**3.3 Toxicity of arsenic (As)**

Arsenic is one of the most important heavy metals, with property of a semi metallic, is found in nature in the form of metalloid (As0 ) inorganic and organic form, and arsine (AsH3) [1, 17, 22, 34]. The main inorganic forms include the trivalent form, arsenite (As3+), and the pentavalent form, arsenate (As5+). Among the organic compounds of arsenic are the methylated metabolites, such as monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and trimethylarsine oxide [9, 22]. Inorganic arsenic compounds, found in water is more toxic than organic compounds, found in seafood, which is less harmful [1, 10, 17, 23, 35]. Studies demonstrated thar trivalent arsenite is 2–10 times more toxic than pentavalent arsenate [22]. The order of increasing toxicity of arsenic compounds is the following, organic arsenicals < metalloid (As0 ) < inorganic forms (As5+ < As3+) < arsine [5, 36, 37].

Arsenite, which is prevalent and more mobile, has the capability to bind to thiol or sulfhydryl groups of proteins and inactivate more than 200 enzymes, with effects on different organ systems, but also to inhibits the uptake of glucose into cells, fatty acid oxidation, production of acetyl coenzyme A, gluconeogenesis, synthesis of glutathione reductase and thioredoxin reductase. Arsenate can replace phosphate, involved in biological processes, including the transport system [3, 17, 22, 23, 38]. Environmental pollution with this heavy metal, occur as a result of volcanic eruptions, soil erosion or some anthropogenic activities [9, 22]. It is used to obtain industrially products, such as, insecticides, herbicides, fungicides, algicides, smelting, mining, sheep dips, ceramics and glass making, wood preservatives, refining of metallic ores, paints, dye stuffs or for some medicinal treatments for syphilis, yaws, amoebic dysentery, trypanosomiasis [1, 22].

The exposure to elevated levels of inorganic arsenic occurs through ingestion (oral route) of food and water contaminated, inhalation of smoking tobacco, dust or burning smoke from arsenic-treated wood, working in a place where this metal is made or used, dermal contact and parenteral route [5, 10, 22]. Diet, and especially water, is the most important source of exposure, with an intake of about 12–50 μg/day, but the dietary requirement has been suggested to be between 12 and 25 12–50 μg/day [22, 23, 39]. Food sources of arsenic are seafood, poultry, grains (especially rice), bread, cereal products, mushrooms, dairy products [23, 40].

Exposure from air and soil is much smaller, but in areas with a high contamination, the intake through these ways may become significant [22]. Inorganic and organic compounds leave the body through renal excretion. Most of inorganic compounds are eliminated within several days, but some will remain stored for several months or even longer. Organic compounds are eliminated by the body much faster than inorganic arsenic, so most of them will leave the body in a few days [10]. After the absorption in the body, the target organs are lungs, spleen, kidneys, liver, but also, hair, skin and nails, but the last three for long-term accumulation [5].

Researcher showed a strong association between arsenic exposure and increased risks of carcinogenic and systemic health effects, including cardiovascular, dermatologic, nervous, hepatobiliary, renal, gastrointestinal and respiratory diseases [3, 9, 22]. So, in the case of poisoning, the symptoms manifested are abdominal pain, hemolysis, keratosis and hyperkeratosis, edema, gangrene and finally skin cancer [3, 23, 35]. The severity of symptoms varies depending upon the oxidation state and chemical species of arsenic, the solubility, frequency and exposure time, exposure dose, individual susceptibilities, age, gender, genetic and nutritional factors of exposed person [3, 9, 22].

It has been observed that in the case of persons exposed to high concentrations, symptoms such as developmental abnormalities, diabetes, cardiovascular and peripheral vascular disease, pulmonary disease, hearing loss, liver fibrosis, cirrhosis, melanosis, hematologic disorders (anemia, leukopenia, eosinophilia), neurologic and neurobehavioral disorders and different carcinoma have occurred [1, 9, 17, 22, 41, 42].

