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DEPARTMENT OF MEDICNAL CHEMISTRY POMERANIAN MEDICAL SCHOOL
SZCZECIN 2009
„ALL SUBSTANCES ARE POISONS. THE RIGHT DOSE DIFFERENTIATES A POISON AND A REMEDY”
Paracelsus
CHEMISTRY OF SUBSTANCE TOXICITY
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TOXICITY
When defining toxicity of particulate substance the When defining toxicity of particulate substance the following criteria are important:following criteria are important:
• amount – dose of substanceamount – dose of substance• how it gets in to the body: by mouth, injection, how it gets in to the body: by mouth, injection,
absorption by skabsorption by skiinn• multiplicity of dosemultiplicity of dose• accumulation accumulation • time after which undesired consequences take place time after which undesired consequences take place
in organism 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:
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:
• 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 absorptionPathways of toxin absorption Skin absorptionSkin 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 transfolikularnyb – transport transepidermalny
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Pathways of toxin absorptionPathways 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 LawFick’s Law
Diffusion speed is propotional to surface area of the Diffusion speed is propotional to surface area of the membrane and difference in concentration on both membrane and difference in concentration on both
sides but inversely propotional to its thicknesssides but inversely propotional to its thickness . . S * A
D = Cd (Pa – Pb) (M)1/2 * dD – 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
membranePa – concentration of substance in aspiration air
Pb – substance concentration in blood
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Pathways of toxin absorption Pathways of toxin absorption Penetration by alimentary ductPenetration 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 factorsToxicity factors
Physical- chemical properties of toxic substances:
SolubilitySolubility Dissociation and toxic effect Dissociation and toxic effect Boiling and evaporation temperature Boiling and evaporation temperature Particle sizeParticle size
Compound structure and its ability to bond with receptorCompound structure and its ability to bond with receptor:: Structual isomerism Structual isomerism Optical isomerism Optical isomerism BondingBonding SubstituentsSubstituents
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Toxicity factorsToxicity factors Toxin solubilityToxin 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 factorsToxicity factors Compound dissociation and toxicityCompound dissociation and toxicity
UUnionized particles can penetrate t 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
COO-
OCCH3
ll O
COOH
OCCH3
ll O
+H+
pKa=3,5 pH=8 pH=1Amount absorbed after 1 h 13% 61%
Excretion ofUrea pH acetylsalicylic acid
6,7 0,5 mg 7,8 5,5 mg
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Toxicity factorsToxicity factors Boiling and evaporation temperaturesBoiling 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 Toxicity and compound structure Influence of bondingInfluence of bonding
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 Toxicity and compound structure Influence of bondingInfluence 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 Toxicity and compound structure Structural isomerismStructural isomerism
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 Toxicity and compound structure Optical isomerismOptical isomerism
hypnotic teratogenic
•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.
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Toxicity and compound structure Toxicity and compound structure Influence of substituentsInfluence of substituents
––OH groups in aliphatic compounds OH groups in aliphatic compounds
Alcohols are less toxic then corresponding hydrocarbons.Alcohols are less toxic then corresponding hydrocarbons.
GroupsGroups::– carboxylic carboxylic – sulfatessulfates
are decreasing toxicity by creating easily soluble compound are decreasing toxicity by creating easily soluble compound to be removed with urea to be removed with urea..
- t- thiol group creates sulphonic compounds with minimum hiol group creates sulphonic compounds with minimum toxicity.toxicity.
- o- organic radicals – acetyl groups, methoxy groups.rganic radicals – acetyl groups, methoxy groups.
Substituents decreasing toxicity:
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Toxicity and compound structure Toxicity and compound structure Influence of substituents cont.
Increased amount of hydroxy groups Increased amount of hydroxy groups Presence of methylene group Presence of methylene group
IIncreased toxicity: ncreased toxicity: benzen, toluen, xylen; benzen, toluen, xylen;
phenol, phenol, krezol, xylenol, xylenol BBrenchingrenching Presence of group:Presence of group:
– AAminesmines– Nitrate and nitroso Nitrate and nitroso – Cyanide group Cyanide group
- F- Fluoro and halogen derivativeluoro and halogen derivativess
Substituents increasing toxicity:
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