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Recent Progress in Nutrition

(ISSN 2771-9871)

Recent Progress in Nutrition (ISSN 2771-9871) is an international peer-reviewed Open Access journal published quarterly online by LIDSEN Publishing Inc. This periodical is devoted to publishing high-quality papers that describe the most significant and cutting-edge research in all areas of nutritional sciences. Its aim is to provide timely, authoritative introductions to current thinking, developments and research in carefully selected topics. Also, it aims to enhance the international exchange of scientific activities in nutritional science and human health.

Recent Progress in Nutrition publishes high quality intervention and observational studies in nutrition. High quality systematic reviews and meta-analyses are also welcome as are pilot studies with preliminary data and hypotheses generating studies. Emphasis is placed on understanding the relationship between nutrition and health and of the role of dietary patterns in health and disease.

Topics contain but are not limited to:

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It publishes a variety of article types: Original Research, Review, Communication, Opinion, Comment, Conference Report, Technical Note, Book Review, etc.

There is no restriction on paper length, provided that the text is concise and comprehensive. Authors should present their results in as much detail as possible, as reviewers are encouraged to emphasize scientific rigor and reproducibility.

 
 

Publication Speed (median values for papers published in 2024): Submission to First Decision: 7.5 weeks; Submission to Acceptance: 15.5 weeks; Acceptance to Publication: 7 days (1-2 days of FREE language polishing included)

 
 
Current Issue: 2025  Archive: 2024 2023 2022 2021
Open Access Review

Impact of Heavy Metals as Trace Elements on the Ecosystem and Health

Rolf Teschke 1,2,*, Nguyen Xuan Chien 3, Tran Dang Xuan 3,4,5

  1. Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, D-63450 Hanau, Germany

  2. Academic Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/Main, Frankfurt/Main, Germany

  3. Faculty of Smart Agriculture, Graduate School of Innovation and Practice for Smart Society, Hiroshima University, 1-5-1 Kagamiyama, Higashi-Hiroshima City, Hiroshima, 739-8529, Japan

  4. Center for the Planetary Health and Innovation Science, the IDEC Institute, Hiroshima University, 1-5-1 Kagamiyama, Higashi-Hiroshima City, 739-8529, Japan

  5. Laboratory of Plant Physiology and Biochemistry, Graduate School of Advanced Science and Engineering, Hiroshima University, 1-5-1 Kagamiyama, Higashi-Hiroshima City, 739-8529, Japan

* Correspondence: Rolf Teschke

Academic Editor: Leonel Pereira

Special Issue: Impact of Trace Elements on the Ecosystem and Health Effects

Received: June 10, 2025 | Accepted: October 09, 2025 | Published: October 21, 2025

Recent Progress in Nutrition 2025, Volume 5, Issue 4, doi:10.21926/rpn.2504023

Recommended citation: Teschke R, Chien NX, Xuan TD. Impact of Heavy Metals as Trace Elements on the Ecosystem and Health. Recent Progress in Nutrition 2025; 5(4): 023; doi:10.21926/rpn.2504023.

© 2025 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Heavy metals are integral parts of our environment, originating initially from the universe and used in the industry, which may contribute to pollution. This book chapter aims to address the impact of heavy metals on the ecosystem and human health. Among the 32 heavy metals, eight belong to the group of essential ones: cobalt, copper, iron, manganese, molybdenum, nickel, selenium, and zinc. They were necessary in physiological amounts for the evolution of flora and fauna, including humans on earth, and are still needed to sustain their wellbeing. For these, however, non-physiological amounts of essential heavy metals are deleterious and have a negative impact similar to that of the 26 non-essential heavy metals if exposed to high or even small amounts. They can disrupt plant growth and yield due to reduced photosynthesis and impair the health of animals, as well as their reproductive properties. To combat hazardous heavy metals, protective measures aimed at improving the ecosystem are mandatory. These measures start with reducing heavy metal release during metallic fabrication processes and are followed by the remediation of soils contaminated with heavy metals. At the human level, precautionary measures are recommended to reduce occupational exposures to heavy metals and to verify the consumption of food and drinking water with normal amounts of heavy metals. In conclusion, essential heavy metals are beneficial to flora and fauna, including humans, when exposed to physiological amounts. In contrast, high amounts are deleterious, as are non-essential heavy metals in both low and high amounts.

Keywords

Heavy metals; trace elements; ecosystem; health; essentiality; toxicity

1. Introduction

Trace elements are essential constituents in the human body and represent a heterogeneous group consisting of about 70 chemicals [1,2]. They are required in amounts ranging from 1 to 100 mg/day to make up 0.005-0.01 wt% of body weight [3]. Among the essential trace elements and micronutrients in the form of minerals are ions of sodium, potassium, magnesium, and phosphorus [4,5]. Sodium in normal amounts is beneficial for humans [5,6]. It participates in the membrane Na+/K+-ATPase as an electrogenic pump [7], provides the principal cation of the extracellular fluid, and plays a significant role in regulating extracellular volume and water balance [6]. However, overconsumption of sodium ions is risky for human health [6], similar to other trace elements that may be toxic if present in excess [8,9,10]. Potassium is a central intracellular cation, preserves acid-base balance, maintains isotonicity and electrodynamic cellular function, and activates many enzymatic reactions within our body [11]. Calcium ions play an essential role in muscle contraction, governed by an action potential that releases calcium stored in the sarcoplasmic reticulum [12]. Calcium binds to tropomyosin, allowing the interaction of myosin and actin in the sarcomere, which leads to muscle contraction. Magnesium engages in over 300 enzymatic reactions, aiding in energy production, and protein, DNA, and RNA synthesis [13]. Phosphorus is required for a diverse range of processes, such as ATP synthesis, signal transduction, and bone mineralization [14]. Finally, among the most important essential elements are heavy metals involved in various metabolic pathways [15].

The book chapter aims to analyze the conditions of heavy metals in the natural and polluted environment, their impact on plants, the food chain, and humans exposed to them. The discussion also covers their implications for human health, highlighting the positive effects of essential heavy metals compared to the potential hazards of non-essential heavy metals, which may be injurious in small amounts. However, crucial heavy metals in higher amounts may also cause dose-dependent toxicities.

2. Heavy Metal Classification

Heavy metals are defined as elements according to their density of greater than 5 g/cm3 [16,17]. Accordingly, heavy metals consist of 32 elements and are traditionally to classified into two groups, essential and nonessential. Humans are exposed to heavy metals of both categories. Still, only eight essential heavy metals are beneficial for their health if amounts are in the physiological range, as provided by a balanced and varied diet that does not require additional supplementation [15]. The 24 non-essential heavy metals have no biological functions. They may be deleterious to human health if provided as metal or their compounds, as opposed to their nanoparticles (NPs), which are promising medications to treat patients with malignancies [18,19] or drug-resistant bacterial infections [20,21].

It is of note and of serious scientific concern, however, that heavy metals are conflicted by contradictive and disturbing variabilities of their nomenclature regarding heavy metals and especially metalloids. These nomenclature issues are far from harmonization and remain largely unresolved by experts in the field. To circumvent these uncertainties, we followed in the text the practicable recommendation to use the term heavy metal as a generic phrase that includes in the heavy metal category, among others, also metalloids [17] and integrated this proposal in the list of essential and non-essential metals as presented to the U.S. Environmental Protection Agency Risk Assessment Forum, Washington [22].

3. Heavy Metals and Environment

3.1 Origin and Sources

All 32 heavy metals from aluminum to zinc are found in various amounts in the environment [16,17,22,23]. From there, they are exposed to humans with detectable amounts found in their bodies [24,25]. However, heavy metals are not generated on our globe but originate from the cosmos [10,26].

3.1.1 From Universe to Human Evolution

Heavy metals formed at various molecular levels from helium and hydrogen in the universe via nuclear fusion in stars during supernova explosions. These metals likely arrived on our globe between ten and twenty billion years ago, more specifically around 13.7 billion years ago [10,27,28,29,30,31,32,33]. Quantitatively, the most abundant element in the known universe is hydrogen (1H), which accounts for about 90% of all atoms [27]. In fact, 1H is the raw material from which all other elements were formed, and 1H and 2He together account for at least 99% of all the atoms in the known universe. The nuclear reactions took place in stars, which transform one nucleus into another and create all the naturally occurring elements, which were provided to and found on Earth. Here, flora and fauna developed, and the evolution of humans was facilitated by essential heavy metals [15,34], but in addition, trace essential minerals were required [5,6,11,14,35,36] and bulk elements, namely oxygen, hydrogen, nitrogen, and carbon [36].

3.1.2 Rocks

Rocks represent natural stone resources like quartz, quartzite, mica schist, gabbro, gneiss, limestone, phyllite, itabirite, and ironstone [37]. They contain a variety of heavy metals like chromium, copper, iron, lead, manganese, nickel, and zinc [37,38]. As fundamental components of primary minerals in rock fragments, heavy metals are detected as natural elements in the nearby environment, including soil and water [37,38,39,40]. The release of heavy metals from rocks is controlled by long-term geological and geochemical processes [39], occurs during their weathering, and is linked to their global circulation [40]. Thus, the natural occurrence of heavy metals in the environment is attributable to their liberation from stones as part of rocks, to be differentiated from polluting heavy metals due to anthropogenic activities.

3.1.3 Mines and Industry

As expected, heavy metals are detected not only within but also around mines [41,42,43,44]. Mining activities as a source of anthropogenic sources release heavy metals in an uncontrolled manner, causing widespread contamination of the ecosystem on exposure to water via dispersal through wind, as shown, for example, for gold mines with the release of arsenic, cadmium, cobalt, copper, gold, iron, lead, nickel, silver, and zinc [41]. Even worse in this context, to separate the gold from the mineral rock, mercury was often mixed with the ores dug to form an amalgam, which, upon burning, leads to evaporation of the elemental mercury into the atmosphere, leaving the gold behind. With respect to copper mines, copper and iron were the predominant heavy metals that polluted the environment [42], whereas arsenic, cadmium, chromium, cobalt, copper, iron, lead, manganese, nickel, and zinc were detected around iron ore mining, while copper was found to exceed the respective guideline value [43]. Other mining activities revealed the release of the heavy metals arsenic, cadmium, chromium, copper, lead, manganese, nickel, and zinc [44].

The metal industry releases the heavy metals barium, cadmium, chromium, cobalt, copper, lead, molybdenum, nickel, selenium, silver, tin, titanium, vanadium, and zinc, as compiled from a database consisting of more than 1300 site-specific measured release factors to air and water of 18 different metals from various EU member states [45]. Releasing industries are confined to the manufacture and recycling of massive metal and metal powder, the manufacture of metal compounds and alloys, and the use in batteries. Additional evidence of industrial release of heavy metals is provided by the large number of non-malignant and malignant occupational diseases found among workers in the metallic branch [46,47,48,49].

3.2 Occurrence

Heavy metals occur naturally in the environment through the erosion of rocks [50] and due to human activities such as those found in smelters, oil refineries, petrochemical plants, pesticide manufacturing, and the chemical industry [15,16]. Whereas the natural heavy metals are detected diffusely throughout the earth in low concentrations, the anthropogenic heavy metals occur in the surroundings of metal mines and industry facilities in higher concentrations [15,16,50,51].

