Heavy metal toxicology and Human Health

Introduction

There are 35 metals that concern us because of occupational or residential exposure; 23 of these are
the heavy elements or "heavy metals": antimony, arsenic, bismuth, cadmium, cesium, chromium,
cobalt, copper, gallium, gold, iron, lead, manganese, mercury, nickel, platinum, silver, tellurium,
thallium, tin, uranium, vanadium, and zinc. Interestingly, small amounts of these elements are
common in our environment and diet and are actually necessary for good health, but large amounts
of any of them may cause acute or chronic toxicity (poisoning). Heavy metal toxicity can result in
damaged or reduced mental and central nervous function, lower energy levels, and damage to blood
composition, lungs, kidneys, liver, and other vital organs. Long-term exposure may result in slowly
progressing physical, muscular, and neurological degenerative processes. Repeated long-term contact
with some metals or their compounds may even cause cancer. Therefore, it is important for us to take
protective measures against excessive exposure.

Definition of a Heavy Metal

"Heavy metals" are chemical elements with a specific gravity that is at least 5 times the specific
gravity of water. The specific gravity of water is 1 at 4°C (39°F). Simply stated, specific gravity is a
measure of density of a given amount of a solid substance when it is compared to an equal amount of
water. Some well-known toxic metallic elements with a specific gravity that is 5 or more times that
of water are arsenic, 5.7; cadmium, 8.65; iron, 7.9; lead, 11.34; and mercury, 13.546.

Commonly encountered toxic heavy metals

 Arsenic
 Lead
 Mercury
 Cadmium
 Iron
 Aluminum

There are 35 metals of concern, with 23 of them called the heavy metals. Toxicity can result from
any of these metals. But above listed 6 heavy metals are most likely encountered in our daily
environment. These 6 heavy metals are included in the Agency for Toxic Substances and Disease
Registry (ATSDR)’s "Top 20 Hazardous Substances" list.

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Exposure to toxic heavy metal

Exposure to toxic heavy metals is generally classified as acute, 24 hours or less; intermediate, up to 3
months; and chronic, more than 3 months. Acute toxicity is usually from a sudden or unexpected
exposure to a high level of the heavy metal (e.g., from careless handling, inadequate safety
precautions etc.,). Chronic toxicity results from repeated or continuous exposure, leading to an
accumulation of the toxic substance in the body. Chronic exposure may result from contaminated
food, air, water, or dust; living near a hazardous waste site, spending time in areas with deteriorating
lead paint. Chronic exposure may occur in either the home or workplace. Symptoms of chronic
toxicity are often similar to many common conditions and may not be readily recognized. Routes of
exposure include inhalation, skin or eye contact, and ingestion.

1. Arsenic Toxicology
Source of arsenic:
Arsenic is a metalloid. It is rarely found as a free element in the natural environment, but more
commonly as a component of Sulphur-containing ores in which it occurs as metal arsenides. Arsenic
occurs in natural waters in oxidation states III and V, in the form of arsenous acid (H3AsO3) and its
salts, and arsenic acid (H3AsO5) and its salts. Anthropogenic sources of arsenic include human
activities such as mining and processing of ores. Most of the paints, dyes, soaps, metals, semi-
conductors and drugs contain arsenic. Certain pesticides, fertilizers and animal feeding operations
also release arsenic to the environment in higher amounts.

Exposure and Symptoms:

Exposure to arsenic occurs mostly in the workplace, near hazardous waste sites, or in areas with high
natural levels. Symptoms of acute arsenic poisoning are sore throat from breathing, red skin at
contact point, severe abdominal pain, vomiting, and diarrhea, often within 1 hour after ingestion.
Other symptoms are anorexia, fever, mucosal irritation, and arrhythmia. Cardiovascular changes are
often subtle in the early stages but can progress to cardiovascular collapse. Chronic or lower levels of
exposure can lead to progressive peripheral and central nervous changes, such as sensory changes,
numbness and tingling, and muscle tenderness. A symptom typically described is a burning sensation
("needles and pins") in hands and feet.

