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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: