11.2.1 History and uses of antimony

Antimony is a fascinating element that has been used by human cultures since the Early Bronze Age. Excavations at Tello in Ancient Chaldea found fragments of an antimony base that dates back to 4000 BC. Antimony is an element present in relatively small concentrations in the earth’s crust. It is rarely found in pure form in nature, a fact recognized since antiquity. This may be the source of the name, which comes from the Greek words ‘anti’ (not) and ‘monos’ (alone). Antimony compounds are found in several types of ore and in petroleum. Although not used in large quantities, antimony is used extensively for many purposes, including being alloyed with a number of metals to improve their properties. Antimony (Sb) and its compounds are mainly used for the production of alloys, flame retardants, and in the glass industry. Antimony has been a constituent not only of printing-metal but also of lead acid batteries, pigments, an opacifier under glazes and enamels (the white oxide), and in the present day it has been used widely as a flame retardant in fabrics and in brake linings of motor cars. The most significant use of antimony is the production of antimony trioxide for flame retardation (ATSDR, 1992; Butterman and Carlin, 2004).

Antimony trioxide (+ 3 antimony), a white powder, is the single most important economic form, used primarily as a fire retardant. It is a stable substance that is not volatile and dissolves in water slightly. According to Butterman and Carlin (2004), ‘More than one-half of the primary antimony consumed goes into flame retardants. The remainder is used principally in glass for television picture tubes and computer monitors, and in ammunition, cable covering, friction bearings, lead-acid (LA) batteries, and solders. It is used in the same applications worldwide, but its distribution among applications differs from country to country.’ Antimony trioxide is also used in the manufacturing of ceramics and in glassware to remove bubbles and stabilize colour (ATSDR, 1992). The oxychloride (Sb₆O₆C₁₄) has wide applications as a flame retardant in which the reaction with Hd and OHd radicals reduces the rate of flame propagation so that the treated material will smoulder rather than burst into flames. Other uses are in semiconductors, pewter, Babbitt metal, and as pigments in paints and lacquers, glass and pottery. Modern use of antimony chloride as a flame retardant means that antimony may be present in domestic and other fabrics in the home, and in conveyor belting in workplaces. Antimony compounds are used as fire-retardants, in an attempt to meet the requirements of legislation designed to reduce the fire risk of furniture and furnishings. Antimony compounds added to fabrics have the property of restraining the spread of fire so that they smoulder and do not burst into flames.

Table 11.2 summarizes the history, uses and properties of antimony.

11.2.2 Structure and properties of antimony

Antimony is a metalloid residing in the fourth row of group 15A in the periodic table between arsenic and bismuth. It has four oxidation states: Sb(− 3), (0), (+ 3), (+ 5) and two stable isotopes of atomic weights 121 (57%) and 123 (43%). Antimony in its elemental form is a silvery white, brittle, fusible, crystalline solid that exhibits poor electrical and heat conductivity properties and can sublimate upon heating. A metalloid, antimony resembles a metal in its appearance and in many of its physical properties, but does not chemically react as a metal. It is also attacked by oxidizing acids and halogens (CRC, 1989). Metallic antimony is insoluble and inert at room temperature, but can burn when heated, forming white fumes of Sb2O3. Antimony compounds are soluble in very strong acid and basic solutions; under neutral conditions the predominant species is Sb(OH)6 for pentavalent forms and Sb(OH)3 for trivalent forms. Antimony is not readily convertible between its two cationic forms under neutral conditions (ATSDR, 1992).

Antimony is geochemically found in the common ore stibnite, which is primarily Sb2S3. The substance has been used since antiquity as a cosmetic to darken eyebrows. In ancient Egypt it was called ‘msdmt’ (variant mesdemet) which is derived from the Coptic CTDM [stem].

11.2.3 Toxicology of antimony

Antimony is a common contaminant of the atmosphere particularly in industrialized societies, largely because of its widespread presence in the surface of the earth, and to this is added contamination with the element from domestic use or from the neighbourhood of factories. Antimony is potentially toxic at very low concentrations and has no known biological functions (Smichowski, 2008). Elemental Sb is more toxic than its salts and inorganic species of Sb are more toxic than the organic ones. Sb(III) compounds are about 10 times more toxic than Sb(V) species. The International Agency for Research on Cancer (IARC) has reported that there is sufficient evidence for the carcinogenicity of antimony trioxide in experimental animals (IARC, http://www.inchem.org/documents/iarc/vol47/47-11.html). On the other hand, the US Environmental Protection Agency and the German Research Community have listed Sb as a priority pollutant but it has not been classified for carcinogenicity (US EPA, 1999; DFG, 1994). There is evidence that Sb is not detoxified via methylation in mammals, but the mechanism responsible for antimony’s genotoxicity is not clearly known. Daily intake of inhalated Sb from ambient air is approximately 0.6 μg assuming a volume of 20 m³ of air to be inhalated daily on average (Patriarca et al., 2000). Absorption from the lungs is on average ~ 15% depending on the size of the particles and the solubility of the specific Sb compounds. Children below five years of age have a higher air intake per unit and may absorb a higher percentage of inhalated metals (Patriarca et al., 2000).

