounds are absorbed after intramuscular injection, and peak concentration in blood is reached in two to six hours. Gold is initially bound to serum albumin, and then distributes to various tissues. With continued therapy, the concentration of gold in synovium of affected joints is 10 times that of muscle, bone, or fat. Gold deposits are also found in macrophages, kidney, liver, testes, and skin. About 60% to 90% of gold is excreted via the kidney while 10% to 40% occurs via biliary excretion into feces. Chelators such as dimercaprol may increase the excretion of gold. Gold has a long biological half-life, and elevated tissue and blood levels can be demonstrated for months after cessation of treatment.

Toxicity

Contact dermatitis is the most frequently reported toxic reaction to gold and is sometimes accompanied by stomatitis, probably involving an allergic mechanism. Gold-induced allergic responses include delayed hypersensitivity, formation of intracutaneous nodules and immunogenic granuloma, as well as the occurrence of eczema (Hostynek, 1997).

The use of gold in the form of organic salts to treat rheumatoid arthritis may be complicated by the development of proteinuria and the nephrotic syndrome, which morphologically consists of immune complex glomerulonephritis, with granular deposits along the glomerular basement membrane and in the mesangium (Bigazzi, 1999; Hostynek, 1997). The pathogenesis of the immune complex disease is not certain, but gold may behave as a hapten and generate the production of antibody complexes for the glomerular deposits (Viol et al., 1977).

The health risks associated with gold mining, especially miners who used elemental mercury to amalgamate and extract gold, have been reviewed (Eisler, 2003). Gold miners have increased frequency of pulmonary diseases, including tumors, and increased prevalence of infectious diseases. Mercury intoxication associated with gold mining activities is well documented (Eisler, 2003).

There are limited data on the human toxicity associated with exposure to gold nanoparticles. In vivo and in vitro studies suggest that toxicity is related to the shape of the nanomaterial (Tarantola et al., 2011). Intravenous injection of gold nanoparticles is associated with inflammatory responses (Khlebtsov and Dykman, 2011).

Lithium

Lithium (Li) is one of the lightest metallic elements. It was discovered in 1817, and the name was derived from the Greek lithos for stone. On the periodic table of the elements, lithium shares its group with sodium and potassium, and is widely distributed in nature. Lithium is used in batteries, alloys, catalysts, photographic materials, and the aerospace industry. Lithium hydride produces hydrogen on contact with water and is used in manufacturing electronic tubes, in ceramics, and in chemical analysis. Groundwater contamination from man-made waste disposal could be a risk factor for the aquatic environment (Kszos and Stewart, 2003). Lithium carbonate and lithium citrate are widely used for mania and bipolar disorders. In this regard, lithium is active possibly through its effects on signal transduction, such as phosphoinositide hydrolysis, glycogen synthase kinase-3, and neurotropic cascades (Lenox and Hahn, 2000; Quiroz et al., 2004). Topical applications of lithium succinate are still used in the treatment of seborrheic dermatitis (Sparsa and Bonnetblanc, 2004).

Toxicokinetics

Lithium is readily absorbed from the gastrointestinal tract, with peak therapeutic levels at 30 minutes to three hours postingestion. It is not bound to plasma proteins, but associates with red blood cells. Lithium is distributed to total body water with higher levels in kidney, thyroid, and bone, as compared with other tissues. Excretion is chiefly through the kidneys with 80% of the filtered lithium reabsorbed. The usual elimination half-life is 12 to 27 hours, but it may rise to nearly 60 hours if renal function is compromised. Lithium can substitute for sodium or potassium on several membrane-bound transport proteins. It enters cells via the amiloride-sensitive sodium channel or the Na/H⁺ exchanger. The greater part of lithium is retained in the cells, perhaps at the expense of potassium. In general, it may be competing with sodium at certain sites, such as in renal tubular reabsorption (Timmer and Sands, 1999).

Toxicity

From the industrial point of view, except for lithium hydride, neither are the other salts considered hazardous nor is the metal very toxic itself. Lithium hydride is intensely corrosive and may produce burns on the skin because of the formation of hydroxides (Cox and Singer, 1981). Intoxications related to lithium exposure are mainly related to its medicinal uses (Timmer and Sands, 1999), as the therapeutic index of lithium is very narrow. In this regard, 0.7 to 1.2 mmol/L is considered an adequate therapeutic blood level, while blood levels only threefold higher commonly result in severe symptoms such as seizures and coma. The toxic responses to lithium include neuromuscular changes (tremor, muscle hyperirritability, and ataxia), central nervous system disorders (blackout spells, epileptic seizures, slurred speech, coma, psychosomatic retardation, and increased thirst), cardiovascular disturbances (cardiac arrhythmia, hypertension, and circulatory collapse), gastrointestinal symptoms (anorexia, nausea, and vomiting), and renal damage (albuminuria and glycosuria). The renal lesions are believed to be due to temporary hypokalemic nephritis. Long-term sequelae from acute lithium poisoning include cognitive losses such as impaired memory, attention and executive functions, and visuospatial deficits (Brumm et al., 1998).

Chronic lithium nephrotoxicity and interstitial nephritis may occur with long-term exposure even when lithium levels remain within the therapeutic range. Lithium nephrotoxicity primarily targets distal and collecting tubes, with a higher incidence of proteinuria and associated glomerular pathology (Markowitz et al., 2000). Chronic lithium-induced neurotoxicity, nephritis, and thyroid dysfunction may occur, especially in susceptible patients with identifiable clinical risk factors such as nephrogenic diabetes insipidus, older age, abnormal thyroid function, and impaired renal function (Oakley et al., 2001).

Acute lithium overdose produces neurological sequelae and cardiac toxicity, which can be fatal (Offerman et al., 2010). The toxicity may be treated by the administration of diuretics (amiloride) and lowering of blood levels via hemodialysis. Treatment with diuretics must be accompanied by replacement of water and electrolytes (Timmer and Sands, 1999).

Platinum

Platinum (Pt) is a malleable, ductile, silvery-white noble metal. Naturally occurring platinum and platinum-rich alloys have been known for a long time. The first European reference to platinum appeared in 1557 and the element was isolated in 1741. In platinum compounds, the maximum oxidation state is 6+, while the 2+ and 4+ valences are most stable. Platinum is found in nature either in the metallic form or in a number of mineral forms in various ores. Environmental platinum levels are very low. Platinum compounds are used as automobile catalysts, in jewelry, in electronics, and in dental alloys. Platinum coordination complexes are very important antitumor agents. Occupational exposure can be higher than the exposure limit of 2 μg/m³ in some settings (WHO, 1991).

Toxicokinetics

Following a single inhalation exposure, most of the inhaled platinum is rapidly cleared from the lungs by mucociliary action, swallowed, and excreted in the feces, with half-life of about 24 hours. A small portion is detected in the urine, indicating very little platinum is absorbed. After intravenous administration of clinical doses, the drug has an initial elimination half-life in plasma of 25 to 50 minutes. More than 90% of the platinum in the blood is covalently bound to plasma proteins. After administration of the main metallochemotherapeutic form, cis-dichlorodiammine platinum(II) (cisplatin), high concentrations are found in the kidney, liver, intestine, spleen, and testes, but there is poor penetration into the brain. Only a small portion of the drug is excreted by the kidney during the first six hours. By 24 hours up to 25% is excreted, while by five days up to 43% of the administered dose is recovered in the urine (WHO, 1991; Hardman et al., 2001).

Toxicity

Platinum can produce profound hypersensitivity reactions in susceptible individuals (WHO, 1991). The signs of hypersensitivity include urticaria, contact dermatitis of skin, and respiratory distress, ranging from irritation to an asthmatic syndrome, following exposure to platinum dust. The skin and respiratory changes are termed platinosis. They are mainly confined to persons with a history of industrial exposure to soluble compounds such as sodium chloroplatinate, although cases resulting from the wearing of platinum jewelry have been reported (WHO, 1991). The complex salts of platinum may act as powerful allergens, particularly ammonium hexachloroplatinate and hexachloroplatinic acid. Platinum salt sensitization may persist for years after cessation of exposure (Brooks et al., 1990). Halogeno complex salts of platinum are potent allergens provoking Type I allergic symptoms in platinum refining workers. Skin prick tests can detect sensitization at an early stage and are the mainstay of surveillance programs (WHO, 1991; Linnett, 2005).

Antitumor Effects of Platinum Complexes

The platinum-coordinated complexes are important antitumor agents, including cisplatin, carboplatin, and oxaliplatin (Hardman et al., 2001; Wang, 2010). They are routinely administered, often in combination with other anticancer drugs, in the treatment of a wide spectrum of malignancies, especially epithelial cancers. Platinum complexes are neutral and have a pair of cis-leaving groups. Low intracellular chloride concentrations favor hydrolysis of chloride-leaving groups in cisplatin to yield a positively charged molecule, which then reacts with DNA and proteins, forming both intrastrand and interstrand DNA cross-links with guanine and/or adenine. In tumor cells, the replication of DNA is impaired due to cisplatin-induced DNA cross-links, while in normal cells, guanine is repaired before replication. The formation of DNA adducts with platinum is also responsible for cytotoxicity (WHO, 1991; Hardman et al., 2001; Wang, 2010).

Carcinogenic Effects of Platinum Complexes

Although cisplatin has antitumor activity in humans, it is considered reasonably anticipated to be a human carcinogen (NTP, 2011h) or a probable human carcinogen (IARC, 1987). Cisplatin is clearly carcinogenic in rodents (NTP, 2011h). In fact, in mice deficient in MT, cisplatin can induce liver carcinoma at clinically relevant doses (Waalkes et al., 2006). There are several other positive rodent studies with cancer end points after treatment with the metallochemotherapeutic (NTP, 2011h). Cisplatin is a strong mutagen in bacterial systems and causes chromosomal aberrations in cultured hamster cells and a dose-dependent increase in sister chromatid exchanges.

Toxicities of Platinum Antitumor Complexes

Cisplatin is a nephrotoxin, which often compromises its usefulness as a therapeutic agent. Platinum compounds with antitumor activity produce proximal and distal tubular cell injury, mainly in the corticomedullary region, where the concentration of platinum is highest. Associated with cisplatin nephrotoxicity is the risk for electrolyte abnormalities. In comparison, carboplatinum and oxaliplatinum, given at standard chemotherapeutic doses, are not considered as highly nephrotoxic (Markman, 2003).

Neurotoxicity is another dose-limiting factor, particular when platinum complexes are combined with other potential neurotoxic drugs such as paclitaxel. Hearing loss can occur and can be unilateral or bilateral but tends to be more frequent and severe with repeated doses. Marked nausea and vomiting occur in most patients receiving the platinum complexes but can be controlled with ondansetron or high dose of corticosteroids. Bone marrow suppression, manifested as anemia, neutropenia, and thrombocytopenia, is relatively common during treatment with platinum complexes, especially when given in combination with fluorouracil. Carboplatin treatment has a higher myelotoxic risk than cisplatin and oxaliplatin (Hardman et al., 2001; Markman, 2003).

Antimony

Antimony (Sb) is a metalloid that belongs to the same periodic group as arsenic. It was recognized in antiquity (3000 bc or earlier) in various compounds for its fine casting qualities, and the description of its isolation appeared in 1540. The name antimony may have come from the Greek words “anti” and “monos,” which means “opposed to solitude” as it was thought never to exist in its pure form. Most antimony compounds are of trivalent and pentavalent states. Antimony has many uses including in alloys, and in production of fireproofing chemicals, ceramics, glassware, and pigments. It is used medically in the treatment of the parasitic diseases, schistosomiasis and leishmaniasis (De Boeck et al., 2003; Sundar and Chakravarty, 2010). Occupational antinomy exposure comes from industrial emissions. Food is the major route for environmental exposure, but the exposure levels are generally low. The average daily intake from food and water is estimated at about 5 μg (ATSDR, 1992; Sundar and Chakravarty, 2010).

The disposition of antimony in the body resembles that of arsenic. Most antimony compounds are absorbed from the lung and the gastrointestinal tract. The major sites of antimony accumulation are the liver, kidney, lung, spleen, and blood. The accumulation of antimony in blood may be due to high affinity of trivalent antimony for erythrocytes (ATSDR, 1992). In humans and rodents, pentavalent antimony is only sparingly reduced to the trivalent form, and evidence of antimony methylation in mammals is low (Ogra, 2009). The pentavalent form is predominantly excreted in urine, whereas trivalent antimony is conjugated to GSH and is excreted via the bile and found mainly in feces.

Toxicity

Most information about antimony toxicity has been obtained from industrial experiences (Sundar and Chakravarty, 2010). Occupational exposures are usually by inhalation of dust containing antimony compounds, such as the pentachloride, trichloride, trioxide, and trisulfide (Sundar and Chakravarty, 2010). Acute toxicity from the pentachloride and trichloride exposures includes rhinitis and, in severe exposures, even acute pulmonary edema. Chronic exposure by inhalation of other antimony compounds results in rhinitis, pharyngitis, trachitis, and, over the longer term, bronchitis and eventually pneumoconiosis with obstructive lung disease and emphysema. Transient skin eruptions (antimony spots) may occur in workers with chronic exposure (Sundar and Chakravarty, 2010). Trivalent forms of antimony appear more toxic and may produce cardiotoxicity involving arrhythmias and myocardial damage, although the evidence of heart disease from industrial exposure to antimony is not strong (Sundar and Chakravarty, 2010). In rodent subchronic/chronic studies with antimony potassium tartrate, relatively low toxicity was reported (Lynch et al., 1999).

The chemicotoxicological similarity between arsenic and antimony has prompted research on mutagenic and carcinogenic potential of antimony compounds. Antimony trioxide is considered an animal carcinogen (IARC, 1987; Sundar and Chakravarty, 2010), but human data on antimony are difficult to evaluate with the frequent coexposure to arsenic (Leonard and Gerber, 1996; De Boeck et al., 2003). Antimony compounds are generally negative in nonmammalian genotoxicity tests, whereas mammalian tests usually give positive results for trivalent but negative results for pentavalent antimony compounds. The in vivo potential of antimony to induce chromosome aberrations appears inconsistent (Leonard and Gerber, 1996; De Boeck et al., 2003).

The metal hydride of antimony, stibine (SbH₃), is a highly toxic gas that can be generated when antimony is exposed to reducing acids or when certain batteries are overcharged. High-purity stibine is also used in the production of semiconductors and, like arsine (AsH₃), causes hemolysis.

Barium

Barium (Ba) is an alkaline earth metal found in the environment in the 2+ oxidation state. It was first identified in 1774, and named from the Greek word barys meaning “heavy.” Barium and barium compounds (barium carbonate, sulfate, chloride, and hydroxide) are used in ceramics, electronics, insecticides, rodenticides, pigments, and as x-ray contrast media. Barium is relatively abundant in nature and is found in plants and animal tissue. Some foods, such as Brazil nuts, pecans, and seafood, may contain high amounts of barium. Barium from natural sources may exceed Federal government standards in some freshwater, although the amount found in food and water usually is not high enough to be a health concern. Occupational exposure to barium primarily occurs in workers who inhale barium sulfate from working with the ore, barite, and barium carbonate dust during mining and manufacturing (ATSDR, 2007).

Insoluble barium sulfate is not absorbed from the gastrointestinal tract, and is nontoxic to humans. Ingested soluble compounds are absorbed, but vary greatly and are affected by many factors such as age, duration, dose, and amounts of other elements in the intestine. Aerosols of soluble barium compounds are well absorbed in the lung. Bone and teeth are the major sites of barium deposition, containing up to 90% of the body burden. The remainder of barium in the body is found in soft tissues, such as the lung, aorta, brain, heart, spleen, liver, and pancreas (Dallas and Williams, 2001). Once filtered by the glomeruli, barium is reabsorbed by the renal tubules with only small amounts appearing in the urine. The major route of barium excretion is the feces. The elimination half-life is about one to two weeks.

