Transcript Metal Compounds Toxicity of Various Metal Compounds General Issues    About 80 of the 105 elements in the periodic table are regarded as metals; fewer.

Metal Compounds
Toxicity of Various Metal
Compounds
General Issues
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About 80 of the 105 elements in the periodic
table are regarded as metals; fewer than 30
have been reported to produce toxicity.
Metals are distributed naturally in the
environment by both geologic and biologic
cycles.
A critical determinant of the metabolism and
toxic behavior of a metal is its biological halflife. The half-life of cadmium and lead are 20
to 30 years whereas for metals such as
arsenic, cobalt, and chromium it is a few
hours to a few days.
General Issues (Continued)
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Cellular targets for toxicity are specific biochemical
processes (enzymes) and/or membranes of cells and
organelles.
Alkyl compounds (organic compounds) are lipid
soluble and pass readily across biological
membranes, and they are only slowly dealkylated to
inorganic salts. Hence their excretion tends to be
slower than inorganic forms and the pattern of
toxicity tends to be different from inorganic forms.
Ex. Methylmercury is primarily a neurotoxin while
mercuric chloride is toxic to the kidneys.
General Issues (Continued)
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FACTORS INFLUENCING THE TOXICITY
OF METALS
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Interactions with essential metals
Formation of metal-protein complexes
Age and stage of development
Lifestyle factors
Chemical form or speciation
Immune status of host
INDIVIDUAL METALS
Mercury
Three Forms of Mercury
Elemental, Inorganic, Organic
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Hgo (elemental mercury)
Hg+ (mercurous inorganic mercury)
Hg++ (mercuric inorganic mercury)
Methylmercury and dimethylmercury
(organic forms)
Global Sources and
Distribution of Mercury
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The major natural source of mercury is
the natural degassing of the earth’s
crust – Volcanic Activity.
Human Activity Source: Fossil fuels
(especially coal) may contain as much
as 1 ppm of mercury.
Sources (Continued)
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Metallic mercury in the atmosphere
represents the major pathway of global
transport of mercury. Metallic mercury may
be oxidized to mono or divalent mercury in
the presence of organic matter.
Residence time of Hg vapor in the air is 0.4 to
3.0 years, global distribution. Hg++ is
removed from air by dry and wet deposition
so therefore it is deposited onto land and
water by rain.
Sources (Continued)
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Methylation of mercury is accomplished
by anaerobic bacteria in the aquatic
environment.
Toxicokinetics
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Metallic mercury volatilizes to mercury vapor
and most human exposure to metallic
mercury is by inhalation. This vapor is lipid
soluble.
G.I. tract absorption of inorganic mercury
salts from food is low (7 – 15%) whereas
absorption of methylmercury from G.I. tract is
high (90 – 95%).
Toxicokinetics (Continued)
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The kidney contains the greatest [ ] of
mercury following exposure to inorganic
mercury and mercury vapor, whereas
organic mercury has a greater affinity
for the brain.
Excretion is mainly by the biliary route
with enterohepatic recirculation in the
case of methylmercury.
Toxicokinetics (Continued)
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Methylmercury, can cross the placenta to the
fetus and additional mercury exposure can
occur during nursing since methylmercury is
also found in milk at ~ 5% of maternal blood.
Biological half-life is about 70 days for
methylmercury and about 40 days for
inorganic forms.
Cellular Targets
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has a particular affinity for compounds
containing sulfhydryl groups
affects enzyme systems in microsomes
and mitochondria
becomes localized in lysosomes of
kidney cells
Toxicity
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Mercury vapor and methylmercury
affect the CNS
Inorganic mercury affects kidney
Toxicity occurs at much lower levels in
the fetus than in adults.
Mercury In Fish
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Methylmercury is produced both in the
sediment and in the water column by
methylation of Hg++ by microbes.
Fish obtain methylmercury from their diet
and, to a much lesser extent, from the water
passed over the gills. Diet accounts for 90%
of uptake.
Assimilation efficiency for dietary uptake is 65
– 80% or greater. 7 – 12% assimilation
efficiency across gills.
