Non-essential Elements

1
Non-essential Elements
There are many metals that have been shown to be
essential trace elements There are also a number
of metals that have no known biological
function Exposure to some of these non-essential
metals can have adverse health consequences
2
Metal Toxicity
Different metals show toxicity at different
concentrations The type of toxicity is defined by
the relative level of exposure
3
Dose-response curvenon-essential elements
For toxic metals the dose-response curves looks
different than those seen for essential metals
Since there are no beneficial effects at any
level for a toxic metal, the only questions
are how low a concentration will lead to
harmful effects? how rapidly will harmful
effects become lethal effects with increasing
concentrations?
4
Human impact on element availability
Various human activities have led to changes in
the levels and in the availability of many
elements
Most of these elements are not particularly
toxic, even at these higher exposure
levels However, exposure to certain metals can be
quite toxic
5
Toxic Metals for Humans
All metals can become toxic at sufficiently high
levels however certain metals have no beneficial
effects and show toxic effects at relatively low
concentrations
It is not just the identity of the metal, but
also the chemical form and the oxidation state
that dictates the toxicity in humans
6
Permissible Levels of Different Metals
The permitted levels of different metals in solid
waste is a measure of their relative toxicities
As3, Cd2 and Hg2 are much more toxic than the
other metals However, Cr6 is at least as toxic
as these metal ions
7
Cadmium levels in non-contaminated foods
Many foods contain natural levels of metal
ions, some of which can be harmful if ingested in
sufficient quantities
8
Effects of chronic cadmium exposure

• Chronic exposure to even moderate levels of
  cadmium salts can lead to
• kidney failure
• bone diseases
• respiratory effects
• carcinogenesis

9
Cadmium metabolismuptake, transport and excretion
J. Occupat. Med. Toxicol., 1, 22 (2006)
10
Mercury Toxicity

• Mercury is highly toxic in all forms
• mercury vapor
• mercury salts
• alkyl mercury

Of these, alkyl mercury is the most toxic form
because it is most easily absorbed Various marine
organisms can metabolize mercury salts into
different alkyl mercury forms
Organomercury cycle in marine organisms
11
Lead Toxicity

• Lead is another highly toxic metal that can lead
  to
• inhibition of heme synthesis
• damaged central nervous system
• kidney damage
• impaired reproduction

12
Aluminum levels
While aluminum can be toxic at higher levels, it
is considerably less toxic than either mercury or
lead In fact, aluminum is found at easily
measurable levels in various biological fluids
and tissues
13
Aluminum Toxicity
However, at high levels aluminum has the
potential to cause a number of health problems
14
Chromium Toxicity
Chromium is another metal ion that can be highly
toxic, especially in its highest (6) oxidation
state This form can easily be taken up by cells
and then reduced to the slowly exchanging 3
oxidation state
Uptake and reduction of chromate
Once chromate is distributed to the various
cellular compartments it will bind to different
targets and then be reduced to the substitution
inert 3 oxidation state This tightly bound form
will inhibit enzyme activities and disrupt DNA
replication
15
Metal Diseases
Essential trace metals can also cause
malfunctions and diseases when present in excess,
but can also cause diseases when deficient



16
Iron Diseases
Excess Iron Hemochromatosis is an iron storage
disorder that results from defects in the HFE
gene. The protein encoded by this gene is a
membrane protein that regulates iron absorption
by controlling the interaction of the transferrin
receptor with transferrin. The clinical features
of this iron overload disorder include cirrhosis
of the liver, diabetes, hypermelanotic
pigmentation of the skin, and heart failure.
Iron deficiency Iron depletion causes the amount
of stored iron in ferritin to be reduced, but has
no immediate effect on the functional iron.
Anemia occurs when the dietary intake or
absorption of iron is insufficient, and
hemoglobin cannot be formed.
17
Copper Deficiencies
Dietary deficiencies can lead to diminished Cu
levels that will impact a number of important
Cu-requiring enzymes
18
Copper Metabolic Diseases
Different genetic diseases can affect copper
levels, leading to either an excess or a
deficiency in copper availability
Wilson disease causes the body to retain copper.
The liver of a person with Wilson disease does
not release copper into bile. As the intestines
absorb copper from food, copper builds up in the
liver and injures liver tissue. Eventually, the
damage causes the liver to release the copper
into the bloodstream, which then carries the
copper throughout the body.
The disease is treated with lifelong use of
D-penicillamine that helps remove copper from
tissue, or zinc acetate, which stops the
intestines from absorbing copper and promotes
copper excretion.
Menkes disease is a genetic disorder of copper
metabolism which follows a progressively
degenerative path involving several organs of the
body but especially the brain. It is caused by
failure of the copper transport systems within
the cell and then across the cell membrane.
Because of the failure of this transport system,
copper is unavailable to various cells where it
is essential for the structure and function of
various enzymes that control the development of
hair, brain, bones, liver and arteries.
19
Menkes diseasecopper and ceruloplasmin levels
Menkes disease is caused by a defect in the
production of ceruloplasmin No new ceruloplasmin
is produced at birth, leading to a rapid decline
in both the protein levels and serum copper levels
20
Zinc Deficiencies
Information about severe zinc deficiency was
derived from the study of individuals born with
acrodermatitis enteropathica, a genetic disorder
resulting from the impaired uptake and transport
of zinc. Although dietary deficiency is unlikely
to cause severe zinc depletion in individuals
without a genetic disorder, zinc malabsorption or
conditions of increased zinc loss such as severe
burns or prolonged diarrhea, may also result in
severe zinc deficiency.
The symptoms of zinc deficiency depend on the
extent of the deficiency
21
Zinc Neurotoxicity
Zinc is one of the most abundant transition
metals in the brain. A substantial fraction
(1015) of zinc in the brain is located in
presynaptic vesicles in a loosely bound state.
This vesicle zinc is released with neuronal
activity or depolarization, probably serving
physiologic functions. However, with excess
release zinc may translocate and accumulate in
postsynaptic neurons, which may contribute to
selective neuronal cell death. Intracellular
mechanisms of zinc neurotoxicity may include
disturbances in energy metabolism, increases in
oxidative stress, and activation of apoptosis.
low excess Zn exposure leads to binding by
Hsp70 Zn can inhibit glycolysis thus depleting
ATP and leading to cell necrosis Zn can also
activate protein kinases (PKC) leading to
oxidative stress Zn can also lead to activation
of caspases which triggers apotosis
Molecular Neurobiology, 24, 99-106 (2001)
22
Metal Carcinogens
Certain metal salts have been shown to induce
tumor formation in mice Their carcinogenic
activities have been classified based on the
levels of metals needed to induce tumor growth
23
Summary

• Metal toxicity can be acute (high exposure level)
  or chronic (low exposure over long periods)
• Metal toxicity depends on the element, its
  chemical form and its oxidation state
• Cadmium, mercury, lead, aluminum and chromium can
  all be highly toxic
• Essential metals can also cause health problems
  either when they are deficient or when present in
  excess
• Metabolic disorders can lead to defects in iron,
  copper and zinc availability
• Exposure to some metals has been shown to lead to
  higher incidents of certain cancers