Toxics, Vol. 10, Pages 716: Characterization of the Toxicological Impact of Heavy Metals on Human Health in Conjunction with Modern Analytical Methods

1. IntroductionAny substance with the potential to produce a negative biological effect can be considered a toxic agent. There are several distinct and intricate classification systems for toxic substances, each based on different standards depending on the desired application. They are classified as pesticides, solvents, food additives, metals, and war gases based on their target purpose. Furthermore, classification based on the chemical structure of toxicants includes metals, non-metals, acids and bases, and organic toxicants, while analytical characterization divides them into volatile toxicants, extractives, metals, and metalloids. Therefore, metal toxicity is regularly encountered in a variety of forms, making the analytical assessment of heavy metals (HMs) highly important in the context of public health [1].HMs are found naturally in the environment, in volcanic eruptions or soil, but they are also the result of various human activities, such as mining, automobile emissions, and industrial waste, etc. The term toxic metals is often synonymous with the term HMs, but there are also light metals which, through accumulation, or in certain forms or doses, become toxic [2]. They adversely affect living organisms, the environment and are non-biodegradable. The criteria for assigning the term HMs are as follows: atomic weight, atomic number, position in the periodic table, and specific gravity >5 g/cm3 (i.e., five times that of water) [3,4,5]. HMs are substances with high electrical conductivity, luster, malleability, and the property to split electrons, forming cations.Concern over HMs contaminating the ecosystem has grown steadily, addressing the issues of environmental and global public health. As a consequence of their use increasing exponentially in a variety of manufacturing, agricultural, residential, and technical applications, human exposure has also increased significantly [6]. Based on the contamination of the air and water, or the accumulation of HMs in plants and meat, the population can be exposed to HMs directly by ingestion, inhalation, or direct skin contact. Furthermore, exposure to HM toxicity is more likely to occur in certain occupations [7].Critical contaminants with the possibility of harming both human health and the ecological balance are non-essential metals. The toxicity manifested by non-essential HMs is different for each chemical element. Effects increase from a low level, as in the case of Barium (Ba), Lithium (Li), Aluminum (Al), and Tin (Sn) to elements with a high degree of toxicity, including Lead (Pb), Arsenic (As), Cadmium (Cd), and Mercury (Hg), responsible for numerous negative health consequences [8]. A classification system of HMs according to their role in the body is depicted in Figure 1.HMs act as cofactors of the enzyme system, in biochemical or metabolic processes. Metal balance in the body is a widely acknowledged fact. When there is an imbalance, lowering or raising specific elements causes a decrease or increase in others. Such a disturbance of the balance can be the cause of many diseases/deficiencies [9].

Framing the already-published information in the literature on the topic (depicted in the bibliometric analysis), this paper aims to provide updated knowledge and a documented and validated database on the recognized toxicity of HMs, the harmful effects of their accumulation on human health, the benefits vs. disadvantages of choosing different biological fluids/tissues/organs for the identification and quantitative measurement of HMs in the human body, as well as on the choice of the optimal method of HMs analysis, depending on the purpose.

4. Exposure Routes to HMs and Toxicity RegulationsAmong the most toxic HMs (affecting human health), the following can be mentioned: As, Al, Hg, Pb, Ni, and Cd. Although they are extremely toxic, the population’s exposure to them is constantly increasing [15]. The HMs pathways into the human body are:

ingestion (via food or water, reaching the bloodstream and various organs, such as the pancreas, and liver, etc., through the absorption process), as is the case for As, Pb, Hg, and Cd;

inhalation (through the inhalation of air, vapors or aerosols, toxic metals enter the respiratory tract, reach the lungs and then the bloodstream), as is the case for Pb, Hg, and Al;

