Environmental Toxicology
and Chemistry
Intoxication Mechanisms I
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Intoxication Mechanisms I
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The Biochemical Lesion
A biochemical lesion is the result of the
interaction of a toxic chemical and a
specific biochemical receptor or target.
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Potential Toxic Mechanisms
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Delivery from the site of
exposure to the target
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Receptors and Targets
Receptor
“ a chemical group or molecule in a
plasma membrane or cell interior that
shows an affinity for another specific
chemical group or molecule”.
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Receptors and Targets
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First described by Paul Ehrlich in 1908.
Lines of evidence:
– Chemical effective at concentrations
down to 10-12 mol require very specific
sites.
– Experiments with optical isomers.
– Enzymatic reactions.
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Targets
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Toxicant and target normally bind by
covalent or noncovalent bonds.
The main reactions between toxicant and
target include hydrogen abstraction, electron
transfer and enzymatic modifications.
Practically all endogenous compounds are
potential targets.
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Mechanisms of General
Toxicity
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They include mechanisms of toxicity
that are common to many forms of life
mainly because they affect biochemical
processes that are shared by many
other living organisms.
Examples: inhibition of oxidative
phosphorilation, inhibition of
respiration.
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Mechanisms of General
Toxicity
Oxidative Phosphorilation
It couples the generation of ATP in the body to
the electron transport system.
2NADH + 2H+ + O2 + 6ADP + 6Pinorg→ 2NAD+ + 2H2O + 6ATP
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Mechanisms of General
Toxicity
Inhibition of Oxidative Phosphorilation
Toxic chemicals such as halo- and nitrophenols
cause toxicity by inhibiting oxidative
phosphorilation.
These lipophilic phenols are strong acids
capable of crossing membranes and
therefore to disrupt ATP synthesis by
altering the proton flow.
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Mechanisms of General
Toxicity
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Mechanisms of General
Toxicity
Inhibition of Respiration by Compounds of
Arsenic
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Mechanisms of General
Toxicity
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Antidote for arsenic poisoning:
– Developed at the beginning of WWII by
Rudolph Peters in England.
– Consisted of administration of massive
amounts of 2,3-dimercaptopropanol.
– Called BAL or British antilewisite.
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Animal-Specific Mechanisms
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The Nervous System
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The Nervous System
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The Nervous System
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Antidote: 2-PAM.
Reaction of 2-PAM with phosphorilated
serine:
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The Nervous System
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Toxicity can also result from direct
action on the ACh receptors.
– Curare, a known South American arrow
poison, blocks nicotinic receptors by
binding to them.
– Atropine, an alkaloid extracted from
Jimson Weed has a similar effect on
muscarinic receptors.
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The Nervous System
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Other toxic effects include damage to
the transmission of nerve impulses.
This is the case of chlorinated
hydrocarbons insecticides such as DDT
and relatives.
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The Nervous System
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DDT toxicity:
– Interference with ion movement by
delaying closing of Na+ channels and
slowing opening of K+ gates.
– Inhibition of the neuronal ATPase that
regulates repolarization.
– Blocking of Ca++ transport.
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The Nervous System
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Lindane:
– More toxic to mammals than DDT.
– Lindane is an excitant that antagonizes
the action of δ-aminobutyric acid (GABA)
and calcium uptake.
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Botulinus toxin:
– Inhibits release of ACh.
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The Liver
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Unique feature of most mammals.
This organ filters blood from the body
extracting large amount of waste
compounds.
Common toxic effects: lipid accumulation,
cirrhosis, lipid peroxidation and necrosis.
Major toxicants:chlorinated solvents,
nitrosamines, aflatoxins, toadstool poisons
and pyrrolizidine alkaloids.
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Hepatotoxicity
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Carbon tetrachloride
– undergoes reductive dechlorination by
cytochrome P-450 enzymes resulting in
the production of a very reactive
trichloromethyl radical.
– This radical is capable of causing damage
to membrane phospholipids, inhibiting
glutathione and affecting the whole P-450
system.
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Hepatotoxicity
Carbon Tetrachloride
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Hepatotoxicity
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Dibenzo-p-dioxins
– TCDD (2,3,7,8-tetrachlorodibenzo-pdioxin) is one of the most toxic of all
manmade substances.
– LD50 of < 2.5 μg/Kg in guinea pig.
– Mechanism of action related to its affinity
for an Ah receptor in the liver.
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Hepatotoxicity
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Intermediary Metabolism
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Fluoroacetic acid
– The mechanism of action is related to the
ability of this compound to alter the TCA
cycle.
– Due to the similarity in size between
hydrogen and flourocitrate, the former
binds to the enzyme aconitase.
– Final result: no energy production by
mitochondria.
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References
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1- Crosby, D.G. Environmental Toxicology and Chemistry.
2000. Oxford University Press, New York.
2- Klaassen, C.D. (Ed), Casarett and Doull’s Toxicology,
The Basic Science of Poisons. Fifth edition, McGraw Hill,
1995
©Chaves, Hofelt,Shea.