**1. Introduction**

Heavy metal exposure has long been associated with major health care concerns pertaining to human health. The metals responsible for these adverse changes in human health need to include and focus on their role in carcinogenicity. As a premise, and for obvious reasons, there has been long-standing research and clinical focus among scientists and oncologists that has produced an extensive database. Using a variety of research engines, such as the National Institute of Medicine database (PubMed) and Google Search to explore the various aspects of heavy metals and their ability to induce cancer, we have attempted to review the reported studies in this area. Importantly, the information presented in the following pages represents linking heavy metal exposure to cancer, and specific human systems most susceptible to heavy metal carcinogenesis.

#### **1.1 Aluminum**

Aluminum is unique based upon the various mechanisms of action whereby it is listed based on its carcinogenic activity. More often, human exposure to aluminum is the result of contamination of food, interestingly in the process of manufacturing vaccines for human use, and when added as a chemical salt during a variety of processes used in industry for manufactured products for commercial purposes [1, 2]. The commercial products most susceptible are those in which aluminum salts are included in the list of added ingredients such as antacid tablets and antiperspirant deodorants [1–3].

Exposure to aluminum has had a direct link to the induction of human cancer, specifically breast cancer. Experimental studies performed in mice exposed to AlCl3, which interestingly is the identical form of aluminum used in the manufacture of antiperspirant deodorants for humans, demonstrated an induction of malignant transformation of epithelial cells located within mammary glands [1]. Similar results were observed following exposure to human breast tissue epithelial cells [1–3]. Aluminum has been implicated in the development of neoplasia, specifically in the development of sarcomas [4]. In the same report it was noted that one patient, following consistent chronic exposure to aluminum, developed an atypical transformation resulting in a neuroectodermal malignancy [4].

Regarding the carcinogenicity of aluminum, it was of importance to best identify the potential or possible mechanism(s) of action responsible for the induction of tumors following exposure. In research studies performed *in vitro* using human breast cells exposed to aluminum, researchers observed a reduction in the levels of the tumor suppressor gene BRCA1 mRNA [3]. This effect took place concurrent with decreased levels of other maintenance genes that regulate normal DNA levels [3]. In a complementary study, researchers exposed human breast cancer cells to aluminum and measured induced uncontrolled cell growth that was consistent [2]. Upon evaluation of these results, researchers concluded the aluminum acted as a metalloestrogen, meaning the reaction acted as an antagonist for the estrogen receptor complex on these breast cells. This kind of biochemical activity has been associated with the carcinogenesis ability following aluminum exposure [2].

When other body tissues were examined following aluminum exposure, in this specific case, the development of bladder cancer, it was revealed the bladder cancer cells had higher levels of aluminum compared to other heavy metals [5]. Although these studies were not able to directly link a cause and effect between aluminum and the induction of bladder cancer, it did provide suggestive evidence that aluminum exposure may play in the development of such cancers. This hypothesis lead to a formative therapeutic modality and that is to remove the aluminum. Use of chemical chelators has been recommended standard therapeutic procedure to be performed whenever aluminum exposure, thus poisoning, has been implicated in any physiological or cellular transformation. Physiological studies have demonstrated that when introduced into the human body, aluminum accumulates in both the soft and skeletal tissues. These are the target tissues for aluminum chelation [6]. The most common chelating agent used to detoxify aluminum exposure is desferrioxamine [6]. This chelator has proven very effective in removing the heavy metal aluminum from tissues, even though use of desferrioxamine is associated with its own level of toxicity that is associated with its clinical use in humans [6]. In order to address desferrioxamine toxicity, other chelating agents have been identified that show promise as candidates to replace desferrioxamine; however, the level of chelation associated with these agents has not yet equaled what has been demonstrated using desferrioxamine. Another option in order to reduce aluminum especially if is measured to be present in high amounts in public consumption, e.g., drinking water [7]. The method used in these conditions is reverse osmosis filtration. The procedure has been demonstrated to reduce significant aluminum levels when applied in a variety of industrial settings such as in the mining of copper and in other areas of industrial usages [7].

#### **1.2 Arsenic**

Arsenic is a heavy metal with known cytotoxicity in human tissues following exposure that can result in serious illnesses to those who are exposed. In a majority of cases, the path of exposure results from ingestion of foods and sources of

drinking water contaminated with arsenic [8–11]. There are also examples of arsenic exposure that are the result of occupational exposure through environmental pollution [8–11]. Examples of occupations that provide direct risks are smelting and arsenic based pesticide industries [12]. Another well documented source of heavy metal arsenic is through contact with contaminated soil thus consumption occurs through the food chain [13].

The correlation between heavy metal arsenic exposure and human cancers is relevant because arsenic detection within tumor tissue. Specific examples of arsenic and cancer development comes from research studies demonstrating a role for arsenic in the development of bladder, lung and skin malignancies [8, 11, 12]. An additional positive correlation linking arsenic with the development of human cancers focused on the relationship between arsenic exposure and mortality rates in patients diagnosed with a variety of cancers – colon, gastric, kidney, lung and nasopharyngeal cancers [13]. Importantly, based on epidemiological data from several studies shows a clear association between the induction of both pancreatic and non-Hodgkin's lymphoma following chronic arsenic low-level exposure [14, 15].

As with all heavy metals the question is what is/are the mechanism(s) responsible for the carcinogenic activity? As it pertains to arsenic, several studies have clearly demonstrated the mechanisms responsible for arsenic induced carcinogenicity involve the formation of reactive oxygen species (ROS) that indues critical epigenetic changes leading to damaging DNA repair mechanisms [8, 9, 12]. Specifically, these important epigenetic changes induced by arsenic have included alterations in DNA methylation, histones, and miRNA, all potentially responsible for the tumorgenicity associated with arsenic exposure [9, 12]. Another postulated mechanism of action for arsenic associated carcinogenicity is arsenic's ability to induce abnormal cell growth cycles in specific cell types such as macrophages and lung epithelial [16]. This was of particular concern because in lung epithelial cells, arsenic promoted a key and significant mechanism of action inducing carcinogenesis. In this cell population arsenic was demonstrated to alter the gene expression of the tumor suppressor protein *p53,* which in turn decreased the expression of *p21,* a downstream target [17]. Thus, the result of this association between heavy metal and tumor suppression gene inactivation was increased cellular proliferation, which demonstrated the most prominent mechanism of cellular transformation. Under these conditions what develops is major oxidative stress in these cells.

In studies conducted to further understand the association between arsenic and tumor cell initiation, another important activity was attributed to arsenic. Based upon further examination, it became clear that in co-existence with changes in cell transformation, intracellular levels of glutathione, a potent ant-oxidant agent, were reduced [18]. Lowering glutathione levels thereby reduces its antioxidant activity, thus allowing altered or transformed cells to escape from being removed by suppressor T-cell lymphocytes and NK cells [18].

Another postulated mechanism of action explaining the tumorgenicity of arsenic was proposed. This alternative mechanism was identified following arsenic exposure to human bladder cells. The mechanism was attributed to the ability of chronic exposure of arsenic to inhibit proper cellular morphology attributed to altered gene expression responsible for base excision repair [19]. The key enzymatic component here is the rate limiting step catalyzed by the enzyme DNA polymerase beta, an active enzyme in the process [19]. In the presence of arsenic, the enzymatic activity was reduced in a dose-dependent manner, meaning higher concentrations of arsenic, correlating with the lack of enzymatic activity [19]. These studies demonstrated chronic exposure to arsenic influenced changes in cellular morphology and altered the gene expression for specific proteins that control cellular proliferation [20].

In order to remove arsenic from the body the use of specific chelating agents have been shown to be most effective [21]. One such example of a very effective chelating agent is 2,3-dimercaptopropanol, otherwise known as British anti-lewisite. The molecule contains 2 functional thiol groups [21]. Significant clinical data has been accumulating over the past several years demonstrating the effective chelating action of this compound. 2,3-dimercaptopropane-1-sulphonate was administered effectively with minimum side-effects to a patient diagnosed with arsenic exposure [22]. This one study provided the clear and effective use of chelators to remove excess amounts of heavy metals [22]. Based on these observations, it was proposed that incorporation of antioxidants as a component of one's dietary consumption should be recommended in order to maximize anti-cancer and reduced oxidative stress [23]. Both rice and apple juice have been found to reduce cellular stress by the presence of antioxidant compounds, in part because they contain levels of vitamin C, a potent antioxidant. Oxidative stress is a major factor leading to a number of cellular disease pathologies.