and by dermal absorption for As, as is depicted in Figure 10 [16].It is increasingly recognized that HMs have an increased affinity for certain target organs (i.e., liver, brain, kidneys, and the bones). The accumulation and toxic effect of HMs depends on several factors, such as concentration, chemical form, sex, age, and the time of exposure. Most of them, once ingested, are distributed through the bloodstream to various organs and tissues, where they cause damage in different systems and organs. HMs’ harmful action derives from stimulating the formation of free radicals and reactive oxygen derivatives, which cause lipid peroxidation and oxidative stress in the body [17,18]. Furthermore, it must be considered the excess of HMs in the human body which may lead to neurological disorders and adverse emotional changes [19,20,21]. Table 5 summarizes the toxic effects on some organs and systems.Several institutions manage substance safety concerns and have developed legislation regulating HM-related issues. As a result of the harmful effects of HMs on human health, the Environmental Protection Agency (EPA) made several decisions, including decreasing the Acceptable Daily Intake (ADI) and establishing a Reference Dose (RfD), with an acceptable safety level on health, for developmental and non-carcinogenic effects [38].The official estimations from Institutions, such as the EPA, Joint Food and Agriculture Organization and World Health Organization (FAO/WHO) Expert Committee on Food Additives (JECFA), Food and Drug Administration (FDA), and Agency for Toxic Substances and Disease Registry (ATSDR) that provide the minimum risk limits for HMs, are used to determine the daily maximum safe exposure levels. All the minimal risk values originate from dose-response measurements correlating chronic exposures with the impacts seen in individuals or animal models. The minimum risk values are all based on the prevention of adverse health consequences. Moreover, the chronic oral minimum risk values regulated by the agencies for adults are 2.14 μg/kg/day for inorganic As (JECFA), 1 μg/kg/day for Cd (EPA), 0.16 μg/kg/day for Pb (FDA), 0.3 μg/kg/day for methylHg (ATSDR), 1500 μg/kg/day for Cr (III), and 3 μg/kg/day for Cr (VI), both results being provided by the EPA [39]. The risk posed by HM pollution to human health, can be assessed by using different indices, such as the daily intake of metals (DIM), the transfer factor (TF), and the health risk index (HRI), etc. [40].Due to the difficulty in quantifying the effects of HMs and due to the low (trace) concentrations in different biological matrices, biological monitoring (BM) of human exposure to HMs has become a real challenge. Therefore, HMs toxicity, related to their concentration and accumulation in the human body, over a long period, are triggering factors of various negative effects on human health [41].The scientific literature includes experimental studies on the acute and subacute toxicity of HMs. The bacterial bioluminescent test of toxicity (BBTT) is utilized to assess the acute toxicity of several HMs. The toxicity assays involved the evaluation of the effective concentration levels over different periods and the relative molar toxicity estimates. An experimental study found that Hg was the most harmful of the group of studied HMs (Hg, Pb, Zn, Cu, Cd, As, Cr, Co, and Ni) to the bioindicator Photobacterium phosphoreum, while Ni has been found to be the least toxic [42]. Another study assessed the acute toxicity of Cu, Pb, and Hg on juvenile Cyprinus carpio, determining the concentration that is lethal to 50% of the species (LC50) after 96 h of exposure (0.30 ppm for Cu, 0.44 ppm for Pb, and 0.16 ppm for Hg) [43]. To study the impacts of acute toxicity on the survival rate and bioaccumulation of HMs in tissues, Oreochromis sp. was examined with increasing HM concentrations and times of exposure. The 96 h LC50 of Cu, Zn, and Cd were found to be 0.45, 2.1, and 0.7 mg L−1, respectively. Inductively coupled plasma optical emission spectrometry (ICP-OES) was used to examine fish tissues. A higher concentration of hazardous metals was associated with considerably higher tilapia fish mortality. The results showed that, in these experimental conditions, Cu was more toxic than Zn or Cd [44]. Furthermore, when HMs are present in the environment (water, soil, and food crops) at levels higher than the reference values, there is a significant risk to human health. The well water standard regulation’s reference values are 0.07 µg L−1 for Cd, 2.52 µg L−1 for Cu, 0.39 µg L−1 for Pb, and 1.36 µg L−1 for As. The mean maximum allowable levels (MALs) for the presence of HMs in soils are 13.7 mg kg−1 for As, 28.5 mg kg−1 for Pb, 0.18 mg kg−1 for Cd, and 32. 8 mg kg−1 for Cu. Moreover, the MALs for the presence of As, Pb, Cd, and Cu in vegetables and cereals are 0.1 mg kg−1, 0.2 mg kg−1, 0.125 mg kg−1, and 10 mg kg−1 [45], respectively.The most commonly used methods for exposure assessment include sample selection and preparation steps, followed by sample digestion prior to qualitative and quantitative analysis. The properties of HMs make atomic absorption spectroscopy (AAS) a frequently used method due to its high sensitivity and specificity. The evaluation of the relevant certified reference materials is used to verify the validity of the analytical processes [46].The basic standard necessary to protect individuals from risks to their health and safety inflicted or anticipated to be caused by the presence of HMs at work or as a result of any occupational activity using chemical agents is regulated by law. Furthermore, it is mandatory to respect the biological limit values tolerable by employees, with the concentrations of chemical agents kept as low as possible. Table 6 presents the binding biological limit values (BBLVs), including HMs, established by the Scientific Committee for Occupational Exposure Limits (SCOEL), Chemical Agents Directive (CAD) 98/24/EC establishing the biological limit value at the European Union level and national regulations [47].According to Omrane et al., three strategies have been applied for the assessment of occupational exposure to HMs in order to correlate with the models’ predictions, including mathematical algorithms to estimate analytes’ concentrations, the determination of indoor HM concentrations, and biological testing of HMs in the urine of consenting adults. Moreover, in this experimental study, inhalation was the principal exposure route based on the selection criteria. The concentration of HMs is predicted by using a variety of methods (i.e., the Eddy Diffusion Turbulent model, the Well Mixed Box, and the Near Field and Far Field) [48].The measurement of a chemical agent or its metabolites in a biological sample is one method of determining exposure through BM (usually blood, urine or breath). The benefit of BM is that it incorporates all exposure pathways and sources [49,50,51,52]. BM can be separated into exposure assessment and effect observation, for which internal dose and effect markers are being used. In the context of environmental health, biomarkers mostly refer to