**2.1 Aluminum**

Aluminum is known for its genotoxic profile in cosmetics, especially underarm anti-perspirant products [96]. Aluminum prevents perspiration by blocking the sweat ducts; it also absorbs through the skin. This environmental carcinogen accumulates in the human breast, transforming MCF-10A human mammary epithelial cells and inducing DNA double strand breaks (DSB). These effects have been exhibited *in vitro* with similar concentrations of aluminum to those measured in the human breast [97]. The concentrations of aluminum in the culture medium transform the MCF-10A human mammary epithelial cells, therefore enabling them to produce tumors that can metastasize [98].

To repair DSB is intrinsically mutagenic; once aluminum was removed from the culture medium, however, DSB were not reversible, therefore suggesting that mammary epithelial cells cultured in the presence of aluminum acquire mutations. In addition, *in vitro* studies have shown that aluminum increases the migratory and invasive properties of MCF-7 or MDA-MB-231, human breast cancer cells [97].

Aluminum is a metalloestrogen, a type of inorganic xenoestrogen that is capable of binding to cellular estrogen receptors and mimicking the actions of physiological oestrogens [99]. The most commonly used aluminum-based compounds in underarm cosmetic products (UCP) are aluminum chloride and aluminum chlorohydrate. Not only do aluminum salts trigger DNA DSB, they can lead to oxidative stress, proliferation, and interference in estrogen action before and with metastasis.

A 1:1 age-matched hospital-based case–control study was performed to examine the impacts that self-reported UCP use had on breast cancer. Between a large series of breast cancer patients (aged 20–85 years) and healthy individuals, the aluminum concentrations in their breast tissue were measured and compared. The study participants were interviewed about their UCP application; their answers were categorized under "never", "1-4 times per month", "2-6 times per week", "daily" and "several times per day." A positive family history of breast cancer resulted in being the most prominent risk factor. However, self-reported use of UCP several times per day during early ages (< 30 years) showed a significant association with an increased risk of breast cancer. In addition, the aluminum in breast tissue was significantly associated with self-reported UCP use [98].

Another study showed that in an aqueous solution with a pH of 7.0, aluminum chloride and aluminum chlorohydrate yield aluminum hydroxide and are absorbed through the human skin. This suggests that with daily application of UCPs to the underarm's skin indicates a pronounced source of exposure to aluminum for the human mammary epithelium.

Aluminum has a transforming effect that is followed by the dose-dependent appearance of DNA DSB. The altered phenotype of MCF-10A cells that were cultured in the presence of aluminum chloride is not reversed by withdrawing the salt, however. These results reveal that a mutagenic effect is at least partly responsible for aluminum's transforming effect. The salt causes mutations in genes that regulate cellular proliferation, migration, metastasis and apoptosis. Mutations are also found in the genes monitoring the Max-binding protein MNT and T-lymphoma invasion and metastasis-inducing protein 2 (*Tiam2*) [1]. MNT functions as a pro-survival protein whose activity suppresses the pro-apoptotic activity of MYC, a family of proteins that contribute to oncogenesis [100]. The *Tiam2* gene serves a significant role in neuron development and human malignancies [101].

#### **2.2 Arsenic**

Arsenic is a naturally deposited metalloid that is widely distributed throughout the Earth's crust. Most arsenic-containing compounds are classified as organic and inorganic forms, with the inorganic form, specifically the trivalent arsenic (As3+), being much more toxic and carcinogenic. Studies have shown that As3+ is an environmental etiological factor for a certain number of human cancers. There has shown to be a significant correlation between human lung cancer and environment As3+ exposure, either from drinking water contamination or air pollution. When As3+ is ingested through drinking water, it is absorbed into the bloodstream; its metabolic products, especially the methylated As3+, is potentially deposited in the lung tissues due to the high partial pressure of oxygen [102].

The exact pathophysiological mechanism through which arsenic induces carcinogenesis is still to be determined; however, the increasing of oxidative stress, chromosome abnormalities (with uncontainable growth), and abnormal immune developments, are likely mechanisms. Reactive oxygen species, 8-Hydroxy-2 deoxyguanosine, is a major form of oxidative DNA damage that was acquired from

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

the urine and skin tissue of individuals exposed by arsenic. DNA strand breaks, micronuclei in cord blood, and nitrative DNA damage were some of the early genetic effects discovered in the arsenic exposed patients. Studies have shown that arsenic also affects DNA repair machinery, which therefore causes oxidative DNA damage and mutations by the impairment of nucleotide excision repair, DNA ligase, DNA base excision repair, and DNA strand break rejoining.