Toxicity

Occupational poisoning by barium is uncommon, but a benign pneumoconiosis (baritosis) may result from inhalation of barium sulfate (barite) dust or barium carbonate. This is not incapacitating and is usually reversible with cessation of exposure. Intentional or accidental poisoning from ingestion of an acute toxic dose (over 200 mg) of soluble barium salt results in intractable vomiting, severe diarrhea, and gastrointestinal hemorrhage. Cardiac arrest is often the cause of death (ATSDR, 2007). Profound hypokalemia and muscle weakness progressing to flaccid paralysis are the hallmarks of barium poisoning (Johnson and VanTassell, 1991). The mechanism of toxicity probably involves the blocking of calcium-activated potassium channels responsible for cellular efflux of potassium. As a result, intracellular potassium rises and extracellular levels fall leading to hypokalemia. The progressive muscle weakness seen in barium intoxication in humans could be due to barium-induced hypokalemia rather than a direct effect on muscles, which is not observed in experimental animals. Treatment with intravenous potassium appears beneficial.

Following long-term exposure to barium, nephrotoxicity has been observed in rats and mice. Animal studies designed to assess cardiovascular function have not found significant alterations. Barium compounds are not considered carcinogenic in rodents and there is no evidence in humans (Dallas and Williams, 2001; ATSDR, 2007).

Cesium

Cesium (Cs) is a soft silvery-gold alkali metal discovered in 1860, and named from the Latin word caesius meaning “sky blue.” Similar to mercury and gallium, metallic cesium exists in the liquid state at slightly above room temperature, and is used in vacuum tubes and in atomic clocks. Cesium compounds only have the 1+ oxidation state, and are used as catalysts in inorganic chemistry, in pharmaceuticals, as well as in scintillation counters. 137Cesium is a by-product of nuclear reactions and is used in radiation therapy (ATSDR, 2004c).

The Chernobyl nuclear plant accident in 1986 resulted in a large release of cesium into the atmosphere, which then spread as radioactive fallout into the soil, rivers, and lakes, causing serious ecological problems in Northern Europe. The transfer of radiocesium into the food chain and into sheep and reindeer may contribute to human cesium exposure (Howard and Howard, 1997). These ecological issues remain in some areas even decades after the original accident (Bell and Shaw, 2005).

Most cesium compounds are water soluble and are well absorbed through inhalation, ingestion, or skin contact. Once in the blood, cesium is rapidly distributed throughout the body, with higher concentrations in kidneys, skeletal muscle, liver, and red blood cells (Leggett et al., 2003). Cesium can cross the placenta and appears in milk. It mimics potassium for cellular transport. Urinary excretion is the primary route of elimination of cesium from the body. The biological half-life of cesium is variable, ranging from 50 to 150 days (ATSDR, 2004c). A physiologically based kinetic model has been developed to describe the distribution and retention of cesium in humans (Leggett et al., 2003).

Toxicity

Radioactive Cesium

Exposure to radioactive cesium (134Cs and 137Cs) is of much greater human health concern than exposure to nonradioactive cesium. The initial symptoms following radioactive cesium exposure include nausea, vomiting, and diarrhea. Local skin blistering is common when there is significant dermal contact. With continued exposure to radioactive cesium, adverse neurological and developmental effects can be observed. Symptoms can eventually progress to bone morrow suppression, infection, hemorrhage, and even death (ATSDR, 2004c).

Nonradioactive Cesium Compounds

Stable cesium (133Cs) compounds are relatively less toxic. High-dose exposure can cause irritation to the gastrointestinal tract and to the eye (ATSDR, 2004c). Cardiac arrhythmia and QT wave prolongation have been observed in several case reports following ingestion of cesium salts as homeopathic remedies for cancer treatment (ATSDR, 2004c; Dalal et al., 2004). Adverse developmental effects of cesium chloride have been observed in rodents (Messiha, 1994). Prussian blue has been approved in the treatment of cesium poisoning (Thompson and Callen, 2004).

Fluorine

Fluorine (F) was isolated in 1886 by Henri Moissan for which he was awarded the 1906 Nobel Prize in chemistry. Fluorides are organic and inorganic compounds containing the nonmetallic element fluorine. Fluoride is an essential component for normal mineralization of bones and dental enamel, and it has been widely used to reduce the prevalence and severity of dental caries in children and adults. Flurosilicic acid and sodium fluorosilicate have been used in water fluoridation since 1940s. Adequate intake level is about 0.05 mg/kg per day in adults but is much lower for infants (ATSDR, 2003a,b). Toxicologically important fluoride compounds include hydrogen fluoride and sodium fluoride. The major sources of fluoride intake in the general population are water, food, and fluoride-containing dental products. However, excessive intake of fluorides has been observed from environmental sources, including from drinking water with naturally high fluoride (Meenakshi and Maheshwari, 2006), or from exposure to indoor fluoride air pollution from the use of high fluoride-containing coal (Liu et al., 2002).

Fluorides are readily absorbed (75%–90%) from the gastrointestinal tract. Once absorbed, fluorides are rapidly distributed throughout the body. Approximately 99% of the fluoride in the body is found in bones and teeth. Fluoride is incorporated into bone by replacing the hydroxyl ion in hydroxyapatite to form hydroxyfluoapatite. Fluoride in bone can be remobilized slowly as a result of the ongoing process of bone remodeling, especially in the young children. Fluoride is readily transferred across the placenta but poorly transferred to breast milk. Fluorides are mainly excreted in urine. Plasma and urine fluoride levels are related to fluoride intake and are a biomarker for excess exposure, while hair, fingernails, and tooth enamel are indicators of long-term response (ATSDR, 2003a,b).

Toxicity

Dental Fluorosis

Excessive fluoride intake from water during the period of enamel formation in children can cause dental fluorosis. In its mild form, dental fluorosis is characterized by white, opaque areas on the tooth surface. In its severe form, it is manifested as yellowish brown to black stains and severe pitting of the teeth. Dental fluorosis incidence and severity in some instances can be decreased by the cessation of water fluoridation (Clark et al., 2006). Inappropriate use of fluoride toothpaste and fluoride supplements in young children is a risk factor for dental fluorosis (Browne et al., 2005). Dental fluorosis is more common and severe in areas of endemic environmental fluorosis (Meenakshi and Maheshwari, 2006).

Skeletal Fluorosis

Long-term exposure to very high oral doses of fluoride or occupational exposure to cryolite dusts can result in skeletal fluorosis. Cases of skeletal fluorosis are predominantly found in developing countries and are associated with high fluoride intake coupled with malnutrition (ATSDR, 2003a,b; Meenakshi and Maheshwari, 2006). Skeletal fluorosis does not usually manifest symptomatically until the disease attains an advanced stage. Fluoride is mainly deposited in the neck, knee, pelvic, and shoulder joints and/or bones, which makes it difficult to move or walk. The symptoms of skeletal fluorosis are similar to arthritis, and early on include sporadic pain, back stiffness, burning-like sensation, pricking and tingling in the limbs, muscle weakness, and chronic fatigue. These symptoms are associated with abnormal calcium deposits in bones and ligaments. In the advanced stage, symptoms include osteoporosis in long bones, and bone outgrowth. The vertebrae may fuse together and eventually the victim may be crippled (crippling skeletal fluorosis), a disability often accompanied by kyphosis (humpbacked) or lordosis (arched back).

There are conflicting data regarding the association between fluoride exposure and the incidence of osteosarcoma, a rare bone tumor (ATSDR, 2003a,b). A case–control study in the United States found an association between fluoride exposure in drinking water during childhood and the incidence of osteosarcoma among males but not among females (Bassin et al., 2006). The National Toxicology Program in a rodent study found no evidence of carcinogenic activity in male or female mice or female rats exposed to sodium fluoride in the drinking water (NTP, 1990), although equivocal evidence of a response was observed in male rats based on a few osteosarcomas that occurred with a weak dose–response trend (NTP, 1990). Caution should be taken before any conclusions are made from such data and more studies are needed (Douglass and Joshipura, 2006).

Other health effects include respiratory tract, skin, and eye irritation following inhalation exposure to hydrogen fluoride or fluorine gas. Gastrointestinal symptoms occur with excess ingestion of fluoride (ATSDR, 2003a,b). Chronic endemic fluorosis may also lead to muscle fiber degeneration, low hemoglobin levels, skin rashes, neurological manifestations, compromised immunity, and endocrine effects (Meenakshi and Maheshwari, 2006). Endemic fluorosis from coal burning in China often occurs concurrently with arsenicosis (Liu et al., 2002).