measurements used for risk evaluation or diagnosis. The phrase is now being used to describe BM measurements in occupational medicine or industrial health, too. The monitoring of exposure and effects correlate with the indicators of exposure and effects [53].In the domain of environmental health, a number of biological methods and biomarkers are helpful for determining the risk of lead exposure. The most popular biomarker for lead exposure is blood lead. While the significant effects of lead on bone marrow can be considered an effect biomarker, this indicator assesses body burden, soft tissue lead, and absorbed dosages of lead. The interaction of lead with certain enzymes involved in heme production is the primary cause of lead’s effects in the bone marrow [53].The suppression of delta-aminolevulinic acid dehydratase (ALAD) and changes in the quantities of certain metabolites, such as delta-aminolevulinic acid in urine (ALA-U), zinc protoporphyrin (ZP) in blood, delta-aminolevulinic acid in plasma (ALA-P), delta-aminolevulinic acid in blood (ALA-B), and coproporphyrin in urine (CP), are the key biomarkers of impact. The aforementioned markers do not, however, all accurately reflect the dose and the internal dose/effect correlation [54].The heme pathway’s rate-limiting enzyme, ALA synthetase (ALAS), creates ALA in the mitochondria from succinyl-CoA and glycine. Lead exposure causes a reduced ALAD activity, and indirect ALAS induction caused by negative feedback control, resulting in an increase in ALA in different tissues and plasma and an increase in ALA excretion in urine. Although ALA in urine (ALA-U) has been suggested as a biomarker of lead toxicity, ALA in plasma or blood indicates the impact of lead on bone marrow more specifically. In a wide spectrum of Pb-B values, an exponential link between plasma and urine ALA was noticed [55].The proportion of biological anomalies may be indicated by the free erythrocyte protoporphyrin (FEP) values. Microcytic anemia is linked to noticeably high BLLs. The importance of FEP measurement may be muddled by iron deficiency, which is also linked to anemia [56].The levels of zinc protoporphyrin (ZPP) are frequently applied as indicators for lead toxicity. The other essential enzyme that facilitates the inclusion of iron into protoporphyrin IX is ferrochelatase. However, this enzyme is suppressed, and the route is blocked in Pb toxicity conditions. Additionally, if there is not enough iron available, Zn is used in place of Fe, which raises the concentrations of ZPP. These increases do not manifest in the blood until Pb levels approach 35 μg/dL, which limits this modification as a significant diagnostic characteristic [57]. 5. The Importance of Tissue Mineral AnalysisIn the United States in the 1970s, the first mineralograms were made by mass spectrometry, a technique used at the time by NASA, to analyze the moon rocks, as well as to analyze the metals from the spacecraft’s shell. Starting from here, this technique was also used in medicine, as an analysis for the determination of the metal content in animal fur, as well as in the human hair [58].The idea of mineral analysis prompted several American researchers, for example: Dr. George Watson (Nobel Prize), Dr. Clivet, Dr. David Watts, Dr. Wilson, and Dr. Paul Eck, to study numerous cases for more than 40 years, and to conclude that the mineral levels from the hair, correlated well with the mineral level from the tissues. In 1980, the EPA recognized the tissue mineral analysis (TMA), as a scientific method of determining toxic substances, minerals, metals from the human body.Research on TMA has shown that it is a very advanced and modern method in medicine, which shows the relationship between human health and the concentration of various HMs/nutrients. We can find information about the time of exposure, absorption, and the distribution of all toxic substances in human tissues/organs. After absorption, HMs pass into the bloodstream and are stored into the target organs/tissues, which shows that the blood does not reflect an older exposure, this fact being found in the studies on children previously exposed to Pb. In conclusion, we can say TMA is probably the most important barometer regarding the evaluation of HMs on human health [19]. With this method, in a single analysis, the most important 36 minerals from the body can be determined, of which 30 are essential and 6 are toxic minerals (HMs), in extremely low quantities—parts per million (ppm) or even per billion.The human body’s organic structure is made up of 80% water and 19% minerals. Minerals play a very important role in the normal functioning of the body, by controlling certain biochemical reactions, stabilizing components of proteins and enzymes, functioning as mineral cofactors for many enzymes and antioxidant molecules [59]. The enzyme with a mineral cofactor (a bivalent ion of Fe, Zn, Mn, and Co) forms an active configuration. HMs, such as Pb, Hg, Cr, As, and Al, can interfere with enzymatic reactions and disrupt their enzymatic activity because of their affinity for thiol groups (-SH) from the enzyme [60].As was mentioned before, using TMA, the concentrations of HMs and minerals are determined, whose values provide information at the intracellular level, enabling us to identify the tendency towards functional imbalances, chronic intoxications, and concentrations, which cannot be determined by blood or urine analysis (this analysis provides information only at the extracellular level). In other words, we can say that this analysis shows the stress response phase, the mineral requirement of each human organism, the HM amount, carbohydrate metabolism, and the tissue hormone efficiency, etc. Thus it can be stated that TMA with an individualized clinical examination, allows an accurate diagnosis, the establishment of a nutritional strategy, the amelioration of various mineral and hormonal imbalances, and can even identify possible HM intoxication [61]. In the last years, TMA has greatly improved through Hair Analysis (HMS—Hair Metabolic System), which is a more representative method in terms of prevention for preventive diagnosis. Therefore by using HMS, the concentrations of different minerals/HMs can be determined, for up to 3 months or even more, and can be used for individual personalized treatments (in HM intoxication: the chelation therapy or homoeopath treatment; in the case of mineral deficiencies by taking dietary supplements or vitamins) [62]. The continuous development of TMA has led to the discovery of many correlations between disease and emotions. It is well known, that most diseases have an emotional character, and emotions are enchained with the biochemical changes in the body. Emotional and mental factors can lead to increased excretion and absorption of minerals/HMs by the human body. From this, we deduce that strong emotional reactions will produce nutritional, hormonal, neurological, and metabolic changes, which may be quantified and TMA can be that barometer/instrument for assessing the psycho–somatic and somatic–psychic relationship [19]. 8. Conclusions and Future Perspectives