Prior to the mid-1990s there was little evidence for microbial methylation of antimony (Craig, 1986). However, this possibility became of interest when a possible cause for sudden infant death syndrome (SIDS) (also known as cot death) was suggested (Richardson, 1994). The hypothesis was that flame retardants in mattresses and covers might undergo methylation to toxic gases by the action of S. brevicaulis or other microorganisms. Since one flame retardant was antimony, trimethylstibine might have been produced. It was claimed that S. brevicaulis had actually been isolated from damp crib mattresses. The hypothesis was vociferously supported by some groups, and there were accusations of a cover-up of important facts by ‘authorities’ (Sprott, 1996). Later work indicated that the predominant organism isolated from crib mattresses was not S. brevicaulis but a mix of common environmental Bacillus spp. (Warnock et al., 1995). A very detailed re-examination of old evidence and consideration of new information, carried out by an independent advisory committee for the British Department of Health, found no justification for the toxic-gas hypothesis (Lady Limerick, final report to British Government Department of Health, 1998, www.doh.gov.uk/limerch.htm).

The non-microbial leaching of antimony (as Sb₂O₃) from polyvinylchloride crib mattresses could account for the high variability associated with antimony levels in livers for both SIDS victims and other infants and for the elevated Sb levels in the hair of some healthy infants (Jenkins et al., 1998). The polyurethane inner foam of crib mattresses might be a site for toxic gas formation of group 15 elements, but determination of the level of Sb in crib mattress foam showed no correlation with the occurrence of SIDS. No volatile forms were detected in the headspace of mixed or monoseptic cultures of anaerobes containing polyurethane foams. There was no evidence for a causal relationship between levels of trimethylantimony or total trimethylantimony forms and SIDS (Jenkins et al., 2000).

Antimony produces an irritating skin rash affecting the trunk and limbs which is worse in warm weather and has been a major nuisance in process workers but quickly resolves on ceasing exposure for a few days. These so-called ‘antimony spots’ have been known for many years and have been likened to smallpox in appearance. They are symptomatic of excessive exposure to dirty working conditions and the remedy lies in controlling the dustiness of the process (Stevenson, 1965). Antimony workers have been considered prone to cardiac disease (Brieger et al., 1954). While it appears that when antimony compounds are given therapeutically, in schistosomiasis or leishmaniasis, there is a risk of toxic action on the heart, the evidence for heart disease from human exposure to antimony is not sustainable, and the findings of this study have not been confirmed.

Pneumoconiosis has been described in antimony miners (Karajovic, 1958; Klucik et al., 1962) although the observation was compounded by simultaneous silicosis. Antimony has been found in the lungs of process workers at very high levels with a long retention period. Lung cancer has also been associated with antimony exposure, especially due to occupational exposure. Animal experiments seem to confirm the carcinogenicity of antimony, but the quality of the investigations and the findings of animal exposures have been questioned. In studies of antimony as a trace element in the lung by neutron activation, small amounts of antimony were found in neoplastic tissue but did not increase with time, and there were no statistically significant differences in quantity between those with and without lung cancer (Kennedy et al., 1962).

11.2.4 Biomonitoring of antimony

In a study carried out by Komaromy-Hiller and coworkers 96% of random and 82% of 24-h urinary data of antimony were below the detection limits of their study (Komaromy-Hiller et al., 2000) (Table 11.3). The highest measured result was 48 μg/l corresponding to 64.9 μg/gCRT. Reference values for urinary antimony from the literature are in general less than 2 μg/l (0.19–1.1 μg/l (Minoia et al., 1990), 1 μg/l (Dezateux et al., 1997), or 1.23 μg/l median (Gebel et al., 1998)). However, a much higher toxic cutoff limit was recommended in another publication, 10 μg/l (Tietz, 1995).

The major metabolic pathway of Sb is oxidation in humans and methylation to a minor extent. Sb(111) is known to have 10 times higher toxicity than Sb(V) (Ogra, 2009).

Regardless of the route of administration, 45–55% of antimony will be excreted within the first four days (most being eliminated on the first day). After intravenous administration of Sb about the same percentage of the administered dose was excreted in the urine and faeces, whereas after intraperitoneal administration, about four times more Sb was excreted in the faeces than in the urine (Bailly et al., 1991). It is mainly excreted in bile and in urine. In bile the metal is combined with glutathione, the hepatic concentration of which may modulate the relative importance of these excretion routes. The Sb excreted in bile is partly reabsorbed in the intestine. Hematuria, dermatitis, nausea, vomiting, diarrhea, pharyngitis, and nephrotoxicity have been reported to be the clinical features of Sb toxicosis (McCallum, 2005).

The concentration of Sb in whole blood, urine, bile, and gastric fluid from an adult woman who had attempted to commit suicide by ingestion of an unknown amount of Sb₂S₃ was followed up for 160 hours. Figure 11.1 illustrates the evolution of the concentration of Sb in the various biological fluids. In bile and in gastric fluid, Sb is not detectable 100 hours after the ingestion, whereas in blood and in urine, the concentration is above the normal value (blood > 0.1 pg/100 ml; urine > 1 pg/g creatinine) one week after the ingestion.

