++
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).
++
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).
++
++
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).
++
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).
++
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).
++
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 (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).
++
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).
++
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).
++
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 (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).
++
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).
++
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).
++
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.
++
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.
++
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.
++
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).
++
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).
++
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 (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).
++
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).
++
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).
++
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 (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).
++
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).
++
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).
++
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).
++
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).
++
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).
++
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).
++
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).
++
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).
++
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).
++
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 (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).
++
++
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).
++
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).
++
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).
++
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 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 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).
++
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).
++
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).
++
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).
++
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 (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).
++
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).
++
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.
++
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).
++
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).