The Concentration of the Potentially Toxic Metals in Human Hair, Nails, Urine, Blood, and Air, and Their Impact on Human Health: A Review

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Introduction
Metals having a specific gravity (density) five times or more than that of water and an atomic weight ranging from 64 to 201 (Cu, Zn, Co, Ni, Cr, Mn, Fe, Ba, Hg, Cd, Pb, As, Mo, and Sn) are called potentially toxic metals. These metals are non-biodegradable and easily bio-accumulated in animals, including humans, and plants. Citizens, including humans and plants, living in the biosphere cannot survive without the intake of a small amount of some of these potentially toxic metals, i.e. Cu, Zn, Co, Cr, Mn, and Fe are essential for different biochemical and physiological functions. Based on their health importance to the citizenry, these potentially toxic elements are classified into four groups, (i) Essential: Needed for different physiological activities (Cu, Zn, Co, Cr, Mn, and Fe); deficiency causes diseases; accumulation beyond their permissible limit becomes toxic. (ii) Nonessential: Metals Ba and Al are non-essential for humans; (iii) Less toxic: Tin is the less toxic metal; (iv) Highly toxic: Metals Hg, Cd, Pb, and As (metalloid) are not only non-essential for citizens (having no biological role in living organisms) but are also highly toxic. More than forty million people in rural India drink water contaminated with heavy metals, arsenic, fluoride, etc., according to the report in the February 20, 2019 edition of Hindu Business. These metals form covalent bonds with organic groups and form lipophilic ions and compounds that bind with non-metallic elements of cellular macromolecules to generate toxic effects. These metals can be accumulated via the blood circulation system in humans on exposure and cause several adverse health effects to live organisms, including humans, on accumulation or exposure, even at low concentrations. Prolonged low-dose exposure to these toxic metals to children causes learning and perception difficulties, resulting in behavioural changes leading towards violence (Mahajan, 2020). Potentially toxic metal toxicity is one of the factors promoting violence in children of the age group 10-19 years (WHO, 2021).
To determine the exposure levels of these metals to humans, biomarkers are used. Hair, nails, urine, and blood are commonly used to determine the level of accumulation of these potentially toxic metals in humans. Nails and hair accumulate these metals for a long period, which allows for evaluating environmental and occupational exposure to the metals. Human hairs can accumulate these metals as these metals are incorporated into the hair's protein structure during their growth process . The concentration of these metals in hair and nails indicates the average level of exposure to the human body and internal body tissues (Pozebon et al., 2017). The concentration of these metals in the hair, blood, and nails of humans depends on several factors, including sex, age, eating habits, environment, smoking, etc. (Solgi & Mahmoudi, 2022). Urine is the biomarker of recently ingested toxic metals from food and water (Wongasuluk et al., 2021). This review reports the concentration of the potentially toxic metals (As, Cd, Co, Cr, Cu, Hg, Ni, Pb, and Zn) in human hairs, nails, urine, and blood. The concentration of these metals in water and air is also documented. (iii) Inhalation: Uptake of toxic metals occurs via inhalation of polluted air, vapours, or aerosols. The inhaled toxic metals reach the lungs and bloodstream via the respiratory tract ( Figure 3).
The potentially toxic metals are accumulated primarily in bones, skin, hair, myocardial tissues, and internal parenchymal organs (liver, kidney). non-degradable, persist for a longer period, and are easily bio-accumulated in humans, animals, and plants, they disturb aquatic environments and ecosystems. Water contamination by potentially toxic metals is mainly due to urbanization and industrialization. By the runoff from villages, towns, cities, and industries, these metals are accumulated in the water bodies' sediments. The groundwater is also contaminated by these metals due to leaching from agricultural fields and dumping grounds. In the food chain series, humans are last, so they are most affected as the concentration of these metals in the food chain increases (Saha et al., 2017). Table 1 records the concentrations of the potentially toxic metals in groundwater, surface water, river water, and lake water.
The potentially toxic metals in the air are due to urbanization and industrialization; these metals in the air enter as droplets, particles, and gaseous forms or gaseous forms associated with particles or droplets (Masindi & Muedi, 2018). Chimneys are the main source of these metals in their gaseous state. The soluble particles are accumulated in water, soil, and land with rain. The concentration of these metals in the air is documented in Table 1.

Biomarkers of Potentially Toxic Metals in Humans
Accumulation of these metals in the human body causes several serious problems, so to assess the health risk, it is important to monitor the level of these metals in the body. Biomarkers used for the study are hairs, nails, urine, and blood.

Hairs
According to the Environmental Protection Agency (EPA), the most important biomarker to monitor the accumulation of potentially toxic metals in the human body is hair, as hair is a stable substrate, can be easily collected and transported, and provides information on shortand long-term exposure. In human hairs, the concentrations for As, Cd, Co, Cr, Cu, Ni, Pb, and Zn ranged from 0.01 to 1.89; 0.009 to 1.2; 0.12-43.68; 0.66 to 129.4; 0.0 to 134.4; 0.62-27.3; 0.8 to 124.1; and 1.2 to 573.2 mg/kg, respectively. The order of average concentration of these metals in hair was Zn> Pb>Cu> Cr>Co>Ni>As>Cd. The data shows that the concentration of these metals in hair depends on age, geographical changes, climate, food habits, and nutrition. ; Fang et al., (2019), during their studies, found that the concentration of metals Cr, Cu, Ni, Co, Cd, Zn, and As in the hair increases with age. The concentration of these metals in the hairs of smokers was higher than that of non-smokers ; Oral (2016) found that the concentration of Pb in the hairs of smokers was 2.5 times that of non-smokers. The accumulation of these metals in the hairs of cigarette smokers was higher than that of pipe smokers (Alrobaian & Arida, 2019). Solgi and Mahmoudi (2022) also found that accumulation was higher in urban than rural populations. Zheng et al., (2021) reported that in different regions of China, the concentration of arsenic in male hair was significantly higher than in female hair. Jaccob (2020), during their research work, found that the concentration of lead and copper in the hairs of workers working in oil stations and refineries was significantly higher than those of other individuals. The concentration of Ni in the hairs of the workers on the production line of a printing press was significantly higher than that of the office workers. Hair tip has a higher concentration of these metals than hair root . The concentration of these metals in hair is given in Table 1.

Nails
Nails are an important biomarker of the toxic metal burden in the human body, as the nail's tissues contain the fibrous, rich protein keratin (as cysteine). The appearance and/or composition of nails indicate a deficiency or accumulation of these metals in the body. In human nails, the concentrations for As, Cd, Co, Cr, Cu, Ni, Pb, and Zn ranged from 0. 0-8.23; 0.0-18.03; 0.38-6.8; 0.32-44.8; 13-16.5; 0.0-7.9; 0.0-123; and 32-176 mg/kg, respectively. The order of average concentration of these metals in nails were Zn>Pb>Cr>Cu>Ni>Co>Cd>As. The concentration of these metals varies according to feeding habits, working environment, and geographical environment. Ahlawat and Shukla (2016), during their research work, found that the concentration of lead and cadmium in the nails of autoworkers is higher than that of non-auto workers. The concentration of toxic metals in the nails of the shallow water drinking population was higher than that of the tap water drinking population . Bobaker et al., (2022) in their research studies found that the concentration of these metals in farmers' nails was higher than that of non-farmers. They further reported that the concentration of these metals decreased with the use of the PPE kit. It was also reported that the concentration of these metals in the nails of smokers was higher than that of non-smokers. The accumulation of these metals in the nails is also correlated with age.  reported that white lines on nails were observed on the nails of 1/3 of the children who were exposed to mines. The concentration of the potentially toxic metals in nails is given in Table 1.