Unanticipated increases in urinary antimony during infernos on buildings are associated with exposure (Edelman et al., 2003). Antimony in plastics is an integral part of fire retardant formulations (Einhorn, 1975; Landrock, 1983; Liepins and Pearce, 1976) as a charring agent, and acts with halogenated hydrocarbons to suppress fire. Plastics may have 7–30% antimony by weight. Combustion of plastics or particulate dusts containing antimony from the building collapse probably explains the increase in exposed firefighters. Although antimony concentrations were significantly higher in firefighters present during the collapse of the World Trade Center, and in Special Operations Command firefighters, they were well below recommendations for maximum exposure guidelines for workplace antimony exposures (35 μg/g creatinine) or the general population (3 μg/g creatinine) (Lauwerys and Hoet, 2001) and were less than reported industrial exposures (Kentner et al., 1995; Ludersdorf et al., 1987).

11.3.1 History and uses of cadmium

The use of cadmium has a short history. It was discovered in the nineteenth century, but the amounts used before the Second World War were limited. The major uses of cadmium have been rechargeable nickel–cadmium (Ni–Cd) batteries, pigments, stabilizers in polyvinylchloride plastics and protective plating for metals. The metal industry, the mining of zinc and lead ores and the manufacturing of phosphorus fertilizers have been the dominant sources of industrial cadmium emissions to the environment. In summary cadmium has five principal uses: (1) in pigments, (2) in stabilizers, (3) in Ni–Cd batteries, (4) as protective plating on steel, and (5) in various alloys (Bergbäck et al., 1994).

Cadmium is a rare element. Estimates of its abundance in the earth’s crust range from 0.1 to 0.2 ppm, making it the 67th element in order of abundance (Bewers et al., 1987). Because there are no separate ores of cadmium, at least none of commercial importance, cadmium is produced exclusively as a by-product, mainly in the recovery of primary zinc from its ores, from zinc-bearing lead ores, or in the processing of secondary materials, e.g. scrap metal.

Table 11.4 summarizes the history, uses and properties of cadmium.

11.3.2 Structure and properties of cadmium

Cadmium is the 48th element and a member of group 12 in the periodic table of elements. The most common oxidation number of cadmium is + 2. About 13,000 tons of cadmium is produced yearly worldwide, mainly for nickel–cadmium batteries, pigments, chemical stabilizers, metal coatings and alloys.

Cadmium is a silver-white metal which is ductile and easily worked; it can be rolled into sheets and drawn into wire and it is easily soldered. Cadmium appears naturally as Cd²⁺, often in complexes with inorganic (e.g. Cl–, F–) or organic ligands. In soil, the solubility of CdCO₃ and possibly Cd₃(PO₄)₂ controls cadmium mobility (Kabata-Pendias and Pendias, 1984). However, the solubility of cadmium is highly dependent on the pH and in acidic soils cadmium is one of the most mobile of heavy metals.

11.3.3 Toxicology of cadmium

The main route of exposure is through the lungs. Soluble cadmium salts accumulate and result in multi-organ toxicity, namely in the kidney, liver, lungs, brain, testes, heart, and central nervous system. Cadmium is listed by the US Environmental Protection Agency as one of 126 priority pollutants. The most dangerous characteristic of cadmium is that it accumulates throughout a lifetime. Cadmium accumulates mostly in the liver and kidney and has a long biological half-life of 17 to 30 years in humans (Hideaki et al., 2008). Cadmium can cause osteoporosis, anaemia, non-hypertrophic emphysema, irreversible renal tubular injury, eosinophilia, anosmia and chronic rhinitis. Cadmium is a potent human carcinogen and has been associated with cancers of the lung, prostate, pancreas, and kidney. Because of its carcinogenic properties, cadmium has been classified as a #1 category human carcinogen by the International Agency for Research on Cancer (IARC, 1993).

Unlike other heavy metals, cadmium does not generate free radicals by itself; however, reports have indicated superoxide radical, hydroxyl radical and nitric oxide radicals could be generated indirectly (Galan et al., 2001). Watanabe et al. (2003) demonstrated generation of non-radical hydrogen peroxide which by itself became a significant source of free radicals via Fenton chemistry. Cadmium could replace iron and copper from a number of cytoplasmic and membrane proteins like ferritin, which in turn would release and increase the concentration of unbound iron or copper ions. These free ions participate in causing oxidative stress via the Fenton reactions (Casalino et al., 1997; Waisberg et al., 2003). Watjen and Beyersmann showed evidence in support of the proposed mechanism. They showed that copper and iron ions displaced by cadmium were able to catalyse the breakdown of hydrogen peroxide via the Fenton reaction (Watjen and Beyersmann, 2004).

Casalino et al. (2002) suggested that cadmium binds to the imidazole group of the His-74 in superoxide dismutase SOD which is vital for the breakdown of hydrogen peroxide, thus causing its toxic effects. Cadmium inhibition of liver mitochondrial MnSOD activity was completely removed by Mn(II) ions, suggesting that the reduced effectiveness of this enzyme is probably due to the substitution of cadmium for manganese. These workers also observed antioxidant capacity of Mn(II) ions, since they normalize the increased TBARS levels occurring when liver mitochondria were exposed to cadmium.

Numerous reports in animal models have depicted that cadmium intoxication significantly increased the malondialdehyde (MDA) and glutathione peroxidase (GSH-Px) (Yang et al., 2003; Cosic et al., 2007). Free radicals generated by cadmium were scavenged by GSH directly or via the GSH peroxidase/GSH system. Acute intoxication of animals with cadmium has shown increased activity of antioxidant defence enzymes like copper–zinc containing superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase (Ognjanovic et al., 2003).