Germanium

Germanium (Ge) is considered a metalloid such as antimony and arsenic, and was named in honor of the discoverers’ homeland Germany. The discovery of germanium as a predicted analog of silicon in the 1880s was a key confirmation of the developing theory of elemental periodicity. Chemically similar to tin, germanium can form a large number of organometallic compounds such as dimethyl germanium and germanium tetrahydride. Stable oxidation states include divalent and tetravalent germanium. In the semiconductor industry, germanium transistors found countless uses in solid state electronics up to the mid 1970s, but then were largely replaced by silicon. Currently it is used in infrared night vision systems, in fiber optics, in electronics, in solar cells, as a polymerization catalyst, and in alloys with other metals. Silicon germanide (SiGe) is rapidly becoming an important semiconductor metal for use in high-speed integrated circuits. Germanium is commercially derived from zinc ore processing or as a combustion by-product of certain coals. Ultrapure germanium can be obtained from other metals by fractional distillation of the volatile germanium tetrachloride.

The diet is the dominant source of germanium exposure in the general population while occupational exposure is predominantly by inhalation. Germanium concentrations in most foods are similar to the natural abundance level of about 0.6 to 1.3 ppm in soils, although higher levels have been reported in some canned foods (Faroon et al., 2007). Daily germanium intake from food in humans is reported to be about 1.5 mg, of which 96% is absorbed (Faroon et al., 2007). Intake of germanium from drinking water appears negligible. Considerable amounts of germanium are emitted into the air by coal combustion, although exposure from air is limited in the general population. There is no evidence of any essential function of germanium.

Inorganic germanium compounds are rapidly and effectively absorbed after oral exposure. Elemental germanium particles are likewise rapidly cleared from the lung and soon appear in distant tissues (Faroon et al., 2007). Absorbed germanium is widely distributed throughout the body with the highest concentrations occurring in many tissues including the liver, kidney, and spleen. Absorption and distribution appears to be largely independent of the germanium compound, as both sodium germanate and tetraethylgermanium are widely distributed without evidence of selective retention or storage after oral exposure in mice. In both humans and laboratory animals, germanium is excreted mainly via the kidneys with whole-body half-life of one to four days. Hair and nails may be useful media for biological monitoring (Faroon et al., 2007).

There appear to be no reports on systemic toxicity of germanium after occupational exposure. There are, however, at least 31 case reports of renal failure in humans after ingestion of inorganic or organometallic germanium compounds mainly through consumption of germanium-containing dietary supplements or elixirs for various diseases (Takeuchi et al., 1992; Tao and Bolger, 1997). Among these cases nine deaths were reported (Tao and Bolger, 1997). Levels of germanium consumed were ~15 to 300 g and were ingested over a period of two to 36 months (Tao and Bolger, 1997). Excessive germanium consumption from such sources induces various symptoms including renal dysfunction involving tubular degeneration, anemia, muscle weakness, and peripheral neuropathy. Recovery of renal function is slow and incomplete (Tao and Bolger, 1997). Although reports on the efficacy of germanium supplementation against diseases such as cancer and AIDS persist, germanium supplementation has not been clearly shown to be of value and the USFDA considers such germanium products to present a potential human health risk (Tao and Bolger, 1997).

Spirogermanium (2-aza-8-germanspiro[4,5] decane-2-propamine-8,8-diethyl-N,N-dimethyl dichloride) was neurotoxic to humans after intravenous injection for the treatment of cancer. The effects were reversible and included ataxia and seizures. Neurotoxic effects are also observed in dogs (Faroon et al., 2007).

There is no evidence of germanium carcinogenicity in humans. In rodents, limited testing indicates germanium is not carcinogenic in rats and it has no mutagenic activity (Faroon et al., 2007). Dimethyl germanium oxide can produce embryonic resorption and fetal malformations in animals (Faroon et al., 2007).

Indium

Indium (In) is a posttransitional metal, named after the indigo line in its atomic spectrum, which was discovered and isolated in the 1860s. It is a rare metal with a principal valence state of 3+ and is recovered as a by-product of zinc smelting. In its metallic forms, indium is used in liquid displays, semiconductors, alloys, solders, and as a hardening agent for bearings. Indium arsenide and indium phosphide are chemical forms commonly used in semiconductors (Tanaka, 2004). The most common isotope of indium is slightly radioactive, a characteristic exploited in medical imaging and nuclear medicine. Indium is considered to be a nonessential metal.

The human daily intake of indium has been estimated in the range of 8 to 10 μg. The most common routes of exposure for the general population are inhalation and ingestion while in occupational exposure inhalation predominates and dermal absorption is possible with the use of indium for nanotechnology. Indium compounds are poorly absorbed when ingested or after intratracheal instillation but may show moderate absorption after inhalation (Zheng et al., 1994; Fowler, 2007). Indium derived from oral or intratracheal instillation of indium phosphide is uniformly distributed between major organs and is excreted in the urine and feces (Zheng et al., 1994). Ionic indium is transported bound to transferrin and is cleared from the blood within three days of an intravenous injection in mice (Fowler, 2007).

Toxicity

There appear to be no meaningful reports of local or systemic indium toxicity in humans after oral or inhalation exposure. Animal data on indium indicate that toxicity is related to the chemical form and route of exposure (NTP, 2001). Acute toxicity in animals is generally greatest after inhalation or intravenous injection, and limited after oral exposure (NTP, 2001). In this regard, intravenous injection of indium chloride in mice or rats produces extensive renal and liver necrosis (Fowler, 2007). Intratracheal instillation of indium chloride produces severe inflammation and pulmonary damage with fibrosis in mice (Blazka et al., 1994). Lung instillation of indium phosphide can produce alveolar or bronchiolar cell hyperplasia in hamsters (Tanaka et al., 1996). The intratracheal instillation of indium phosphide produces little systemic toxicity (Oda, 1997). Inhalation of indium tin oxide is a potential risk for lung diseases in humans (Nagano et al., 2011). The developmental toxicity of indium has been recently reviewed by Nakajima et al. (2008). Indium trichloride showed no evidence of reproductive toxicity in mice, although it did adversely affect fetal survival. Teratogenic effects have been observed with intravenously injected indium compounds in rats and hamsters, but not in mice. Oral indium is teratogenic only at doses that induce maternal toxicity. Inhalation of indium phosphide or oral exposure to indium chloride by pregnant rats results in fetal indium concentrations that are similar to maternal blood levels (NTP, 2001; Nakajima et al., 2008) indicating the placenta does not perturb indium.

Because of its use in the microelectronics industry, indium phosphide was tested recently by the National Toxicology Program (NTP, 2001). After inhalation of indium phosphide for up to two years there was clear evidence of pulmonary carcinogenic activity in both male and female rats and mice. This included production of lung adenoma and carcinoma after inhalation of indium phosphide. Concurrent genetic toxicity testing, specifically micronucleated erythrocytes in peripheral mouse blood, was negative (NTP, 2001). Further study indicated inhaled indium phosphide particles likely acted through chronic inflammation in conjunction with production of ROS and epithelial cell proliferation (Gottschling et al., 2001). Inhalation of indium tin oxide aerosol for two years increased the incidence of malignant lung tumors in male and female rats, but had no carcinogenic effect in mice (Nagano et al., 2011).

Palladium

Palladium (Pd) belongs to the platinum group metals. It was discovered in 1803, and named after the asteroid Pallas. Palladium occurs together with other platinum group metals (platinum, rhodium, ruthenium, iridium, and osmium) at a very low concentration in earth crust, and is recovered as a by-product of refining nickel, platinum, and other base metals. Palladium compounds commonly exhibit oxidation state of 2+, although compounds with oxidation state 4+ are observed. Organopalladium compounds also exist. Palladium is used in automobile catalysts, in dentistry (for crowns and bridges), in electrical appliances, and in jewelry and coinage. Environmental palladium levels are increasing, but exposure in the general population is low. Dental alloys and work in metal refining or catalyst manufacture can be major sources of palladium exposure (WHO, 2002; Satoh, 2007).

Palladium chloride is poorly absorbed from the gastrointestinal tract or from subcutaneous injection sites. After intravenous administration of palladium compounds, palladium is distributed to kidney, liver, spleen, lung, and bone. In cells, palladium compounds likely complex with amino acids, proteins, DNA, and other macromolecules. Orally administered palladium is poorly absorbed and eliminated in feces, whereas intravenous palladium is mainly eliminated in the urine. Half-lives range from five to 12 days (WHO, 2002; Satoh, 2007).

Toxicity

Palladium sensitization is a health concern, as very low doses are sufficient to cause allergic reactions in susceptible individuals (Satoh, 2007). Persons with known nickel allergy may be especially susceptible. Contact dermatitis is a main manifestation of palladium sensitivity, unlike that with platinum. Immediate hypersensitivity (type I) reactions to palladium have been reported in refinery workers sensitized to platinum (Ravindra et al., 2004). Palladium sensitization is often from dental alloys or jewelry. Occupational exposure to palladium salts may cause skin and eye irritation, and occasionally asthma (WHO, 2002; Satoh, 2007).

There is limited evidence that palladium chloride is carcinogenic after oral exposure in rodents, but the validity of this study has been questioned based on increased longevity of the treated group and lack of a specific target site (Ravindra et al., 2004; Satoh, 2007). Palladium compounds are negative in bacterial mutagenicity tests and in micronucleus test in human peripheral lymphocytes. Tetraammine palladium hydrogen carbonate induced a clastogenic response to lymphocytes in vitro but did not produce positive results in the micronucleus test (WHO, 2002). Some organopalladium complexes have been shown to have antitumor potential similar to that of cisplatin (WHO, 2002; Abu-Surrah and Kettunen, 2006).

Silver

Sliver (Ag) is a rare, naturally occurring element found as a soft, “silver”-colored metal. It was known since ancient times and was separated from lead as early as 4000 bc. The chemical symbol for silver, Ag, is from its Latin name argentum. Metallic silver and 1+ oxidation forms are common. Silver metal is used for jewelry, silverware, electronic equipment, and dental filling. Soluble silver salts (eg, silver nitrate, silver sulfide) have been used to treat bacterial infection. Silver halide is used in the manufacture of photographic plates, while silver sulfadiazine is used in the treatment of burns. Occupational exposure occurs mainly from inhalation of silver fumes and dusts in a number of settings (ATSDR, 1990; Drake and Hazelwood, 2005). Dietary intake is in the range of 70 to 90 μg per day, which is much less than the silver intake from medicinal uses. For drinking water disinfection, WHO permissible level is 0.1 mg silver/L (Pelkonen et al., 2003).

One of the recent uses of silver is in silver nanoparticles (AgNP), materials with sizes ranging from 1 to 100 nm, containing 20 to 15,000 atoms of silver. Because of their antimicrobial activity, AgNP are used in a variety of consumer products including medical devices, disinfectants, appliances, textiles, and water treatment. The primary routes of exposure for AgNP include lung skin and gastrointestinal tract (Chen and Schluesener, 2008; Ahamed et al., 2010). It has been reported that levels of AgNP >20 mg/kg iv is toxic (Shoults-Wilson et al., 2011).

Sliver compounds can be absorbed orally, by inhalation, and through damaged skin. Ingested silver compounds are absorbed at a level of less than 10%, and only 2% to 4% is retained in tissues. Metallic silver and insoluble silver compounds are not readily taken up by the body, and pose minimal health risk (Drake and Hazelwood, 2005). In mice given drinking water containing silver nitrate (0.03 mg/L for two weeks), silver was widely distributed to most tissues including muscle, cerebellum, spleen, duodenum, heart, lung, liver, and kidney (Pelkonen et al., 2003). Silver can cross the blood–brain barrier and produce long-lasting deposits in many structures of the nervous system (Rungby, 1990) and is located almost exclusively in lysosomes of neuronal cells (Stoltenberg et al., 1994). Uptake of silver into lysosomes probably occurs through a carrier-mediated process (Havelaar et al., 1998). Autopsy findings after silver treatment of burn victims indicate the highest levels occur in skin, gingiva, cornea, liver, and kidneys. Urine sliver analysis as a biomarker is useful only following a high degree of exposure because little silver is excreted in urine.

Toxicity

The most common health effects associated with prolonged exposure to silver compounds are the development of a characteristic, irreversible pigmentation of the skin (argyria) and/or the eyes (argyrosis). The affected area becomes bluish-gray or ash gray. This is most prominent in the areas of the body exposed to sunlight, as light acts as a catalyst by triggering the photoreduction of these compounds to form metallic silver, similar to the process of developing a photographic negative. Metallic silver is subsequently oxidized by tissue and is bound as silver sulfide. Black silver sulfide and silver selenide complexes bound to tissue are identified as silver particle deposits. Argyria has two forms, local and general. Localized argyria is caused by direct, local contact with silver such as through jewelry, and involves the formation of gray-blue patches on the skin or may manifest itself in the conjunctiva of the eye. In generalized argyria, the skin shows widespread pigmentation, often spreading from the face to most uncovered parts of the body.

Chelating therapy and dermal abrasion are ineffective in removing silver deposits from the body and there is no effective treatment for argyria. Argyria can be considered a mechanism for detoxication of silver by sequestering it in the tissues as nontoxic silver–protein complexes or silver sulfide (ATSDR, 1990; Drake and Hazelwood, 2005).

The respiratory tract may be affected in severe cases of silver intoxication. Chronic bronchitis has also been reported to result from medicinal use of colloidal silver (ATSDR, 1990). Large oral doses of silver nitrate may cause severe gastrointestinal irritation due to its caustic action. Lesions of the kidneys and lungs and arteriosclerosis have been attributed to both industrial and medicinal exposures. Animal experiments indicate that silver may disturb copper metabolism (Hirasawa et al., 1994) and that MT may protect against the toxic action of silver (Shinogi and Maezumi, 1993).

Relatively little is known concerning the human toxicity of AgNP. Prolonged exposure to high levels of AgNP in rodents is associated with alveolar inflammation and slight liver damage (Ahamed et al., 2010, Table 1). In addition, AgNP produced damage to the blood–brain barrier, astrocyte swelling, and caused neuronal degeneration in rodents (Tang et al., 2009).

Tellurium

Tellurium (Te) is a metalloid chemically related to selenium and sulfur. Discovered in the 1780s, tellurium is named after the Latin word for earth (tellus). It is naturally found as the telluride of gold or combined with various other metals. Produced most often as a by-product of electrolytic copper refining, tellurium is used as an additive to improve metallurgic characteristics of copper, steel, and lead alloys (Gerhardsson, 2007). Tellurium vapor is used in “daylight” lamps and as a semiconductor in combination with other metals. It is also used in explosives, specialized glass, and thermoelectric and electronic devices.

Tellurium in food is probably in the form of tellurates. The estimated human daily intake is about 100 μg. Condiments, dairy products, nuts, and fish have relatively high concentrations of tellurium. Some plants, such as cactus, accumulate tellurium from the soil. The average body burden in humans is about 600 mg, mainly in bone.

The biochemistry and toxicity of inorganic and organometallic tellurium compounds have been reviewed (Taylor, 1996; Nogueira et al., 2004). Soluble tetravalent tellurates, absorbed into the body after oral administration, are reduced to tellurides, partly methylated, and then exhaled as dimethyl telluride. The dimethylated form is responsible for the characteristic garlic odor in persons intoxicated by tellurium compounds. Food is the main source of tellurium for the general population, while in industrial exposure inhalation would predominate. Some organometallic tellurium compounds are absorbed through the skin. Respiratory absorption data are limited, but inhaled tellurium compounds are likely well absorbed. After oral exposure of tellurides, 10% to 20% of the ingested dose is absorbed (Gerhardsson, 2007). The kidney, bone, and liver accumulate tellurium and it is estimated that bone stores may have a half-life of up to two years or more (Gerhardsson, 2007). The urine and bile are the principal routes of excretion. Tellurium crosses the blood–brain barrier and the placenta.