Long term exposure influences the promotion of carcinogenesis in various tissues or organs, so in areas with higher pollution, was observed a higher mortality rate for different types of cancers, such as kidney, skin, liver, lungs and bladder [3, 9, 10, 22]. For this reason, arsenic and arsenic compounds has been classified as carcinogenic to humans by International Agency for Research on Cancer (IARC) [3, 10]. Also, symptoms like, pigmentation changes, skin lesions, hyperkeratosis, was observed, which may be a precursor to skin cancer. Even at low concentration for a long time, it could change the color of the skin [1, 10]. Chronic arsenic toxicity is termed arsenicosis [1].

At lower concentration, for shorter exposure, arsenic and its compounds may cause nausea and vomiting, reduced production of erythrocytes and leukocytes, abnormal heart beat, damage of blood vessels [1].

This heavy metal could cross the placenta, particularly during early gestation, and affect the fetus, leading to adverse pregnancy outcomes, such as spontaneous abortion, stillbirth, preterm birth, low birth weight), higher infant mortality [5, 10, 43]. Numerous studies demonstrated that in utero or in childhood exposure to this metal, can lead to increases mortality in young adults due to multiple cancers, cardiovascular diseases, kidney failure, lung damage [10, 44], but also negative impact on cognitive developments, intelligence and memory [10, 45].

Their genotoxicity was demonstrated through its capacity to inhibit DNA repair, induce some chromosomal anomalies and DNA damage, sister-chromatid exchanges, arrest cells in mitosis, induce expression of some genes and gene amplification, interfere with formation of micronuclei in different cells, promote oxidative stress, altered growth factors, interfere with cell signaling pathways, inhibition of cell proliferation, promote apoptotic mechanism in various cell (monocytes, T-cells, cancer cells, melanocytes, dermal cells, keratinocytes), mitochondrial disfunctions [5, 17, 22, 46].

In addition to the ability to bind certain structures or to replace some compounds, at cellular level, arsenic compounds could inhibit the mitochondrial enzymes involved in cellular respiration, inactivate some enzymes, such as thiolase and dihydrolipoyl dehydrogenase and affects the oxidative phosphorylation [22].

Animal studies released that arsenic could produce deficits of growth, altered liver and breast milk triglyceride levels [17, 47], decrease of cell viability, induced apoptosis in some cells, increased oxidative stress, increased phosphorylation [17, 48], lower levels of corticosterone receptor, reduced learning and memory [17, 49].

#### **3.4 Toxicity of mercury (Hg)**

Mercury or hydrargyrum is a heavy metal which belong to the transition elements series of periodic table [9, 22] and exist in the nature in three chemical forms, such as elemental or metallic or elementary mercury (Hg0 ), inorganic mercurous (Hg+1) and mercuric (Hg+2) and organic mercury compound, methylmercury (MeHg or CH3-Hg) and ethylmercury (EtHg or CH3CH2-Hg), the last two being obtained through methylation of inorganic mercuric form by microorganisms found in water and soil [5, 9, 17, 22, 50, 51]. Each chemical form has its own toxicity and chemical properties [9, 22]. Organic Hg compounds are more harmful than inorganic Hg, the

order of increasing toxicity being following: metallic mercury (Hg0 ) < inorganic mercuric (Hg2+) < inorganic mercurous (Hg1+) < organic compounds [5]. At room temperature, elementary mercury is a liquid with high vapor pressure and released into nature as Hg vapor, which are more hazardous than liquid form [5, 9, 23].

It is used in numerous industrial processes, including mining (for extraction of gold), electrical industry (switches, thermostats, batteries), in lamp production factories (for fluorescent light bulbs), caustic soda production, measurement instruments (thermometers, manometers, barometers, mercury switches), nuclear reactors, paint industries, antifungal agents for wood processing, fungicides in agriculture (methylmercury and ethylmercury), soaps and some skin lightening creams (as mercury chloride) [1, 5, 22, 23, 52].

This metal can reach into the body through inhalation and ingestion of food contamination, especially of fish and seafood, but also by dental amalgams (which contain over 50% elemental mercury), preventive medical practices, industrial and agricultural operations, occupational operations [17, 22].