3.2.1 Soils

Soils have harbored heavy metals from the earth's crust since its formation, originating from natural sources like rocks or human industrial activities [52,53]. In a region of intense industrialization and urbanization, surface soil contained arsenic, cadmium, cobalt, chromium, copper, iron, lead, mercury, manganese, and nickel, while the analysis revealed that cobalt, chromium, iron, manganese, and nickel were primarily derived from lithogenic sources, with cadmium, copper, and zinc originating from anthropogenic sources, and arsenic with mercury were controlled by both natural and anthropogenic sources [54].

3.2.2 Water

In drinking water, aluminum, arsenic, cadmium, chromium, copper, iron, lead, manganese, and mercury were detected [55,56,57,58]. Pollution of heavy metals damages water quality by altering water characteristics such as pH, electric conductivity, and total dissolved solids, or by modifying natural processes and reducing the quality of the aquatic environment [56]. Concentrations of heavy metals increased rapidly due to anthropogenic activities, as they were widely used in industrial products [56,57].

3.2.3 Atmosphere

Heavy metals are discarded into the atmosphere due to the rapidly growing agriculture and metal industries, improper waste disposal, and the use of fertilizers and pesticides [59]. They enter the atmosphere as particles, droplets, or in the gaseous form, or associated with particles or droplets. Particles and droplets do not travel long distances and usually fall on the ground after a short distance, though if small in size, they can travel a longer distance. However, particles in the gaseous state can be transported over long distances. More specifically, most European countries are confronted with a polluted atmosphere by heavy metals [60].

3.2.4 Plants

Heavy metals enter the plants during growing on polluted soils through uptake via their roots and rhizomes, which allows for the transport of heavy metals up to the shoots and leaves [60,61,62]. Non-essential plant heavy metals include arsenic, cadmium, chromium, cobalt, lead, mercury, nickel, and vanadium, which are phytotoxic in low and high amounts. In contrast, others are essential, such as copper, iron, manganese, and zinc, which are of benefit in low quantities but phytotoxic in high amounts [60].

Copper. The deficiency of copper, as an essential heavy metal in plants, is a common observation [63,64]. Copper is a cofactor of many enzymes that control metabolic pathways with a focus on photosynthesis, the respiratory electron transport chain, cell wall metabolism, oxidative stress protection via antioxidant systems, and the biogenesis of molybdenum cofactor [64,65]. Features of plant copper deficiency include growth retardation, premature senescence, and impaired productivity, attributed to disruption of the electron transport chain, cellular respiration, and photosynthesis [63,64]. Due to the poor migration rate of copper in the phloem, typical changes first appear in young leaves, manifesting as chlorosis at the top, leaf edge curling, leaf deformity, or final necrosis [63].

Excessive copper in plants has diametral effects on the ecosystem, including plants, because soils may be contaminated by copper from copper-containing fungicides and industrial pollution [63,64]. High levels of copper reduce plant photosynthesis and increase cellular oxidative stress [63]. This can affect plant productivity and potentially pose serious health risks to humans via bioaccumulation in the food chain. Plants have evolved mechanisms to strictly regulate copper uptake, transport, and cellular homeostasis during long-term environmental adaptation [63,64]. However, excessive amounts of copper can disrupt normal physiological steps and crucial metabolic pathways, thus hindering plant growth and development and reducing yield [63,64,65].

Iron. Iron deficiency in plants may lead to chlorosis and can reduce yield through the diminished vegetative growth associated with quality losses, conditions that cause primary syn. genuine plant iron deficiency is attributed to low iron uptake from an iron-deficient soil [66]. As opposed, features of plant iron deficiency can also be attributed to the five heavy metals cadmium, cobalt, manganese, nickel, and zinc, if they are taken up from contaminated soils, mimicking iron deficiency in the sense of a secondary plant iron deficiency despite iron uptake from the soils in normal amounts [62]. As an example, increased zinc uptake leads to reduced plant chlorophyll content by stimulating the transcriptional response of typical iron-regulated genes, suggesting that zinc disturbs the cellular iron homeostasis at the level of iron sensing. Manganese antagonized iron at the level of transport, while cadmium, cobalt, and nickel act at different mechanistic levels. Metabolic disruptions upon primary and secondary plant iron deficiency affect carbon or protein metabolism and the photosynthetic pathways at the thylakoid membranes, where the multiprotein complexes photosystems I and II are responsible for converting light energy into chemically bound energy, along with the cytochrome b6/f and ATPase complexes [66]. To compensate for the multiple disruptions, plants are rearranging the cellular iron homeostasis and improving the iron acquisition through swelling of root tips and formation of lateral roots, root hairs, and transfer cells that increase the root surface area, and cellular iron homeostasis may be restored by the induction of a plasma-membrane Fe(III)-reductase and an Fe(II) transporter [66,67,68,69].

Excess uptake of iron can be toxic to plants because iron generates ROS via the Fenton reaction, which leads to leaf bronzing, impairs plant growth, and reduces yield [70]. However, some plants like rice with specific genotypes can tolerate high amounts of iron, as evidenced by transcriptome analyses, which proposed core genes and proteins that are regulated by iron excess in rice roots and shoots.

Manganese. Manganese deficiency is found in plants growing on soils with poor manganese availability. It may affect the plant photosystem II by destabilizing its super- and subcomplexes, which are the primary targets of the injury [71,72]. Despite substantial disruption of the photosystem II, plant manganese deficiency can easily be overlooked because growth may be slightly impaired, and leaves may appear normal [71], thereby masking the extent of the manganese deficiency issue [72]. Significant manganese deficiency impairs root endodermal suberization and affects various processes in plant shoots. In contrast, mild manganese deficiency increases the length of the unsuberized zone close to the root tip, and increases the distance from the root tip at which the fully suberized zone develops [72]. Traditional cereal landraces constitute a valuable germplasm for reintroducing genotypic diversity that helps increase nutrient efficiency and improve crop robustness [71].

