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Environmental Toxicology and Chemistry

Environmental Toxicology and Chemistry. Intoxication Mechanisms I. Intoxication Mechanisms I. The Biochemical Lesion. A biochemical lesion is the result of the interaction of a toxic chemical and a specific biochemical receptor or target. Potential Toxic Mechanisms.

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Environmental Toxicology and Chemistry

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  1. Environmental Toxicologyand Chemistry Intoxication Mechanisms I

  2. Intoxication Mechanisms I

  3. The Biochemical Lesion A biochemical lesion is the result of the interaction of a toxic chemical and a specific biochemical receptor or target.

  4. Potential Toxic Mechanisms

  5. Delivery from the site of exposure to the target

  6. Receptors and Targets Receptor “ a chemical group or molecule in a plasma membrane or cell interior that shows an affinity for another specific chemical group or molecule”.

  7. Receptors and Targets • First described by Paul Ehrlich in 1908. • Lines of evidence: • Chemical effective at concentrations down to 10-12 mol require very specific sites. • Experiments with optical isomers. • Enzymatic reactions.

  8. Targets • Toxicant and target normally bind by covalent or noncovalent bonds. • The main reactions between toxicant and target include hydrogen abstraction, electron transfer and enzymatic modifications. • Practically all endogenous compounds are potential targets.

  9. Mechanisms of General Toxicity • They include mechanisms of toxicity that are common to many forms of life mainly because they affect biochemical processes that are shared by many other living organisms. • Examples: inhibition of oxidative phosphorilation, inhibition of respiration.

  10. Mechanisms of General Toxicity Oxidative Phosphorilation It couples the generation of ATP in the body to the electron transport system. 2NADH + 2H+ + O2 + 6ADP + 6Pinorg→ 2NAD+ + 2H2O + 6ATP

  11. Mechanisms of General Toxicity Inhibition of Oxidative Phosphorilation Toxic chemicals such as halo- and nitrophenols cause toxicity by inhibiting oxidative phosphorilation. These lipophilic phenols are strong acids capable of crossing membranes and therefore to disrupt ATP synthesis by altering the proton flow.

  12. Inhibition of Respiration by Compounds of Arsenic Mechanisms of General Toxicity

  13. Inhibition of Respiration by Compounds of Arsenic Mechanisms of General Toxicity

  14. Mechanisms of General Toxicity • Antidote for arsenic poisoning: • Developed at the beginning of WWII by Rudolph Peters in England. • Consisted of administration of massive amounts of 2,3-dimercaptopropanol. • Called BAL or British antilewisite.

  15. Animal-Specific Mechanisms

  16. The Nervous System

  17. The Nervous System

  18. Antidote: 2-PAM. Reaction of 2-PAM with phosphorilated serine: The Nervous System

  19. The Nervous System • Toxicity can also result from direct action on the ACh receptors. • Curare, a known South American arrow poison, blocks nicotinic receptors by binding to them. • Atropine, an alkaloid extracted from Jimson Weed has a similar effect on muscarinic receptors.

  20. The Nervous System • Other toxic effects include damage to the transmission of nerve impulses. • This is the case of chlorinated hydrocarbons insecticides such as DDT and relatives.

  21. The Nervous System • DDT toxicity: • Interference with ion movement by delaying closing of Na+ channels and slowing opening of K+ gates. • Inhibition of the neuronal ATPase that regulates repolarization. • Blocking of Ca++ transport.

  22. The Nervous System • Lindane: • More toxic to mammals than DDT. • Lindane is an excitant that antagonizes the action of δ-aminobutyric acid (GABA) and calcium uptake. • Botulinus toxin: • Inhibits release of ACh.

  23. The Liver • Unique feature of most mammals. • This organ filters blood from the body extracting large amount of waste compounds. • Common toxic effects: lipid accumulation, cirrhosis, lipid peroxidation and necrosis. • Major toxicants:chlorinated solvents, nitrosamines, aflatoxins, toadstool poisons and pyrrolizidine alkaloids.

  24. Hepatotoxicity • Carbon tetrachloride • undergoes reductive dechlorination by cytochrome P-450 enzymes resulting in the production of a very reactive trichloromethyl radical. • This radical is capable of causing damage to membrane phospholipids, inhibiting glutathione and affecting the whole P-450 system.

  25. Carbon Tetrachloride Hepatotoxicity

  26. Hepatotoxicity • Dibenzo-p-dioxins • TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) is one of the most toxic of all manmade substances. • LD50 of < 2.5 μg/Kg in guinea pig. • Mechanism of action related to its affinity for an Ah receptor in the liver.

  27. Hepatotoxicity

  28. Intermediary Metabolism • Fluoroacetic acid • The mechanism of action is related to the ability of this compound to alter the TCA cycle. • Due to the similarity in size between hydrogen and flourocitrate, the former binds to the enzyme aconitase. • Final result: no energy production by mitochondria.

  29. References • 1- Crosby, D.G. Environmental Toxicology and Chemistry. 2000. Oxford University Press, New York. • 2- Klaassen, C.D. (Ed), Casarett and Doull’s Toxicology, The Basic Science of Poisons. Fifth edition, McGraw Hill, 1995

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