Toxicity

Of toxicological importance are elemental tellurium, the gases hydrogen telluride and tellurium hexafluoride, and the water-soluble sodium or potassium tellurites and tellurates (Gerhardsson, 2007). Many organometallic forms of tellurium exist. Tellurates and tellurium are of generally low toxicity, but tellurites are typically more toxic. Acute intoxication by inhalation results in sweating, nausea, a metallic taste, and garlic smelling breath. In fact, garlic breath is an indicator of exposure to tellurium by dermal, inhalation, or oral routes. The cases of tellurium intoxication reported from industrial exposure do not appear to have been life-threatening. Two deaths occurred within six hours of accidental poisoning by mistaken injection of sodium tellurite (instead of sodium iodine) into the ureters during retrograde pyelography (Gerhardsson, 2007). The victims had garlic breath, renal pain, cyanosis, vomiting, stupor, and loss of consciousness. The amount of sodium telluride injected was about 2 g.

In rats, chronic exposure to high doses of tellurium dioxide produces renal and hepatic injury (Gerhardsson, 2007). Rats fed metallic tellurium at 1% of the diet develop demyelination of peripheral nerves (Goodrum, 1998), probably due to the inhibition of cholesterol biosynthesis (Laden and Porter, 2001). Remyelination occurs after cessation of tellurium exposure (Morell et al., 1994). Tellurium compounds are genotoxic and/or mutagenic in hamster fibroblasts, fungus and bacteria (Degrandi et al., 2010), rat astrocytes (Roy and Hardej, 2011), human blood cells (Santos et al., 2009), and human promyelocytic cells (Sailer et al., 2004). In most cases, exposure to these compounds led to oxidative stress and DNA damage, and apoptosis was the predominant mechanism of cell death.

There are no data on human or animal carcinogenicity of tellurium; however, there are studies indicating an anticarcinogenic effect of tellurium (Gerhardsson, 2007). Lifetime exposure to sodium tellurite at 2 mg Te/L drinking water had no effect on tumor incidence in rats. Some tellurium compounds show mutagenic potential (Gerhardsson, 2007). Tellurium compounds produce hydrocephalus in rats after gestational exposure between days nine and 15.

Thallium

Thallium (Tl) is one of the most toxic metals. Thallium (from the Greek thallos meaning “a green shoot or twig”) was discovered in 1861. The thallium ion has a similar charge and ion radius as the potassium ion, and its toxic effects may result from interference with the biological functions of potassium. In addition, thallium disrupts mitochondrial function leading to increases in intracellular oxidative stress and apoptosis (Hanzel and Verstraeten, 2006, 2009).

Thallium is obtained as a by-product of the refining of iron, cadmium, and zinc, and is used as a catalyst in alloys, and in optical lenses, jewelry, low-temperature thermometers, semiconductors, dyes, pigments, and scintillation counters. It has been used medicinally as a depilatory. Thallium compounds, chiefly thallous sulfate, were used as rat poisons and insecticides. Once the commonest sources of human thallium poisoning, the use of thallium as rodenticides or insecticides is now banned (WHO, 1996; Peter and Viraraghavan, 2005). Industrial poisoning is a special risk in the manufacture of fused halides for the production of lenses and windows. Naturally high thallium concentration in soils and consequent uptake into edible plants in Southwest Guizhou, China, caused locally endemic chronic thallium poisoning (Xiao et al., 2004).

Thallium is absorbed through the skin and gastrointestinal tract. The highest concentrations after thallium poisoning are in the kidney. Following the initial exposure, large amounts are excreted in urine during the first 24 hours, but after that urinary excretion becomes slow and the feces become an important route of excretion. The half-life of thallium in humans has been reported to range from one to 30 days and depends on the initial dose. Thallium undergoes enterohepatic recirculation. Prussian blue, the most commonly used antidote, is given orally to break the enterohepatic recycling by trapping thallium secreted into bile and carrying it into the feces (WHO, 1996). Thallium can transfer across the placenta and is found in breast milk, and may cause toxicity in the offspring (Hoffman, 2000).

Toxicity

The triad of gastroenteritis, polyneuropathy, and alopecia is regarded as the classic syndrome of thallium poisoning (WHO, 1996). Other signs and symptoms also occur depending on the dose and duration of exposure. The estimated acute lethal dose in humans is 10 to 15 mg/kg. Death is due mainly to renal, central nervous system, and cardiac failure within a few days to two weeks (WHO, 1996; Galvan-Arzate and Santamaria, 1998; Peter and Viraraghavan, 2005).

Alopecia is the best known effect of thallium poisoning. Depilation begins about 10 days after ingestion and complete hair loss can occur in about one month. Other dermal signs may include palmar erythema, acne, anhydrosis, and dry scaly skin due to toxic effects of thallium on sweat and sebaceous glands. After oral ingestion of thallium, gastrointestinal symptoms occur, including nausea, vomiting, gastroenteritis, abdominal pain, and gastrointestinal hemorrhage. Neurological symptoms usually appear two to five days after acute exposure, depending on age and the level of exposure. A consistent and characteristic feature of thallium intoxication in humans is the extreme sensitivity of the legs, followed by the “burning feet syndrome” and paresthesia. Central nervous system toxicity is manifest by hallucinations, lethargy, delirium, convulsions, and coma. The acute cardiovascular effects of thallium are initially manifested by hypotension and bradycardia due to direct effects of thallium on sinus node and cardiac muscle. This is followed by hypertension and tachycardia due to vagal nerve degeneration. In severe cases, cardiac failure occurs (Mulkey and Oehme, 1993).

Major symptoms of chronic thallium poisoning include anorexia, headache, and abnormal pain. Other toxic effects of thallium include fatty infiltration and necrosis of the liver, nephritis, pulmonary edema, degenerative changes in the adrenals, and degeneration of the peripheral and central nervous system. In severe cases, alopecia, blindness, and even death have been reported as a result of long-term systemic thallium intake.

A recent review on thallium poisoning during pregnancy in humans gives a range of fetal effects from severe toxicity to normal development. The only consistent effect identified is a trend toward prematurity and low birth weight in children exposed to thallium during early gestation (Hoffman, 2000). Evidence that thallium is mutagenic or carcinogenic is scanty (Leonard and Gerber, 1997). In contrast, it may be teratogenic, especially with regard to cartilage and bone formation, but most of the evidence comes from birds and not mammals.

Treatment

Therapy for thallium intoxication combines forced diuresis, use of activated charcoal, prevention of reabsorption by administration of Prussian blue, and administration of potassium ferric hexacyanoferrate (WHO, 1996). Prussian blue is the recommended drug of choice in acute thallium poisoning (Hoffman, 2003). Desferrioxamine has also been tested and shown to remove thallium from the body (Fatemi et al., 2007).

Tin

Tin (Sn) is a silver-white metal. The name tin derives from the Anglo-Saxon, tin, through the Latin, stannum. Tin is one of the earliest metals known and was used as a component of bronze from antiquity. Because of its hardening effect on copper, tin was used in bronze implements as early as 3500 bc. However, the pure metal was not used until 600 bc. Metallic tin can combine with chloride, sulfur, or oxygen to form inorganic tin compounds (stannous, Sn²⁺; and stannic, Sn⁴⁺). Tin can also bind with carbon to form a number of toxicologically important organotin compounds including dimethyltin, dibutyltin, dioctyltin, triphenyltin, and tricyclohexyltin (ATSDR, 2005e). Currently, tin is used in the manufacture of various alloys, such as bronze and brass, for fabricating window glass and in solders, but was previously widely used in food packaging. Stannic chlorides are used in dyeing textiles. Organic tin compounds have been used in fungicides, bactericides, and slimicides, as well as in plastics as stabilizers. The average daily intake of tin from all sources is about 4.0 mg, considerably lower than the 17 mg estimated in previous decades, thanks to better food packaging technology (Winship, 1988; Blunden and Wallace, 2003). Organotin compounds are ubiquitous contaminants in the environment. Bioconcentration in aquatic organisms and ecotoxicity are dependent on the bioavailability of the particular compounds. Some tin compounds, especially organotins, show high bioavailability and may pose adverse effects toward aquatic ecosystems (Fent, 1996; Ostrakhovitch and Cherian, 2007).