Mercury In Fish (Continued)
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Feeding habits and food-chain structure
influences methylmercury uptake in fish.
Get biomagnification: [ ] of methylmercury
progressively increases from primary
producers to fish. Piscivorous fish have
greater [ ] than fish of lower trophic levels.
Lake trout have a greater [ ] of
methylmercury when forage fish are present
versus invertebrates.
Fish from smaller, warmer lakes also have
greater [ ]s.
Mercury In Fish (Continued)
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The [ ] of methylmercury in fish increases
with increasing age or size of fish.
Acidic bodies of water have greater
methylmercury production.
Fish from newly flooded reservoirs have high
[ ]s of methylmercury.
Mercury In Fish (Continued)
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Nearly all of the mercury in fish is
methylmercury (95 – 99%).
The greatest amount of mercury in the
body of a fish is found in the skeletal
muscle even though mercury is at a
lower [ ] in skeletal muscle than in
brain.
Mercury In Marine Mammals
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Marine mammals store the majority of
mercury in the inorganic forms because they
have a very good ability to demethylate
organic mercury within their bodies.
Transfer to fetus is low because only
methylmercury is able to cross the placenta.
Human Exposure To
Methlymercury
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Minamata Japan
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Iraq
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Seychelle Islands
INDIVIDUAL METALS
Arsenic
Forms of Arsenic
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Found as As+3 or As+5
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The most common As+3 inorganic forms are
arsenic trioxide, sodium arsenite, and arsenic
trichloride.
The most common As+5 inorganic forms are
arsenic pentoxide, lead arsenate, and calcium
arsenate.
Organic forms may be +3 or +5 As and may occur
as methylated forms due to methylation by
organisms in soil, fresh water, and sea water.
Forms (Continued)
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Trivalent forms of As are the principal
toxic forms. Pentavalent forms
generally have little or no effect.
However, +5 forms can be converted to
+3 forms in vivo.
Toxicokinetics
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Exposure is through inhalation, drinking
water, and soil
Almost complete absorption from G.I.
Tract
Toxicokinetics (Continued)
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Excretion of inorganic forms is largly through
the urine. Methylated forms have a longer
half-life. Methylated forms seem to be a
detoxification product with dimethyl-As the
principal detox product.
As also has a predilection for skin and is
excreted by desquamation of skin and in
sweat, particularly during periods of profuse
sweating.
Toxicokinetics (Continued)
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Also concentrates in nails and hair.
Human milk contains some As and As
can be transferred across the placenta
([ ] in fetal blood same as maternal
blood).
Cellular Targets
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Sulfhydryl-containing proteins and enzymes
systems are altered by exposure to As
compounds.
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Affects mitochondrial enzymes. Mitochondria
accumulate As. Succinic dehydrogenase activity is
inhibited and oxidative phosphorylation is
uncoupled.
As chelates with alpha-lipoic acid forming a ringlike structure. Alpha-lipoic acid is an essential
cofactor for pyruvate dehydrogenase, an enzyme
required for energy production in the Krebs Cycle.
Cellular Targets (Continued)
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Some As forms mimic the phosphate anion
in cells. Substitution of As for phosphate
would disrupt a number of metabolic
reactions that require phosphorylation.
Noncancer Effects
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Large doses (70 – 180 mg) can be fatal.
Acute effects = sensory loss in peripheral
nervous system (degeneration of axons).
Chronic exposure to inorganic As leads to
neurotoxicity of both the peripheral and
central nervous systems.
Liver injury is also characteristic of chronic
exposure.
Cancer Effects
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Skin cancer. Hyperpigmentation and
hyperkeratosis. Basal cell carcinoma and
squamous cell carcinomas.
Occupational exposure to airborne As may be
associated with lung cancer. The time period
between initiation of exposure and
occurrence of As-associated lung cancer is on
the order of 34 to 45 years.
Cancer Effects (Continued)
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Several studies suggest that As +3
compounds are capable of producing
chromosome breaks.