Mechanism of arsenic toxicity:

In arsenic biotransformation, harmful inorganic arsenic compounds get methylated by bacteria,

algae, fungi and humans to give monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA).

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In this biotransformation process, these inorganic arsenic species (iAs) are converted enzymetically
to methylated arsenicals which are the end metabolites.
iAs (V) iAs (lll) MMA (V) MMA (lll) DMA (V)
Biomethylation is a detoxification process and end products are methylated inorganic arsenic such as
MMA (V) and DMA (V), which excreted through urine are bioindication of chronic arsenic
exposure. However MMA (III) is not excreted and remains inside the cell as an intermediate product.
Monomethylarsonic acid (MMA III), an intermediate product, is found to be highly toxic compared
to other arsenicals, potentially accountable for arsenic-induced carcinogenesis.

Effects on Human Health:

In humans arsenic toxicity occurs due to ingestion of As containing powders or solutions
accidentally, suicide, or consumption of contaminated food or drinking water. The inorganic forms
of arsenic such as arsenite and arsenate are found to be more dangerous to human health. They are
highly carcinogenic and can cause cancer of lungs, liver, bladder and skin. Chronic arsenicosis
results in many irreversible changes in the vital organs and the mortality rate is higher. There is
correlation between arsenic exposure and diabetes mellitus (type II). Besides, inorganic arsenic
ingestion arsenic leads to various dermal effects like hyperkeratosis, hyperpigmentation, the
occurrence of spontaneous abortion and damage of the nervous system.

2. Lead Toxicology
Sources of lead:
Food is one of the major sources of lead exposure, the others are air (mainly lead dust originating
from petrol) and drinking water. Plant food may be contaminated with lead through its uptake from
ambient air and soil, humans and animals may then ingest the lead contaminated vegetation. Lead
(Pb) is used in storage batteries, cable coverings, sound absorbers, radiation shields around X-ray
equipment, paints, while the oxide of lead is used in producing fine "crystal glass" and "flint glass"
and insecticides. Cosmetics are also an important source of Pb contamination. Few brands had lead
content above 20 PPM that might put consumers at the risk of lead poisoning.

Exposure and Symptoms:

Acute exposure to lead occur in the workplace, particularly in manufacturing processes that include
the use of lead (e.g., where batteries are manufactured or lead is recycled). Even printing ink,
gasoline, and fertilizer contain lead. Symptoms include abdominal pain, hypertension, renal
dysfunction, loss of appetite, and sleeplessness. Other symptoms are hallucinations, headache,
numbness, arthritis, and dizziness. Chronic exposure to lead may result in birth defects, mental
retardation, autism, psychosis, allergies, dyslexia, hyperactivity, weight loss, shaky hands, muscular

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weakness, and paralysis. Symptoms of chronic lead exposure could be allergies, arthritis, autism,
colic, hyperactivity, mood swings, numbness, and weight loss.

Mechanism of lead toxicity:

Lead metal causes toxicity in living cells by following ionic mechanism and that of oxidative stress.
Oxidative stress: Many researchers have shown that oxidative stress in living cells is caused by the
imbalance between the production of free radicals and the generation of antioxidants to detoxify the
reactive intermediates or to repair the resulting damage. Antioxidants, e.g. glutathione, present in the
cell protect it from free radicals such as H2O2. Under the influence of lead, however, the level of the
reactive oxygen species (ROS) increases and the level of antioxidants decreases. Glutathione exists
both in reduced (GSH) and oxidized glutathione disulfide (GSSG) state. In the presence of the
enzyme glutathione peroxidase, reduced glutathione readily binds with another molecule of
glutathione after donating the electron and forms glutathione disulfide (GSSG). The reduced form
(GSH) of glutathione accounts for 90% of the total glutathione content and the oxidized form
(GSSG) accounts for 10% under normal conditions. Yet under the condition of oxidative stress, the
concentration of GSSG exceeds the concentration of GSH.
Ionic mechanism: The ionic mechanism of lead toxicity occurs mainly due to the ability of lead
metal ions to replace other bivalent cations like Ca2+, Mg2+, Fe2+ and monovalent cations like Na+,
which ultimately disturbs the biological metabolism of the cell. The ionic mechanism of lead toxicity
causes significant changes in various biological processes such as cell adhesion, intra- and inter-
cellular signaling, protein folding, maturation, apoptosis, ionic transportation, enzyme regulation,
and release of neurotransmitters. Lead can substitute calcium even in picomolar concentration
affecting protein kinase C, which regulates neural excitation and memory storage.