The most absorbed chemical species are elementary and methyl mercury (Me-Hg) [5, 22]. Metallic mercury, which is highly lipophilic, is absorbed by lungs (80%) and tissues lining the mouth and then passed into the cell through cell membranes when in oxidized and became inorganic mercuric (Hg2+), highly reactive. The elementary mercury has the capacity to cross the blood-brain barrier and the placental barrier [5, 22], having a higher neurotoxicity compared to inorganic mercury, which passes the cell membrane in a slower rate, but cannot cross the blood brain barrier and placenta [5]. Metallic mercury is slightly absorbed in the gastrointestinal tract, the toxicity in this case being reduced [5].

Methyl mercury is easily absorbed in gastrointestinal tract (95%) and circulated in the body, where bound to thiol groups, such as cysteine, with which it can form compounds able to pass the blood brain barrier [5, 17, 53]. Toxicokinetic of ethylmercury is similar with that of methylmercury [5, 53].

Methyl mercury entered in organism through the consumption of fish [5, 54], is absorbed in the gastrointestinal tract and due to its lipophilicity can pass the blood-brain barrier and placental barrier [22]. Cooking of fish does not diminish or eliminate mercury content [5]. Exposure to methyl mercury can produce mental retardation, cerebral palsy, deafness, blindness, dysarthria (especially at children exposed in utero) [17]. Instead, at higher concentration for short time, this could produce lung damage, nausea, vomiting, skin rashes, increased heart rate and blood pressure. Symptoms of organic mercury poisoning are depression, fatigue, memory problems, headache, tremors, hair loss [1].

Mercury and its compounds excretion rate depends on its oxidation state [10]. Elemental and inorganic mercury is eliminated by the kidney (urine) and minimally through gastrointestinal tract (feces), having a half-life of 30–60 days [10, 55, 56]. Organic compounds are excreted by feces, but are recirculated enterohepatic, in this case the half-life being 70 days.

Major of absorbed mercury accumulates into kidneys (where produce adverse effects on proximal tubules), hair, neurological tissues and liver [5, 22]. Because it accumulates in hair, it represents an index of exposure to methylmercury [5].

Elemental mercury exposure is associated with cough, dyspnea, fever, tremors, polyneuropathy of axonal sensor motor, malaise, gingivitis, delusions, hallucinations, mercurial erythrism, while exposure to inorganic mercury produce insomnia, renal tubular damage, wight loss, erythema, pruritus, hypersalivation, excessive perspiration [17].

Chronic mercury exposure produces neurological disorders, such as ataxia, shyness, tremors, numb limbs, memory problems, inability to speak, irritability, chewing, swallowing, muscle weakness, but also renal system disorders [1, 5, 23, 57]. Patients exposed to higher levels of methylmercury present increased tendon reflex [5, 57]. Low dose mercury can produce effects on neuronal systems, both on developing fetus and adolescent stage [17, 58], but also cell cytotoxicity, oxidative stress, which are associated with neurodegenerative disorders like Alzheimer and Parkinson [17, 51, 59]. At low concentration, it can affect the human endocrine system, through reduced production of thyroid gland hormone, affecting physiological functions of endocrine glands, reduced binding capacity of hormone to receptor, the most affected hormones being adrenaline, estrogen, testosterone and insulin [3].

On reproductive system, studied demonstrated their capacity to produce infertility in both, men and women. In male the spermatogenesis is affected, while in women could affect the levels of progesterone and estrogens, which produce disfunctions in ovaries, irregular menstruation and sloped uterus [5].

Because mercury can pass the placenta during pregnancy, it can affect fetus and can cause various abnormalities of the baby, such as developmental disabilities, dysplasia of the cerebral and cerebral cortexes and neuronal ectopia, especially after exposure to methylmercury [3, 5, 17, 57].

Into the cell, inorganic compounds and methylmercury interact with cysteine residues of proteins, product oxidative stress through generation of reactive oxygen species (ROS), which can produce enzymes, nucleic acid and lipids damage and may proceed to cell death [17]. They can affect the calcium homeostasis, by increasing intracellular calcium through acceleration the influx from extracellular medium and mobilizing intracellular stores [22]. Methylmercury also interact with sulfhydryl (**–**SH) and selenohydryl (**–**SeH) groups of the proteins and could produce damage of nucleophilic groups involved in catalytic, binding and transport functions [17]. Inorganic mercury also produces reactive oxygen species (ROS) through affecting oxidative phosphorylation and electron transport [22].