Arsenic additionally affects epigenetic regulations. Chanda *et al.* claims that DNA hypermethylation of the crucial promoter region of the *p53* and *p16* genes was present in the DNA from arsenic-exposed individuals [103]. Since high exposure of arsenic is related to DNA hypermethylation of *p53* and *p16* genes, this suggests the notion that epigenetic silencing of these key tumor suppressors genes may be a notable mechanism by which arsenic induces cancer initiation [104].

Recent evidence has been reported to show that arsenic can alter miRNA expression patterns in *in vitro* and *in vivo* models of arsenic-induced carcinogenesis. Dysregulated miRNAs contribute to cancer development and progression, with the potential of acting as a novel class of oncogenes or of tumor suppressor genes. microRNAs are significant in tumorigenesis; for example, the overexpression of miR-504 negatively regulates the *p53* gene, decreasing the *p53*-mediated apoptosis, in addition to negatively regulating the cell cycle arrest in response to stress [105]. Production of reactive oxygen species (ROS) is one of the most reviewed mechanisms in arsenic carcinogenicity; as ROS reacts with DNA and induces structural DNA damage, genetic defects result, and the overexpression of antioxidant enzymes will desensitize cells to apoptosis. Arsenic can inflict oxidative stress through two different routes: direct Fenton-type reactions to produce ROS, or indirect depletion of critical antioxidants [106].

In immortalized human keratinocytes (HaCaT cells), miR-21, miR-200a, and miR-141 are overexpressed after a 4-week treatment with 500 nM sodium arsenic. For miR-21 and miR-141, these microRNAs have exhibited strong associations with the majority of human tumors. The miR-200 family has been reported to have a role in the epithelial-mesenchymal transition and cancer progression. For lung cancer development, the overexpression of miR-155 in normal cells has been a leading cause. Results indicate that urothelial human cancer is induced by miR-200 family members; the expression of miR-200a, miR-200b, and miR-200c was downregulated in arsenic-exposed human urothelial cells (HUC1) in comparison to nonexposed HUC1 cells. The levels of these miR-200 family members in the urine of arsenic-exposed patients were also decreased [105].

#### **2.3 Beryllium**

Beginning in 1952, a collection of case reports in the Beryllium Case Registry at the Massachusetts General Hospital and cohort studies established the basis for several overlapping epidemiological reports on how beryllium induces cancer. Elevated ratios of lung cancer were shown among workers who had experienced acute berylliosis; however, the results were not similar in workers with chronic berylliosis [107]. Acute beryllium disease is mostly considered an irritative chemical phenomenon associated with high exposures; on the other hand, chronic beryllium disease is an immune-mediated granulomatous reaction to beryllium [108]. Studies showed that the increased cancer death started to occur 15 years after the onset of beryllium exposure.

Experiments were conducted by injecting zinc beryllium silicate in rabbits intravenously. Results indicated that the administration produces consistently metastasizing osteosarcomas in the long bones. Outcomes parallel to these results were obtained with the injection of beryllium oxide, beryllium phosphate, and beryllium metal into the medullary cavity of bones. This route of administration was the only route that led to the formation of osteosarcomas. Splenectomy was additionally shown to increase carcinogenicity with the IV-injected beryllium in bones; the spleen, being an important storage organ, most likely allowed the retention of a higher proportion in the reticuloendothelial system and bone.

Exposing the rats to beryllium sulfate, beryllium phosphate, beryllium fluoride, zinc beryllium manganese silicate, and beryl ore, through inhalation also produced carcinogenic properties. Throughout the duration of a 35-hour week exposure schedule, 10 micrograms of BeSO4 was determined to be threshold for the induction of pulmonary adenocarcinoma in rats. The majority of malignancies were adenocarcinomas with a predominantly alveolar pattern.

In Chinese hamster V79 cells (lung fibroblasts) and in Chinese hamster ovary (CHO) cells, the induction of 8-azaguanine-resistant mutants by BeCl2 and by BeSO4, respectively, has demonstrated beryllium's ability to inflict gene mutations in cultured mammalian cells. BeSO4 did not cause chromatid or chromosomal aberrations in Chinese hamster lung cells. In CHO cells and cultured human lymphocytes, however, BeSO4 produced chromosomal breaks and sister-chromatid exchanges [107].

