The Heavy Metals in Human Body Fluids Related to the Tobacco Smoke: A Systematic Review

,

Heavy metals in human body fluids http://thj.hums.ac.ir http human metabolism and may be required in the various concentrations (8,13). The essentiality and toxicity of the metals depend on the dose of exposure (14). This category includes 19 elements, among which the most important are Mn, iron (Fe), Cu, Zn, Ni, and Cr (8). According to the classification by the World Health Organization, trace elements can be divided into three groups, including essential (Zn, iodine, molybdenum, Cu, selenium, and Cr), probably essential (Mn, silicon, boron, vanadium, Ni, and potentially toxic elements (Pb, Cd, fluorine, Hg, Al, As, barium, lithium, and tin [Sn]) elements (14,15). ETS can be produced in houses, at workplaces, and in public places. The health hazards related to exposure to ETS have increased over the past two decades. The bestestablished health effects are lung cancer in nonsmoker adults and childhood disorders such as respiratory tract ailments (16). Public understanding of health risks has grown up due to the release of scientific knowledge on health risks related to ETS exposure in recent decades. It caused a change in public attitudes toward ETS (17), and the detrimental health effects of exposure to ETS are now well established. One of the most comprehensive reviews of the health consequences of ETS to date has been the 1992 report of the US Environmental Protection Agency (18). It is well known that human body fluids are composed of various electrolytes, proteins, metabolites, and HMs (19). A variety of HMs can be found in human body fluids (e.g., blood, sweat, and urine) and are significantly related to health condition (20)(21)(22)(23). For instance, Cu and Zn are essential trace elements that can have detrimental effects on an individual's health when there is an excess or deficiency (22). High Cu accumulations in the human body can lead to Wilson's disease (24), heart and kidney failure, liver damage, brain disease and disorder, and even death in extreme cases, whereas low levels of Cu can cause anemia and osteoporosis. A lethal form of diarrhea and pneumonia can occur when a body has low Zn concentrations, whereas high levels of Zn can be toxic enough to cause liver damage and even decrease cardiac functionality and pancreatic enzyme count in the cases of prolonged exposure (22). Regarding the influence of metals on health and the relation of inhaled metals to tobacco smoke, the aim of this study was established to survey the concentration of metals in body fluids and its relationship to tobacco smoking.

Methods
In the current systematic review, the databases of Springer, ScienceDirect, and PubMed were searched by applying the keywords of "Heavy metal", "ETS"," Tobacco", "Breast milk", "Blood", and "Urine" in the time period from November 1, 2022, to November 27, 2022. The searched term and the results are depicted in Figure 1. In the next step, articles including the words  http "Heavy metal" and "Tobacco" or "ETS" in their title or summary or keyword were selected, and 40 articles were selected in this regard. After studying the full papers, 27 articles remained and were included in the current review.

The Concentration of Heavy Metal in Hair
The determination of HMs on hair is one of the methods to know exposure to tobacco smoke. Children exposed to tobacco smoke (Child E-ETS) showed a higher concentration of Pb on their hair than children not exposed to tobacco smoke (Child NE-ETS) (2.43 ± 1.16 vs. 2.33 ± 1.14 µg/g); however, the concentration of As was equal for both of them (0.32 µg/g). Further, adult smokers demonstrated a higher concentration of Pb, Cd, Al, silver (Ag), and Hg on their hair than non-smoker adults, except for Cr (0.045 ± 0.77 vs. 0.077 ± 0.103 µg/g). Furthermore, children who were exposed to tobacco smoke (child E-ETS) were reported to have a higher concentration of Pb than adult smokers (2.43 ± 1.16 vs. 1.98 ± 1.67 µg/g), the details of which are illustrated in Figure 2 (25)(26)(27).

The Concentration of Heavy Metals in Blood
HMs enter the body along with smoking and exposure to tobacco smoke and reach different parts of the body by the circulatory system. In this regard, their measurement in the blood is one of the common methods for calculating exposure. Based on the results, the concentration of Pb, Cd, and As in the blood of adult smokers was significantly higher than that of adult non-smokers (22.07 ± 22.32, 1.37 ± 0.79, and 22.42 ± 23.44 vs. 13.81 ± 17.38, 0.57 ± 0.27, and 7.51 ± 6.34 µg/L) ( Figure 3). Moreover, the concentration of Pb in the blood of children who were exposed to environmental tobacco smoke (child E-ETS) was higher than that of children who were not exposed to environmental tobacco smoke (NE-ETS), while no significant difference was observed in the concentration of Cd (32.47 ± 12.25 vs. 28.2 ± 9.64 µg/L, 0.11 ± 0.04 vs. 0.1 ± 0.035 µg/L); the obtained data are depicted in Figure 4 (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39).