Urine
Urine is another biomarker for the estimation of the degree of accumulation of these metals in the human body, as the data from a urine sample reflects a better understanding than biological fluids. The concentration of these metals in urine is based on the concentration of these metals in drinking water, food consumed, and environmental conditions. As concentrations in urine ranged from 0.19 to 10.7 mg/L, Cd concentrations ranged from 1 to 93 ug/L, Cr concentrations ranged from 2 to 52 ug/L, Cu concentrations ranged from 0.0 to 2.47 mg/L, Ni concentrations ranged from 0.35 ug to 3.99 mg/L, Pb concentrations ranged from 0.001 to 19 mg/L, and Zn concentrations ranged from 0.0 to 2.55 mg/L. Akan (2014), during their studies, found that the concentration of these metals in urine was higher than in water, indicating that in the human body, these metals are not only accumulated but also concentrated. The concentration of these metals increases with age, indicating that the accumulation of metals depends on age. The concentration of Pb and Cu in the urine of the population living in industrial areas was higher than that of the population living in non-industrial areas, according to . Ni in the urine of production line workers of a printing factory was higher than in the urine of office workers . Kafaei et al., (2017), during their studies in Iran, found that the concentration of these metals (especially As) in the urine of boys was higher than that of girls. Several researchers (Mizuno et al., 2021;Castiello et al., 2020;Franceschini et al., 2017) have reported that urinary Cd and/or Pb concentration is significantly positively correlated with systolic and diastolic blood pressure. In Table 1, the concentrations of the potentially toxic metals in urine are documented.

Blood
For bio-monitoring the level of accumulation of potentially toxic metals in the human body, blood is a conventional biomarker (Parmar et al., 2016). The concentration of potentially toxic metals in the blood varied with feeding habits, area of residence, workplace, and the concentration of these metals in the drinking water. In the reported studies, the concentrations of these metals in the blood were as follows: arsenic (5-327 ug/L); cobalt (0.15-4.83 mg/L); copper (0.193-2.94 ug/L); chromium (4.82 ug/L to 9.25 mg/L); lead (1.99-2.25 ug/dL); mercury (0.88-1.07 ug/L); nickel (0.02-23.9 ug/L); and zinc (6.55 ug/L to 4.4 mg/L);  have reported that the concentration of these metals in the plastic industry workers was higher than that of nonplastic industry workers. The concentration of As and Hg in the non-vegetarian people in Kerala was higher than that in the vegetarian people, while the amount of Pb in the vegetarian people was higher than that in the nonvegetarian people (Jose and Ray, 2018). The concentration of these metals in the blood of the smokers was higher than that of the nonsmokers; the concentration of these metals in the blood was in the following order: cigarette smokers > pipe smokers> non-smokers (Alrobaian & Arida, 2019). Jose and Ray (2018) also reported that the amount of arsenic and mercury in the blood of female people in Kerala was higher than that of male people, while lead was more prevalent in the male population. The concentration of these metals in the blood varied as per age; the maximum concentration was in the people of the age group 26-40, followed by 25, and then >40 years. The amount of these metals in a blood sample is given in Table 1.

Toxicity of Probably Toxic Metals
Contamination of terrestrial and aquatic environments by potentially toxic metals is a foremost point of concern to scientists as these metals are easily bio accumulated in humans (hairs, nails, blood, kidneys, and liver) via food chains and water, and in the human body they not only disrupt the endocrine system but also negatively impact the metabolism of living cells in the body (Briffa et al., 2020). The accumulation of these metals in humans harms the central nervous system (Charkiewicz & Backstrand, 2020), respiratory system (Ikechukwu et al, 2019), cardiovascular system (Gambelunghe et al, 2016), skeletal system ), gastrointestinal system (Bjørklund et al, 2020), hepatorenal system (Ikechukwu et al, 2019. These metals in the human body inhibit the normal functioning of the enzymes, negatively impact DNA repair mechanisms, and protein function, and damage antioxidants and membranes occurring in the living cells (Fu and Xi, 2019).