Inorganic tin compounds are poorly absorbed after oral, inhalation, or dermal exposures. For example, only 3% of stannous and <1% of stannic compounds are absorbed from the gastrointestinal tract (Rudel, 2003). The majority of an oral dose of inorganic tin is excreted in the feces, while only a small portion of absorbed tin is eliminated via urine (Rudel, 2003; Ostrakhovitch and Cherian, 2007). Studies on animals reveal that administration of inorganic tin compounds reduces copper absorption (Yu and Beynen, 1995). The organotin compounds, particularly trimethyltin and triethyltin compounds, are better absorbed than inorganic tins (Ostrakhovitch and Cherian, 2007). The tissue distribution of tin from these organometallic compounds shows the highest concentration in the bone, liver, kidney, and lung, with smaller amounts in the muscle, spleen, heart, or brain. Tetraethyltin, triethyltin, and diethyltin undergo dealkylation to ethyltin compounds, whereas tributyltin is dealkylated to di- and mono-butyltin compounds. Phenyltin compounds undergo dearylation, mainly by microsome monooxygenase and P450 enzymes (Winship, 1988; ATSDR, 2005e).

Toxicity

Metallic tin and inorganic tin compounds are relatively nontoxic. Ingestion of food items contaminated with high levels of inorganic tins may cause acute gastroenteritis, while chronic inhalation of inorganic tins (eg, stannic oxide dust or fumes) may lead to benign nonfibrotic pneumoconiosis called stannosis (ATSDR, 2005e; Ostrakhovitch and Cherian, 2007).

Some organic tin compounds are highly neurotoxic, particularly triethyltin and trimethyltin, and cause encephalopathy and cerebral edema (Ostrakhovitch and Cherian, 2007). Toxicity declines as the number of carbon atoms in the chain increases. An outbreak of neurotoxicity of almost epidemic nature took place in France in the 1950s due to the oral ingestion of a preparation (Stalinon) containing diethyltin diodide for the treatment of skin disorders (WHO, 1980). Trimethyltin produces degenerative lesions in the hippocampus and associated structure of the limbic system in primates and rodents. The lesions are characterized by neuron cell apoptosis with astrocyte swelling and gliosis. Microglia and astrocyte activation with the production of proinflammatory cytokines may well contribute to the lesion. Triethyltin produces cerebral edema in experimental animals (Rohl and Sievers, 2005; ATSDR, 2005e).

Triphenyltin, tributyltin, dibutyltin, and dioctyltin compounds produce immunotoxicity in experimental animals, characterized by thymic atrophy, and suppression of T-cell-mediated immune response (ATSDR, 2005e; Ostrakhovitch and Cherian, 2007). Acute burns or subacute dermal irritation has been reported among workers as a result of dermal tributyltin exposure (Ostrakhovitch and Cherian, 2007). Exposure of pregnant animals to organotin compounds such as tributyltin and triethyltin may induce developmental and endocrine-disrupting effects (Adeeko et al., 2003; ATSDR, 2005e; Ostrakhovitch and Cherian, 2007).

Experimental studies have failed to find convincing evidence of carcinogenicity, mutagenicity, or teratogenicity of inorganic tin compounds (Winship, 1988). There is inadequate information to assess carcinogenic potential of organotin compounds in animals, and they are considered not classifiable as to human carcinogenicity (ATSDR, 2005e). Inhalation of indium tin oxide increased the incidence of malignant lung tumors in male and female rats (Nagano et al., 2011), but these effects may be due to exposure to the indium (see the section “Indium”). Studies of genotoxicity of organotin compounds have given mixed results depending on the specific compound and test system. Triphenyltin compounds are potential chromosome mutagens, inducing production of micronuclei and sister chromatid exchange in Chinese hamster cells (Ostrakhovitch and Cherian, 2007).

Titanium

Discovered in 1791, titanium is named for the Titans of Greek mythology. Most titanium compounds are in the 4+ oxidation state (titanic), but the 3+ oxidation state (titanous) and 2+ compounds can occur. Titanium can form organometallic compounds. Because of its resistance to corrosion, inertness, and tensile strength, titanium has many metallurgic applications, and finds use in aircraft, armor plating, naval ships, missiles, and as a component of surgical implants and prostheses. Titanium dioxide (TiO₂), the most widely used titanium compound, is used as a white pigment in paints, paper, toothpaste, and plastics, as a food additive to whiten flour, in dietary products and confections, and as a whitener in cosmetics (Lomer et al., 2004). Titanium complexes (such as titanium diketonate and budotitane) and titanocene complexes (such as titanocene dichloride) have undergone clinical trials as cancer chemotherapeutics (Caruso and Rossi, 2004; Kostova, 2009). Titanium tetrachloride (TiCl₄) is used to make titanium metal and other titanium-containing compounds. Occupational exposures to TiCl₄ can be of toxicological concern (ATSDR, 1997).

Approximately 3% of an oral dose of inorganic titanium is absorbed. The majority of the absorbed dose is excreted in the urine while unabsorbed titanium is excreted in the feces. The normal urinary concentration of titanium has been estimated at 10 μg/L (Kazantzis, 1981), and the estimated total body burden of titanium is about 15 mg. As a result of inhalation exposure, titanium accumulates in the lungs where it remains for long periods of time. Lung burdens increase with age and vary according to geographic location. Concentrations of titanium in liver (8 μg/g) and kidney (6 μg/g) are similar. Titanium may circulate in plasma bound to transferrin (Messori et al., 1999), which is thought to be a mediator for delivery of titanium to tumor cells (Desoize, 2004).

Toxicity

Occupational inhalation exposure to TiCl₄ can produce mild to severe pulmonary injury because it undergoes rapid hydrolysis on contact with water to form hydrochloric acid, titanium oxychloride, and TiO₂. Occupational exposure to titanium dioxide occurs during production. TiO₂ is classified as a nuisance particulate with a threshold limit value of 10 mg/m³ (ACGIH, 2005). Inhalation and instillation of titanium particles coated with alumina and/or amorphous silica produce mild and reversible pulmonary effects. The base pigment-grade and/or nanoscale TiO₂ particles produce minimal pulmonary toxicity, regardless of particle size and surface area (Warheit et al., 2005, 2006). In general, TiO₂ has been considered toxicologically inert regardless of route of exposure.

Epidemiological studies in humans have not found the association of titanium exposure with increased risk of lung cancer and chronic respiratory diseases (Fayerweather et al., 1992; Fryzek et al., 2003; IARC, 2010). Exposure of rats to TiO₂ via inhalation or intratracheal instillations caused malignant lung tumors (Jin and Berlin, 2007; IARC, 2010). The titanium compound, titanocene, when suspended in trioctanoin and injected intramuscularly, is carcinogenic in rats and mice (Jin and Berlin, 2007). According to IARC, there is inadequate evidence in humans and sufficient evidence in animals for the carcinogenicity of TiO₂ (IARC, 2010).

Titanium compounds and related metallocenes have recently shown chemotherapeutic activity toward gastrointestinal, breast, lung, and skin cancer (Desoize, 2004; Kostova, 2009; Olszewski and Hamilton, 2010). The mechanism of action of titanium compounds appears different from platinum compounds, and nephrotoxicity and myelotoxicity are not prominent. TiO₂ nanoparticles have photocatalytic activity raising concerns over their use in sunscreens. While some studies show TiO₂ particles cause oxidative damage to DNA (IARC, 2010), much about the safety or toxicity of these nanoparticles is still unknown making their use in sunscreens somewhat controversial (Burnett and Wang, 2011; Wiesenthal et al., 2011).

Uranium

Uranium (U) is an actinide metal with a long history of human use. It was discovered by the German chemist Martin Kloproth in 1789 in a mineral called pitchblende, and was named after Uranus, the planet, which had been discovered eight years earlier. Uranium naturally occurs in three radioisotopes: ²³⁴U, ²³⁵U, and ²³⁸U. The isotope ²³⁵U is of particular interest in nuclear weapons and nuclear reactions. Thus, uranium ore is chemically enriched to increase ²³⁵U content from 0.72% to 2% to 4%. The by-product of this process is called depleted uranium, which has decreased ²³⁵U and has 40% less radioactivity than natural uranium (ATSDR, 1999a,b). Depleted uranium has been used in military applications as warheads and tank armor. Nonmilitary uses include counterweights in airplanes and shields against radiation in hospitals (Craft et al., 2004). The chemical toxicity of uranium compounds is a health concern, rather than their radiation. Depleted uranium has the same chemical toxicity potential as natural uranium (ATSDR, 1999a,b; Craft et al., 2004).