The Concentration of Heavy Metal in Plasma
Plasma is a part of blood that is often neglected in applications. White blood cells (WBC), red blood cells (RBC), and platelets are essential for body function, but plasma also plays a vital role that is not usually taken into consideration. Plasma transports all the components of the blood in the body. For this reason, plasma is another fluid that can be used for determining the concentration of metals. The results showed ( Figure 6) that the concentration of metals in plasma was higher than in other body fluids, and the concentration of these metals     (41)(42)(43).

The Concentration of Heavy Metals in the Urine
With exposure to metals, some metals are eliminated by the excretory mechanisms of the body through sweat, urine, feces, and the like. In this regard, the level of exposure to metals can be determined by their measurement in the urine. The results indicated that the concentration of Cd in the urine of adult smokers (0.3286 ± 0.0982 µg/g) was higher than in the adult non-smokers (0.2759 ± 0.1239 µg/g) (32,33,37,44,45). Additionally, in the urine of children who were exposed to environmental tobacco smoke (child E-ETS), the concentration of Co and Sn was significantly higher than that of children who were not exposed to environmental tobacco smoke (child NE-ETS) (1.09 ± 0.91 and 1.43 ± 1.63 vs. 0.77 ± 0.54 and 1.13 ± 1.44 µg/L), the details of which are shown in Figure 7 (29,46).

The Concentration of Heavy Metal in Breast Milk
Breast milk is the best food for a newborn. Human milk consists of 87% water, 1% protein, 4% lipid, and 7% carbohydrate (including 1-2.4% oligosaccharides).
It also contains many minerals such as calcium (Ca), phosphorus, magnesium, potassium, sodium, and the like and vitamins (47). Therefore, mother's milk is especially important among body fluids. In this regard, Szukalska et al conducted a study on the concentration of metals in breast milk and its relationship with smoking. Their results (Figure 8) indicated that the concentration of Cd and Pb in the milk of smoking mothers was significantly higher than that of non-smoking mothers (0.32 ± 0.27 and 3.08 ± 1.47 vs. 0.06 ± 0.03 and 0.815 ± 0.43 µg/L) (48). In another study, Dursun et al investigated the concentration of some metals in cord blood, breast milk, and newborn baby hair. Based on their results, the concentration of Pb in cord blood for mothers who were exposed to environmental tobacco smoke (E-ETS) and mothers who were not exposed to environmental tobacco smoke (NE-ETS) was 16.4 ± 15.5 and 17.4 ± 17.8 µg/L, respectively. Likewise, they reported that the concentration of Pb and mercury (Hg in breast milk for the mothers who were E-ETS and mothers who were NE-     (49).

Other Body Fluids
The serum is a part of blood that is similar in composition to plasma but does not contain clotting factors. The components of plasma and serum are similar because they both contain hormones, glucose, electrolytes, antibodies, antigens, nutrients, and some special particles, except for clotting factors that are only present in plasma. Blood serum is one of the body fluids that can be used for measuring the concentration of metals. In this regard, Badea et al investigated the concentration of metals in the blood serum of smokers and non-smokers. The results showed that smokers had higher concentrations of metals in their serum than people who did not smoke, except for Fe, beryllium, Cd, and Sn (1060.68 ± 569.15, 0.28 ± 0.3, 0.035 ± 0.1 and 4.36 ± 1.2 vs. 1182.7 ± 862.1, 0.75 ± 0.4, 0.04 [IQR = 0], and 8.95 ± 11.7 µg/g, Figure 9) (50). Saliva is a clear liquid that is secreted by salivary glands. This liquid is one of the most important factors that facilitates swallowing and tasting. Most of the saliva is made up of water. For this reason, one of the ways to detect exposure to foreign substances such as metals is to measure them in the saliva. In this regard, Khabour et al evaluated metals in the saliva of smokers. The results demonstrated that the concentrations of Pb, Cd, and Zn in the saliva of smokers and non-smokers were 4.8 ± 0.58, 5.1 ± 0.36, and 940 ± 70 µg/L, as well as 2.8 ± 2.7, 0.64 ± 0.2, and 450 ± 60 µg/L, respectively (43).