Arsenic
Based on the potential threat to human health arsenic (As) which is a non-essential carcinogenic metalloid is ranked first. The arsenic in the environment enters from natural sources (weathering of rocks, volcanic eruption) as well as from anthropogenic activities. Arsenic is used in the preservation of wood, the bronze industry, insecticide formulations, smoking, the glass industry, and pyrotechnics and in the semiconductor industry. The arsenic is also present in the food products viz, fish, shellfish, and dairy products, meat, and poultry products and in cereals. Accumulation of inorganic arsenic in humans causes abdominal and gastric dysfunction, abdominal pain, loss of appetite (Charkiewicz & Backstrand, 2020;Sharma et al., 2014), pulmonary fibrosis, pulmonary oedema, asthma, tuberculosis (Ikechukwu et al., 2019), skin lesions, skin depigmentation, dermatitis, alopecia (Bjørklund et al, 2020), oxidative stress, high risk of cardiovascular problems (Andrade et al, 2017), infertility, high risk of miscarriage, reduction in sperm count and mobility (Charkiewicz & Backstrand, 2020), metabolism of blood cell and blood are adversely affected, decreased production of red and white blood cells (Ikechukwu et al,2019), fatigue, allergies, neurodegenerative diseases like Parkinson's, Alzheimer, neurotoxicity, dementia, memory loss (Bjørklund et al, 2020;Rao et al, 2017). Accumulation of arsenic in the human body also causes enlargement of the kidney, nuclear, and mitochondrial, liver damage as it causes homeostasis (Livertox 2017;Bhattacharya et al., 2016). Damage to deoxyribose nucleic acid in the human body due to the accumulation of arsenic is also reported (Briffa et al., 2020). The threshold concentration of arsenic in drinking water is 0.01-0.05mg/L and in the air is 0.0015-1 ug/m 3 .

Cadmium
Cadmium, which is a non-essential metal for humans, is ranked seventh on the list of dangerous substances (Ulrich, 2019). Cadmium, the 64 th most abundant metal found in nature, is found in combination with zinc and in the mineral Greenockite. Cadmium is used in Ni-Cd batteries, nuclear reactors, fertilizers, pesticides, the plastics industry, and corrosion-resistant plating. Mussels, shellfish, shrimp, mushrooms, liver, and dried seaweeds are food items besides water from which the cadmium accumulates in the human body. Cadmium in humans is considered an endocrine disrupter that causes, aside from neurodevelopmental toxicity, breast and prostate cancer (Yousif et al., 2021). In humans, accumulation of cadmium causes nephrotoxicity (Ke et al., 2015), gastrointestinal disorders (Huang et al., 2017)

Chromium
On the earth's surface, chromium is the 21 st most abundant metal and is extracted as chromite ore. For the general population, chromium is an essential trace metal. This metal is used in electroplating, leather tanning, dye paints, metal ceramics, the coloured glass industry, and synthetic rubies. The global annual output of Cr is approximately 7.5 million tonnes. Fruits and vegetables, meats, fish, shellfish, yeasts, and grains are chromium-containing food items. Accumulation of chromium in the human body causes liver and kidney damage, vertigo, gastrointestinal ulcers, nausea, allergic contact dermatitis, bronchitis, DNA damage, haemolysis, lung cancer, and irritation of mucous membranes (Georgaki & Charalambous, 2023;Achmad et al., 2017;Sneddon, 2016). Healing of fractured bones is delayed in the presence of higher concentrations of chromium, as it retards the secretion of collagen type I. If the concentration of chromium in the human body is far below the required amount, the metabolism of glucose, lipids, and proteins is disturbed (Akoto et al., 2017). The threshold concentration of Cr in drinking water is 0.05-0.1 mg/L, and in air, it is 0.001-0.5 mg/m3.

Cobalt
Cobalt, a component of vitamin B12 (cobalamin), is an essential metal for humans and other animals. Cobalt is ranked as the 32 nd most abundant metal on the earth's surface and exists as cobaltite. Cobalt is used for electroplating, jet turbines, gas turbine generators, paints, and CO 60 for the treatment of cancer. Butter, cheese, meat, and chocolates contain cobalt. Accumulation of cobalt beyond the permissible limit causes asthma, respiratory irritation, decreased pulmonary function, cardiac effects, cardiomyopathy (Packer, 2016), nausea, wheezing, and dyspnoea in humans. Respiratory tract hyperplasia, pulmonary fibrosis, pneumonia, an increase in the number of red blood cells, emphysema, paralysis of the nervous system, seizures, growth retardation, and thyroid deficiency occur if a very high amount of cobalt is accumulated in the human body (Hafiz Uddin & Rumman, 2020;Dedoussis, 2015). The threshold concentration of cobalt in the air is 0.1 mg/m 3 .