As mentioned above, safety regulators have identified apple juice and rice as two food stuffs that can often serve as source of arsenic exposure in children. The level of 5 μg/L arsenic has been set as the lowest level of toxicity exposure [24]. With these dietary links identified other alternative methods to curb the toxicity linked to food stuffs have been presented to limit arsenic uptake using genetic modifications to rice that would inhibit the absorption of arsenic [24]. Another strategy has been to use specific micro-organisms that when co-existing with arsenic in the environment reduce metal uptake [24]. Alternatively, in the cultivation of rice, use of certain watering methods in agricultural would ultimately reduce the concentration of the heavy metal when present in the environment [24, 25].

#### **1.3 Beryllium**

The heavy metal beryllium is associated with human use through its application tied to industrial processes. Thus, human consumption is linked to environmental contamination documented to most often occur from its association in power plants where it is often found in dust [26, 27]. Thus, human contact occurs via inhalation as the most common method of contact. As an environmental contaminant, it has been linked to a number of respiratory ailments including carcinogenesis of the lung [27–29]. Initially the relationship between beryllium and lung cancer was suspect, but additional studies demonstrated a clear association between exposure, especially following higher levels of beryllium exposure [28–30]. Subsequently it was shown that use of beryllium in the dental industry was another opportunity for exposure through occupational risk [29]. Thus, the intervention of personal protective equipment (PPE) had a marked ability to reduce occupational exposure related to dentistry [31]. Importantly, patients diagnosed with stage III breast cancer were found to have elevated levels of beryllium [32]. However, in this study, beryllium was not the only heavy metal to be detected thus limiting a direct cause effect situation [32]. Another cancer, osteosarcoma has also been implicated to be the result of beryllium exposure [33].

There has been a paucity of defined experimental studies conducted to determine cause and effect between beryllium and the conduction of cancer and the mechanisms involved. Much of the focus has been to address issues correlated with lung exposure. One carcinogenic mechanism studied was the link between the elevated levels of tumor necrosis factor alpha (TNF-α), which is a cytokine secreted from a specific type of T-cell (CD4+ ) that are present in the lung [30, 34]. This factor plays an important role in the development and induction of inflammation [30, 34].

#### *Role of Heavy Metals in the Incidence of Human Cancers DOI: http://dx.doi.org/10.5772/intechopen.98259*

The association between TNF-α and beryllium implicates a direct link to the action of chronic inflammation exposure [30, 34].

Genetic changes are associated with beryllium exposure and have been observed to methylate the *p16* gene, which as stated previously is a known tumor suppressor gene that is activated following exposure to beryllium [30]. How to best address the removal of beryllium following exposure, in order to reduce its carcinogenetic properties, has focused on the use of chelators. Chelators are often used to remove heavy metal contamination from the body and in doing so they effectively reduce the toxic effects of exposure. Examples of effective chelators include – 4-dihydroxy-1,3-benzene disulphonic acid disodium salt [Tiron] and D-pencillamine (DPA), which demonstrated effectiveness following animal exposure [35–37]. It is of interest that a benzene derived compound would be used under any conditions because of the known carcinogenetic activity of benzene. Another chelator, meso-2,3-dimercaptosuccinic acid (DMSA) has been demonstrated to be effective when used and reported as a case-study to successfully treat a young child who was suffering from high level beryllium poisoning [38]. This experience suggested it is an effective treatment and therefore is worthy of further investigation [38]. Taken together this collective response indicates reduced exposure of beryllium will impact the overall health risks associated with its exposure [39, 40]. Addressing specific companies and other industrial sources linked to beryllium exposure should be used to support screening other methods to test employees for beryllium exposure among them. Furthermore, such companies should screen their employees using blood samples in addition to providing proper ventilation control measures in these plants and factories [40]. Along with instituting proper screening methods for employees to minimize exposure, additional strategies should be implemented, like better educating plant workers to use personal protective equipment the need arises [39, 40].

#### **1.4 Cadmium**

The heavy metal cadmium is a toxic element related to significant health consequences as an environmental contaminant. The sources of environmental exposure are generally associated with industries where it is present in their emissions. The element is used in industries such as mining, research with metallurgy, battery development, and preventing pigment precipitation when used in textiles [41]. A very serious issue regarding environmental cadmium exposure is soil contamination, as human exposure of cadmium most often is the result of ingesting contaminated food and water, inhalation and/or smoking [41, 42]. Regarding soil contamination, a specific source of cadmium contamination occurs as a result of landfills. High levels of cadmium have been found in landfills at concentrations that are much higher than recommended as tolerable in the maintenance of human health [43].Given that landfills are a major source of soil and water contamination, human exposure to cadmium more often is associated with the ingestion of contaminated foods [14, 44].

The main health issue associated with cadmium is the carcinogenicity following toxic exposure in humans, in particular, cancers of the breast, esophagus, intestines, lungs, stomach, testes [41, 45, 46], and possibly the gallbladder. The link to the gallbladder is identified in studies where gallstones have been associated as a pre-cancerous situation in many cases, when analyzed for the heavy metal contact in patients with cancer of the gallbladder [47]. When analyzed statistically significant levels of heavy metal content, cadmium and other heavy metals were found to be elevated [47]. The link between cadmium and carcinogenicity is still a significant human health concern. In other types of studies, in particular laboratory generated

experiments, the results of liver cells cultured in the presence of cadmium demonstrated the oncogenic transformation of these liver cells [44]. In patients with gliomas (cancer of the brain) heavy metal analysis detected high levels of cadmium, indicating cancer of the brain may be linked to heavy metal exposure [48].

Another body organ that has also been linked to cancer following cadmium exposure is the pancreas [15, 49]. Cadmium has also been linked to the development of blood disorders, in particular, the development of chronic myeloid and lymphoblastic leukemia. When analyzed compared to controls, patients with leukemia when tested were found to have increased concentrations of cadmium in the presence of reduced levels of magnesium in both blood and serum [50]. Another significant correlation between increased levels of cadmium and carcinogenicity is the association between cadmium in urine and the development of cancer of the gastrointestinal system [51].

As was observed with other heavy metals, the overall effects correlated with the development of a variety of cancers, focused attention to determine what were the exact mechanisms involved that led to initiation of the carcinogenic processes. With respect to cadmium, the focus of the carcinogenic mechanism involved the generation of reactive oxygen species (ROS) and epigenetic changes. Both contributed to the restriction of repair mechanisms that generated altered or damaged DNA. Both also contributed to the loss of apoptosis in affected cells [41, 46, 52, 53]. Whether the exposure to cadmium is either acute or chronic, the result targets the altered signal transduction mechanisms that induce altered gene regulation, which collectively contribute to the initiation of tumor growth [44]. In this key sequence of intracellular changes that takes place following cadmium exposure, important proteins are dysregulated either via upregulation or enhanced activity or perhaps via suppression of key molecular pathways. Such an example is the inhibition of EGR-1, which is a key protein that regulates cell destructive pathways, such as transcription [44].

Adverse toxic human exposure resulting from cadmium poisoning unfortunately is not associated with any standard therapeutic measures designed to address cadmium toxicity, if presented following acute or chronic exposure [54]. With that said, research has developed compounds that upon co-administration would be effective in reducing the toxicity of cadmium exposure. Examples of compounds developed to reduce cadmium toxicity are peptide ligands that have specificity for cadmium [54]. Importantly because of their widespread availability, meaning they occur naturally are flavonoid compounds that are present widely in fruits and in fact in most plants. Collectively whether they are fruits or vegetables, they all contain flavonoids. Flavonoids are potent antioxidants, thus chemically they reduce the development of ROS and also, they can assist in cadmium chelation [55]. With that said, it is still important to more fully understand how flavonoids, specifically via their structure inhibit the development of cadmium toxicity [55].

There is experimental evidence exploring whether the use of stem cells would be effective in ameliorating the cellular damage associated with cadmium toxicity. In a study performed using rats, the testicles were exposed to cadmium causing tissue damage [56]. Following the toxic exposure, animals received bone marrow derived mesenchymal stem cells. Upon clinical treatment it was observed that within the testes the levels of proteins responsible for apoptosis reached appropriate levels to restore apoptosis, thus effecting cell regulation [56]. Within the affected tissue there was evidence that the damaged tissue had been repaired. The implications of these observations suggested that the target of recovery delivered by mesenchymal stem cells was the restoration of mitochondrial apoptosis [56].

*Role of Heavy Metals in the Incidence of Human Cancers DOI: http://dx.doi.org/10.5772/intechopen.98259*

### **1.5 Lead**

One of the most researched heavy metals, in part because of its well-established effects on human health is lead. It has long been recognized as a significant environmental pollutant. There have been a number of pathways that either singularly or in concert attribute to impairing human health especially after chronic lead exposure [57–59].

A very common method of human lead exposure is the result of environmental contamination that involves soil and water contamination, especially sources of drinking water. Lead levels accumulate in deposits and exposure is manifested through the human food chain, thus its eventual presence in consumed food [57–59]. Another common source of lead that contributed to its exposure to humans was the presence of lead added as additive to gasoline. However, since 1995 lead has been banned as additive to gasoline for use in automobiles, yet it is still added to the fuel used for aviation purposes [59]. Another alarming link to human lead exposure was the discovery that lead was present in cigarette smoke; therefore, the lead levels in blood of smokers was reported to be high, as there is no safe concentration of lead regarding impact on human health [60]. Other occupational hazards also exist such as mining that contributes to the presence of lead exposure in those workers [57].

What have been the studies conducted to determine the overall level of toxicity of lead exposure to human health? A number of epidemiological studies have been conducted to determine the impact of lead on human health that has implicated the heavy metal as a causative factor in a number of human cancers. Whether lead exposure functions in terms of a direct cause vs. effect on inducing a specific cancer type is still under investigation [61]. In particular, interest has centered on a supportive, perhaps an additive, role in the maintenance of cancer rather than an initiating agent [61]. Lead has been detected along with other heavy metals that are also known for their impact on human health especially in children where it can impact the development of myelin, thus causing impairment in neurological development. An example was the detection of very high levels of lead in the water systems of Flint, MI and along with cadmium when analyzed in patients with gliomas (brain cancer) [61]. This observation demonstrated an increased toxic consequence to human health when such heavy metal contaminants are found together in human tissue or body fluids [61].

A study of patients with kidney cancer came to the conclusion that the cancer developed associated with high levels of lead [58]. This observation was later supported by evidence linking the development of renal cell carcinoma as associated with the presence of lead in the blood [60]. A link to the development of liver disease as the result of high lead concentrations levels along with a number of other heavy metals when tested in gallstones [47] suggested there may be a correlation between lead levels and disease of the gallbladder, perhaps inducing a pre-cancerous lesion [47]. When examined in workers exposed to high levels of lead, it was clearly demonstrated there was a significant positive correlation between the heavy metal and the presence of cancer in the lungs, along with a positive correlation linking lead exposure to the development of cancer of the brain, larynx, and bladder tissues [62]. In patients detected with pancreatic cancer, increased levels of lead in addition to several other heavy metals were measured, suggesting heavy metal exposure may contribute to the overall carcinogenicity of these heavy metals [15, 61].

The scientific literature has been devoid of studies devoted to the understanding of the mechanisms of lead induced carcinogenicity; however, several potential mechanisms have been proposed. Based on the current understanding of how lead can be carcinogenetic, one hypothesis has implicated lead as effectively disrupting internal genetic processes that result in the inability of tumor regulatory genes to function, inducing damage to DNA, and at the same time inhibiting repair of DNA damage [63]. In animal studies using mice exposed to lead, they showed that the heavy metal was capable of inducing reactive oxygen species (ROS) and by doing so the exposure effectively altered the sequence of specific gene function [63]. Another critical observation related to the ability of lead to disrupt normal cellular physiological processes were the results showing lead was effective in normal reactions controlling transcription. The reaction that mediates this transition was the substitution of lead for zinc that serves as a metal catalyst for several key enzymatic reactions that control DNA transcription [63]. Along with this observation was the important association of calcium in these enzymatic reactions based on epidemiological studies showing an increase in calcium correlated with a lower risk level for developing renal cell cancer. Consequently, as pointed out by the investigators, it clearly showed the need to have a clinical trial to determine the overall significance when these important cations and heavy metals come into contact with one another [60].

For clinical cases where heavy metals such as in lead poisoning are implicated in disease etiology and pathology, the therapeutic remedy recommended is chelation [64]. The most common chelators being used for reducing elevated lead levels are British, Anti-Lewsite, calcium disodium ethylenediaminetetraacetic acid (EDTA), D-penicillamine and Meso-2,3-dimercaptosuccinic acid. The use of any specific chelator depends on the individual clinical case [64]. Unfortunately, several of these chelating agents are associated with their own level of toxicity. Thus, to reduce the toxicity potential of these chelating agents, substitution using garlic in the clinically was found to effectively reduce blood levels of lead when lead toxicity was at moderate levels and also restricted lead associated symptoms when used clinically [64]. With the collective results, it goes worth saying the most effective treatment is to prevent lead exposure [58]. To achieve such a goal requires that all industries known to be associated with lead toxicity must address emissions of the toxic metal to the environment as well as to reduce with the goal to completely eliminate emissions such that workers are not exposed, which implies factories need to have established quality control guidelines for limiting lead exposure [64]. It stands to reason that the best and most effective way to remove lead contamination is to eliminate the sources of lead contamination [64]. In communities such as has been the case in Flint, MI that have been impacted because of lead leaching from old water pipes, the only remedy is to completely remove the old lead-based pipes for modern substitutes.

#### **1.6 Mercury**

Another heavy metal that has shown severe health consequences in humans following exposure is mercury. A minor portion of the heavy metal is found as a mineral in trace amounts with the major portion of mercury exposure the result of the environmental exposure following industrial use [65]. There are many different areas where mercury use has caused environmental problems. Common usage includes the long-term use of mercury in thermometers, dental fillings, in the manufacture of certain types of batteries, and in the burning of medical waste [65, 66]. Burning of fossil fuels has also been identified as a source of mercury pollution [65, 66]. Another contributing factor to environmental pollution and mercury is the fact that mercury often will be vaporized thus entering the atmosphere along with the other substances that when in the atmosphere, can then be incorporated into the soils and water systems [65, 67]. Regarding foods, consumption of large amounts of seafood,

#### *Role of Heavy Metals in the Incidence of Human Cancers DOI: http://dx.doi.org/10.5772/intechopen.98259*

e.g., tuna and shellfish has been identified as another link to environmental exposure especially methyl mercury [65, 68, 69]. Collectively these sources have contributed to the environmental contamination associated with mercury.

Regarding the association between the development of cancer and mercury, there has been suggestive evidence linking mercury exposure and kidney cancer. This association is based on the physiological role of kidney in removing toxic substances when present in the body, especially within the blood [65]. Several other cancers associated with mercury are both liver and gastric cancers [70]. Also related to liver and gastric cancers, in patients with cancer of the gallbladder, mercury has been detected in gallstones at significant concentrations [47].

As has been mentioned when discussing the other heavy metals, mercury has the potential to be associated with the development of malignancies that utilize specific mechanisms that regulate the control of tumor development. The mechanisms implicated are the capacity to generate free radicals (ROS), in addition to the disruption of DNA, whether it be related to transcription events, changes in or maintenance of its molecular structure [66]. With that said there are reported other carcinogenic mechanisms that are unique to mercury. One such mechanism that addresses the carcinogenic potential of mercury is its ability to reduce levels of glutathione [71]. As mentioned earlier, glutathione is a naturally occurring antioxidant and as such it can reduce the antioxidant activity of mercury via reactive oxidant species, by inhibiting the development of oxidative stress mediated through reactive oxidant production, thus minimizing its carcinogenic potential [71]. Cells that are exposed to oxidative stress have been demonstrated to have increased rates of peroxidation of lipids, which has been proposed as another functional mechanism inducing cancer [65]. Within cells mercury has been implicated to influence the function of microtubules, which by their very nature can disrupt cellular mitosis [66].

As was stated with the other heavy metals previously mentioned, the use of chelators has been a common therapeutic approach for removing mercury from the body. For mercury two of the most effective chelating agents are dimercaptosuccinic acid (DMSA) and dimercaptopropane (DMPS) [72, 73]. With that said, there are substances that have been untested in terms of their chelating abilities for their effect against mercury. Two of these substances, desferairox and deferiprone, were tested experimentally in rats where it was observed that the combination was able to effectively chelate mercury and reduce toxic effects of mercury [74]. An experimental chelating agent that has been postulated is thiol-modified nanoporous, a silica material [75]. When tested experimentally in animals, it was observed that this substance had the potential to chelate mercury with minimal toxicity [75].

## **1.7 Nickel**

The heavy metal nickel originally discovered as a major component constituting the earth's core has in recent years been the focal point of investigations to determine if its exposure, occupational or environmental, is involved in any carcinogenic action that compromises human health, through occupational exposure occurring primarily in the mining and refinement of nickel ore and producing metal alloys [76–78]. Nickel pollution of the environment results in its accumulation in organs and tissues within exposed organisms. As an example, nickel can enter the food chain through fish [79]. Alternatively, another route can take occur once contamination of the soil takes place [76]. On an industrial scale, nickel is often present in emissions released from oil refineries that have been identified as significant sources of environmental exposure and pollution, thus increasing the risk of exposure to those residents living close to these refineries [80].

Nickel exposure in humans has been associated with the development of a variety of cancers. Through epidemiological studies, evidence has shown there is a correlation between nickel exposure and the induction of cancer development in the lungs and in nasal and sinus tissues [13, 17, 81, 82]. In a study performed in breast cancer patients, when blood serum was analyzed for nickel it was found to be elevated significantly suggesting a potential relationship between the high nickel levels and the induction of breast cancer [83]. The correlation between nickel exposure and cancer has also been linked to the development of acute myeloid and lymphoblastic leukemia [84]. Additionally, when the urine was analyzed in patients with childhood leukemia, elevated levels of both nickel and 8-hydroxydehydrogenase implicating a causative role for nickel in inducing this childhood disease [84]. The role of nickel as a carcinogenic agent is implicated because of its ability to induce oxidative cellular damage as a primary mechanism of action [84].

Patients with pancreatic cancer, when measured for nickel levels, demonstrated elevated levels suggesting there is a positive correlation, even though other heavy metals were detected [15]. In addition, a study came to the conclusion that there may be a link between chronic nickel exposure, along with concomitant exposure of other heavy metals, to the development of T-cell lymphoma [85] and also liver cancer [13]. Collectively, the implications of these reports suggest the carcinogenic action of nickel.

Discussion of nickel and cancer addresses the need to focus on potential mechanisms of action. Several have been implicated. One mechanism involves the ability of nickel to influence noncoding RNA expression. A study demonstrated that nickel was effective in inducing materially expressed gene regulation (gene 3 MEG3) by its ability to influence the methylation of its associated promoter element [81]. This process was an effective inhibitor of PHLPPI and up-regulator of hypoxia-inducible factor-1α. Both are proteins recognized for their effective role in the processes involved in carcinogenesis [81]. As has been reported for other heavy metals, nickel as well can induce the formation of free radicals, a known carcinogenic action [86]. Exposure to nickel has been demonstrated to influence the status of the transcription and regulation status of mRNAs and also involve microRNAs [78]. Implicated in these reactions is the ability of nickel to influence immunity and the immune response, especially when it involves inflammation and the immune response, which in itself has also been implicated as having a significant role in carcinogenicity [78]. Nickel and its role in influencing the inflammatory response has been researched using animals and in combination with human cells [82]. These studies came away with the observation that there is an association between nickel exposure and cancer [78].

In addition to nickel's association with cancer, inflammation has also been investigated when tested using both animal and human cells. After dose–response studies were conducted it was determined that exposure to nickel increased the expression of certain proteins, specifically SQSTM1 and TNF. Both are known to have specific functions in the inflammation process [82]. As was observed with other heavy metals, nickel has been suggested to induce cellular following exposure epigenetic changes, an example is alteration in DNA methylation [82]. This conclusion is suggested from results that demonstrated exposure to nickel induced histone H3K4 tri-methylation [87]. The reactions associated with nickel exposure have been correlated with faulty transcriptional activation that can be a blueprint for the development of cancer [87].

Although chelation has been widely applied as a mechanism to remove heavy metal contamination, when applied to alleviate nickel contamination has produced different results. A very effector for chelating nickel, especially the cancerlinked nickel carbonyl, sodium diethyldithiocarbamate to the extent that it is the

recommended remedy in the clinical setting [88]. With respect to environmental contamination, the compound ethylene diaminetetraacetic acid (EDTA) was shown to decrease the uptake of nickel when exposed to soil [89], indicating the potential for EDTA to be considered as an effective remedy for experimental exposure. The chelating compound CaNa(2+)-EDTA effectively removed nickel [90].