With a soluble beryllium compound and upon incubation of a continuous human cell line, there was shown to be a reduction of the expression of messenger RNA coding for DNA repair proteins. This observation was suggested to be a relevant mechanism for potential carcinogenicity of beryllium. To further study this claim, the DNA of rat primary hepatocytes was purposely damaged by incubation with a known DNA damaging agent, 2-acetylaminofluorene. In addition, the DNA was co-incubated with beryllium metal extracts. In the results, there was a reduction in DNA repair synthesis with the beryllium metal extract. Beryllium metal has not been confirmed to directly damage the DNA of cells; nevertheless, there is strong evidence that the metal can cause morphological cell transformation and the inhibition of DNA repair synthesis [109].

The carcinogenic properties of beryllium have been mostly demonstrated when in its metal form, some of its alloys, and a variation of its compounds. Lung cancer induced by beryllium is a main result from pulmonary instillation or inhalation with consequent direct action on the lung. The bone tumors that beryllium stimulates, a characteristic of osteogenic sarcoma, reflects the metal's bone seeking propensities [110].

#### **2.4 Cadmium**

Cadmium is a dangerous metal for humans as the human body is limited in its response to cadmium exposure; the metal is incapable of metabolic degradation to less toxic species [111]. Cadmium is a toxic heavy metal that is commonly known as a human carcinogen. Their main sources of exposure include food, cigarette smoking, and cadmium related industry. Reactive oxygen species (ROS) are measured to be the most prominent mechanism in cadmium-induced carcinogenesis. The intracellular oxidative stress that reactive oxygen species induce potentially damage macromolecules and eventually grow responsible in the formation of cancer.

There are two stages referred to when discussing cadmium-induced carcinogenesis. In the first stage, normal cells transition into transformed cells. The reactive oxygen species contribute in the malignant cell transformation of BEAS-2B (human bronchial epithelial) cells in their exposure to cadmium. For the second stage, morphologically transformed cells advance into tumorigenesis. Cadmium-transformed cells, *p62* and Nrf2, are activated and their downstream antioxidants and antiapoptotic proteins are elevated, therefore causing a reduction in ROS, apoptosis

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

resistance (permitting cancer cells to persist and not die), and tumorigenesis. The decrease in ROS generation in the second stage provides an optimal environment for transformed cells to survive and engage in tumorigenesis [112].

Cadmium exposure is shown to induce consistent low levels of ROS production, which causes endoplasmic reticulum stress that causes defective autophagy, which protects cadmium exposed damaged cells and encourages malignant transformation in prostate carcinogenesis. In order to maintain the quality of intracellular components, autophagy, a highly complex lysosomal-mediate degradation process, is accountable for the removal and recycling of damaged organelles. This deficient form of this activity assists in cancer cell survival as autophagy protects the cells from hypoxia and oxidative damage, in addition to promoting chemoresistance [113].

The *p62* protein performs several cellular functions for autophagy, apoptosis, ROS signaling, and cancer. The protein has been found to accumulate in autophagydeficient cells, and the overall accumulation of *p62* due to autophagy dysfunction encourages cell survival and tumorigenesis through the activating of nuclear factor, κB. The *p62* protein is highly expressed in human lung cancer. As *p62* accumulates, it activates Nrf2 and Nrf2 target gene expression. Autophagy deficiency results in the up-regulation of *p62,* which therefore leads to the transcriptional activation of the Nrf2-dependent genes, involving antioxidant enzyme genes [114].

Similar to metal arsenic, cadmium is weakly genotoxic and mutagenic. To determine whether cadmium exposure induces properties analogous to cancer stem cells, researchers exposed immortalized human pancreatic ductal epithelial (HPDE) cells to low dose cadmium for 29 weeks. Using suspension culture spheroid formation assay, the chronic cadmium-exposed HPDE cells exhibited significantly higher levels of molecular markers for cancer stem cells, yielding 3-fold more suspension spheres than the controlled cells [115].

Cadmium does not form adducts with DNA; however, it is capable of inflicting oxidative stress that could indirectly attack DNA. This process is not instigated through participation in Fenton type chemical reactions [111]. The Fenton reaction is defined by a redox pair of ferrous ion and hydrogen peroxide (H2O2) that ultimately generates a reactive hydroxyl radical [116]. The potential mechanisms for cadmium-carcinogenesis include aberrant gene activation and signal transduction, suppressed apoptosis and disruption of E-cadherin-mediated-cell–cell adhesion, and altered DNA repair [111].