Effects on Human Health:

Lead has no known biological function in the body and once it enters the body, it is known to cause
severe health effects that might be irreversible. It affects almost all the major organ systems of the
body like hematopoietic, renal, nervous and cardiovascular systems.
 Cardiovascular effects: Both chronic and acute lead poisoning causes cardiac and vascular
damage with potentially lethal consequences including hypertension and cardiovascular
disease. Other major disorders include ischemic coronary heart disease and cerebrovascular
accidents.
 Effect on the Nervous System: Encephalopathy (a progressive degeneration of certain parts
of the brain) is a direct consequence of lead exposure and the major symptoms include
dullness, irritability, poor attention span, headache, muscular tremor, loss of memory and
hallucinations. Fetuses and young children are especially vulnerable to the neurological
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 effects of lead as the developing nervous system absorbs a higher fraction of lead. At higher
levels, lead can cause permanent brain damage and even death.
 Effects on hematopoietic system: Lead directly affects the hematopoietic system through
restraining the synthesis of hemoglobin by inhibiting various key enzymes involved in the
heme synthesis pathway. It also reduces the life span of circulating erythrocytes by increasing
the fragility of cell membranes. Lead poisoning cause hemolytic anemia and frank anemia.
 Reproductive Health Effects: Lead causes a number of adverse effects on the reproductive
system in both men and women. Common effects seen in men include reduced libido,
abnormal spermatogenesis (reduced motility and number), chromosomal damage, infertility,
and changes in serum testosterone. Women on the other hand, are more susceptible to
infertility, miscarriage, premature membrane rupture, pregnancy hypertension and premature
delivery.

3. Mercury Toxicology
Sources of mercury:
Mercury exists mainly in three forms: metallic elements, inorganic salts and organic compounds.
These forms of mercury are present widely in water resources such as lakes, rivers and oceans where
they are taken up by the microorganisms and get transformed into methyl mercury within the
microorganism, eventually causing significant disturbance to aquatic lives. Consumption of this
contaminated aquatic animal is the major route of human exposure to methyl mercury. Mercury (Hg)
use in dental amalgams, thermometers and barometers. Hg occurs in nature in mineral, cinnabar,
metacinnabar and hypercinnabar. Diet can be the main source of inorganic and organomercurials
especially seafood while dental amalgams are the main exposure source to elemental Hg.

Exposure and Symptoms:

Acute mercury exposure may occur in the mining industry and in the manufacturing of fungicides,
thermometers, and thermostats. Children are more likely to incur acute exposure in the home from
ingesting mercury from a broken thermometer. Symptoms of acute exposure are cough, sore throat,
and shortness of breath, metallic taste in the mouth, abdominal pain, vomiting and diarrhea,
headaches, weakness and visual disturbances. Dental amalgam is also suspected as being a possible
source of mercury toxicity from chronic exposure.

Mechanism of mercury toxicology:

Mercury binds to freely available thiols as the stability constants are high. Mercury plays a key role
in damaging the tertiary and quaternary protein structure and alters the cellular function by attaching
to the selenohydryl and sulfhydryl groups which undergo reaction with methyl mercury and hamper
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the cellular structure. It also intervenes with the process of transcription and translation resulting in
the disappearance of ribosomes and the activity of natural killer cells.