Beside oxidative stress-mediated toxicity, cadmium is also known to cause its deleterious effect by deactivating DNA repair activity (McMurray and Tainer, 2003). Although a number of mechanisms exist to prevent DNA mismatch such as direct damage reversal, base excision repair, nucleotide excision repair, double stand break repair and mismatch repair (MMR), cadmium inhibits only the MMR mode of repair. Jin et al. have shown that cadmium-induced inhibition of MMR in human extracts leaves about 20–50% of DNA mismatch unrepaired (Jin et al., 2003). Inhibition of MMR leads to the propagation of cellular errors, thus the toxic effects of cadmium can be amplified in cells by creating mutations in genes that induce further faulty functions. Studies have also shown that the number of cells with DNA single strand breaks and the levels of cellular DNA damage were significantly higher in cadmium-exposed animals.

Reports have shown that antioxidants like vitamin C and Vitamin E have shown protection against cadmium-induced toxicity in different animal models (Ognjanovic et al., 2003; Beytut et al., 2003).

11.3.4 Biomonitoring of cadmium

According to the IARC, cadmium and cadmium compounds are classified as class 1 human carcinogens. Besides that, Cd may affect renal function (Kjellstrom et al., 1977). For biological monitoring, blood, and urine cadmium levels are used. Blood cadmium generally reflects current exposure and the levels are usually between 0.2 and 0.8 pg/l (0.0018–0.007 pmol/l). Considerably higher concentrations (1.4–4.5 pg/l, i.e. 0.012–0.04 pmol/l) are observed in smokers (Elinder et al., 1994). According to McKelvey et al. (2007), crude weighted geometric blood cadmium concentrations range from 0.73–0.79 μg/l in males and 0.76–0.82 μg/l in females with means of 0.76 and 0.79 μg/l (95% Cl) respectively. This data, which was obtained in a US population, showed that Asian non-Hispanic subjects had the highest mean blood cadmium level of 0.99 μg/l (95% Cl).

In the study by Komaromy-Hiller and coworkers (Table 11.3), the pattern of urinary cadmium was shown to follow a lognormal distribution. A second group of individuals forming a second peak at higher concentration correspond to those with significant cadmium exposure. Their representative values for urinary cadmium agreed well with the results from two European study groups (0.38–1.34 |g/l (Minoia et al., 1990); 0.05–1.24 μg/l and 0.05–1.23 μg/g CRT (White and Sabbioni, 1998)) but were between some previously published results (0.5–4.7 μg/l (Iyengar and Woittiez, 1988); 0.59–0.77 μg/l (Kowal et al., 1979)). The 24-h urinary excretion of cadmium is a biomarker of lifetime exposure, while the concentrations of cadmium in blood reflect more recent exposure (Staessen et al., 1996).

11.4.1 History and uses of chromium

Chromium is a critical metal used in dozens of products that we rely on every day, but it is seldom used alone. The most common application is in metallurgical end uses in alloys, consuming 90% of virgin chromium. The addition of chromium adds corrosion and oxidation resistance to metals, making steel ‘stainless’. While other alloying elements, such as nickel and molybdenum, may also be added, chromium is an essential ingredient and no suitable substitute is known. Corrosion resistance extends the life of products, allows industrial activities to occur in harsh environments and with harsh chemicals, and reduces replacement costs.

On a worldwide basis, about 80% of the chromium mined goes into metallurgical applications. Much of this goes into the manufacture of stainless steel. About 15% is used in chromium chemicals manufacture and the remainder is used in refractory applications. In nearly all of these uses, the chemical properties of chromium are integral to its effectiveness. In metallurgical applications, the physical properties that chromium imparts to alloys are a major factor in its selection. However, in addition, the corrosion-resistant properties that are provided by chromium are usually essential. Indeed, chromium is what makes stainless steel ‘stainless’. In refractory applications, the inert nature of trivalent chromium oxide, either by itself or in combination with other refractory oxides such as those of iron, aluminium and magnesium, is the reason it is used in the most severe applications.

In addition to metallurgical uses, chromium is also used in refractoriness and foundry sands for its heat resistance, and in chemicals for leather tanning, pigmentation and wood preservation (Johnson et al., 2006). Copper chrome arsenic (CCA) wood preservatives contain arsenic pentoxide, hexavalent chromium (chromium trioxide or sodium dichromate) and copper(II) oxide or copper(II) sulphate. They are supplied as pastes or water-based concentrates that are diluted to between 1 and 10% w/w total salts and used in the industrial vacuum-pressure impregnation of timber. These products are used as a wood preservative to prevent fungal decay and infestations by wood-boring insects (Cocker et al., 2006).

Table 11.5 summarizes the history, uses and properties of chromium.