#### **2.5 Lead**

Lead is a metal that can be classified as an environmental pollutant and is commonly known for its usage in many industrial settings worldwide. With high lead exposure, health effects can include damage to the brain and nervous system, gastrointestinal problems, anemia, liver and kidney damage, fertility problems, and developmental delays. Inorganic lead is also suggested to be a carcinogen; epidemiological evidence for carcinogenicity in industrial workers that have been exposed to inorganic lead indicates a significant relationship with cancers of the stomach, lung, kidney, brain, and meninges.

The two primary routes through which lead enters and accumulates in the body is inhalation and oral ingestion. With this being said, even though lead has the capacity to enter the bloodstream and impact other organs of the body, the lungs and stomach are what first come into contact with lead. Due to lead's ability to pass through the blood–brain barrier, the brain and nervous system are especially vulnerable to the potential toxic effects of lead. The mechanisms that lead uses in playing a role in carcinogenesis include oxidative damage, induction of apoptosis,

altered cell-signaling pathways, inhibition of DNA synthesis and repair of damage, and interaction with DNA-binding proteins [117].

In one study, results provided support for an association between occupational lead exposure and brain cancer risk. Among industrial workers who were potentially exposed to lead, the brain cancer mortality rates were greater as compared to unexposed subjects, with indications of an exposure-response trend [118]. Results, however, of many studies have showed inconsistency in determining the relationship between lead exposure and brain tumors. For results that support the association, the results suggest that lead can cross the blood–brain barrier and concentrate in the brain parenchyma due to its ability to replace calcium ions. Once the lead is absorbed, it is generally allocated to plasma, the nervous system, and soft tissues, therefore potentially developing micronucleus formation, chromosomal aberrations, and DNA damage in most mammals.

Lead's mechanism in which it causes brain cancer remains unclear; nevertheless, studies suggest the most probable mechanism is the metal's inhibiting of DNA synthesis and repair and the interacting with binding proteins that eventually hinder tumor suppressor proteins [119].

#### **2.6 Mercury**

Mercury is one of the most toxic heavy metals due to its persistence in the environment. Mercury inflicts oxidative stress and induces apoptosis. Methylmercury (MeHg) is a metalloestrogen, a small ionic metal that activates the estrogen receptor. Studies indicate that once metalloestrogens activate the estrogen receptor, there is an increase in transcription and expression of estrogen-regulated genes, therefore inducing proliferation of estrogen-dependent breast cancer [120].

The phases of cancer development are initiation, latency, promotion, and then progression. In the promotion phase, mercury has shown to cause an imbalance in the reactive oxygen species homeostasis through selectively inhibiting selenocysteine antioxidant enzymes. Mercury fulfills both the capacity to induce an inhibition of the gap junction intercellular communication and the proinflammatory cytokine release. These two mechanisms have potential to isolate cells from tissue-specific homeostasis, promoting their proliferation. In addition, they have potential to overcome the immune system defenses, checkmating the entire organism. The International Agency Research Cancer (IARC) does not classify mercury as an identified carcinogen to humans; nevertheless, if the toxic compound inhibits the gap junction intercellular communication, mercury is suggested to be a potential cancer "promoter" [121].

Animal experiments were performed to investigate the carcinogenic effects that methylmercury had on mice. They were fed with 10 mg/kg of methylmercury, and as a result, chronic kidney failure, adenoma, and carcinoma were observed. With these results, rodents that were exposed to methylmercury were reported to show a higher incidence of kidney cancer. The International Agency for Research on Cancer claims there is a satisfactory amount of evidence for methylmercury's impact in cancer on experimental animals, only classifying it as a possible carcinogenic to humans. On the other hand, the U.S. Environmental Protection Agency (EPA) judges that evidence of methylmercury's carcinogenic potential in humans was insufficient and the justification of the carcinogenicity in experimental animals was limited. Therefore, they classified methylmercury as a Group C material (possible human carcinogen) [122].