Excessive manganese may be toxic to plants to varying extents, depending on the cultivar and its genotype [73]. The phytotoxicity is attributed to disrupted photosynthesis and enzyme activities that reduce plant growth and production [74]. To overcome the issue of toxicity, plants have evolved a wide range of adaptive strategies to improve their development. Manganese tolerance mechanisms are genetically controlled and include activation of the antioxidant system, regulation of manganese uptake and homeostasis, and compartmentalization of manganese into subcellular compartments such as vacuoles, endoplasmic reticulum, Golgi apparatus, and cell walls.

Zinc. Zinc deficiency reduces crop yield and nutritional quality, as evidenced by chlorosis of young leaves, reduced leaf size, and stunted and thin stems. At the same time, older leaves also exhibit leaf bronzing, stunted growth, chlorosis, curling, and wilting [75]. Zinc participates in several transporter protein families, including the heavy metal ATPase family protein and the metal tolerance proteins that regulate zinc transport and cellular zinc homeostasis. Plants can adapt to low levels of soil zinc supply, to improve zinc acquisition and utilization, and defend against zinc deficiency stress. Zinc deficiency responses are tightly controlled by transcriptional regulation via transcription factors, epigenetic regulation at the level of chromatin, and post-transcriptional regulation mediated by small RNAs and alternative splicing.

Excessive amounts of zinc reduce plant growth, associated with photosynthetic reduction, including a decrease in photosynthetic pigments, inhibition of electron transport, a decrease in CO2 fixation, chloroplast disorganization, and photooxidative damage [76]. These disturbances are due to the generation of ROS, the inhibition of antioxidative enzymes, cellular redox imbalance, DNA damage, and protein oxidation. High amounts of zinc in plants are harmful to animals and humans as a result of long-term or acute exposure.

Issue of Vegetables Nearby Waste Landfill. Crops growing near municipal solid waste landfills are at specific risk of contamination by heavy metals, which can contaminate the surrounding soil and water [77,78,79,80]. As an example, the municipal solid waste landfill in Vientiane, Laos, receives more than 300 tons of waste daily, of which approximately 50% is organic matter [77]. In this study, accumulated levels of the HMs cadmium, chromium, copper, nickel, lead, and zinc in surface water, groundwater, soil, and plants were detected in variable amounts. Some values exceeded the standards of the Agreement on the National Environmental Standards of Laos (ANESs), Dutch Pollutant Standards (DPSs), and the World Health Organization (WHO) and reached the eco-toxicological risk levels. Among the tested plants was the vegetable Ipomoea aquatica, which is consumed by the nearby villagers and was seriously contaminated by chromium, copper, lead, and zinc, with accumulation of these HMs above WHO standards. Considering that the villagers commonly consume leaves and stems of I. aquatica, the accumulated HMs in this vegetable may become a health hazard for exposed users [77]. Since many plants absorb HMs from contaminated soils [77,81,82,83,84], it is tempting to use plants that help remove heavy metals from soils. However, this phytoremediation does not really solve the problem of pollution if plants accumulating HMs are not discarded ecologically after harvesting, because keeping HMs in the environment at other places establishes a vicious cycle. Instead, the primary goal must be the prevention of environmental and occupational hazards by industrial activities.

Herbal Medicinal Products. It is well known that herbal medicinal products contain not only herbs but also HMs [85,86,87]. Among these were detected arsenic, cadmium, chromium, copper, iron, lead, manganese, mercury, nickel, thallium, tin, and zinc; some of these are potentially hepatotoxic [86]. However, many herbal medicinal products carry the risk of liver injury, as evidenced by studies on patients with diagnoses verified by the use of the Roussel Uclaf Causality Assessment Method (RUCAM) published as the original version of 1993 [88,89] or its updated version of 2016 [90]. Notably, in many cases, it remained unclear whether the clinical liver injury was attributable to the contaminating or adulterating HMs or to the herbal constituent.

3.2.5 Animals

Animals, including livestock, are continuously exposed to HMs via their food chain [91,92,93]. While essential HMs in low amounts were required for their evolution and subsequently for sustaining their health, higher amounts are risky in a similar way as for low and high amounts of non-essential HMs [92,93]. In more detail, arsenic, cadmium, copper, lead, and mercury may impair the health, reproductive properties, and productive performance [92]. The uptake of toxic HMs by animals occurs through contaminated feed and water, resulting from anthropogenic environmental pollution, which causes cellular disruption of copper homeostasis due to the excess generation of ROS. Elevated HM levels in consumable animal products raise public concerns.

3.2.6 Other Living Organisms

Algae and Fishes. Arsenic, cadmium, chromium, and lead were detected at variably increased levels in samples of 23 commonly consumed seafood species, including crustaceans, bivalves, algae, and fish, purchased from markets in Haikou, China [94]. Methylmercury and other mercury compounds were found in high concentrations in fish and shellfish caught in Minamata Bay, Japan. The bay is heavily polluted with methylmercury discharged from a chemical plant in Minamata City, the southwest region of Kyushu Island [95,96].

Bacteria and Fungi. Bacteria and fungi are essential in improving polluted soil ecosystems because they are sensitive to changes in environmental conditions, especially in the presence of contaminating HMs, whereby the composition of microorganisms in different heavy metal polluted soils is variable [97]. The dominant phyla in lead/zinc smelters were Proteobacteria, Firmicutes, Actinobacteria, Bacteroidetes, and Acidobacteria [98]. In cadmium-contaminated soil, Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria prevailed, supported by rhizobia and arbuscular mycorrhiza fungi co-inoculation [99]. In contrast, in other studies, Proteobacteria, Actinobacteria, Acidobacteria, and Chloroflexi were the most abundant bacterial taxa [100]. To survive in harsh metal-contaminated environments, bacteria can accept HMs, and due to specific resistance mechanisms, they can metabolize HMs into less hazardous forms [101]. In addition, such endophytic bacteria could play an essential role in understanding the uptake mechanism of HM ions and providing immunity to plants against metal toxicity [102]. Thus, the recent developments in the putative mechanisms by which endophytic microorganisms affect plant resistance to HMs and influence the phytoextraction of metals from contaminated soil are encouraging.

4. Heavy Metals and Humans

4.1 Exposure Routes

Humans are exposed to essential and non-essential HMs throughout their lives, which are often taken up concomitantly and may enter the body through the gastrointestinal tract, skin, or via inhalation [24]. The most common way to ingest heavy metals is through the daily consumption of food and drinking water derived from contaminated environments and agriculture. More specifically, HM contamination of foods originates from the weathering of the bedrock, air pollution directly, as well as soil irrigation with polluted waters and polluting groundwater [77,103]. Environmental contamination develops primarily by industrial and human activities, and refers to soil or groundwater, which are the most common access routes for heavy metals such as lead, mercury, chromium, arsenic, and cadmium [24,103,104].

4.2 Beneficial Effects of Essential HMs

Essential HMs were required for human evolution on our globe [34,35] and are still needed to help sustain their health [24]. In analogy to flora and fauna species, low levels of essential HMs are pivotal in humans for many metabolic pathways and enzymes involved in vital processes [15]. Intake of insufficient essential HM amounts will cause corresponding clinical deficiency syndromes. In contrast, excess levels of essential HMs in cells of selected organs may result in disruption of metal homeostasis [17] as evidenced, for example, by genetic disorders leading to accumulation of copper in patients with Wilson disease due to impaired biliary excretion of copper [105] or due to intestinal iron absorption in excess amounts among patients with hemochromatosis [106]. The eight essential HMs in normal amounts have different roles sustaining human health (Table 1) [107,108,109,110,111,112,113,114,115,116,117,118,119,120].

Table 1 Listing of essential heavy metals with their biological properties in humans.

It is obvious that for cellular functioning and homeostasis, the presence of the eight essential HMs with their fine-tuning action is needed, supported by their crosstalk among each other, although this may be impaired if individual HMs interact and compete at the same target. The concomitant presence of non-essential HMs within the cells may complicate the cellular performance.

4.3 Essential and Non-Essential HMs and Their Compounds as Medicines

Both essential and non-essential HMs were used in the past to treat a variety of ailments, often without the expected therapeutic efficiency, and ignoring adverse effects. Nowadays, most of the previously used HMs are replaced by chemical drugs with a positive benefit-to-risk ratio. A list of 32 HMs is provided, 26 of them were used as medicinal products or supplements, while 5 were not (Table 2) [121,122,123,124,125,126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197].

Table 2 Listing of heavy metals used as medicines to sustain health and treat diseases.

4.4 Issue of Therapeutic Nanoparticles of HMs

Metallic nanotechnology is specifically appreciated in cancer diagnosis through biomedical imaging and therapy due to its excellent biocompatibility and controllable chemical properties [198]. It is provided by several heavy metals in form of nanoparticles (NPs) with a promising future as pharmaceuticals in modern medicine while awaiting for more completed preclinical trials and clinical RCTs to ascertain a positive benefit versus risk ratio [183,198]. Among the NPs of interest are, for instance, those of gold, silver, platinum, palladium, titanium, copper, iron, and zinc that are used to cure patients with malignancies and represent excellent candidates for improving other cancer therapies [18,183,199,200,201,202,203,204]. There is also a potential for metallic NPs as new antibacterial drugs [205]. Metallic NPs range from 1 to 100 nm in size [18,204], are multifunctional [18,183], and are appreciated as personalized cancer treatment, which is tailored to the unique molecular characteristics of individual tumors and affected patients [18,183], targeting also overexpressed receptors in cancer cells [199]. The tailoring of specific features of NPs can be ascribed to their tunable characteristics and multifunctional properties [18,183]. Therapeutic cytotoxic effects of metallic NPs are initiated through the generation of reactive intermediates, which provoke oxidative mitochondrial or endoplasmic reticulum stress, DNA damage, cell cycle arrest, and finally lead to apoptotic/necrotic cell death or autophagy [200]. Their therapeutic efficacy can be enhanced if combined with antibodies, DNA, RNA, peptides, and proteins [201,202,203,204]. Issues of biosensing, catalysis, and bioimaging are strongly associated with the properties of NPs [202]. NPs traffic to the spleen and lymph organs and the relevant immune cells therein, making them good candidates for delivery of immunotherapeutic agents [203]. In addition, NPs are easily integrated in cancer immunotherapy, aiming to recognize and eliminate cancer cells [183,204]. Progress is also underway by utilizing metallic NPs as adjuvants for vaccines against cancer, leveraging their synergistic immunomodulatory properties to facilitate antigen presentation and immune cell activation, with the aim of tumor regression [183]. Similarly, NPs of heavy metals can be prepared to modulate immune checkpoint pathways to release antitumor immune responses [183].

For a few promising NPs, specific details are provided [18,21,183,198,199,200,201,202,203,204,205,206,207,208]. (1) NPs of gold (AuNPs) are known for their exceptional biocompatibility, tunable surface chemistry, and distinct optical properties [183,201] and allow for the generation of reactive radicals [204]. They deliver drugs directly to the cancer cells of specifically targeted tumors, which is associated with reduced systemic toxicity [18,183,202]. Due to their propensity to accumulate at the tumor site, AuNPs facilitate laser hyperthermia therapy [18]. AuNPs are also able to increase vaccine delivery [203]. (2) NPs of silver (AgNPs) participate in cancer therapy [202], especially if resistant to chemotherapy or radiotherapy [183,201]. AgNPs showed antiproliferative and proapoptotic effects in glioma cells after radiation therapy [18], are known for their antimicrobial effects [202], and facilitate vaccine release [203]. (3) NPs of platinum (PtNPs) were found to be effective as breast cancer therapy in several preclinical studies [101,102,103]. (4) Palladium NPs (PdNPs) with their excellent catalytic property and high surface area are ideal candidates for nano-radiopharmaceuticals for treating breast cancers [199,200,201]. (5) Titanium dioxide NPs (TiNPs) are appreciated for their increased photocatalytic activity and improved UV absorption efficiency [18] and are prepared to increase vaccine delivery [203]. (6) Copper oxide NPs (CuNPs) are cytotoxic to lung cancer cells while causing apoptosis due to increased production of toxic radicals [18], have the potential of facilitating vaccine delivery [203], and facilitate toxic radical generation [204]. (7) Iron oxide NPs (FeNPs) are magnetosensitive and, as such, they are used in conjunction with doxorubicin, which increases the anticancer effects through the paramagnetic properties of doxorubicin and the potential for electron transitions into nano-complexes with more free radical formation [18]. FeNPs are privileged to enhance vaccine release [203]. (8) Zinc oxide NPs (ZnNPs) enter the cancer cells and cause DNA damage like a genotoxic medicine [18], improve vaccine delivery [203], and are capable of toxic radical generation [204]. (9) NPs of bioactive heavy metals and their compounds can be combined with antibiotic drug molecules; they may function as effective nanocomposites and have the option to become carriers in targeted drug delivery systems of antibacterial drugs. Under consideration are NPs of gold, silver, titanium, copper, and iron, which exhibit antibacterial potential against gram-negative and gram-positive bacterial strains and may be effective to treat multi-resistant infections [21,205,206]. (10) NPs of titanium used in nanostructured ceramics can reduce friction and wear problems associated with artificial joint titanium replacements [207,208], in addition to being effective for treating bacterial infections often seen in patients with joint replacements [21,205]. (11) Progress is also underway by utilizing NPs as adjuvants for vaccines against cancer, leveraging synergies for their immunomodulatory properties to facilitate antigen presentation and immune cell activation, aiming to achieve tumor regression [183,206]. (12) NPs of heavy metals augment vaccine delivery through facilitating antigen uptake by dendritic cells and other antigen-presenting cells (APCs), thus improving the respective anti-tumor cytotoxic T cell response [203].

4.5 Hazardous Health Effects of High Essential HM Levels

Although beneficial in physiological amounts (Table 1) and partially used as medicines (Table 2), the eight environmental essential HMs may have deleterious effects on human health if excessively accumulated in the body (Table 3) [10,105,106,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224].

Table 3 Listing of high essential HM levels with their health hazards.

4.6 Toxicity of Non-Essential HMs

The 24 environmental non-essential HMs pose a risk to human health in a dose-dependent way, not only when present excessively in the body but also in low amounts (Table 4) [122,225,226,227,228,229,230,231,232,233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249,250,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269,270,271,272,273,274,275,276].

Table 4 Listing of non-essential heavy metals and their impact on human health.

The non-essential heavy metals enter the human body continuously and uncontrolled via ingestion, inhalation, or the dermal route [1,6]. Ingested heavy metals are confronted with the intestinal microbiome that plays a pivotal role in the protection against toxins and regulation of the immune system [101]. Heavy metals may modify the intestinal bacteria with an overgrowth of pathogens that can impair the gut barrier and facilitate the intestinal uptake of toxic bacterial metabolites via the development of a leaky gut.

5. Clinical Manifestations and Management of Toxic Diseases by HMs

5.1 Clinical Characteristics

Clinical features vary depending on the type of HM found in excess in the human body, the route and degree of exposure, the modification of the intestinal microbiome, the amount absorbed from the intestinal tract, and conversion of the HM to less toxic compounds [8,9,10,17,277,278]. Intoxication by most ingested HMs leads to liver injury because the liver is the primary organ filtering the contaminated blood originating from the intestinal tract [8,9,10,17]. Clinical manifestations are listed (Table 3) and provided below in short form as examples for selected HMs [277,278].

5.1.1 Arsenic

Arsenic ingestion causes acute toxicity like abdominal pain, nausea, emesis, and watery or bloody diarrhea, followed by hypotension, heart failure, torsade de pointes, ventricular fibrillation, and shock. In contrast, chronic arsenic uptake causes malignancies of the skin, lung, liver, bladder, and kidney [10,277,278].

5.1.2 Bismuth

Bismuth taken up by ingestion in high doses is nephrotoxic, as evidenced by proximal tubular necrosis that may end up as Fanconi syndrome, which presents with hypophosphatemia, hypouricemia, metabolic acidosis, renal glucosuria, and tubular proteinuria. In contrast, prolonged bismuth intake may lead to neuropsychiatric disorders like depression, anxiety, irritability, and ataxia, in addition to gingivostomatitis [278].

5.1.3 Cadmium

Acute intoxication from inhalation exposure to cadmium oxide causes cough, fever, hypoxia, respiratory insufficiency, or even death, and intestinal uptake can lead to bloody diarrhea and vomiting. In contrast, chronic ingestion of cadmium may result in emphysema, nephrotoxicity, musculoskeletal toxicity, and malignancies of the liver, pancreas, stomach, thyroid, and hematopoietic system [10,277,278].