11.4.2 Structure and properties of chromium

Chromium and its compounds have a long history of industrial uses in the manufacture of a large number of high-volume products, such as stainless steel and pressure-treated wood. Occupational exposure to chromium is found among about half a million industrial workers in the US and several million worldwide (Zhitkovich, 2002; OSHA, 2006). Environmental exposure likely impacts dozens of millions of people drinking Cr-containing water, residing in the vicinity of numerous toxic sites and chemical manufactures and other industrial users. Although chromium can exist in several valence states, the most commonly encountered products contain this metal in the + 6, + 3 and 0 oxidative forms (Zhitkovich, 2005). Cr(0) is usually present in its metallic form, which typically occurs in alloys with other metals, particularly Fe and Co. Welding and other strongly oxidizing conditions convert chromium(0) to chromium(III) and chromium(VI). Chromium(III) is thermodynamically stable and is the final oxidative form found in all biological systems. Depending on the nature of the counterion, the solubility of Cr(VI) compounds varies from very high (salts with alkali metals) to moderate (salts of Ca, Mg, Sr, Zn) to very low (barium and lead salts).

Exposure to hexavalent chromium, Cr(VI), is associated with a wide range of toxic effects (Whiting et al., 1979; Costa et al., 1996). The greatest human exposures are from industrial uses, including chromate pigments, zinc chromate primer paints and other corrosion inhibitors, stainless steel machining and welding, chrome plating, leather tanning, and others.

11.4.3 Toxicology of chromium

Significant attention has been paid to the adverse health effects of chromium, which are highly dependent on oxidation state. There is sufficient evidence to demonstrate carcinogenicity in humans of hexavalent chromium in the chromate, chromate pigment, and chromium plating industries; limited evidence for carcinogenicity of chromic acid and sodium dichromate; and inadequate evidence for metallic and trivalent compounds (IARC, 1990a). Effects of hexavalent chromium exposure include respiratory cancer, kidney damage, and skin irritation (Fig. 11.2). The highest exposure to Cr(VI) occurs in chromate manufacturing, chrome plating, ferrochrome production and stainless steel welding. Welders employed in construction and small car repair shops are at particular risk of heavy exposure because of the absence or practical difficulties in the installation of exhaust systems removing Cr(VI)-containing fumes from the breathing area.

Exposure to Cr(VI) compounds, but not other oxidative forms of Cr, is a well-documented cause of respiratory cancers (IARC, 1990; Langard, 1990; Gibb et al., 2000). Cr(VI)-associated neoplasms are typically located in the lung, but risk of nasal cancers is also significantly increased (Davies et al., 1991; Satoh et al., 1994; Sunderman, 2001). Contrary to some very optimistic views that Cr(VI) carcinogenesis is caused only by massive exposures and therefore is no longer a concern (De Flora, 2000), recent epidemiological and risk assessment studies have actually found as much as 25% lifetime risk of dying of lung cancer under 52 μg/m³ permissible exposure limit (Gibb et al., 2000; Park et al., 2004). This standard originally adapted by OSHA in 1971 was lowered 10-fold to 5 μg/m³ in 2006 (OSHA, 2006), but even the new standard is expected to result in an additional 10–45 deaths per 1000 exposed workers (Salnikow and Zhitkovich, 2008).

Several Cr(VI) compounds are soluble (e.g. sodium or potassium chromates) and readily enter cells via an anion carrier (Buttner and Beyersmann, 1985). Once inside cells, Cr(VI) is reduced by a variety of chemical and enzymatic reductants (Myers et al., 2000; Borthiry et al., 2007), eventually to the next stable oxidation state, Cr(III). During this reduction, reactive Cr species (Cr(V) and/or Cr(IV)) are formed. These can directly cause oxidative-like damage (Sugden, 1999; Sugden et al., 2001) or they can generate ROS via redox cycling (Tsapakos et al., 1983; Borthiry et al., 2007). Inhalation of Cr-containing fumes, dusts, and particles is a prominent form of exposure, so respiratory effects of Cr (pulmonary fibrosis, chronic bronchitis, and lung cancer) are of special concern (Franchini et al., 1983; Deschamps et al., 1995). In the lung, bronchial epithelial cells line the airways and are therefore directly exposed to inhaled chromium.

The redox balance of cellular thiols is critical for normal function and viability. A major role of the thioredoxins is to maintain intracellular proteins in their reduced state (Arner and Holmgren, 2000), and the redox status of the thioredoxin (Trx) system in some cells may be more critical to cell survival than is glutathione. The thioredoxins are presumed to be essential for cell survival as knockout mice lacking either Trx1 or Trx2 do not survive (Powis and Montfort, 2001; Nonn et al., 2003). Genetic suppression or inhibition of Trx results in increased ROS and apoptosis (Hansen et al., 2006) and increased sensitivity of cells to oxidants (Chen et al., 2006), whereas overexpression of Trx2 enhances protection from oxidant-induced apoptosis (Chen et al., 2006; Hansen et al., 2006). Factors which enhance Trx oxidation would therefore be expected to interfere with Trx activity and could decrease cell survival. Some heavy metals can cause Trx oxidation (Myers et al., 2008) but the mechanisms involved are not clear.

11.4.4 Biomonitoring of chromium

The scientific literature is replete with reports of biological monitoring of urine chromium in exposed populations (Minoia and Cavalieri, 1988; McAughey et al., 1988; Randall and Gibson, 1987). However, little use has been made of biological monitoring to investigate the exposure of residential populations potentially exposed to environmental chromium. This is largely due to the difficulty in the interpretation due to extremely high levels of urine chromium in both exposed and control populations.