Individual Metals
Lead
General Issues
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Lead is the most ubiquitous metal
Most susceptible populations are
children, particularly toddlers, infants in
neonatal period, and fetus
There is no demonstrated biological
need for lead
Intake of Lead
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Oral absorption
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Food
Lead based indoor paint
Contaminated drinking water
Hand to mouth activity in children
Lead-glazed pottery
Inhalation absorption
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Lead dust from environmental sources
Air from lead-containing industrial/auto emissions
Intake of Lead (Continued)
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Dietary intake has decreased
dramatically since the 1940s (400 – 500
ug/day) to present (20 ug/day) in US.
Since the introduction of lead-free
gasoline in US, airborne exposure from
auto exhaust in minimal.
Absorption
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Adults absorb 5 to 15% of ingested lead
and usually retain less than 5% of that
absorbed
Children absorb ~ 40% of ingested lead
and retain about 32% of that absorbed
About 90% of inhaled lead is small
enough to be retained in alveoli and get
100% absorption
Distribution
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> 90% of the Pb in the blood is in the
red blood cells (RBCs)
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One compartment is the RBC membrane
Second compartment is hemoglobin
Redistribution of Pb from blood to
skeleton with half-life of 20 years
Pb crosses placenta to fetus to match
levels in maternal blood
Toxicity of Lead
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Neurotoxicity
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Significant affect on timing of cell-to-cell
connections – get modified neural circuits
in central nervous system
Demyelination and axon degeneration in
peripheral nervous system
Interference with synaptic transmissions –
Pb substitutes for Ca at synapse
Toxicity (Continued)
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Hematological Toxicity
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Anemia
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Fragile RBC membrane shortens RBC lifespan
Impairment of heme synthesis
Effects on myoglobin and CYP
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Myoglobin and CYPs also contain heme
Heme Synthesis Inhibition
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Pb inhibits heme synthesis at several
key points in pathway
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Aminolaevulinate synthetase
Aminolaevulinate dehydrase
Ferrochelatase
Haem oxidase
Coproporphyronogen oxidase
Heme (Continued)
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Significant inhibition of
amionolaevulinate dehydrase is
detectable in people with Pb blood
levels of 0.4 ug/ml, which results from
normal exposure to the urban
environment.
Toxicity (Continued)
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Renal Toxicity
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Acute exposure can cause reversible renal
damage
Chronic exposure causes permanent renal
damage. Get impaired ATP production in
mitochondria of proximal tube cells of
nephron
Toxicity (Continued)
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Organic Lead (tetraethyl Pb) is lipid
soluble, targets brain of developing
fetus resulting in Encephalophathy
Organic Lead does not effect heme
synthesis or kidney.
Individual Metals
Cadmium
General Issues
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Cadmium is a modern toxic metal;
industrial use was minor until about 60
years ago
Use today is in electroplating, color
pigments in paints, batteries
Absorption
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Airborne exposure in workplace
Shellfish accumulate Cd from water
Cigarette smoke
Oral absorption is low
Inhalation absorption is high
Distribution
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In blood, binds to RBCs and to plasma
proteins (particularly albumin)
50 to 75% of body burden is in liver
and kidneys
Half-life is ~ 30 years
Toxicity
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Pulmonary, Renal, and Bone Toxicity
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Damage to alveolar macrophages which
release enzymes that damage alveolar
basement membranes – fibrosis
Cd-Metallothionein – Renal toxicity
Cd-Metallothionein – Reproductive
Protection
Cd replaces Ca in bone – Itai-Itai disease
Toxicity (Continued)
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Carcinogen
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Lung cancer
Testicular cancer
Prostate cancer
Individual Metals
Tin
Toxicity of Tin Compounds
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Organic tin compounds are potent
neurotoxins
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These compounds are often used as antifouling paints on boats and ships
Compounds are also involved as endocrine
disrupting compounds
Individual Metals
Selenium
General Issues
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Selenium is a required metal for
humans at low doses
Selenium can be toxic at high doses
Embyotoxic and teratogenic to animals