Discussion
The findings indicated that the concentrations of nicotine and cotinine in hair were positively correlated with Pb, Ag, Cd, and Hg, whereas they were not correlated with Cr (25). HMs enter the body along with smoking and exposure to tobacco smoke and reach different parts of the body through the circulatory system. In this regard, measuring them in the blood is one of the common methods for calculating exposure. It was expected that smoking has an influence on the concentration of Cd and Pb in the blood (31). The blood parameters showed a decrease in RBC and hemoglobin levels that might be linked to the presence of HMs detected in the blood of the exposed individuals. As RBC is generated by the hematopoietic tissues of the kidney/spleen, studies have confirmed that internal bleeding from a damaged kidney due to HM exposure may result in the decreased generation of RBC (28). Pregnant women are a group whose biological indicators are highly important as disturbing the balance of metals in their body can harm both the mother and the infant (51). Lower blood concentrations of Cd in pregnant women have been associated with lower birth weight, a consistent risk factor for common chronic diseases and conditions. These results support that the spatial analysis of the blood concentrations of HMs can aid in focusing limited screening resources on smaller sub-populations with the highest risk of exposure. It was found that Cd, Pb, and As co-occurred in the blood of pregnant women, whereas women with elevated Hg concentrations were more likely to have lower Cd, Pb, and As (52). Plasma is a part of blood that is often neglected to applications. WBCs, RBCs, and platelets are essential for body function, but plasma also plays an important role that is not typically taken into account. Plasma transports all the components of the blood in the body. Accordingly, plasma is considered another fluid that can be employed to determine the concentration of metals. With exposure to the metals, some metals are eliminated by the body's excretory mechanisms through sweat, urine, feces, and the like. In this respect, the level of exposure to the metals can be estimated by measuring them in the urine. Breast milk is the best food for a newborn. Human milk consists of 87% water, 1% protein, 4% lipid, and 7% carbohydrate (including 1-2.4% oligosaccharides). It also contains various minerals (Ca, phosphorus, magnesium, potassium, sodium, and the like) and vitamins (47). Therefore, mother's milk is especially important between body fluids. The concentration of Pb has been indicated to be mostly higher than the concentration of Hg and Cd in the same cohort of breast milk. This is probably because, unlike Hg and Cd, Pb accumulates in the bones of mothers over a long period of time and is then released into the blood and breast milk along with Ca during pregnancy. Moreover, only an extremely small proportion of maternal Cd is released into the mothers' breast milk because proteins that bind Cd in breast milk often bind more to Ca due to the high amount of Ca released into the   breast milk. Hence, there is a competitive inhibition of the binding proteins of Cd. Therefore, the amount of Cd in breast milk is influenced by a mother's Ca level. Finally, the biochemistry of the interactions of these metals and proteins in breast milk is reasonably expected to vary and therefore will contribute to the inherent variation of these toxic metals in breast milk (53). Serum is a part of the blood that is similar in composition to plasma, but does not contain clotting factors. The components of plasma and serum are similar because they both contain hormones, glucose, electrolytes, antibodies, antigens, nutrients, and some special particles, except for clotting factors that are only present in plasma. Blood serum is one of the body fluids that can be used to measure the concentration of metals. Saliva is a clear liquid that is secreted by salivary glands. This liquid is one of the most important factors that facilitates swallowing and tasting.
Most of the saliva is made up of water. For this reason, one of the ways to detect exposure to foreign substances such as metals is to measure them in the saliva.

Conclusion
Some of the metals in the body do not have a toxic effect on certain concentrations and even help improve the functioning of the body system. Smoking, which is highly common among young people today, is one of the factors that disturbs the balance of the concentration of these metals in the body. Smoking causes a significant increase in HMs in body fluids and even decreases essential metals such as Fe. People exposed to tobacco smoke, especially children, are affected by the disturbance of the balance of metal concentrations in the body. In addition, pregnant women who are E-ETS or smoker mothers are affected, and even the concentration of metals in their milk will change and can even significantly decrease the concentration of Fe in their milk.