Uranium has five oxidation states but only the 4+ and 6+ forms are stable enough to be of practical importance. The 6+ oxidation state forms the uranyl ion (UO²⁺), which further forms water-soluble compounds and is an important species of uranium in body fluids. The uranyl ion is also the most prevalent form in the environment (Sheppard et al., 2005). The ecotoxicity of uranium and uranyl carbonate complexes to plants, aquatic life, and birds has been recently reviewed (Sheppard et al., 2005).

Absorption of uranium compounds is low by all exposure routes. Absorption of inhaled uranium compounds occurs in respiratory tract via transfer across cell membranes, and is dependent on the particle size and solubility. Absorption from the gastrointestinal tract can vary from 0.1% to 6%, depending on the specific uranium compound. Once in the blood, uranium is distributed to the organs of the body. Uranium in body fluids generally exists as uranyl ion complexed with citrate and bicarbonate. Uranium preferentially distributes to bone (66%), liver (16%), kidney (8%), and then other tissues (10%). Two-thirds of the uranium in the blood is excreted in urine over the first 24 hours, but bone deposits of uranium last for about 1.5 years (ATSDR, 1999a,b; Craft et al., 2004).

Toxicity

The kidney is the most sensitive organ for uranium toxicity. The primary target is the renal proximal tubule, but the glomeruli may also be affected. Biomarkers of tubular effects include enzymuria, and increased excretion of low-molecular-weight proteins, amino acids, and glucose. Glucosuria is the most persistent biomarker for uranium-induced tubular dysfunction. Biomarkers for glomerular toxicity include urinary albuminuria, and elevated blood creatinine and urea nitrogen. Pathological and functional changes occur within days following acute exposure and are manifested by injury to renal tubular epithelial cells. Renal effects from acute exposure to uranium appear to have some relationship to peak kidney concentrations regardless of chemical form and route of exposure and are usually transient or reversible (Diamond and Zalpus, 2005). Overt renal effects are observed with peak kidney uranium concentrations above 2 μg U/g, but mild renal tubular dysfunction from chronic exposure may occur at even lower renal concentrations. There appears to be a trend toward increase in severity of renal toxicity with increase in length exposure and urinary uranium levels (Thun et al., 1985; Squibb et al., 2005).

Challenges remain for establishing any causal relationship between human uranium exposure and birth defects and/or gonadal endocrine dysfunction, because these studies are confounded by coexposure to other toxicants and inadequate exposure assessments (Craft et al., 2004; Hindin et al., 2005). However, uranium and depleted uranium can be developmental toxicants when given orally or subcutaneously to mice. Decreased fertility, embryo/fetal toxicity, teratogenicity, and reduced growth of the offspring have been observed in rodents following uranium exposure during different periods of gestation. Bone is a major site of uranium accumulation, and chronic uranium intoxication may result in diminished bone growth and osteoporosis. There is also increasing concern of potential neurotoxicity of uranium (Craft et al., 2004; Jiang and Aschner, 2006).

A higher incidence of lung cancer has been found in uranium miners and is probably due to radon and its daughter products, but not to uranium itself (ATSDR, 1999a,b). Gulf war veterans who were wounded subsequent to the explosion of armor-piercing shells containing depleted uranium often retain small fragments of the metal. This has created concern for the potential long-term effects of such embedded uranium fragments. Although there are no human data, a study in rats indicates that embedded depleted uranium fragments can cause localized proliferative reactions and sarcomas in rats (Hahn et al., 2002). However, many types of implanted pellets will cause local sarcomas in rats (Hahn et al., 2002).

Vanadium

Vanadium (V) is a transition metal discovered in the early 1800s and is named after the goddess of beauty in Scandinavian mythology, Vanadis, because of its beautiful multicolored chemical compounds. It is an essential trace element for microorganisms and bacteria, but definitive evidence for essentiality in mammals is lacking and no specific biochemical function for vanadium has been defined in humans (Lagerkvist and Oskarsson, 2007). Vanadium has several oxidation states, the most common being 3+, 4+, and 5+. The metal can be found as halides, such as the tetrachloride, and oxides, such as vanadium pentoxide. Organometallic vanadium compounds are generally unstable. Vanadium is recovered from vanadium-containing ores and from fossil fuels. Vanadium compounds are used in the production of special steels and alloys, in the manufacture of pigments, in photography, and as catalysts.

Food is the major source of human exposure in the general population (Lagerkvist and Oskarsson, 2007). Significant amounts of vanadium are found in seafood, mushrooms, dill seed, milk, meat, cereals, and vegetables. Concentrations in the drinking water largely depend on geographic location. Concentrations in rural air are much lower than in urban air, largely due to fossil fuel combustion. The dietary daily intake is estimated in the range from 10 to 60 μg (Lagerkvist and Oskarsson, 2007).

The lungs absorb about 25% of soluble vanadium compounds, but the absorption of vanadium salts from the gastrointestinal tract is generally poor (Lagerkvist and Oskarsson, 2007). Some dermal absorption of soluble compounds is possible but probably represents a minor route for humans. Once absorbed, extracellular vanadium will be in the form of vanadate (5+) and most likely in the vanadyl (4+) form after entering cells. After experimental exposure by various routes in rodents, the highest amounts of vanadium are found in the bone, kidney, liver, and spleen (Lagerkvist and Oskarsson, 2007). Brain levels are considerably lower than other tissues indicating limited transport across the blood–brain barrier. After oral exposure, vanadium shows a multicompartmental pattern with potential for accumulation and retention particularly in the bone (Lagerkvist and Oskarsson, 2007).

Toxicity

The toxicity of vanadium compounds usually increases as the valence increases, the pentavalent compounds being the most toxic. After occupational exposure to airborne vanadium, its toxic actions are largely confined to irritation of the respiratory tract, eyes, and skin (Lagerkvist and Oskarsson, 2007). Interestingly, there is usually a latent period of one to six days before the adverse effects of vanadium appear, although the effects are usually reversible. Bronchitis and bronchopneumonia are more frequent in workers exposed to vanadium compounds. In industrial exposures to vanadium pentoxide dust, a characteristic greenish-black discoloration of the tongue occurs due to deposition of vanadium. There is some evidence that a sensitization reaction may occur with repeated exposures (Lagerkvist and Oskarsson, 2007). Gastrointestinal distress, nausea, vomiting, abdominal pain, cardiac palpitation, tremor, nervous depression, and kidney damage have also been linked with industrial vanadium exposure (Barceloux, 1999a,b).

There is clear evidence that inhaled vanadium pentoxide is carcinogenic in mice and rats producing benign and malignant lung tumors in a large NTP study (Ress et al., 2003). Vanadium can act as a tumor promoter in the mouse lung (Rondini et al., 2010). There are no data indicating a carcinogenic potential for vanadium compounds in humans, although vanadium pentoxide inhalation causes a variety of DNA damage in exposed workers (Ehrlich et al., 2008). Vanadium compounds can be mutagenic in some systems (Lagerkvist and Oskarsson, 2007). Further work is required on vanadium carcinogenicity. Reproductive toxicology data are sparse and inconsistent, but there is some evidence of teratogenic potential in hamsters or mice (Lagerkvist and Oskarsson, 2007).

There are a variety of proposed pharmacological uses for vanadium compounds, including lowering cholesterol, triglycerides, and glucose levels, and some evidence indicates it can prevent tumor growth or formation in rodents (Lagerkvist and Oskarsson, 2007).

This work was supported by the Division of the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS). This chapter may be the work product of an employee or group of employees of the NIEHS, National Institutes of Health (NIH); however, the statements contained herein do not necessarily represent the statements, opinions, or conclusions of the NIEHS, NIH or the US government. Neither the content of this publication necessarily reflect the views or the policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government.