Transcript Lecture No. 2

Basics of general toxicology
Lecture No. 2
Copyright © Prof. MVDr. Zdeňka Svobodová,
DrSc., Mgr. Zuzana Široká, PhD.
Definition of toxin:
• Toxin is any substance that even in small quantities or
low concentrations, after a single administration or
repeated exposure, cause severe damage to, or the
death of, the organism
• To quote Professor Švagr, "any substance qualitatively
or quantitatively foreign to the organism that causes
chemical or physical damage to that organism should
be classified as a toxin"
• Factors affecting toxicity:
Playe's principle of CCC (DCC) can be applied:
- Concentration (Doses)
- Complexation
- Competition
Concentration:
• The dose (concentration) issue has been mentioned
above (it is generally true that the higher the dose, the
stronger the effects)
• Some toxins also exhibit a phenomenon called
hormesis. Such substances have the opposite effect in
small doses than in large doses:
- We most frequently come across the so-called
radiation hormesis – small dose of radiation has
protective effects
- Methylene blue used as a reduction agent in cases of
NO2- poisoning causes methaemoglobinemia at higher
concentrations
Complexation:
• A general principle of toxicology says that what is soluble is
toxic
• Eg. LC50 of CuSO4.5 H2O for carp is 10 mg.l-1 in pond water or
1 mg.l-1 in ground water
the explanation of the difference
is that pond water contains much more organic substances,
which form with copper less soluble and absorbable
organocopper complexes, therefore less toxic
• Complexation characteristics are used in treating metal
poisoning cases. A proven home remedy is milk with whisked
egg whites. The proteins and the metal salts form insoluble
complexes and these cannot be absorbed
• The so-called chelate-forming substances administered in the
case of metal poisoning also prevent the absorption of metals
because of formation of insoluble complexes
They include:
- ethylenediaminetetraacetic acid
(EDTA) - mainly in lead poisoning
- compounds containing SH
groups, e.g. dimercaprol (BAL) –
no longer used in clinical practice
today
- SH ligands – macromolecular
sorbents – used to block the
absorption or to interrupt the
enterohepatic circulation of metals
- D – penicilamin – used for
chelation of practically all metals
EDTA
Penicilamin
Competition:
• Substances compete for the receptor, enzyme or site of
absorption
• The competition between Cl- and NO2- on fish gills may serve
as an example. Both Cl- and NO2- are absorbed to the body
through eosinophilic cells, the so-called chloride cells in the
gills. Chloride ions always have primacy. It means that in water
with abundance of chloride ions, the chloride cells are all
occupied by chlorides, which block the absorption of NO2- to
the bodies of fish and negative effects related with it
• Another example is the competition between methyl alcohol
and ethyl alcohol for the alcohol dehydrogenase enzyme, whose
affinity to the ethyl alcohol is 100 times higher. This
characteristic is taken advantage of in the treatment of methyl
alcohol and ethylene glycol poisonings
• Other examples are competition between toxic metals (Cd, Pb,
Hg) and Zn and Cu for SH groups contained in amino acids or
competition of anticoagulation rodenticides and vitamin K in
formation of active clotting factors
Synergism and antagonism
Synergism
• Interaction of 2 or more agents so that their effects are combined
• There are two types of synergism, the additive and the
potentiation synergism
• Additive synergism means that effects of two types of agents are
added up. An example is the interaction between
organophosphates and carbamates. The mechanism of action of
the two agents is the same – they inhibit the acetylcholinesterase
enzyme, which results in an accumulation of acetylcholine at
nerve synapses
• In the case of potentiation synergism, effects of the interacting
agents are multiplied. Pyrethroids and piperonylbutoxid are an
example of potentiation synergism. Piperonylbutoxid markedly
potentiates the effect of pyrethroids, and in practise pyrethroids
are used as insecticides potentiated by piperonylbutoxid
Antagonism
• interaction of two or more agents that in
combination have an overall effect which is less
than the sum of their individual effects
• We distinguish between two types of
antagonism, i.e. the chemical and the functional
type
- Chemical antagonism is exemplified by
neutralization occurring when an acid combines
with a base, or a combination of cation-active
and anion-active tensides in water. The same
principle of chemical antagonism is also used in
chelate treatment of metal poisoning
- Functional antagonism - the principle is used for
symptomatic treatment in poisoning cases barbiturates with strongly anticonvulsive effects are
administered to victims of strychnine poisoning
(strychnine has convulsive effects). Methyl alcohol
poisoning is treated by administration of ethyl
alcohol. The alcohol dehydrogenase enzyme in the
liver "prioritizes" ethyl alcohol oxidation, and the
conversion rate of methyl alcohol to formaldehyde
and formic acid is thus slowed down. A similarly
antagonistic relation exists between ethylene glycol
and ethyl alcohol
Toxicokinetics – the fate of toxin in
the organism
Includes absorption, transport and distribution
biotransformation and excretion
• Routes of absorption:
- gastrointestinal tract
- respiratory apparatus
- skin and external mucous membranes
- parenterally (s. c., i. m. or i. v. injections), or an
injection of snake venom or some other zootoxin
• Transport and distribution:
- Poisons are transported in the blood, where they are either free
or bound
- The free form is mostly dissolved in the aqueous component of
blood plasma
- The bound form is fixed to some other blood component, mainly
blood plasma proteins (albumin – binds most toxic substances;
transferrin and ceruloplasmin – bind metals) and to cellular blood
elements and their components (e.g. erythrocytes, haemoglobin)
- With regard to distribution, the greatest concentrations of the
majority of toxic agents are in the liver and kidneys (e.g. toxic
metals bind there to polypeptide metallothionein)
- Many toxic substances show specific affinity to specific organs
– we speak about tropism of poisons (e.g. hepatotropic poisons –
CCl4, aflatoxin B1, microcystin, etc.; nephrotropic – ochratoxin,
ethylene glycol; neurotropic – organophosphates, carbamates,
pyrethroids; hematotropic – CO, NO2-)
• Biotransformation:
- Some chemical substances are eliminated from the organism in
an unchanged form (e.g. organic compounds of arsenic –
arsenobetaine, arsenocholine – pass through the mammalian
digestive tract without any changes)
- A large majority of toxic substances are altered by
biotransformation, while their toxicity is either activated or reduced
(detoxification)
 One type of biotransformation takes place in the pre-absorption
phase:
- phosphane (PH3) is released from zinc phosphide (Zn3P2) by
stomach HCl
- HCN is released from cyanogenic glycosides by hydrolytic
enzymes activated by stomach HCl
- NO3- is reduced to NO2- by the gastrointestinal tract microflora
- NH3 is released from urea by urease in the rumen
- decomposition of digitalised glycosides in the proventriculi of
ruminant (reduction of toxicity)
 But, the main organ of biotranformation is the liver! Most of
organic biotoxicants are biotransformed in two stages:
stage 1
XH
stage 2
X – OH
X – O – conjugate
The XH xenobiotic is transformed by oxidation (or hydrolytic
or reduction) enzymes to a more polar metabolite X – OH,
which becomes a substrate for conjugating enzymes
stage 1 – monooxygenation (by cytochrome P450)
XH → X – OH
more polar, but hazardous and potentially mutagenic and carcinogenic
substances may be produced
stage 2 – conjugation by conjugating enzymes, e.g. glutathion-Stransferase – GST or glucuronyl transferase
bind glutathion or
glucuronic acid to X – OH and the resulting conjugate is excreted from
the body in bile or urine
C P450
e.g. benzo(a)pyren
GST
epoxydiol
l-hydroxypyrene
- In the process of metal detoxication, metals are being bound to SH
groups of metallothioneins. In the case of metal contamination of an
organism, its liver increases the production of methallothioneins.
Metallothioneins are polypeptides, every third amino acid of is cystein,
and they therefore contains a large quantity of SH groups
• Routes of excretion:
- kidney (urine)
- liver (bile, and then by faeces)
- gastrointestinal tract (faeces)
- lungs
- mammary gland
- salivary glands
- sweat, lacrimal and sebaceous glands and
their products