Effects on Human Health:

Increases in methylmercury exposures can cause harmful effects on the cardiovascular system,
blisters in the upper gastrointestinal tract, vomiting, abdominal pain, constipation and gastritis. Renal
toxicity of organic forms expressed by glomerulonephritis with proteinuria (glomerular and tubular)
and nephritic syndrome. It is a potent neuro-toxin to human due to their ability to cross the blood-
brain barrier. It is absorbed in the gastrointestinal track, immediately entering the blood stream. It
readily passes the placental barrier affecting the developing nervous system of the fetus The acute
exposure to elemental Hg vapors can cause "pink disease" or acrodynia (Acrodynia is a condition of
pain and dusky pink discoloration in the hands and feet).

4. Cadmium Toxicology
Sources of cadmium:
Cadmium is naturally present in the environment, in air, soils, sediments and even in unpolluted
seawater. Cadmium is emitted to air by mines, metal smelters and industries using cadmium
compounds for alloys, batteries, pigments and in plastics. Cadmium is predominantly found in fruits
and vegetables due to its high rate of soil-to plant transfer. Tobacco smoke is one of the largest single
sources of cadmium exposure in humans. Tobacco in all of its forms contains appreciable amounts of
the metal. In food, inorganic cadmium salts are present.

Exposure and Symptoms:

Humans may get exposed to this metal primarily by inhalation and ingestion and can suffer from
acute and chronic intoxications. Acute exposure to cadmium generally occurs in the workplace,
particularly in the manufacturing processes of batteries and color pigments used in paint and plastics,
as well as in electroplating and galvanizing processes. Symptoms of acute cadmium exposure are
nausea, vomiting, abdominal pain, and breathing difficulty. Symptoms of chronic exposure could
include alopecia, anemia, arthritis, learning disorders, migraines, emphysema (shortness of breath),
osteoporosis, loss of taste and smell, poor appetite.

Mechanism of cadmium toxicity:

The mechanism of cadmium toxicity is not understood clearly but its effects on cells are known.
Cadmium concentration increases 3,000 fold when it binds to cystein-rich protein such as
metallothionein. Cadmium has the capability to bind with cystein, glutamate, histidine and aspartate
ligands and can lead to the deficiency of iron. Cadmium and zinc have the same oxidation states and

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hence cadmium can replace zinc present in metallothionein, thereby inhibiting it from acting as a free
radical scavenger within the cell.

Effects on Human Health:

Cadmium is a cumulative toxicant and carcinogenic that affects kidneys, genrates various toxic
effects in the body, disturbs bone metabolism and deforms reproductive tract as well as endocrine
system. Cadmium exposure, during human pregnancy, leads to reduced birth weights and premature
birth. Other damages that have been observed include hepatic, haematological and immunological
effects.

5. Iron toxicology
Sources of iron:
Iron is the second most abundant metal on the earth’s crust. Most overdoses appear to be the result of
children mistaking red-coated ferrous sulfate tablets or adult multivitamin for candy. Other sources
of iron are drinking water, iron pipes, and cookware. The source of iron in surface water is
anthropogenic and is related to mining activities.

Exposure and Symptoms:

Humans exposed to elevated levels of iron through drinking water, as the collected groundwater
exceeded the permissible limit. The amount of iron that will cause poisoning depends upon the size of
the child. An 8-year-old may show no symptoms from an amount that would cause serious symptoms in
a 3-year-old. Symptoms appear at doses greater than 20 mg/kg. Symptoms of iron poisoning usually
become evident within 6 hours after an excessive amount of iron is swallowed. Symptoms are
severe vomiting, diarrhea, abdominal pain, dehydration , blood vomit.

Mechanism of iron toxicity:

A wide range of harmful free radicals are formed when the absorbed iron fails to bind to the protein,
which in turn severely affects the concentration of iron in mammalian cells and biological fluids. When
extremely higher level of iron enters into the body crossing the rate-limiting absorption step and it
becomes saturated. These free irons penetrate into cells of the heart, liver and brain. Due to the disruption
of oxidative phosphorylation by free iron, the ferrous iron is converted to ferric iron that releases
hydrogen ions, thus increasing metabolic acidity. The iron produced hydrogen free radicals attack DNA,
resulting in cellular damage, mutation and malignant transformations which in turn cause an array of
diseases.

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Effects on Human Health:
Biologically it is the most important nutrient for most living creatures but if it is not shielded properly, it
can catalyze the reactions involving the formation of radicals which can damage biomolecules, cells,
tissues and the whole organism. Iron toxicosis occurs in four stages. The first stage occurs after 6 hrs
of iron overdose is marked by gastrointestinal effects such as gastro intestinal bleeding, vomiting and
diarrhea. The second stage progresses within 6 to 24hrs of overdose and it is considered as the latent
period, a period of apparent medical recovery. The third stage occurs between 12 to 96 hrs. This
stage is characterized by shocks, hypotension, lethargy, tachycardia, hepatic necrosis, metabolic
acidosis and sometimes death. The fourth stage occurs within 2–6 weeks of iron overdose. This stage
is marked by the formation of gastrointestinal ulcerations. Workers who are highly exposed to
asbestos that contains almost 30% of iron are at high risk of asbestosis ( non-cancerous respiratory
disease), which is the second most important cause for lung cancer. Iron can initiate cancer mainly
by the process of oxidation of DNA molecules.

6. Aluminium Toxicology

Source of aluminum: Aluminium is the third most abundant element found in the earth’s crust.
Aluminium occurs naturally in the air, water and soil. Mining and processing of aluminium elevates
its level in the environment. The main routes of aluminium consumption by humans are through
inhalation, ingestion and dermal contact and sources of exposure are drinking water, food, beverages,
and aluminium containing drugs.

Exposure and Symptoms:

Acute exposure is more likely in the workplace (e.g., unintentional breathing of aluminium from
manufacturing or metal finishing processes). Chronic exposure may occur in the workplace. In the
home, we are in constant contact with aluminum in foods and in water; from cookware and soft drink
cans. Symptoms that indicate the presence of higher amounts of aluminium in the human body are
nausea, mouth ulcers, skin ulcers, skin rashes, vomiting, diarrhea and arthritic pain.

Mechanism of aluminium toxicity:

Aluminium interferes with most physical and cellular processes. The exact mechanism of absorption
of aluminium by the gastrointestinal tract is not understood completely. Based on literature surveys,
aluminium toxicity probably results from the interaction between aluminium and plasma membrane,
apoplastic and symplastic targets. In humans Mg2+ and Fe3+ are replaced by Al3+, which causes many
disturbances associated with intercellular communication, cellular growth and secretory functions.
The greatest complications of aluminium toxicity are neurotoxicity effects such as neuronal atrophy
in the locus ceruleus, substantia nigra and striatum.
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Effects on Human Health:
Aluminium exposure is probably a risk factor for the onset of Alzheimer disease (AD) in humans, as
hypothesized by the WHO. Aluminium showed adverse effects on the nervous system and resulted in
loss of memory, problems with balance and loss of coordination. People suffering from kidney
diseases find it difficult to eliminate aluminium from the body, resulting in aluminium accumulation
in the body leading to bone and brain damage. Higher levels of aluminium exposure can change the
evolution of secondary hyperparathyroidism, leading to other diseases such as aluminium-induced
adynamic bone disease and aluminium-induced osteomalacia. Some of the other complications
associated with aluminium toxicity are lung problems, anemia, impaired iron absorption, nervous
system problems, etc.

Conclusion

Conclusively, the advances of toxicology has improved our knowledge about human exposure to
toxic elements (heavy metals) and their health effects, such as developmental retardation, several
types of cancer, kidney damage, endocrine disruption, immunological, neurological effects and other
disorders. Effective legislation, guidelines and detection of the areas where there are higher levels of
heavy metals are necessary. Failure to control the exposure will result in severe complications in the
future because of the adverse effects imposed by heavy metals on human health.

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