Transcript toxicity

CHEMISTRY OF
SUBSTANCE TOXICITY
DEPARTMENT OF MEDICNAL CHEMISTRY
POMERANIAN MEDICAL SCHOOL
SZCZECIN 2009
„ALL SUBSTANCES ARE POISONS.
THE RIGHT DOSE DIFFERENTIATES A POISON AND A REMEDY”
Paracelsus
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TOXICITY
When defining toxicity of particulate substance the following
criteria are important:
• amount – dose of substance
• how it gets in to the body: by mouth, injection, absorption
by skin
• multiplicity of dose
• accumulation
• time after which undesired consequences take place in
organism
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SUBSTANCE TOXICITY
Range and degree of damage
Results of intoxication may appear after very long time.
Characteristic evidence of long term toxicity can be:
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Cancer deaseses
Genetic deseases,
Immunological damages
Mental (psychical) damages
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SUBSTANCE TOXICITY
Chemical compunds which are present in small amounts are
neccessary for normal functioning but in increased
concentration are causing toxicity or elevation of already
toxic state:
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Vitamin A
Vitamin PP
Selen
Some heavy metals such as: copper, cobalt
Toxicity reversibility may occur:
• Disorder of organs functionality did not progress too far.
• Toxin will be removed by excretory system.
• Toxin will be disactivated by metabolism and organism may
recover .
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Pathways of toxin absorption
Skin absorption
Absorption by :
Fissures at pilar capsules
 Sudoral tubules

 Diffusion by epidermis – passive absorption of
ksenobioticss
 Polar substances penetrate to cells through
albuminous fibers
 Nonpolar substance penetrate through lipid matrix
 Hydration of epidermis improves penetration of
polar substances
 Lipophilic substances easily penetrate outer layer of
epidermis
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a – transport transfolikularny
b – transport transepidermalny
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Pathways of toxin absorption
Penetration by respiratory sysytem
 Blood vessels are in direct contact with respiratory
epithelium cells in pulmonary alveolus.
 Unconstraint gas diffusion and substances dissolved in this
gases can take place.
 Inhaled ksenobiotics may cause :
 Demage of respiratory system tissues
 Intoxication af entire organism as a result of blood
vascular system penetration
 Amount of toxin introduced to lungs in form of gas, aerosol
or small particles depends on toxin concentration in air and
so called breathing minute volume
(breathing minute volume– product of inspiration volume,
(about 500 ml) times number of inspiratin per minute (1.5)
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Penetration by respiratory system cont.
Fick’s Law
Diffusion speed is propotional to surface area of the
membrane and difference in concentration on both
sides but inversely propotional to its thickness
.
S*A
D = Cd
(M)1/2 * d
(Pa – Pb)
D – diffusion speed
[g/cm2/s]
Cd – diffusion coefficient [cm2/s]
M – molar mas
S – gas solubility in blood
A, d – constant characterizing lungs area and thickness of membrane
Pa – concentration of substance in aspiration air
Pb – substance concentration in blood
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Pathways of toxin absorption
Penetration by alimentary duct
 Absorption of chemical compounds by mouth takes place
along entire alimentary duct.
 Compunds present in alimentary duct may change toxicity of
the compund.
 There are qualitatiive differences in toxicity between
compound beeing administrated with or without food, on
empty stomach.
 Some ksenobiotics are abasorbed in similar way as food in
small intestine.
 Soluble acids and organic bases are abasorbed in nonionic
form by passive diffusion.
 Bigger particles with diamater of several nanometers might
be absorbed from digestive duct in process called pinocytosis.
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Toxicity factors
 Physical- chemical properties of toxic substances:
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Solubility
Dissociation and toxic effect
Boiling and evaporation temperature
Particle size
 Compound structure and its ability to bond with
receptor:
 Structual isomerism
 Optical isomerism
 Bonding
 Substituents
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Toxicity factors
Toxin solubility
 Toxicity of chemical compounds is characterized by
distribution coefficient R which is a quotient of
concentration of substance presence in two inmiscible
liquids after equlibriom state is reached.