Copper
Copper, which is ranked the 26 th most abundant metal on the earth, is a vital dietary nutrient, essential metal for citizens and plants. In humans, copper helps in forming energyproducing enzymes, acts as a co-factor for several essential enzymes, regulates gene expression, promotes the functioning of the immune system, helps in developing new blood vessels, and balances nerve cell hormones. Nuts and seeds, dark chocolate, leafy green vegetables, lobster, oysters, and mushrooms are the major food sources of copper. Copper is used in the preservation of wood, fabrics, plating, wires, pipes, fertilizers, laboratories, barrier creams, etc. For different catabolic and metabolic processes, a healthy human requires approximately 0.9 mg of copper daily. Copper is required for the synthesis of haemoglobin. When copper is accumulated beyond its permissible limits, it may cause genetic diseases, Wilson's disease, and Mense diseases (Barber et al., 2021). Excessive intake of copper causes rheumatoid arthritis. mucosal irritation and corrosion, hepatocellular degeneration, anaemia, jaundice, brain damage, gastroenteritis, central nervous system damage, speech impairment, hepatic cirrhosis, and melena (Karim, 2018;Andrade et al., 2017;Nastoulis et al., 2017). A deficiency of copper causes anaemia; a low number of leucocytes, disorders, and osteoporosis in infants. The threshold concentration of copper in drinking water is 1.3 mg/L, and in air, it is 0.1 mg/m 3 .

Lead
Lead, which is a toxic non-essential metal, is the 37 th most abundant metal on the earth, found in the form of galena. Grains, fruits and vegetables, seafood, red meat, wine, and soft drinks are the major sources of uptake by humans. Lead is used in lead-acid batteries, computer screens, lead piping, ammunition and projectiles, sports equipment, and stained glass windows; earlier, lead was also used in hair dyes, pottery products, and insecticides. Approximately 3 million metric tonnes of lead are released into the environment. Distribution of the lead in the human body depends on the blood flow into various tissues, and about 95% of the body's lead is deposited as insoluble phosphate in the skeletal bones, causing calcium deficiency and an enhanced blood lead level. Lead in the human body disturbs haemoglobin synthesis (causing deficiency of the iron) and the metabolisms of Zn, Cu, Fe, and vitamin D. Acute exposure to lead causes hypertension (Lamas et al., 2021;Zheng et al., 2019), renal impairment, abdominal pain, arthritis, vertigo, hallucinations, antisocial behaviour, and a high risk of miscarriage (Assi et al., 2016). Chronic exposure may cause mental retardation, weight loss, brain damage, kidney damage, muscular weakness, paralysis, and peripheral nerve damage (Obeng-Gyasi, 2019; Orr and Bridges, 2017). Secretion of γcarboxyglutamic acid-containing protein in the human body decreases the accumulation of lead beyond its permissible limit as lead affects somatic cell function by lowering active vitamin D3 level and parathyroid level within the plasma. In children who are more susceptible to the accumulation of lead, it causes reduced IQ, a decrease in attention interval, a lower education level, and an alteration in the development of the brain and nervous system (ATSDR, 2019). The threshold concentration of lead in drinking water is 0.015 mg/L, and in air, it is 0.01 mg/m 3 .