The potential of HMs to damage DNA and membranes, as well as to interfere with the activity of proteins and enzymes has demonstrated that they represent a significant risk to human health.

At the present moment, AAS is the dominant analytical technique for the detection of trace elements (metals, and oligo-elements) in the human body, and we are witnessing a more and more evident shift from flame-electro thermal atomic spectrometry to ICP-MS, a more modern and effective method. However, the choice of the analytical method used for the detection of the different metals will remain at the discretion of the toxicologist/chemist who considers the metals to be detected, their number, the analyzed matrix (biological samples), the concentration of the analyte in the matrix, and the intended purpose (toxicological/nutritional screening, therapeutic purpose, and prevention, etc.).

TMA is of great importance for monitoring the health of the population, not only for studying the effects of occupational exposure, but also for health in general, by determining both nontoxic minerals in the human body and toxic minerals (HMs). Although some authors claim that TMA is an alternative method of investigation or even a fraud (some considered TMA to be “unscientific, economically wasteful and probably illegal”), its importance cannot be denied [146]. In 2011, a publication emerged in the scientific literature that clarified to some extent the status of TMA. This diagnostic method cannot accurately, clearly, and realistically determine what causes an abnormal concentration of minerals in the hair. However, it can be stated that the results of the TMA, in conjunction with laboratory biochemical analyses (i.e., determination of δ-aminolevulinic acid (ALA), coproporphyria/Pb poisoning, or determination of As acute hemolytic anemia, the dark color of urine, detection of plasma Hg, coproporphyria or DMPS challenge test etc.) can lead to an accurate diagnosis in terms of the disorders that the patient suffers from, possible intoxication or possible procedures that the patient undergoes [22].

In the case of an HM detection in forensic practice, it is extremely important to collect as many biological fluids, tissues, and organs as possible, to process them as quickly as possible and to analyze them with modern high-performance equipment. All of these factors, together with a histopathological examination and an investigation into possible diseases and habitual behaviors, can lead to the most accurate determination of the cause of death.

Hyphenated techniques, which combine multimodal detectors with chromatographic separative methods, are becoming effective substitutes with potential use in the evaluation of HMs.

Given the fact that HMs are toxic elements for both human health and the environment, and due to the high degree of bioaccumulation in the human body, it would be advisable to monitor them continuously. Nowadays, due to the modernization of laboratories, the development of biological methods of identification and quantification, using biomarkers it is possible to establish certain criteria and standards that would help protect human health and the environment from HM contamination. TMA, combined with high-performance laboratory analysis, can be considered a vital barometer of the population’s health, as it creates a true mapping of all the biochemical reactions in the body, which through their disturbances can trigger various diseases or even intoxications.

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