Operator exposure occurs during the handling of copper chrome arsenic (CCA) treated timber and associated equipment contaminated with CCA (Garrod et al., 1999). Dermal exposure and ingestion were thought to be the main routes of absorption, and exposure by inhalation was considered to be low. Workers exposed to copper chrome arsenic (CCA) wood preservatives have concentrations of chromium in urine that are significantly higher than those from non-occupationally exposed people but below the biological monitoring guidance value (BMGV) that would indicate inhalation exposure at UK occupational exposure limits for hexavalent chromium and arsenic.

A significant problem with the biomonitoring of residential chromium exposure is that, except in cases of gross exposure, it may be difficult to detect relatively small statistical increases above the background variation inherent in the normal population. This is particularly the case when there is a significant degree of misclassification in the potentially exposed population. Using dust sampling techniques, Stern et al. (1992) identified an elevated exposure to chromium in household dust in a population in Hudson County, New Jersey, residing on or adjacent to chromate production waste sites. They showed a statistically significant elevation in creatinine-adjusted urine chromium levels in a subgroup of this population with the highest levels of chromium in household dust. This association between elevated exposure to chromium in household dust and elevated chromium concentration in urine is consistent with environmental exposure to the chromate production waste.

Distribution of urinary chromium has been shown to follow a lognormal pattern (Komaromy-Hiller et al., 2000) (Table 11.3). The upper limit of their representative range was significantly higher than published reference values (0.04–1.5 μg/l (Minoia et al., 1990), 0.05–0.48 μg/l and 0.02–1.2 μg/g CRT (White and Sabbioni, 1998), 0.10–0.52 μg/l and 0.09–0.46 μg/g CRT (Brune et al., 1993), 0.68 μg/l (Kristiansen et al., 1997), and 0.57 μg/l (Kiilunen et al., 1987)).

11.5.1 History and uses of mercury

Mercury is one of two elements that are liquid at ambient temperature. It is 13 times heavier than water, and its unique properties have led to a wide variety of uses in industry and elsewhere. It is also found in a number of technological applications such as thermometers, barometers, thermostats, switches, gas meters, and especially fluorescent lights that may be found in residential buildings. In the past, organic mercury compounds were widely used as preservatives in household paints, and mercury antiseptics are still in use. Both the technologic applications and cultural uses of mercury provide the opportunity for it to be an indoor air pollutant in residential settings. Elemental mercury evaporates at a rate of 7 μg/cm²/h at 20 °C (Andren and Nriagu, 1979).

Mercury (Hg) is a globally spread pollutant due to characteristics such as low melting and boiling points, conversions between chemical forms and participation in biological cycles. As a result of anthropogenic emissions, the global atmospheric Hg deposition rate is approximately three times higher than in pre-industrial times and has increased by a factor of 2–10 in and around the most industrialized regions (e.g. Lamborg et al., 2002).

Mercury compounds are widely used as anti-fouling and mildew-proofing additives in paints, and smaller quantities are often added as preservatives against bacterial attack during storage. Mercury-containing paints are sold for both industrial and domestic purposes. The mercury content of a commercial paint is about 0.05% and the compounds are more or less volatile and may cause air pollution (Taylor, 1965).

Table 11.6 summarizes the history, uses and properties of mercury.

11.5.2 Structure and properties of mercury

Mercury is the 80th element of the periodic table of elements. Mercury is unique in that it is found in nature in several chemical and physical forms. At room temperature, elemental (or metallic) mercury exists as a liquid with a high vapour pressure and consequently is released into the environment as mercury vapour. Mercury also exists as a cation with an oxidation state of + 1 (mercurous) or + 2 (mercuric). Of the organic forms of mercury, methyl mercury is the most frequently encountered compound in the environment. It is formed mainly as the result of methylation of inorganic (mercuric) forms of mercury by microorganisms in soil and water. In the environment, humans and animals are exposed to numerous chemical forms of mercury, including elemental mercury vapour (Hg), inorganic mercurous (Hg(I)), mercuric (Hg(II)) and organic mercuric compounds (Fitzgerald and Clarkson, 1991). Mercuric fulminate is explosive in its dry state.

11.5.3 Toxicology of mercury

Mercury has been known as a toxic agent since the time of the earliest medical authors, and as an occupational hazard, in certain industries, it has received much attention. On the other hand, the general contamination of the biosphere has only recently been recognized by ecologists. The consumption of mercury and its compounds has, since World War II, shown a strong upward trend, especially in such uses that empirically lead to considerable losses of mercury to the environment. A large percentage of these losses include highly toxic and persistent mercury compounds.

