DEPARTMENT OF MEDICNAL CHEMISTRY POMERANIAN MEDICAL SCHOOL SZCZECIN 2009

1. CHEMISTRY OF SUBSTANCE TOXICITY DEPARTMENT OF MEDICNAL CHEMISTRY POMERANIAN MEDICAL SCHOOLSZCZECIN 2009 „ALL SUBSTANCES ARE POISONS. THE RIGHT DOSE DIFFERENTIATES A POISON AND A REMEDY” Paracelsus

2. 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

3. 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

4. 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 .

5. Pathways of toxin 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

6. a – transport transfolikularny b – transport transepidermalny

7. Pathways of toxin absorptionPenetration 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 breathingminute volume (breathingminute volume– product of inspiration volume, (about 500 ml) times number of inspiratin per minute (1.5)

8. 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 (Pa – Pb) (M)1/2 * d 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

9. 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.

10. Toxicity factors • Physical- chemical properties of toxic substances: • 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

11. Toxicity factorsToxin 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.

12. Toxicity factorsCompound dissociation and toxicity COO- OCCH3 ll O COOH OCCH3 ll O +H+ Excretion of Urea pH acetylsalicylic acid 6,7 0,5 mg 7,8 5,5 mg pKa=3,5 pH=8 pH=1 Amount absorbed after 1 h 13% 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

13. Toxicity factorsBoiling 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.

14. Toxicity and compound structure Influence 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.

15. Toxicity and compound structure Influence of bondingcont. • Aromatic compounds are more toxic than aliphatic. • Unsaturated bond in chemical compund make easier absorption by lungs and can lead to narcotic effect.

16. Toxicity and compound structure Structural 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

17. 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

18. –OH groups in aliphatic compounds Alcohols are less toxic then corresponding hydrocarbons. Groups: carboxylic sulfates are decreasing toxicity by creating easily soluble compound to be removed with urea. - thiol group creates sulphonic compounds with minimum toxicity. - organic radicals – acetyl groups, methoxy groups. Toxicity and compound structure Influence of substituents Substituents decreasing toxicity:

19. 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 Toxicity and compound structure Influence of substituentscont. Substituents increasing toxicity: