Toxicology Mechanisms and Methods

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The effects of heavy metals on human metabolism

Zhushan Fu & Shuhua Xi

To cite this article: Zhushan Fu & Shuhua Xi (2020) The effects of heavy metals
on human metabolism, Toxicology Mechanisms and Methods, 30:3, 167-176, DOI:
10.1080/15376516.2019.1701594

To link to this article: https://doi.org/10.1080/15376516.2019.1701594

Published online: 17 Dec 2019.

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TOXICOLOGY MECHANISMS AND METHODS
2020, VOL. 30, NO. 3, 167–176
https://doi.org/10.1080/15376516.2019.1701594

REVIEW ARTICLE

The effects of heavy metals on human metabolism

Zhushan Fu and Shuhua Xi
Department of Environmental and Occupational Health, School of Public Health, China Medical University, Shenyang, China

ABSTRACT ARTICLE HISTORY

As technology continues to advance, heavy metals in drinking water have exceeded recommended Received 2 July 2019
limits from regulators around the world. The main source of human exposure to heavy metals is from Revised 23 November 2019
contaminated drinking water. The effects of drinking water contaminated with heavy metals, such as Accepted 25 November 2019
arsenic, lead, nickel, cadmium and mercury, have gradually caught the attention of the relevant
KEYWORDS
departments and personnel. It is well known that occupational exposure to heavy metals occurs as a Heavy metals; arsenic; lead;
result of using these metals in a variety of industrial processes in and/or a variety of materials, includ- nickel; cadmium;
ing color pigments and alloys. A series of adverse effects on human metabolism has resulted from mercury; metabolism
exposure to heavy metal-contaminated drinking water, which has been recorded from around the
world. The general mechanism of heavy metal toxicity is through the production of reactive oxygen
species, the appearance of oxidative damage, and subsequent adverse effects on health. Therefore,
water contaminated with heavy metals causes high morbidity and mortality worldwide. In order to
address concern regarding the health effects of different heavy metals, this paper reviews its sources,
distribution and effects of heavy metal on human metabolism.

HIGHLIGHTS
1. The accumulation of heavy metals such as lead, arsenic, mercury, cadmium and nickel will destroy
the main metabolic process of human body.
2. Redox reactions in biological systems are caused by carcinogenic metal ions such as nickel and
arsenic. The free radicals produced by these reactions cause oxidative damage to proteins
and DNA.
3. The accumulation of heavy metals eventually produces reactive oxygen species that can cause
oxidative stress, which may lead to the production of various diseases.

Abbreviations: ALAD: d-aminolevulinic acid dehydratase; AS: arsenic; Cd: Cadmium; CNS: central ner-
vous system; DMA: dimethylric acid; ETC: electron transport chain; G6PD: glucose-6-phosphate
dehydrogenase; HIF- 1a: hypoxia-inducible factor-1 alpha; LDH: lactate dehydrogenase; Pb: Lead; MDA:
malondialdehyde; MT: metal sulfur protein; Hg: mercury; mTOR: mammal rapamycin target; MAPK:
mitogen-activated protein kinase; Ni: nickel; OXPHOS: oxidative phosphorylation; ROS: reactive oxy-
gen species

1. Introduction
Heavy metal naturally exists in earth’s crust (Al-Samman
2015) but can cause serious problems for all living things
and are toxic pollutants for the natural environment (Fu and
Wang 2011). Due to exponential growth in the use of various
products and industries, human exposure to heavy metals
has dramatically increased over the past 50 years (Bedrin
et al. 2003).
Metal waste pollutes the surface of water and soil, result-
ing in harmful impacts on human health. In order to ensure
that humans are protected from the adverse effects of heavy
metals, especially heavy metals in drinking water, inter-
national organizations have developed standards for the use
of each individual metal (Lane and Morel 2000). Heavy met-
als can interfere with the metabolic function of the body
through various means. Some metals, such as manganese,
zinc, copper and iron, are required by the human body (Lane
and Morel 2000). However, if they were ingested at higher
concentrations, they would have toxic effects on the human
body (Asubiojo et al. 1997). Other heavy metals, such as,
mercury and lead, have no healthy effects but are detrimen-
tal to human health, when they accumulate in the human
body (Asubiojo et al. 1997).
The accumulation of heavy metals in the body has been
demonstrated to have an adverse effect on human health.
The main heavy metals that that is possible to cause adverse
effects include arsenic, lead, aluminum, iron, mercury and
cadmium. These metals can enter the body through various
ways, such as skin or inhalation routes, or intake of heavy
metals through contaminated drinking water and food.
Heavy metals can also react with certain compounds in the
body, such as oxygen and chloride, exerting their own toxic

CONTACT Shuhua Xi shxi@cmu.edu.cn Department of Environmental and Occupational Health, School of Public Health, China Medical University,
Shenyang, 110122, China
ß 2019 Informa UK Limited, trading as Taylor & Francis Group
168 Z. FU AND S. XI
effects (Rusyniak et al. 2010). Persistent exposure to heavy
metals can lead to an imbalance in the body when heavy
metal accumulate in the body and are used as substitutes
for essential elements. Examples of heavy metals replacing
essential elements of the human body include calcium
replaced by lead, zinc by cadmium, and most trace elements
by aluminum (Genestra 2007). Lead metal ions can replace
other divalllions such as Ca2þ, Mg2þ, Fe2þ and unital cations
such as Naþ to ultimately disrupt the biological metabolism
of cells. The ion mechanism of lead toxicity causes significant
changes in various biological processes. Even at picomolar
concentrations, lead can replace calcium and affect protein
kinase C, which regulates nerve excitability and memory stor-
age (Flora et al. 2008). Cadmium and zinc with the same oxi-
dation state, so cadmium can replace zinc present in metal
sulfur protein, causing zinc metabolism disorders that inhibit
it as a free radical scavenger in cells (Flora et al. 2008). In
addition, the accumulation of heavy metals destroy the main
metabolic process of the human body, and at the same time
lead to an imbalance of antioxidation. Similarly, the function
of essential enzymes and the activity of numerous hormones
are also affected (Dhir et al. 2011). Researchers have identi-
fied various carcinogenic pathways caused by heavy metal
exposure. Some studies have shown that the mutagenicity
and carcinogenicity of heavy metals are related to their abil-
ity to cause oxidative stress. In this aspect, researchers have
found that redox reactions in biological systems are caused
by carcinogenic metal ions, such as chromium, nickel, cobalt,
and arsenic. The free radicals that are produced by these
reactions cause oxidative damage to proteins and DNA.
Besides direct DNA damage, products produced by redox
reactions have two other functions that lead to carcinogen-
esis in humans. One is the activation of redox-sensitive tran-
scription factors, while the other function involves its role as
a mitogenic signal. Similarly, the carcinogenicity of heavy
metal pathways may interfere with the process of DNA repair
(Genestra 2007).
Figure 1. Toxic effect mechanism of heavy metals.
Therefore, this paper gives an overview of the current sta-
tus of heavy metals pollution, expounds the effects of accu-
mulation of heavy metals in the body on metabolic enzymes
and metabolic processes, and explains possible mechanisms
of action.
2. Heavy metals and metabolism
Heavy metals naturally exist in the earth’s crust (Al-Samman
2015), and accumulate in different sections of plants, which
can in turn affect human health. Although zinc, manganese,
cobalt, copper and iron are essential for the human body,
they can be toxic to the human body when their concentra-
tion becomes too high (Asubiojo et al. 1997).
Heavy metals can interfere with the metabolic functions
of the human body in a various of ways. In addition, they
may accumulate in important organs of the human body,
such as the brain, heart, liver, and kidneys, ruining normal
biological functions. However, the biggest issue is that there
can be no environment without heavy metals at all. Heavy
metals can enter the human body through various access,
such as the consumption of contaminated food and drinking
water, and through the air, which can lead to a series of
effects on the human body (Al-Samman 2015). The accumu-
lation of heavy metals in the human body has a detrimental
effect on human health. The main heavy metals that cause
this effect include cadmium, arsenic, aluminum, mercury and
iron. Due to increased industrialization of society and
increased exposure to heavy metals worldwide, the harmful
effects on human health associated with exposure to heavy
metals have increased over the past few years (Rusyniak
et al. 2010).
Researchers have found a variety of carcinogenic path-
ways caused by heavy metal exposure (Figure 1). Numerous
studies have shown that the carcinogenicity and mutagenic-
ity of heavy metals are associated with the induction of oxi-
dative stress. In this regard, some studies have shown that

redox reactions in biological systems are carried out by car-
cinogenic metal ions, such as nickel, chromium, cobalt and
arsenic. Therefore, the free radicals produced by these reac-
tions cause oxidative damage to proteins and DNA. Despite
the direct damage of DNA, species produced by these redox
reactions also have two other important functions that cause
cancer in humans. One is the activation of redox-sensitive
transcription factors, while the other functions involves its
role as a mitotic signal (Genestra 2007). Similarly, another
pathway of heavy metal carcinogenesis is thought to be a
process that interferes with DNA repair (Rehman et al. 2018).
The heavy metals stored destroy the body’s main meta-
bolic processes and cause an imbalance of antioxidants.
Similarly, the activity of various hormones and the function
of indispensable enzymes are also affected (Jayawardena
et al. 2017). With changes in carbohydrate, protein and lipid
metabolism, the body’s susceptibility to infections is apt to
increase. Ultimately, all of these mechanisms alter the syn-
thesis and application of neurotransmitters in the body,
which in turn modify a range of functions of the central ner-
vous system (CNS) (Qayyum et al. 2012). Therefore, regard-
less of the molecular pathways that are affected by heavy
metals, they eventually produce reactive oxygen species that
can cause oxidative stress, a process that can lead to differ-
ent types of cancers, impaired kidney function, neurological
diseases and other endocrine diseases (Qayyum et al. 2012).
2.1. The effects of lead on metabolism
Lead(Pb) is a common environmental and industrial contam-
inant (Qayyum et al. 2012; Rahman and Sultana 2006) which
is found in the form of elements, both inorganic and organic,
and in trace amounts in food, water and soil (Patocka and
Cerny 2003). Most of the environmental pollution caused by
lead is the result of the use of lead paint on the outer side
of buildings (Godwin 2001). At the same time, more than
900 occupations, including refining, mining, smelting, weld-
ing, and painting, making stained glass and ceramic glass,
are exposed to lead, resulting in lead poisoning (Patocka and
Cerny 2003). Inorganic lead compounds and elemental lead,
such as lead dust, can be absorbed through the digestive
system and the respiratory system (Patocka and Cerny 2003).
The presence of lead determines its toxicity in the environ-
ment. Organic lead compounds based on covalent bonds
have different toxicological effects from that of inorganic
lead salts (such as lead acetate). Organic lead compounds
can be absorbed through the skin and then enter the brain,
giving rise to a toxin in the central nervous system (Marshall
et al. 2007). Subsequently, lead is absorbed into the plasma,
after the extracellular fluid are in a state of and lead accumu-
lates in soft tissues and hard tissues. Finally, lead is mainly
excreted through the urinary system and the digestive sys-
tem (Patocka and Cerny 2003).
The main mechanisms of lead affecting metabolism are
shown in Figure 2. Due to the release of free radicals, the
damage caused by lead to living systems involve two separ-
ate mechanisms (Ercal et al. 2001). The first mechanism is
the direct production of reactive oxygen species (ROS), such
TOXICOLOGY MECHANISMS AND METHODS 169
Figure 2. Lead affects the main mechanisms of metabolism.
as O2þ, H2O2 and hydroperoxides, Studies have shown that
lead can raise reactive oxygen levels and Ca2þ within cells,
which in turn leads to a decrease in mitochondrial potential
and apoptosis through the release of cytochrome c (Moreira
et al. 2001).
While the second mechanism is achieved by the con-
sumption of antioxidants of cells (Ercal et al. 2001). Previous
studies indicate that lead can inhibit mitochondrial oxidative
phosphorylation, thereby changing the d-aminolevulinic acid
dehydratase (ALAD) of cells. Lead also causes oxidative stress
and destroys the oxidant/antioxidant balance of cells
(Kasperczyk et al. 2012). Oxidative stress caused by lead is
the main mechanism of its toxicity. In addition to changes in
antioxidant enzymes, it is directly involved in free radical-
mediated reactions (Knowles and Donaldson 1990), enzyme
activity and changes in the concentration of antioxidant mol-
ecules, such as glutathione (Mudipalli 2007). As an antioxi-
dant present in cells, Glutathione protects them from free
radicals. Under normal conditions, the reduced form (GSH) of
Glutathione accounts for 90% of the total Glutathione and its
oxidized accounts for 10%. However, in the case of oxidative
stress, GSSG concentration exceeds GSH concentration
(Samadi et al. 2001).
Permpongpaiboon et al. (2011) and Kasperczyk et al.
(2005), found that significantly elevated malondialdehyde
(MDA) levels were observed in workers exposed to lead
(other signs of lipid oxidative damage were also observed)
(Kasperczyk et al. 2005; Permpongpaiboon et al. 2011). The
effects of lead acetate on human red blood cell metabolism
in vitro, and the results are consistent with the results of
Kasperczyk et al. (2005), Xia et al. (2018). In the study, the
function of the pentose phosphate pathway was found to
have been reversed as a result of decreased Glucose-6-phos-
phate dehydrogenase (G6PD) activity (Kasperczyk et al.
2005). However, Garier-Orchan et al. reported conflict-
ing outcome.
Paglia et al. (1975) investigated the activity of enzymes in
human red blood cells exposed to lead in vitro and obtained
the same results as those of Antonowicz et al. (1990), (Paglia
et al. 1975; Rosenberg et al. 2002), who studied lead expos-
ure in workers. The results of this study found that the lead
170 Z. FU AND S. XI
exposure group had significantly higher than the average
PBB levels of lead exposed workers, as reported in the study
by Kasperczyk et al. (2005). The difference in these results
may be due to lead exposure time, lead concentration and
intracellular oxidative stress intensity.
Wang et al. (2010) studied the damage of cadmium in
renal cortex by combined exposure of lead and cadmium.
The conclusion that low concentrations of lead acetate can
improve the respiratory rate is consistent with that of
Kasperczyk et al. (2005). This is the indirect result of the malic
acid-aspartic acid shuttle in cells, which increases pyruvate
oxidative decarboxylation and Nicotinamide adenine
dinucleotide (NADH) transportation from the cytoplasm to
mitochondria, which may lead to a decrease in Lactate
dehydrogenase (LDH) activity. However, there was no signifi-
cant change in FBA activity, indicating that lead has a limited
effect on the glycolysis pathway. The in vitro study by Yun
and Hoyer (2000) on rat brains indicate that lead can inhibit
the glycolysis enzyme and mitochondrial respiration (Yun
and Hoyer 2000). It interferes with many body functions
inside the body, affecting most organs. The organic form of
ingestion is absorbed by the liver and is therefore metabo-
lized, compared to inorganic lead that is not metabolized by
the liver (Banfalvi 2011).
2.2. The effects of arsenic on metabolism
Human exposure to arsenic (AS) may be caused by exposure
through drinking water contaminated by industrial waste or
agricultural chemical waste (Hughes et al. 2011). Another
source of water pollution may be smoke or arsenic fog.
Poisoning may be caused by eating pesticide-contaminated
foods, arsenic-rich foods, or foods that grow in fertile soils
(Antonowicz et al. 1990). Incredibly, drinking milk is also one
of the sources of arsenic poisoning, since adulterated milk
contains a mixture of arsenic-containing water. In addition to
these sources, AS access to the human body also includes
inhalation and skin contact. Additionally, another major
source of arsenic poisoning is the use of acids and crude
metals. Inorganic arsenic has acute and chronic toxicity
Figure 3. Mechanism of arsenic poisoning.
(Korrick 2004). More than 140 million people worldwide con-
sume arsenic-contaminated drinking water that exceeds the
World Health Organization’s 10 ppb limit (Lenczewski 2009),
with groundwater in Bangladesh and West Bengal having
the highest levels of arsenic (Rahman 2002). In this part of
the world, 35 million to 77 million people are exposed to
arsenic, concentrations of which in drinking water that range
from less than 10 ppb to more than 4 ppm, resulting in the
death of about 1/5 people due to exposure to arsenic.
Therefore, arsenic pollution is of global concern (Rahman
2002; Argos et al. 2010).
Arsenic metabolites exist in both organic and inorganic
forms, and both types can be presented in trivalent or penta-
priced oxidation states. Sodium arsenate or arsenic dioxide
in triaval form reacts with many biosites with sulfur groups,
and as a result, arsenic compounds inhibit many enzymes
(Challenger 1947; Sharma et al. 2015). Methyl oxide and
glutathione concosering are thought to be the main path-
ways due to metabolism (Hayakawa et al. 2005). The toxic
effect mechanism of arsenic is shown in Figure 3. Urine
removes most of the arsenic ingested in inorganic form, and
the first step after methylation can bioconvert a small
amount of as to convert inorganic AS (III) methylation into
dimethylric acid (DMA).These processes usually detoxify
organic arsenic, but some organic arsenic metabolites may
contribute to arsenic toxicity (Bernstam and Nriagu 2000).
Apart from affecting the skin (Yu et al. 2006) and leading
to bladder cancer (Marshall et al. 2007), arsenic also affects
the liver (Liaw et al. 2008), kidneys (Yuan et al. 2010) and
lungs (Smith et al. 2006). Studies by Ditzel et al. (2016) and
Shi et al. (2014) found that arsenic is associated with cancer
(Shi et al. 2014; Ditzel et al. 2016), metabolic syndrome and
other metabolism-related diseases and symptoms (Arteel
et al. 2008; Ditzel et al. 2016). However, even after decades
of research, the exact mechanism by which arsenic causes
disease is still unclear. The production of reactive oxygen
species (ROS) (Shi et al. 2004), altered DNA methylation
(Zhao et al. 1997), DNA damage (Wang et al. 2001) and
enzyme inhibition are considered to play a role (Kitchin and
Wallace 2008). Arsenite can enter the mitochondria through

hydroglycerin, where it binds to and suppresses many
enzymes involved in energy production, including pyruvate,
succinic acid, isocitrate and a-ketoglutarate dehydrogenase
(Braeckman et al. 2009; Higashi et al. 1965). The electron
transport chain (ETC) complexes II and IV indicate that mito-
chondrial dysfunction caused by arsenic may be present in
arsenic-related pathological processes (Naranmandura
et al. 2011).
The results of Zhao et al. (2013) show that chronic, low
dose (75 ppb) arsenite exposure induces the Warburg effect
(Zhao et al. 2013), which is defined as the conversion from
mitochondrial oxidative phosphorylation (OXPHOS) to aer-
obic glycolysis, which is also a common sign of cancer devel-
opment. Importantly, the observed glycolytic transformation
is accompanied by a decrease in Krebs circulating activity, an
increase in aneuploidy and loss of anchorage-dependent
growth, all of which are dependent on the stability of the
transcription factor, hypoxia-inducible factor-1 alpha (HIF- 1a)
(Zhao et al. 2014). These results reveal that the destruction
of mitochondrial energy metabolism is one of the important
mechanisms of arsenic carcinogenesis. Robey et al. (2015)
reviewed the possibility of carcinogenesis through environ-
mental exposure by changing mitochondrial metabolism
(Robey et al. 2015), but there are few examples for these
mechanisms. High arsenic levels were observed to inhibit the
activity of hexalysinkinse (Zhang et al. 2015), Furthermore,
arsenite exposure result in severe mitochondrial dysfunction,
reduced ATP levels (Luz et al. 2016).
2.3. The effects of cadmium on metabolism
Cadmium (Cd) is a type of heavy metal that exists naturally
in ores and is usually used as a stabilizer for different prod-
ucts, such as color pigments, alloys and other related prod-
ucts (Jarup et al. 1998). Occupational exposure to cadmium
includes, smoke inhalation, the nickel-cadmium battery
industry, electroplating and paint pigments (Pang et al.
2016). Oral exposure to cadmium is the consumption of con-
taminated food and/or water. This pathway is the most
important pathway for nonsmokers and those with no occu-
pational exposure to cadmium (Pang et al. 2016).
Studies have found that cadmium exposure has an inhibi-
tory effect on the main antioxidant enzymes: glutathione
reductase and superoxide dismutase (Stohs et al. 2001; Valko
et al. 2006). Increased lipid peroxidation has been observed
in some brain regions after cadmium exposure, such as the
cerebellum and cortex (Mendez-Armenta et al. 2003).
Through various experimental studies, it has been found that
cadmium has a disturbing effect on the levels of enzymes
that maintain the redox reaction. Due to this disorder, the
occurrence of lipid peroxidation eventually induces damage
to the brain microvasculature (Shukla et al. 1996). Cadmium
binds mainly to metal sulfur protein (MT) in the body to
form Cd-MT, which is reabsorbed in the small tube of the
kidney, degrades in the lysozyme of the near-curved tube,
isolates and releases free cadmium, thus interfering with the
metabolite of the chowtoral epithelial cell mitochondrial
energy metabolism and oxidation phosphorylation, which in
TOXICOLOGY MECHANISMS AND METHODS 171
turn leads to renal cell damage and death (Ohta and Cherian
1991; Jomova and Valko 2011). Cadmium produces ROS and
induces oxidative stress by replacing copper and iron, caus-
ing fenton reactions, reducing the number of copper and
iron ions participating in oxidative stress response or increas-
ing the number of uncombined free radicals (Watjen and
Beyersmann 2004). Recent studies have shown that oxidative
stress is a potential cause of neuronal toxicity, at the same
time, oxidative stress is also considered to be one of the
related mechanisms of genotoxicity. Oxidative stress caused
by cadmium exposure can damage (Valko et al. 2006) and
destroy the normal function of organelles and produce DNA
mutations that lead to changes in gene expression and
finally, inducing apoptosis (Ognjanovic et al. 2010). In add-
ition, cadmium can impair the repair function of DNA dam-
age, which can lead to the accumulation of DNA damage,
inducing genetic mutations and thus cancer (Giaginis et al.
2006; Zhou et al. 2012). Some DNA damage repair enzymes
have zinc finger structure, cadmium can replace the activity
of zinc inhibitory enzymes on this enzyme, thereby inhibiting
DNA damage repair (Zhou et al. 2012).
Reactive oxygen plays a leading role in cadmium cancer-
causing process because reactive oxygen causes apoptosis,
abnormal gene expression and inhibits DNA damage repair.
Although studies generally indicate that reactive oxygen lev-
els in normal cells are lower than in tumor cells, there are
also studies showing that reactive oxygen levels in normal
cells are higher than in tumor cells (Zhou et al. 2012).
Studies have shown that two neuronal cell types: PC 12 and
SHSY5Y cells increase ROS production after cadmium expos-
ure (Chen et al. 2008). The two signaling pathways produced
by ROS leading to apoptosis are the mTOR (mammal rapa-
mycin target) pathway and the mitogen-activated protein
kinases(MAPKs)ignaling pathway (Chen et al. 2008, 2011).
Studies have also shown that cadmium alters the activity
of many carbohydrate-related metabolic enzymes. Cadmium
has the potential to limit the glycozy process in the liver and
muscles by reducing the activity of fructose kinase phos-
phate (Almeida et al. 2001). Cadmium also increases the
activity of several other enzymes involved in amino acid
decomposition metabolism, such as amino acid oxidase, glu-
tamate dehydrogenase, etc (Cicik and Engin 2005). Similar to
arsenic, Maria et al. found that cadmium also inhibits hexaly-
sinkinase (Ramirez-Bajo et al. 2014), the results of Li et al.’s
research show that cadmium promotes glycolysis at the
beginning of the experiment. Long-term exposure to cad-
mium, but inhibited glycolysis. Therefore, it is concluded that
by increasing cadmium concentration, glycolysis can be
inhibited earlier (Zhou et al. 2012) (Figure 4).
2.4. The effects of nickel on metabolism
Nickel(Ni) is the 24th most abundant element on earth, and
3% of the earth’s crust is composed of nickel. Nickel is widely
distributed in drinking water around the world (Coogan et al.
1989). Nickel is considered to be important for various func-
tions of the human body. However, increased exposure may
cause human poisoning (Diagomanolin et al. 2004; Haber
172 Z. FU AND S. XI
Figure 4. The role of cadmium in glycolysis.
et al. 2000; Ognjanovic et al. 2010). The two main pathways
of oral nickel exposure are through water and food contami-
nated with nickel-containing compounds (Haber et al. 2000).
Ni has many industrial and commercial applications, render-
ing it accessible to these types of workers. Nickel emissions
are naturally found from forest fires, volcanic emissions and
wind dust. Other sources of nickel emitted into the air
include coal combustion and waste incineration, while
another source of nickel exposure for humans is tobacco
smoke (Yang and Ren 2010).
In the human body, nickel binds to mercaptan to form a
nickel-mercaptan complex. Then, the complex reacts with
molecular oxygen to produce free radicals, which eventually
leads to nickel toxicity (Das et al. 2006). Experimental studies
by Das et al. have shown that nickel binds to thiol proteins,
leading to a decrease in glutathione levels, which in turn
leads to nickel toxicity in the body (Valko et al. 2005).
Researchers have found that physicochemical properties in
the human body may change owing to nickel exposure, as a
result of reduced calcium excretion in urine. In addition,
nitrogen retention is also reduced due to nickel exposure
(Kumar et al. 2019). The pathway of oxidative phosphoryl-
ation is impaired by reduced levels of nicotinamide resulting
from chronic nickel exposure. M’Bemba-Meka et al. studied
cultured human red blood cells and found that these cells
were under oxidative stress because of nickel exposure
(2006). There is evidence that nickel plays a role in inducing
blood toxicity. Salnikow et al. conducted a study in which
nickel exposure in rats and mice was induced through inhal-
ation. Blood red blood cell count, hemoglobin concentration
and other indicators increased. It was also found that the
changes in all these parameters were due an increase in
erythropoietin synthesis caused by nickel-exposure induced
hypoxia (Denkhaus and Salnikow 2002).
Nickel is a necessary auxiliary factor for SOD to regulate
cell ROS level and protect nitrogenase. The excess
production of reactive oxygen species caused by Redox
homeostasis disruption may lead to cell death and decrease
the number of living cells (Oukarroum et al. 2017). Studies
by Martınez-Ruiz and Martınez-Jer Nimo have shown that
nickel induces the production of reactive oxygen species and
increases the activity of antioxidant enzymes through the
generation of free radicals by Fenton reaction (Miazek et al.
2015). Excess nickel can also induce the production of free
radicals and reactive oxygen species by direct electron trans-
fer, which inactivates enzymes in the antioxidant defense
systems of other photosynthetic organisms, such as
Glutathione reductase, mitochondrial (Nagajyoti et al. 2010).
2.5. The effects of mercury on metabolism
Mercury (Hg) is a common heavy metal pollutant found in
the natural environment, mainly in the following forms:
element, inorganic and organic (Li et al. 2016). These three
forms have different toxicity, among which the least toxic
form is the element (Clarkson 1997). Although mercury is
found at low levels in the environment, its toxicity, persist-
ence and bioaccumulation may still pose a health threat to
humans and other organisms (Eagles-Smith et al. 2016).
Elemental mercury is oxidized in the air into an inorganic
form. In its vapor form, metallic mercury is usually absorbed
through the respiratory tract and difficult to absorb through
the gastrointestinal tract. Because of its soluble properties,
elemental mercury spreads highly through the cell mem-
brane and blood brain, reaching the target organ. Once
enter in the bloodstream, elemental mercury is easily oxi-
dized into inorganic Hg and Hg in red blood cells and tissues
in the presence of hydrogen peroxide and peroxidase.
Compared with the organic form that mainly affects the cen-
tral nervous system, inorganic Mercury follows non-regular
distributed, accumulating mainly in the kidneys; causing
acute renal failure (Al-Saleh et al. 2012). Mercury is a major
cause of autoimmune diseases and antinuclear antibodies
produced by individuals exposed to inorganic mercury
(Crowe et al. 2017). Hg is also a causative agent of
Alzheimer’s disease and Parkinson’s disease (Chin-Chan et al.
2015). Therefore, all forms of mercury have strong toxic
effects on the central nervous system and digestive system
(Crowe et al. 2017).
Some studies have shown that exposure to mercury
increases the production of free radicals, ROS and superoxide
anions due to the Fenton reaction (Ehara et al. 2001; Magos
1997; Miller et al. 1991). Wildemann et al. (2016) argue that
the pivotal roles of mercury-induced toxicity are inhibition of
antioxidant defense systems, changes in the oxidant-antioxi-
dant balance, and the increase of ROS (Wildemann et al.
2016). Methylmercury is a neurotoxic compound that causes
lipid peroxidation, mitochondrial damage, microtubule dam-
age, and the accumulation of neurotoxic molecules (Patrick
2002). Methylmercury significantly increases the level of free
calcium ions in nerve cells in the cerebral cortex, disrupting
calcium stability and, in turn, affecting the physiological
processes of cells, inducing oxidative stress by interfering

with mitochondrial breathing chains, affecting DNA repair
and leading to apoptosis (Ho et al. 2013).
HgCl2 is one of the most important forms of mercury that
is widely used in various acess. HgCl2 compounds have been
proven to be organotoxic and carcinogenic (Risher et al.
1999). Nava et al. (2000) have both shown that HgCl2 can
destroy the function of mitochondrial intima, while Mahboob
et al. (2001) found that HgCl2 can alter membrane perme-
ability. In cells, Hg2þ ions interact with antioxidant proteins,
DNA repair enzymes and protein active sites involved in
intracellular homeostasis (Crespo-Lopez et al. 2009). Studies
have shown that mercury ions have a high affinity for the
protein in cells, leading to nonspecific inhibition and damage
of cell enzyme systrms (Clarkson and Magos 2006). However,
overexpression of metal sulfur protein after mercury expos-
ure may acts as a protective role in the body (Chan 2011).
Ekinci et al. (2007) found that exposure to heavy metals
interfere with the normal activity of metabolic enzymes. For
example, HgCl2 can inhibit only two metabolic pathways, the
glycolysis pathway and hexose-phosphate lysis pathway, in
red blood cells by downregulating the activity of labeling
enzymes. The enzyme hexokinase in the first step of glycoly-
sis, and the activity of the last enzyme of the glycolysis pro-
cess, pyruvate kinase, were found to be significantly reduced.
Hexokinase and pyruvate kinase are known to be inactivated
by oxidative stress (Anastasiou et al. 2011). Since the glyco-
lytic process is the only source of ATP in red blood cells,
which lack mitochondria, these changes can lead to a drop
in energy levels. Schutt et al. (2012) found that the depletion
of ATP makes cells more vulnerable to oxidative damage.
G6PD is the first enzyme to be identified to shunt hexose
monophosphate, and the product of Hexokinase is glucose
6-phosphate. Hexokinase and substrate G6PD activity were
found to have decreased as a result of exposure. Studies by
Rabbani and Thornalley (2012) show that glyoxal-i inhibits
the formation of glyoxal-derived deleterious products, and
that the enhancement of its activity provides an enzyme
defense mechanism for methoxyl-induced protein
modifications.
3. Conclusions
This article discusses the various hazards associated with
heavy metal exposure on human metabolism. However, it is
important to understand the methods by which the public
come into contact with heavy metals, in order to avoid fur-
ther contact. Based on previous research results, for many
people regulatory limits have been exceeded and they are
at the threshold of developing major organ toxicity.
Governments must therefore take important steps to protect
the population from this potential hazard to people’s health
by advising people to avoid fish species that contain high
levels of arsenic and mercury(Salnikow and Zhitkovich 2008).
Therefore, contaminated water must be treated before it can
be released into the environment to ensure that safe drink-
ing water is available to the public. In terms of agricultural
safety, arsenic-containing herbicides should be replaced by
safer alternatives. Unlike Amalgam fillings, dental composite
TOXICOLOGY MECHANISMS AND METHODS 173
fillings should always be used. Removal of heavy metals
from water can be done through ion exchange (Tariq et al.
2008), adsorption, membrane filtration and electrodialysis
(Chen 2004). Therefore, we need to establish a defense
mechanism to prevent exposure to heavy metals, which
increases the content of reactive oxygen species (Ros) in the
human body and eventually induces a series of oxidative
damage processes. In future, more research is needed to
ensure that human health is protected and is safe from the
effects and hazards of heavy metals.
Author Contributions
Zhushan Fu conceived and drafted this manuscript. Shuhua Xi revised
and approved the final manuscript.
Disclosure statement
The authors declare that they have no known competing financial inter-
ests or personal relationships that could have appeared to influence the
work reported in this paper.
Funding
This work was supported by the National Natural Science Foundation of
China (NSFC) [81972982 and 81673207].
References
Al-Saleh I, Al-Sedairi AA, Elkhatib R. 2012. Effect of mercury (Hg) dental
amalgam fillings on renal and oxidative stress biomarkers in children.
Sci Total Environ. 431:188–196.
Al-Samman T. 2015. Effect of heavy metal impurities in secondary Mg
alloys on the microstructure and mechanical properties during
deformation. Mater Des. 65:983–988.
Almeida JA, Novelli ELB, Silva MD, Alves R. 2001. Environmental cad-
mium exposure and metabolic responses of the Nile tilapia,
Oreochromis niloticus. Environ Pollut. 114(2):169–175.
Anastasiou D, Poulogiannis G, Asara JM, Boxer MB, Jiang JK, Shen M,
Bellinger G, Sasaki AT, Locasale JW, Auld DS, et al. 2011. Inhibition of
pyruvate kinase M2 by reactive oxygen species contributes to cellular
antioxidant responses. Science. 334(6060):1278–1283.
Antonowicz J, Andrzejak R, Smolik R. 1990. Influence of heavy metal mix-
tures on erythrocyte metabolism. Int Arch Occup Environ Heath.
62(3):195–198.
Argos M, Kalra T, Rathouz PJ, Chen Y, Pierce B, Parvez F, Islam T, Ahmed
A, Rakibuz-Zaman M, Hasan R, et al. 2010. Arsenic exposure from
drinking water, and all-cause and chronic-disease mortalities in
Bangladesh (HEALS): a prospective cohort study. Lancet. 376(9737):
252–258.
Arteel GE, Guo L, Schlierf T, Beier JI, Kaiser JP, Chen TS, Liu M, Conklin
DJ, Miller HL, von Montfort C, et al. 2008. Subhepatotoxic exposure to
arsenic enhances lipopolysaccharide-induced liver injury in mice.
Toxicol Appl Pharmacol. 226(2):128–139.
Asubiojo OI, Nkono NA, Ogunsua AO, Oluwole AF, Ward NI, Akanle OA,
Spyrou NM. 1997. Trace elements in drinking and groundwater sam-
ples in southern Nigeria. Sci Total Environ. 208(1–2):1–8.
Banfalvi G. 2011. Cellular effects of heavy metals. Dordrecht; New York:
Springer.
Bedrin AG, Bubnov IA, Dashuk SP, Mironov IS, Borypaev GG. 2003.
Compact spectral analyzer of heavy-metal impurities in air. J Opt
Technol. 70(4):234–237.
Bernstam L, Nriagu J. 2000. Molecular aspects of arsenic stress. J Toxicol
Environ Health B-Crit Rev. 3:293–322.
174 Z. FU AND S. XI
Braeckman BP, Houthoofd K, Vanfleteren JR. 2009. Intermediary metabol-
ism. WormBook. 3:1–24.
Challenger F. 1947. Biological methylation. Sci Prog. 35(139):396–416.
Chan TY. 2011. Inorganic mercury poisoning associated with skin-lighten-
ing cosmetic products. Clin Toxicol (Phila). 49(10):886–891.
Chen G. H. 2004. Electrochemical technologies in wastewater treatment.
Sep Purif Technol. 38(1):11–41.
Chen L, Liu L, Luo Y, Huang S. 2008. MAPK and mTOR pathways are
involved in cadmium-induced neuronal apoptosis. J Neurochem.
105(1):251–261.
Chen L, Xu B, Liu L, Luo Y, Zhou H, Chen W, Shen T, Han X, Kontos CD,
Huang S. 2011. Cadmium induction of reactive oxygen species acti-
vates the mTOR pathway, leading to neuronal cell death. Free Radic
Biol Med. 50(5):624–632.
Chin-Chan M, Navarro-Yepes J, Quintanilla-Vega B. 2015. Environmental
pollutants as risk factors for neurodegenerative disorders: Alzheimer
and Parkinson diseases. Front Cell Neurosci. 9:124.
Cicik B, Engin K. 2005. The effects of cadmium on levels of glucose in
serum and glycogen reserves in the liver and muscle tissues of
Cyprinus carpio (L., 1758). Turk J Vet Anim Sci. 29:113–117.
Clarkson TW. 1997. The toxicology of mercury. Crit Rev Clin Lab Sci.
34(4):369–403.
Clarkson TW, Magos L. 2006. The toxicology of mercury and its chemical
compounds. Crit Rev Toxicol. 36(8):609–662.
Coogan TP, Latta DM, Snow ET, Costa DM. 1989. Toxicity and carcino-
genicity of nickel compounds. Crit Rev Toxicol. 19(4):341–384.
Crespo-Lopez ME, Macedo GL, Pereira SI, Arrifano GP, Picanco-Diniz DL,
do Nascimento JL, Herculano AM. 2009. Mercury and human genotox-
icity: critical considerations and possible molecular mechanisms.
Pharmacol Res. 60:212–220.
Crowe W, Allsopp PJ, Watson GE, Magee PJ, Strain JJ, Armstrong DJ, Ball
E, McSorley EM. 2017. Mercury as an environmental stimulus in the
development of autoimmunity – a systematic review. Autoimmun
Rev. 16(1):72–80.
Das KK, Gupta AD, Dhundasi SA, Patil AM, Das SN, Ambekar JG. 2006.
Effect of L-ascorbic acid on nickel-induced alterations in serum lipid
profiles and liver histopathology in rats. J Basic Clin Physiol
Pharmacol. 17(1):29–44.
Denkhaus E, Salnikow K. 2002. Nickel essentiality, toxicity, and carcino-
genicity. Crit Rev Oncol Hematol. 42(1):35–56.
Dhir B, Sharmila P, Pardha Saradhi P, Sharma S, Kumar R, Mehta D. 2011.
Heavy metal induced physiological alterations in Salvinia natans.
Ecotoxicol Environ Saf. 74(6):1678–1684.
Diagomanolin V, Farhang M, Ghazi-Khansari M, Jafarzadeh N. 2004.
Heavy metals (Ni, Cr, Cu) in the Karoon waterway river, Iran. Toxicol
Lett. 151(1):63–68.
Ditzel E. J, Nguyen T, Parker P, Camenisch T. D. 2016. Effects of arsenite
exposure during fetal development on energy metabolism and sus-
ceptibility to diet-induced fatty liver disease in male mice. Environ
Health Perspect. 124(2):201–209.
Eagles-Smith CA, Wiener JG, Eckley CS, Willacker JJ, Evers DC, Marvin-
DiPasquale M, Obrist D, Fleck JA, Aiken GR, Lepak JM, et al. 2016.
Mercury in western North America: a synthesis of environmental con-
tamination, fluxes, bioaccumulation, and risk to fish and wildlife. Sci
Total Environ. 568:1213–1226.
Ehara S, Ueda M, Naruko T, Haze K, Itoh A, Otsuka M, Komatsu R,
Matsuo T, Itabe H, Takano T, et al. 2001. Elevated levels of oxidized
low density lipoprotein show a positive relationship with the severity
of acute coronary syndromes. Circulation. 103(15):1955–1960.
Ekinci D, Beydemir S, Kufrevioglu O. I. 2007. In vitro inhibitory effects of
some heavy metals on human erythrocyte carbonic anhydrases. J
Enzyme Inhib Med Chem. 22:745–750.
Ercal N, Aykin-Burns N, Gurer-Orhan H. 2001. Assessment of lead toxicity
in PC-12 cells. Free Rad Biol Med. 31:S116.
Flora SJ, Mittal M, Mehta A. 2008. Heavy metal induced oxidative stress
& its possible reversal by chelation therapy. Indian J Med Res. 128(4):
501–523.
Fu F, Wang Q. 2011. Removal of heavy metal ions from wastewaters: a
review. J Environ Manage. 92(3):407–418.
Genestra M. 2007. Oxyl radicals, redox-sensitive signalling cascades and
antioxidants. Cell Signal. 19(9):1807–1819.
Giaginis C, Gatzidou E, Theocharis S. 2006. DNA repair systems as targets
of cadmium toxicity. Toxicol Appl Pharmacol. 213(3):282–290.
Godwin HA. 2001. The biological chemistry of lead. Curr Opin Chem Biol.
5(2):223–227.
Haber LT, Erdreicht L, Diamond GL, Maier AM, Ratney R, Zhao Q,
Dourson ML. 2000. Hazard identification and dose response of inhaled
nickel-soluble salts. Regul Toxicol Pharmacol. 31(2):210–230.
Hayakawa T, Kobayashi Y, Cui X, Hirano S. 2005. A new metabolic path-
way of arsenite: arsenic-glutathione complexes are substrates for
human arsenic methyltransferase Cyt19. Arch Toxicol. 79(4):183–191.
Higashi T, Maruyama E, Otani T, Sakamoto Y. 1965. Studies on the isoci-
trate dehydrogenase. I. Some properties of isocitrate dehydrogenase
of beef heart muscle. J Biochem. 57(6):793–798.
Ho NY, Yang LX, Legradi J, Armant O, Takamiya M, Rastegar S, Strahle U.
2013. Gene responses in the central nervous system of zebrafish
embryos exposed to the neurotoxicant methyl mercury. Environ Sci
Technol. 47:3316–3325.
Hughes MF, Beck BD, Chen Y, Lewis AS, Thomas DJ. 2011. Arsenic expos-
ure and toxicology: a historical perspective. Toxicol Sci. 123(2):
305–332.
Jarup L, Berglund M, Elinder CG, Nordberg G, Vahter M. 1998. Health
effects of cadmium exposure–a review of the literature and a risk esti-
mate. Scand J Work Environ Health. 24(1):1–51.
Jayawardena UA, Angunawela P, Wickramasinghe DD, Ratnasooriya WD,
Udagama PV. 2017. Heavy metal-induced toxicity in the Indian green
frog: biochemical and histopathological alterations. Environ Toxicol
Chem. 36(10):2855–2867.
Jomova K, Valko M. 2011. Advances in metal-induced oxidative stress
and human disease. Toxicology. 283(2-3):65–87.
Kasperczyk S, Birkner E, Kasperczyk A, Kasperczyk J. 2005. Lipids, lipid
peroxidation and 7-ketocholesterol in workers exposed to lead. Hum
Exp Toxicol. 24(6):287–295.
Kasperczyk A, Machnik G, Dobrakowski M, Sypniewski D, Birkner E,
Kasperczyk S. 2012. Gene expression and activity of antioxidant
enzymes in the blood cells of workers who were occupationally
exposed to lead. Toxicology. 301(1–3):79–84.
Kitchin KT, Wallace K. 2008. The role of protein binding of trivalent
arsenicals in arsenic carcinogenesis and toxicity. J Inorg Biochem.
102(3):532–539.
Knowles SO, Donaldson WE. 1990. Dietary modification of lead toxicity:
effects on fatty acid and eicosanoid metabolism in chicks. Comp
Biochem Physiol C. 95(1):99–104.
Korrick S. 2004. Effects of exposure to chemicals from industrial contam-
ination in new Bedford, Massachusetts. Neurotoxicology. 25:673–673.
Kumar S, Islam A, Ahmad H, Zaidi N. 2019. Graphene oxide supported
on amberlite resin for the analytical method development for
enhanced column preconcentration/sensitive flame atomic absorption
spectrometric determination of toxic metal ions in environmental
samples. Ind Eng Chem Res. 58:8309–8316.
Lane TW, Morel FM. 2000. A biological function for cadmium in marine
diatoms. Proc Natl Acad Sci USA. 97(9):4627–4631.
Lenczewski E. 2009. Arsenic pollution: a global synthesis. Choice Curr
Rev Acad Libr. 47:326–326.
Li L, Tian X, Yu X, Dong S. 2016. Effects of acute and chronic heavy
metal (Cu, Cd, and Zn) exposure on sea cucumbers (Apostichopus
japonicus). Biomed Res Int. 2016:4532697.
Liaw JG, Marshall Y, Yuan C, Ferreccio C, Steinmaus, Smith AH. 2008.
Increased childhood liver cancer mortality and arsenic in drinking
water in northern Chile. Cancer Epidemiol Biomarkers Prev. 17:
1982–7.
Luz AL, Godebo TR, Bhatt DP, Ilkayeva OR, Maurer LL, Hirschey MD,
Meyer JN. 2016. From the cover: arsenite uncouples mitochondrial
respiration and induces a Warburg-like effect in Caenorhabditis ele-
gans. Toxicol Sci. 152(2):349–362.
M’Bemba-Meka P, Lemieux N, Chakrabarti S. K. 2006. Role of oxidative
stress, mitochondrial membrane potential, and calcium homeostasis
in human lymphocyte death induced by nickel carbonate hydroxide
in vitro. Arch Toxicol. 80:405–420.

Magos L. 1997. Physiology and toxicology of mercury. Met Ions Biol Syst.
34:321–370.
Mahboob M, Shireen KF, Atkinson A, Khan AT. 2001. Lipid peroxidation
and antioxidant enzyme activity in different organs of mice exposed
to low level of mercury. J Environ Sci Health B. 36(5):687–697.
Marshall G, Ferreccio C, Yuan Y, Bates MN, Steinmaus C, Selvin S, Liaw J,
Smith AH. 2007. Fifty-year study of lung and bladder cancer mortality
in Chile related to arsenic in drinking water. J Natl Cancer Inst. 99(12):
920–928.
Mendez-Armenta M, Villeda-Hernandez J, Barroso-Moguel R, Nava-Ruiz C,
Jimenez-Capdeville ME, Rios C. 2003. Brain regional lipid peroxidation
and metallothionein levels of developing rats exposed to cadmium
and dexamethasone. Toxicol Lett. 144:151–157.
Miazek K, Iwanek W, Remacle C, Richel A, Goffin D. 2015. Effect of met-
als, metalloids and metallic nanoparticles on microalgae growth and
industrial product biosynthesis: a review. IJMS. 16(10):23929–23969.
Miller DM, Lund BO, Woods JS. 1991. Reactivity of Hg(II) with superoxide:
evidence for the catalytic dismutation of superoxide by Hg(II). J
Biochem Toxicol. 6(4):293–298.
Moreira EG, Vassilieff I, Vassilieff VS. 2001. Developmental lead exposure:
behavioral alterations in the short and long term. Neurotoxicol
Teratol. 23(5):489–495.
Mudipalli A. 2007. Lead hepatotoxicity & potential health effects. Indian
J Med Res. 126(6):518–527.
Nagajyoti PC, Lee KD, Sreekanth TVM. 2010. Heavy metals, occurrence
and toxicity for plants: a review. Environ Chem Lett. 8(3):199–216.
Naranmandura H, Xu S, Sawata T, Hao WH, Liu H, Bu N, Ogra Y, Lou YJ,
Suzuki N. 2011. Mitochondria are the main target organelle for triva-
lent monomethylarsonous acid (MMA(III))-induced cytotoxicity. Chem
Res Toxicol. 24(7):1094–1103.
Nava M, Romero F, Quiroz Y, Parra G, Bonet L, Rodriguez-Iturbe B. 2000.
Melatonin attenuates acute renal failure and oxidative stress induced
by mercuric chloride in rats. Am J Physiol Renal Physiol. 279(5):
F910–F918.
Ognjanovic BI, Markovic SD, Ethordevic NZ, Trbojevic IS, Stajn AS, Saicic
ZS. 2010. Cadmium-induced lipid peroxidation and changes in anti-
oxidant defense system in the rat testes: protective role of coenzyme
Q(10) and vitamin E. Reprod Toxicol. 29:191–197.
Ohta H, Cherian M. G. 1991. Gastrointestinal absorption of cadmium and
metallothionein. Toxicol Appl Pharmacol. 107(1):63–72.
Oukarroum A, Zaidi W, Samadani M, Dewez D. 2017. Toxicity of nickel
oxide nanoparticles on a freshwater green algal strain of Chlorella vul-
garis. Biomed Res Int. 2017:1.
Paglia DE, Valentine WN, Dahlgren JG. 1975. Effects of low-level lead
exposure on pyrimidine 5’-nucleotidase and other erythrocyte
enzymes. Possible role of pyrimidine 5’-nucleotidase in the pathogen-
esis of lead-induced anemia. J Clin Invest. 56(5):1164–1169.
Pang Y, Jones MR, Tellez-Plaza M, Guallar E, Vaidya D, Post WS, Kaufman
JD, Delaney JA, Navas-Acien A. 2016. Association of geography and
ambient air pollution with urine metal concentrations in six US cities:
the multi-ethnic study of atherosclerosis. Int J Environ Res Public
Health. 13:324.
Patocka J, Cerny K. 2003. Inorganic lead toxicology. Acta Medica (Hradec
Kralove). 46(2):65–72.
Patrick L. 2002. Mercury toxicity and antioxidants: part 1: role of glutathi-
one and alpha-lipoic acid in the treatment of mercury toxicity. Altern
Med Rev. 7(6):456–471.
Permpongpaiboon T, Nagila A, Pidetcha P, Tuangmungsakulchai K,
Tantrarongroj S, Porntadavity S. 2011. Decreased paraoxonase 1 activ-
ity and increased oxidative stress in low lead-exposed workers. Hum
Exp Toxicol. 30(9):1196–1203.
Qayyum S, Ara A, Usmani JA. 2012. Effect of nickel and chromium expos-
ure on buccal cells of electroplaters. Toxicol Ind Health. 28(1):74–82.
Rabbani N, Thornalley PJ. 2012. Methylglyoxal, glyoxalase 1 and the
dicarbonyl proteome. Amino Acids. 42(4):1133–1142.
Rahman M. 2002. Arsenic and contamination of drinking-water in
Bangladesh: a public-health perspective. J Health Popul Nutr. 20(3):
193–197.
TOXICOLOGY MECHANISMS AND METHODS 175
Rahman S, Sultana S. 2006. Chemopreventive activity of glycyrrhizin on
lead acetate mediated hepatic oxidative stress and its hyperprolifera-
tive activity in Wistar rats. Chem Biol Interact. 160(1):61–69.
Ramirez-Bajo MJ, de Atauri P, Ortega F, Westerhoff HV, Gelpi JL,
Centelles JJ, Cascante M. 2014. Effects of cadmium and mercury on
the upper part of skeletal muscle glycolysis in mice. PLoS One. 9(1):
e80018.
Rehman K, Fatima F, Waheed I, Akash MSH. 2018. Prevalence of expos-
ure of heavy metals and their impact on health consequences. J Cell
Biochem. 119(1):157–184.
Risher JF, De Rosa CT, Jones DE, Murray HE. 1999. Updated toxicological
profile for mercury. Toxicol Ind Health. 15(5):480–482.
Robey RB, Weisz J, Kuemmerle NB, Salzberg AC, Berg A, Brown DG,
Kubik L, Palorini R, Al-Mulla F, Al-Temaimi R, et al. 2015. Metabolic
reprogramming and dysregulated metabolism: cause, consequence
and/or enabler of environmental carcinogenesis? CARCIN. 36 (Suppl
1):S203–S231.
Rosenberg CE, Salibian A, Fink NE. 2002. An enzyme-linked immunosorb-
ent assay for measuring anti-sheep red blood cells antibodies in lead-
exposed toads. J Pharmacol Toxicol Methods. 47(2):121–128.
Rusyniak DE, Arroyo A, Acciani J, Froberg B, Kao L, Furbee B. 2010.
Heavy metal poisoning: management of intoxication and antidotes.
EXS. 100:365–396.
Salnikow K, Zhitkovich A. 2008. Genetic and epigenetic mechanisms in
metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chro-
mium. Chem Res Toxicol. 21(1):28–44.
Samadi A, Martinez L. A, Miranda M. A, Morera I. M. 2001. Mechanism of
lipid peroxidation photosensitized by tiaprofenic acid: product studies
using linoleic acid and 1,4-cyclohexadienes as model substrates.
Photochem Photobiol. 73(4):359–365.
Schutt F, Aretz S, Auffarth GU, Kopitz J. 2012. Moderately reduced ATP
levels promote oxidative stress and debilitate autophagic and phago-
cytic capacities in human RPE cells. Invest Ophthalmol Vis Sci. 53:
5354–5361.
Sharma S, Kaul D, Singh D. 2015. Arsenic toxi-RNomics has the ability to
tailor the host immune response. Exp Mol Pathol. 99(2):360–364.
Shi H, Shi X, Liu KJ. 2004. Oxidative mechanism of arsenic toxicity and
carcinogenesis. Mol Cell Biochem. 255(1/2):67–78.
Shi X, Wei X, Koo I, Schmidt RH, Yin X, Kim SH, Vaughn A, McClain CJ,
Arteel GE, Zhang X, et al. 2014. Metabolomic analysis of the effects of
chronic arsenic exposure in a mouse model of diet-induced Fatty liver
disease. J Proteome Res. 13(2):547–554.
Shukla A, Shukla GS, Srimal RC. 1996. Cadmium-induced alterations in
blood-brain barrier permeability and its possible correlation with
decreased microvessel antioxidant potential in rat. Hum Exp Toxicol.
15(5):400–405.
Smith AH, Marshall G, Yuan Y, Ferreccio C, Liaw J, von Ehrenstein O,
Steinmaus C, Bates MN, Selvin S. 2006. Increased mortality from lung
cancer and bronchiectasis in young adults after exposure to arsenic
in utero and in early childhood. Environ Health Perspect. 114(8):
1293–1296.
Stohs SJ, Bagchi D, Hassoun E, Bagchi M. 2001. Oxidative mechanisms in
the toxicity of chromium and cadmium ions. J Environ Pathol Toxicol
Oncol. 20(2):12–88.
Tariq SR, Shah MH, Shaheen N, Jaffar M, Khalique A. 2008. Statistical
source identification of metals in groundwater exposed to industrial
contamination. Environ Monit Assess. 138(1–3):159–165.
Valko M, Morris H, Cronin MT. 2005. Metals, toxicity and oxidative stress.
Curr Med Chem. 12(10):1161–1208.
Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. 2006. Free radicals,
metals and antioxidants in oxidative stress-induced cancer. Chem Biol
Interact. 160(1):1–40.
Wang TS, Hsu TY, Chung CH, Wang AS, Bau DT, Jan KY. 2001. Arsenite
induces oxidative DNA adducts and DNA-protein cross-links in mam-
malian cells. Free Radic Biol Med. 31(3):321–330.
Wang L, Li J, Li J, Liu Z. 2010. Effects of lead and/or cadmium on the oxi-
dative damage of rat kidney cortex mitochondria. Biol Trace Elem
Res. 137(1):69–78.
Watjen W, Beyersmann D. 2004. Cadmium-induced apoptosis in C6 gli-
oma cells: influence of oxidative stress. Biometals. 17:65–78.
176 Z. FU AND S. XI
Wildemann TM, Siciliano SD, Weber LP. 2016. The mechanisms associ-
ated with the development of hypertension after exposure to lead,
mercury species or their mixtures differs with the metal and the mix-
ture ratio. Toxicology. 339:1–8.
Xia J, Lu L, Jin C, Wang S, Zhou J, Ni Y, Fu Z, Jin Y. 2018. Effects of short
term lead exposure on gut microbiota and hepatic metabolism in
adult zebrafish. Comp Biochem Physiol C Toxicol Pharmacol. 209:1–8.
Yang K, Ren YB. 2010. Nickel-free austenitic stainless steels for medical
applications. Sci Technol Adv Mater. 11:014105.
Yu HS, Liao WT, Chai CY. 2006. Arsenic carcinogenesis in the skin. J
Biomed Sci. 13(5):657–666.
Yuan Y, Marshall G, Ferreccio C, Steinmaus C, Liaw J, Bates M, Smith AH.
2010. Kidney cancer mortality: fifty-year latency patterns related to
arsenic exposure. Epidemiology. 21(1):103–108.
Yun SW, Hoyer S. 2000. Effects of low-level lead on glycolytic enzymes
and pyruvate dehydrogenase of rat brain in vitro: relevance to spor-
adic Alzheimer’s disease? J Neural Transm. 107(3):355–368.
Zhang HN, Yang LN, Ling JY, Czajkowsky DM, Wang JF, Zhang XW, Zhou
YM, Ge F, Yang MK, Xiong Q, et al. 2015. Systematic identification of
arsenic-binding proteins reveals that hexokinase-2 is inhibited by
arsenic. Proc Natl Acad Sci USA. 112(49):15084–15089.
Zhao F, Malm SW, Hinchman AN, Li H, Beeks CG, Klimecki WT. 2014.
Arsenite-induced pseudo-hypoxia results in loss of anchorage-
dependent growth in BEAS-2B pulmonary epithelial cells. PLoS One.
9(12):e114549.
Zhao F, Severson P, Pacheco S, Futscher BW, Klimecki WT. 2013. Arsenic
exposure induces the Warburg effect in cultured human cells. Toxicol
Appl Pharmacol. 271(1):72–77.
Zhao CQ, Young MR, Diwan BA, Coogan TP, Waalkes MP. 1997.
Association of arsenic-induced malignant transformation with DNA
hypomethylation and aberrant gene expression. Proc Natl Acad Sci
USA. 94(20):10907–10912.
Zhou Z. H, Lei YX, Wang CX. 2012. Analysis of aberrant methylation in
DNA repair genes during malignant transformation of human bron-
chial epithelial cells induced by cadmium. Toxicol Sci. 125(2):412–417.