Divalent mercury is covalently linked to a carbon atom to form organic mercury compounds. Methyl mercury (CH₃Hg⁺), thus formed, is extremely toxic and readily absorbed from the gastrointestinal tract of humans and animals. Environmental mercury is ubiquitous and consequently it is practically impossible for humans to avoid exposure to some form of mercury. All forms have toxic effects in a number of organs, especially in the kidneys (Zalups, 2000). Elemental, inorganic, and organic forms of mercury exhibit toxicologic characteristics including neurotoxicity, nephrotoxicity, and gastrointestinal toxicity with ulceration and haemorrhage. However, organic mercury has a lesser insult on the kidneys. Pars recta of the proximal tubules of the nephrons are the most susceptible region for the toxic effects of mercury (Zalups, 2000). Mercurous and mercuric ions impart their toxicological effects mainly through molecular interactions, for instance mercuric ions have a greater affinity to bind to reduced sulphur, especially in the thiol-containing molecules like GSH, cysteine, and metallothionein (MT) (Hultberg et al., 2001). However, the binding affinity of mercury to oxygen and nitrogen atoms is relatively very low when compared to sulphur (Valko et al., 2005). Therefore, toxic effects in the kidneys are mainly controlled by the biological interactions between MT, GSH and albumin (McGoldrick et al., 2003). Once inorganic mercuric ions gain entry into proximal tubular cells, it appears that they distribute throughout all intracellular pools (Houser and Berndt, 1988; Baggett and Berndt, 1985). The cytosolic fraction was found to contain the greatest content of mercury. Interestingly, the relative specific content of mercury was shown to increase to the greatest extent in the lysosomal fraction when rats were made proteinuric with an aminoglycoside or when rats were treated chronically with mercuric chloride (Madsen and Hansen, 1980). Although the current model of mercury-induced nephrotoxicity revolves around the conjugation of mercury ions with GSH and cysteine, other thiols, especially homocysteine and NAC, also play a vital role in handling mercury in the kidneys (Zalups and Barfuss, 1998; Zalups, 1998).

One of the major molecules that help in scavenging and reducing the toxic effects of mercury is metallothionein, a small, low molecular weight (6–7 kDa) protein, rich in sulphydryl groups (Yoshida et al., 2006). Not only mercury chloride but even mercury vapours have been shown to elevate the levels of MT (Cherian and Clarkson, 1976).

There are several in vivo and in vitro reports suggesting that when experimental animals were exposed to mercury (organic or inorganic) there was an induction of oxidative stress mainly because of the depletion of the naturally occurring thiols, especially GSH. Lund et al. (1993) demonstrated that administration of mercury resulted in GSH depletion and lipid peroxidation and also increased the formation of H₂O₂ in the kidneys of rats. They further demonstrated that it was the mitochondria of the rat kidney which were responsible for oxidative stress (Lund et al., 1991). In the in vitro experiment they showed that when mitochondria were supplemented with the respiratory chain substrate (succinate or malate) and blocker of complex I (rotenone) or complex III (antimycin A), there was a four-fold increase in the H₂O₂ formation with inhibition of complex III and a two-fold increase with complex I inhibition (Lund et al., 1991).

Mahboob et al. (2001) showed that when CD-1 mice were exposed to mercuric chloride, there were alterations in the lipid peroxidation (LPO), glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD) and GSH levels in different organs apart from kidneys (Yee and Choi, 1996).

Toxic insult of mercury also induces a number of stress proteins (Papaconstantinou et al., 2003; Goering et al., 2000). These large groups of proteins include heat shock proteins (HSPs) and glucose regulated proteins (GRPs). Papaconstantinou et al. (2003) showed an enhanced de novo synthesis of several stress proteins when chick embryos were exposed to mercury. Goering et al. (2000) also evaluated the differential expression of four HSPs in the renal cortex and medulla of rats exposed to mercuric chloride. It has also been demonstrated that there is a time-and dose-dependent accumulation of HSP72 and GRP94 stress proteins on mercury(II) exposure (Mahboob et al., 2001). While the accumulation of HSP72 was localized in the cortex, the GRP94 was accumulated in the medulla. In whole kidney, Hg(II) induced a time- and dose-related accumulation of HSP72 and GRP94. Accumulation of HSP72 was predominantly localized in the cortex and not the medulla, while GRP94 accumulated primarily in the medulla but not the cortex. The high, constitutive expression of HSP73 did not change as a result of Hg(II) exposure, and it was equally localized in both the cortex and medulla. HSP90 was not detected in kidneys of control or Hg-treated rats (Valko et al., 2005).

Delayed detoxification of mercury severely impairs methylation reactions (such as DNA, RNA, cobalamin, protein, phospholipids, histone, and neurotransmitter methylation), which further adversely affects growth factor-derived development of the brain and attention performance. Studies on monkeys have shown that ethyl mercury, like mercury vapour, crosses the cell membrane and is then converted intracellularly to inorganic mercury (Hg^2 +), which accumulates preferentially in the brain and the kidneys (Magos et al., 1985). Intracellular accumulation of mercury was shown to be higher for ethyl than for methyl mercury but the clearance rate was higher for ethyl mercury (Magos et al., 1985).

Toxic effects of mercury have also been observed in oligodendrocytes, astrocytes, cerebral cortical and cerebellar granular neurons obtained from embryonic and neonatal rat brains (Yee and Choi, 1996). The foetal brain is more susceptible than the adult brain to mercury-induced damage. Methyl mercury inhibits the division and migration of neuronal cells and disrupts the cyto-architecture of the developing brain.

11.5.4 Biomonitoring of mercury

Although dermal exposure and ingestion of metallic mercury are unlikely to cause acute toxicity, mercury vapour is efficiently absorbed into the bloodstream when inhaled (WHO, 1991) and distributed to other tissues. Up to 80% of inhaled mercury is absorbed and readily crosses the blood–brain barrier (Clarkson, 2002). Significant mercury excretion occurs within one week following exposure and can be found in urine and faeces at low levels after many months (Goldfrank et al., 1994) Blood mercury levels higher than 35 μg/dl and 150 μg/dl in urine are considered toxic in man (NPIS, 1996). Safety standards require that Hg vapour should not exceed 0.1 mg m^− 3 in air. Harada et al. (1997) reported that 200 mg l^–1 of Hg in blood and 50 mg g^–1 in hair are the provisionally established standards and anyone with higher concentrations is considered to be at risk of poisoning.