Mercury
Mercury, which is the 66 th most abundant metal on earth, is the third most hazardous substance. Hg, a non-essential metal, is naturally found in the rocky parts of the earth's crust (coal deposits). Seafood and mushrooms are mercurycontaining foods. Mercury is used in electrical switches, fluorescent lights, batteries, disinfectants, thermometers, dental fillings, photochemistry, and insecticide. Inhalation of vapours of Hg produced from the burning of coal causes eye and lung irritation, rashes, and vomiting. Accumulation of Hg in the human body beyond its permissible limit causes neurodegenerative diseases like Parkinson's, Alzheimer's, and dementia; neurotoxicity (death of neuronal cells); nervousness; speech defects; tremors and muscle incoordination; paralysis; vision complications; damages DNA and chromosomes (Li et al., 2017;Genchi et al., 2017); affects the reproductive system (sperm damage; miscarriages); and also affects the development of the fetus and influences the maternal-fetal balance (Mallozzi et al., 2016). The threshold concentration of Hg in drinking water is 0.001-0.02 mg/L, and in air, it is 0.05 mg/m 3 .

Nickel
Nickel, the 22 nd most abundant metal on earth, exists in a many mineral forms. Legumes, peas, nuts, baked beans, kidney beans, millet, oats, rye, tea, cocoa, chocolate, and baking powder are nickel-containing foods. Nickel is used in coins, jewellery, welding, batteries, chocolates, rocket engines, armour plating, steel, and other metal products, as well as pigments and valves. The accumulation of nickel in the human body causes fibrosis, lung inflammation, asthma, pneumonia, skin rashes, and miscarriage. Psoriasis is also due to the accumulation of nickel. Prolonged exposure to nickel enhances the chances of developing carcinoma of the nose, lung, larynx, and prostate (Kaur et al., 2021;Genchi et al., 2020;Buxton et al., 2019). The threshold concentration of Ni in drinking water is 0.02-0.1 mg/L, and in air, it is 0.38 ug/m 3 .

Zinc
Zinc, an essential metal for all animals and plants, is ranked as the 24 th most abundant metal on Earth. It is found in zinc blende and calamine ore, which have a density of 7.134 g/cm 3 . The foods that contain zinc are sunflower seeds, cheese, beef, and lamb. Zinc is used in diecasting, and galvanization to prevent metal rust, in cosmetics, paints, batteries, rubber, textile, plastic, and pharmaceutical industries. Zinc sulphide is used in X-ray screens and fluorescent lamps. In metalloenzymes dehydrogenase, alkaline phosphatase, carbonic anhydrase, superoxide dismutase, and leucine aminopeptidase, zinc acts as a cofactor (Sangeetha et al., 2022;Shen et al., 2019). Zinc is also involved in the enzymes involved in deoxyribonucleic acid (DNA) and ribose nucleic acid (RNA) polymerase and also in the structural stabilization of several proteins (Yousif et al., 2021). Accumulation of zinc in humans causes nausea and vomiting, anaemia, stomach cramps, impaired immune function, pancreatic complications, neutropenia, pharyngitis, chest tightness, pulmonary inflammation, copper deficiency, and a decrease in HDL-cholesterol level (Sharafi et al., 2022). Reduction of nerve conduction, lethargy due to mental effects, pathology of neurosensory ability, pathology of psychiatric ability, poor pregnancy, and cardiovascular disease occur if zinc is deficient in the human body (Bartzatt, 2017). The threshold concentration of Zn in drinking water is 5 mg/L, and in air, it is 1 mg/m 3 .

Conclusions
Globally, the health of so many people is affected due to pollution by potentially toxic metals caused by human activities.
Due to leaching from toxic industrial waste dumps, municipal landfills, leaching from soils, agricultural run-off, and sewage water, worldwide most water bodies, especially in developing countries, are contaminated with potentially toxic metals.
These pollutants, when they enter or accumulate in the human body via a food chain, water, or the air, have many adverse effects on humans. These pollutants may cause breast, lung, or prostate cancer; neurodegenerative diseases; obesity; cardiovascular diseases; reproductive problems; immunodeficiency disorder; adversely affect the metabolism of blood cells and blood; inhibit the activity of the enzyme acetylcholinesterase; cause neurodegenerative diseases; disrupt the activity of endocrine glands; and cause developmental abnormalities in the Biomarkers such as hair, nails, urine, and blood are used to assess health risks.
The results showed that for all the biomarkers, the concentration of these metals was higher in the smoking population than in the nonsmoking population.