5.1.4 Chromium

Acute ingestion of chromium can cause the deleterious multi-organ failure in connection with gastrointestinal hemorrhage and the risk of bowel perforation, intravascular hemolysis, acute renal insufficiency, and metabolic acidosis. At the same time, chronic exposure manifests primarily as cancers, such as in the lung, presenting as small cell and poorly differentiated carcinomas [277].

5.1.5 Copper

Copper intoxication causes acute symptoms of metallic taste, nausea, or heart, kidney, and liver failure [278]. In contrast, chronic toxicity is commonly seen in connection with genetic Wilson disease, a copper-storing disorder, characterized by neuro-psychiatric symptoms like dysarthria, dysphagia, tremors, ataxia, and concentration deficits, and liver disease stages up to cirrhosis and liver failure [10,105,278].

5.1.6 Iron

Acute iron intoxication commonly starts with symptoms of nausea, diarrhea, and hematemesis, followed by circulatory shock, cardiopathy, renal insufficiency, and progression of liver failure [278]. In contrast, prolonged iron uptake, as seen in hereditary hemochromatosis, causes the deposition of large amounts of iron in multiple organs, leading to cirrhosis and diabetes mellitus [10,106,278].

5.1.7 Lead

Both acute and chronic lead exposure are risk factors for various deleterious effects, such as hypertension, anemia due to impaired heme production, abdominal pain, vomiting, constipation, loss of appetite, weight loss, cognitive impairment, peripheral neuropathy, renal insufficiency, sterility, immune imbalances, and delayed skeletal and dental development [277,278,279].

5.1.8 Mercury

Acute mercury intoxication by ingestion presents a low toxicity risk due to a low absorption rate of 0.01% from the gastrointestinal tract, and few reports are available [277,278,280]. In a patient who ingested metallic mercury, severe pneumonia, acute renal failure, and anuria developed [281]. Acute inhalation of metallic or inorganic mercury vapors mainly injured the lungs [280].

Prolonged mercury exposure is associated with a higher risk of cardiovascular disease, ischemic heart disease, cardiovascular disease mortality, and all-cause mortality [259]. The ingestion of fish and shellfish contaminated with methylmercury was hazardous and caused the so-called Minamata disease [282,283]. Methylmercury has been discharged in wastewater from a chemical plant in Minamata City, the southwest region of Kyushu Island, Japan. The first well-documented outbreak of methylmercury poisoning by consumption of contaminated fish occurred in Minamata, Japan, in 1953. Since methylmercury spread from Minamata to the Shiranui Sea, residents living around the sea were exposed to low-dose methylmercury through fish consumption. These chronically intoxicated patients suffered from somatosensory disorders, distal paresthesias of the extremities, paresthesias of the lips [282], and neurocognitive impairment [283].

5.1.9 Selenium

Acute intoxication from selenium ingestion was rarely reported. Symptoms of toxicology included severe irritation of the respiratory tract with the risk of edema of the lung and bronchopneumonia, tingling of the nose, and rhinitis [278]. The metallic taste in the mouth is also typical. There is the risk of skin lesions like erythema and even necrosis.

Chronic intoxication of selenium presents with functional musculoskeletal impairment, neuropathy, liver failure, and risk of lethal outcome [278]. Standard features included itching of the scalp, generalized alopecia, skin lesions with reddish pigmentation, nail dystrophy, and dental anomalies such as tooth decay and mottling.

5.1.10 Thallium

Acute intoxications with thallium salts present initially as painful paresthesia of hands and legs, vomiting, diarrhea, abdominal pain, followed by alopecia, skin desquamation, keratosis on palms and soles, painful glossitis, and Mee’s lines in the nails [278]. Prolonged intake of environmental thallium resulted in sleep disorders, headache, fatigue, psychasthenia, and polyneuritis [284].

5.2 Diagnosis

Symptoms of heavy metal intoxications are variable and mostly uncharacteristic; they rarely lead to an initial diagnosis because many diagnoses unrelated to the metals have to be excluded [277,278]. Alopecia and changes of the integument, including nails, can be specific for selected heavy metals as a cause of the diseases and may require extensive laboratory analyses, including quantitative determinations of heavy metals in blood, urine, or hair. It is also essential to have a careful occupational history and questions around living conditions, including sources of food and drinking water.

5.3 Treatment Options and Prognosis

5.3.1 Therapy and Management

Treatments modalities of acute intoxications vary among the HMs or their compounds, depending strongly on the route of exposure and the amount finally entering the human body [277,278,285,286]. In general, patients in life-threatening conditions require treatment in an intensive care unit equipped for technical toxicological analyses and specific devices. A bundle of therapeutic approaches is under consideration for the treatment of acute or chronic intoxications by HMs, with options to be decided on a case-by-case basis. First, the exposure of the incriminated HMs must be terminated. Second, if ingestion occurred a few hours before hospital admissions, gastrointestinal lavage can facilitate the removal of HMs from the intestinal tract. Third, chelating drugs can be tried, although efficacy has not been established for all HMs, and for a limited HMs, antidotes are available. Fourth, other options include forced diuresis and hemofiltration. Fifth, charcoal is occasionally used to bind HMs in the intestinal tract to help fecal excretion and to interrupt the entero-hepatic circulation. Specific therapies are available for patients with Wilson's disease. Chelators like D-penicillamine are effective in facilitating the removal of circulating copper bound to albumin and increasing urinary copper excretion [105]. For hemochromatosis, regular venesection is indicated to remove excessive iron from the blood [106]. As the worst-case scenario, a liver transplantation may be indicated for the end stages of the two genetic diseases [105,106].