Blood and urine are common biological samples for the assessment of occupational mercury exposure, whereas hair is considered the best indicator for environmental exposure to methylmercury (Satoh, 2000). For those chronically exposed to mercury vapour, a good correlation has been observed between intensity of exposure and blood mercury concentration at the end of a work shift (Roels et al., 1987). Mercury in the blood peaks rapidly, however, and decreases with an initial half-life of approximately two to four days (Cherian et al., 1978). Thus, evaluation of blood mercury is of limited value if a substantial amount of time has elapsed since exposure. Without selective determination for organic and inorganic mercury (and this is usually the case), dietary methylmercury also contributes substantially to the amount of mercury measured in blood at low levels of elemental mercury exposure, limiting the sensitivity of this biomarker.

In general, the atmospheric concentration of mercury vapour equals the urinary concentration. The mean urinary concentration in the US general population is 0.72 μg/l (95% confidence interval, 0.6 to 0.8), and the mean blood concentration is 0.34 μg/l (95% confidence interval, 0.3 to 0.4) (CDC, 2003). In Europe (Brune et al., 1993) and other parts of the world (WHO, 1990), blood concentrations appear to be somewhat higher.

For most occupational exposure events, urinary mercury has been used to estimate exposure. The toxicokinetics of mercury in urine are much slower than in blood: urinary mercury peaks approximately 2–3 weeks after exposure and decreases at a half-life of 40–60 days for short-term exposures and 90 days for long-term exposures (Roels et al., 1991; Barregard et al., 1992). Therefore, urine is a more appropriate indicator for longer exposures than blood. Moreover, little dietary methylmercury is excreted in the urine, rendering the contribution of ingested methylmercury less significant. Although good correlation has been observed between urinary mercury levels and air levels of mercury vapour, such correlation was obtained after adjusting data for creatinine or specific gravity and after standardizing the amount of time elapsed after exposure (Roels et al., 1987) as considerable intra- and inter-individual variability has been observed in the urinary excretion rate (Barber and Wallis, 1986; Piotrowski et al., 1975). Exhaled air has been suggested as a possible biomarker of exposure to elemental mercury vapour because a portion of absorbed mercury vapour is excreted via the lungs.

Blood and scalp hair are the primary indicators used to assess methylmercury exposure. Methylmercury freely distributes throughout the body, and thus blood is a good indicator medium for estimating methylmercury exposure. Blood levels may not necessarily reflect mercury intake over time, however, as levels fluctuate with dietary intake (Sherlock and Quinn, 1988; Sherlock et al., 1982). Blood haematocrit and mercury concentration may be measured in both whole blood and plasma/serum, allowing the red blood cell to plasma mercury ratio to be determined, and interference from exposure to elemental or inorganic mercury to be estimated.

Scalp hair is also a good indicator for estimating methylmercury exposure (Phelps et al., 1980). Methylmercury is incorporated into scalp hair at the hair follicle in proportion to its content in blood. The hair-to-blood ratio in humans has been estimated as approximately 250–300:1 expressed as μg Hg/g hair to mg Hg/l blood. However, some difficulties in measurement do arise, such as inter-individual variation in body burden, differences in hair growth rates, and variations in fresh and saltwater fish intake, leading to varying estimates (Skerfving, 1974; Birke et al., 1972). Methylmercury is stable once incorporated into hair, and therefore the mercury concentration in hair gives a longitudinal history of blood methylmercury levels (Phelps et al., 1980; WHO, 1990).

Urine mercury concentrations show a bimodal distribution with the majority of the results at lower concentration values showing a lognormal distribution (Komaromy-Hiller et al., 2000) and calculated representative ranges agreed with an Italian study (0.1–6.9 μg/l, Minoia et al., 1990). However, the values presented by Komaromy-Hiller et al. (2000) were less than those from previous studies (10 μg/l (White and Sabbioni, 1998), 20 μg/l (Iyengar and Woittiez, 1988), and 20.1 μg/l and 17.7 μg/g CRT (Lie et al., 1982)).

Because mercury has a short half-life in blood (3 days), blood analysis is typically performed only shortly after an acute exposure (Agocs and Clarkson, 1995). All three forms of mercury (elemental, organic, and inorganic) can be detected in blood after an acute exposure, although the absorption and distribution to body tissues varies with the form. In contrast, urine is the best biological specimen when chronic inorganic mercury exposure is suspected (Agocs and Clarkson, 1995). Organic mercury is not detected appreciably in urine because it is excreted through the biliary system and faeces (Koos and Longo, 1976). The optimal sample for detecting inorganic mercury is a 24-hour urine collection, but improper collection and storage of the specimen may skew the results. The spot urine specimen can provide a close approximation of a 24-hour collection, particularly if it is adjusted for the concentration of the urine using specific gravity or the amount of creatinine present (Agocs and Clarkson, 1995). In addition, the spot urine has the practical advantage of easy collection, which may prevent collection and storage problems encountered with the 24-hour specimen.

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