 R values are indicating on lipophilic substance character and
consequently it ability to overcome lipido-protein barriers.
 Substance toxicity increases with increased R value.
Substances with high value of R easily penetrate through lipid
barrier and by accumulation for example in fatty tissue are
become very toxic.
Substance
R
Ethanol
0,1
Ethylene glicol
0,5
Aniline
6,1
Chloroform
75
Benzen
120
Xylenes
6000
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Toxicity factors
Compound dissociation and toxicity
COO-
+H+
OCCH3
ll
O
pKa=3,5
Amount absorbed after 1 h
COOH
OCCH3
ll
O
pH=8
13%
Urea pH
6,7
7,8
Excretion of
acetylsalicylic acid
0,5 mg
5,5 mg
pH=1
61%
Unionized particles can penetrate through biological membranes.
pK value alows to determine ability of the compound to travel through
cell’s membrane.
pH>pK – dissociated acids, undissociated bases
pH<pK – undissociated acids, dissociated bases
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Toxicity factors
Boiling and evaporation temperatures
Influence of boiling and evaporation temperatures on
absorption of toxic substances applies only for
substances in liquid form.
Lower boiling point is causing easier transformation
into the gas phase. (acetone bp. ~57C, water 100C)
High vapor pressure = high volatility, leads to easier
absorption by lungs.
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Toxicity and compound structure
Influence of bonding
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Aliphatic compounds with inceased amount of carbon atoms in
chain and chain branching are become more toxic for humans.
Increased amount of methylene groups (-CH2) creates ability to
form consecutive Van der Waals bonds which allows it to bond
throug several receptors.
– In amines increased amount of methylene group is causing
increased solubility.
– Presence of unsaturated bond in aliphatic compounds
influences its hydrophility and causing increased toxicity.
– Unsaturated bond in cyclic compounds posesses big
oxidation-reduction potencial which is causing oxidation of
thiol groups.
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Toxicity and compound structure
Influence of bonding cont.
• Aromatic compounds are more toxic than
aliphatic.
• Unsaturated bond in chemical compund make
easier absorption by lungs and can lead to
narcotic effect.
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Toxicity and compound structure
Structural isomerism
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Compounds with substituent :
para - are usually toxic
meta – are less toxic
orto – are very rarely toxic
High biological activity of many medicines have
isomers para, for example p-aminosalicylic acid and
p-acetylaminobenzoic acid.
Affinity to enzyme:
 Kinetisc of bonding with active center of enzyme
 Stability of new joint enzyme-inhibitor
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Toxicity and compound structure
Optical isomerism
•Enantiomers which show biological activity are called –entomer.
•Enantiomers with no biological activity are called – diastomers.
•DOPA, medicine used in Parkinson,s desease is effective only in
L-enantiomer form.
•Ibuprofen – is used only as racemic mixture.
Laevorotatory isomers of compuonds and medicines
are for humans more toxic.
hypnotic
teratogenic
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Toxicity and compound structure
Influence of substituents
Substituents decreasing toxicity:
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–OH groups in aliphatic compounds
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Alcohols are less toxic then corresponding hydrocarbons.
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Groups:
– carboxylic
– sulfates
are decreasing toxicity by creating easily soluble compound
to be removed with urea.
- thiol group creates sulphonic compounds with minimum
toxicity.
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organic radicals – acetyl groups, methoxy groups.
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Toxicity and compound structure
Influence of substituents cont.
Substituents increasing toxicity:
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Increased amount of hydroxy groups
Presence of methylene group
Increased toxicity:
benzen, toluen, xylen;
phenol, krezol, xylenol
 Brenching
 Presence of group:
– Amines
– Nitrate and nitroso
– Cyanide group
- Fluoro and halogen derivatives
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