A number of compounds, such as vitamin C, vitamin E, selenium, melatonin and enzymes, including, glutathione reductase, glutathione peroxidase, catalase, superoxide dismutase, can have a protective effect on the body through antioxidant mechanisms to reduce or avoid the formation of reactive oxygen species. Mercury genotoxicity was associated with DNA damage, conformational changes in proteins responsible for DNA repair, genetic mutations, mitotic spindle, chromosomal segregation, action on nucleic acids [22].

#### **3.5 Toxicity of aluminum (Al)**

Aluminum, the third most common metal of the earth crust, exist in the environment in only one oxidation state (Al3+). It is naturally present in food, but also in the environment, as silicates, oxides and hydroxides. Aluminum and its compounds are poorly absorbed through ingestion and inhalation, but the rates of absorption are not yet known [1, 10].

The ways in which this metal can reach the body are ingestion, inhalation, dermal contact or drugs [3, 10, 60]. Human exposure takes place through the consumption of drinking water, food and beverages that are high in aluminum content, working in environment with high levels of this metal, hemodialysis, long term intravenous nutrition, cosmetic products, utensils and medicines which contains it, dusty environments [1, 3, 10]. Patients with kidney dialysis are more exposed to this metal,

#### *Toxicity of Heavy Metals DOI: http://dx.doi.org/10.5772/intechopen.102441*

through contaminated dialysates and phosphate binders [1]. The bioavailability of aluminum from diet is influenced by its form, as well as the presence of other food constituents which help him to form complexes [10].

The primary way of excretion is through urine. Due to the its natural presence and intake from food, all people have some levels in the body, and also in the urine [10]. People suffering from kidney disease has a low rate of elimination from the body, which involves its accumulation in the body, affecting the bones and brain [1, 3]. Also, their accumulation in the body, leading to changes in proximal tubules, such as increases in number and size of lysosomes, damage of mitochondria [3].

After entry to body, aluminum accumulates in soft tissues where interact with proteins and lipids and may produce changes in their structure [3].

In case of poisoning, the principal symptoms are nausea, ulcer of mouth and skin, skin rashes pain, vomiting, diarrhea and arthritic pain [1, 3].

On nervous system, aluminum may produce loss of memory and coordination, problems with balance, neurodegenerative disorders, such as Alzheimer, dementia, Parkinson, sclerosis. The studies demonstrated that higher concentration of aluminum found in different parts of brain could initiate the development of Alzheimer disease in humans [1, 3]. This metal could form a complex with adenosine triphosphate (ATP) from neuronal cells, which can affect their signaling and cause excitotoxicity [3].

Dialysis patients treated with dialysis fluids which contain aluminum, showed neurotoxic effects, while humans exposed to high aluminum dust in the workplace, manifested aluminosis [10, 61].

Humans exposed to higher levels could manifest changes of secondary hyperparathyroidism, adynamic bone disease, osteomalacia, the last two being characterized by low bone remodeling. Their toxicity is associated with lung disorders, anemia, nervous system problems, impaired iron absorption [1]. The accumulation of aluminum in bones impaired the bone formation process, known as osteodystrophy and put antiproliferative effects on osteoblasts [3]. Workers chronically exposed to aluminum, developed contact dermatitis and irritant dermatitis [1].

At cellular level, studies conducted demonstrated that it can disturbs the homeostasis of magnesium, calcium and iron, lower cholinergic elevations, apoptotic death of neuronal cells, inhibition of enzymes involved in DNA repair, inhibition of activity of antioxidant enzymes, cross linking of DNA, affecting cell viability, plasma membrane, microvilli and cell function in cells kidney [3, 62]. This increases the peroxidation of lipids from plasma membrane, by enhancement of lipid hydroperoxides, which can reduce the molecular arrangement of lipoprotein at the surface of membrane, but, also physical and chemical properties change in high density lipid (HDL). Also, aluminum is involved in high production of reactive oxygen species (ROS), which may obstruct normal process of mitochondria, initiation of inflammatory events and accumulation of iron, which induces genotoxicity in neuronal cells and death cells, affects the gene expression through interaction between aluminum and nucleic acid and monophosphate nucleotides [3].