5.3.2 Prognosis

The outcome of HM intoxications is variable, depending on the amount and duration of the metal exposure, and whether treatment was quickly initiated. The range of the prognosis starts with complete health restoration, but morbidity often is unavoidable (Table 3 and Table 4) [277,278]. Regretfully, various HMs occur after prolonged exposure to malignancies that may be effectively treated, leading to death. Malignancies of organs include bladder (arsenic), brain (beryllium), breast (aluminum, antimony, cadmium), colorectum (antimony), kidney (arsenic, beryllium), liver (antimony), lungs (arsenic, beryllium, bismuth, cadmium, lead, and uranium), nasopharynx (cadmium), pancreas (cadmium), prostate (antimony, cadmium), and skin (arsenic) (Table 4). However, mortality is also possible in patients with non-malignant but otherwise severe disorders (Table 4).

5.4 Prevention

Prevention of human toxic diseases due to non-essential HMs is mandatory and is achievable through different ways: (1) Workers in the metallic industry or in mines must be protected effectively from exposure to prevent possible occupational disease; (2) waste water of metallic firms and municipal should not pollute nearby soils and surface or ground water; (3) consumption of food products contaminated by HMs must be avoided, the Minamata disease due to mercury in fishes is a disturbing ecological and fatal human example.

HMs are not biodegradable, and remediation of soils contaminated with HMs by physical and chemical measures is costly, time-consuming, and non-sustainable [287]. Instead, phytoremediation may solve the polluting issues of soils, whereby plants absorb contaminating HMs from polluted soils [77,81,82,83,84,287]. Progress is observed with special plants focusing on metal-microbe interactions. An emerging technology termed rhizomediation can be exploited to reduce both soil pollution and plant HM stress. In selected plants, several rhizosphere microorganisms are found that can accumulate, transform, or detoxify HMs [287]. Other HM-tolerant plants specifically absorb HMs from the soil and store them without detoxification in different parts such as roots, rhizomes, or leaves [77,81,82,83,84]. Ideally, plants are harvested and subjected to sustainable biotechnology, then burned in special facilities where the HMs can be recycled, and biogas can be produced.

6. Recent Developments

Actual challenges focus on the decreasing groundwater quality and a link between declining groundwater quality and adverse health outcomes, in addition to its impact on the environment [288]. The decline in groundwater quality was attributed to industrial pollutants, agricultural contaminants, and urbanization issues. This calls for an urgent need for administrative initiatives to implement interventions Sustainable Development Goals (SDGs) 3 and 6, addressing not only aspects of good health and well-being (SDG §) but also clean water and sanitation (SDG 6).

A recent report reminded us that heavy metal contamination remains a growing global environmental and health issue due to continued population growth and industrialization [289]. To cope with these challenges, monitoring programmes are mandatory under the supervision of governmental agencies. It was outlined that soil heavy metal contamination is the most critical environmental threat, alongside wastewater. Artificial intelligence (AI) can help estimate and predict heavy metal dynamics in contaminated soils. AI focuses on developing algorithms that replicate human brain functions and can learn from specific patterns in already existing databases.

7. Conclusion

Based on a thorough analysis provided in this book chapter, an attempt was made to close the information gap regarding the impact of heavy metals on the ecosystem and human health. As a result, and in analogy to the ecosystem, humans benefit from essential heavy metals in physiological amounts. Still, if confronted with them in high amounts, they may experience adverse health effects. These poor events are similar to those of non-essential ones if they expose humans to low or high amounts. As evidenced by a bundle of different diseases. The organs affected include the liver, kidney, heart, lungs, bones, brain, peripheral nervous system, skin, and reproductive system. Disturbing are malignancies caused by long-term exposure to some heavy metals: bladder (arsenic), brain (beryllium), breast (aluminum, antimony, cadmium), colorectum (antimony), kidney (arsenic, beryllium), liver (antimony), lungs (arsenic, beryllium, bismuth, cadmium, lead, and uranium), nasopharynx (cadmium), pancreas (cadmium), prostate (antimony, cadmium), and skin (arsenic). In addition, Minamata disease, caused by mercury in consumed fish, is a fatal ecological and human example. In general, however, all humans primarily benefit from the essential role of this process, which ensures the functionality of virtually all cellular metabolic pathways and helps sustain cellular homeostasis. In addition, both types of heavy metals and their compounds are known to have been used in previous and current medicines with variable efficacy. Currently, nanoparticles of selected heavy metals and their compounds, such as gold, silver, platinum, palladium, titanium, copper, iron, and zinc, ranging from 1 to 100 nm in size, are promising drugs for treating patients with malignancies or infections. Patients intoxicated acutely or chronically with heavy metals require instant diagnosis confirmation and subsequent therapy. This may include, in acute intoxication, on a case-by-case basis, gastrointestinal lavage, application of charcoal, application of chelators, forced diuresis, hemofiltration, surgical intervention, and chemotherapy for malignancies. Specific therapies are available for patients with Wilson's disease. Chelators like D-penicillamine are effective in facilitating the removal of circulating copper bound to albumin and increasing urinary copper excretion. For hemochromatosis, regular venesection is indicated to remove excessive iron from the blood. As the worst-case scenario, a liver transplantation may be shown for the end stages of the two genetic diseases. As a result, all humans benefit from essential heavy metals in small amounts, and only a small proportion experience health risks due to exposure. Considering soil heavy metal contamination as the most critical threat to the global ecosystem and human health, regulatory programs are needed to reduce soil contamination. Among various processes, AI can help estimate and predict heavy metal dynamics in contaminated soil with the aim of better managing the contamination.

Author Contributions

RT provided the outline of the article; NXC and TDX conceptualized the tables and collected the relevant literature. RT wrote the first draft, which was edited by NXT and TDX. All authors agreed on the final version to be submitted for publication.

Competing Interests

The authors declare that they have no conflict of interest.

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