Mercury can affect multiple organ systems, especially the nervous and renal systems. One particular study wanted to determine mercury's capacity to induce centrosome amplification. Centrosomes, microtubule organizing centers of the cell, play a crucial role in cell division; they aid in the proper segregation of chromosomes into the resulting daughter cells. When metals induce cellular and genotoxic stress, however, this can interfere with the strict coordination between the centrosome and DNA cycles that ensures the cell to enter mitosis with only two chromosomes. This disrupted linkage stimulates centrosome amplification, potentially resulting in chromosome segregation and aneuploidy. For the aneuploid cells that survive, they can eventually lead to tumor formation and cancer. The study reported that methylmercury, but not inorganic mercury, prompted both a mitotic arrest and centrosome amplification in mitotic cells, therefore suggesting a possible carcinogenic mechanism [123].

### **2.7 Nickel**

Nickel is considered a major carcinogenic heavy metal, mainly through the mechanism of DNA damage. Demonstrated by *in vitro* and *in vivo* studies, nickel destructs DNA processes through direct DNA binding and reactive oxygen species (ROS) stimulation. Nickel's carcinogenic properties also include their repressing of DNA damage repair systems through direct enzyme inhibition and downregulation of DNA repair molecule expression. Studies have shown that Ni2+ has potential to induce DNA damage in certain human cell systems; some include hepatocellular carcinoma (HepG2), human TK6, Chinese hamster lung fibroblast, A375, and HCT-116 cells [124, 125].

With reactive oxygen species, when they excessively attack the DNA, this results in genomic instability, a promoter of tumorigenesis. This oxidative stress or genomic instability, being a major driving force of oncogenesis, is the basic toxicological mechanism of nickel overexposure [124]. Oxidative stress is known to occur as a result of overproduction of reactive oxygen and nitrogen species through endogenous and exogenous insults. The production of these reactive oxygen species is enabled by nickel's capacity to bind with amino acids, peptides, and proteins [125].

The metal has the ability to dissolve in the human body, releasing ionic nickel, an active and occasionally genotoxic carcinogenic form of nickel. When a carcinogen is classified as 'genotoxic', this refers to chemicals that are capable of directly altering genetic material, opposed to 'non-genotoxic' carcinogens that produce cancer through indirect or secondary mechanisms. Most of the chemical carcinogens that induce direct DNA damage are therefore categorized as 'genotoxic' in their carcinogenic mechanisms. Nickel's carcinogenic potential also originates from its capacity to raise the intracellular concentration of nickel ions [126]. The nickel ions exhaust intracellular iron by hindering the membrane ion transporters, in addition to displacing iron from the active site of dioxygenase enzymes. This all leads to the inhibition of their catalytic activity [127].

DNA hypermethylation and subsequent silencing of tumor suppressor genes potentially serve as an epigenetic mechanism responsible for nickel's carcinogenicity. Promoter hypermethylation induced by nickel was observed *in vivo* as nickel sulfide was injected into *p53* heterozygous mice to induce tumor formation. Malignant fibrous histiocytomas advanced in both wild type and *p53* heterozygous mice, with all tumors exhibiting promoter hypermethylation of *p16* (a tumor suppressor gene). Additionally, Wistar rats exhibited muscle tumors that displayed DNA hypermethylation in the promotor regions of *RARβ2*, *RASSF1A* and *p16* genes, following intramuscular injection of nickel sub-sulfide [128].

#### **2.8 Radium**

Along with X-rays, radium has a carcinogenic effect of ionizing radiation in humans. The danger of ionizing radiation involves the risk of developing cutaneous squamous cell carcinoma. Additionally, studies suggest that radium treatment for the benign skin lesions may only increase the risks of sarcoma of the bone. For example, in one particular case, a patient developed a mixed tumor of carcinoma and sarcoma at the specific site where she had received radium treatment; a malignancy that developed in the same location supports the notion that the previous radium treatment caused it [129].

At elevated concentrations, naturally occurring dissolved radium can potentially be classified as carcinogenic to the human body. Following digestion, the radium can become deposited within the body where its radioactive characteristic threatens human health through cell damage, therefore increasing the overall risk of cancer [130].

Other experiments show that intra-uterine radium application or X-irradiation of the uterus can induce rat malignant uterine tumors, usually endometrial adenocarcinomas. One rat subject's uterus was exposed to direct X-irradiation and a composite endometrial tumor, also classified as an adeno-sarcoma, was produced. The tumor was not structurally similar to the mixed endometrial tumors seen in women; nevertheless, the composite structure and the potential that the tumor may also exhibit carcinomatous areas, implies that it may strongly represent the rat counterpart of the human neoplasm. Results of the experiment strengthened the suspicion that pelvic radiation can lead to an increase in long-term incidence of uterine cancer, particularly mixed tumors [131].
