ORGANOPHOSPHOUS POSIONING

1. ORGANOPHOSPHOUS POSIONING

2. WHAT ARE ORGANOPHOSPHORUS dichlorvos diazinon • They are organic chemicals containing phosphous atoms . • They can be classified as three categories: A:derivatives of phosphoric acid(H3PO4), phosphorus acid(H3PO3), phosphinic (H3PO2) acid. Examples : dichlorvos,glufosinate B:derivatives of phosphine (PH3). C:derivatives of phosphorothioates(C=S). Examples : diazinon, parathion, and bromophos, glufosinate bromophos pentaphenylphosphorane.

3. General formulae phosphine phosphine oxide phosphonium salt phosphinite phosphonate phosphorus ylide

4. What they look like? derivatives of phosphine (PH3):

5. Porperties & Usages • They are volatile colorless or brown liquids with fruity smell or odorless . • They are potent neurotoxic chemicals to insects , widely used pesticides . • more than 200,000 people die from organophosphorus poisoning every year.

6. Organophosphorus pesticide occurrence and distribution in surface and ground water of the United States, 1992-97

7. Absorption routes • Inhale absorption usually caused by spraying OP pesticides without proper protection. • Skin is important route of absorption because OPs are lipophlic. • Ingestion of OPs can happen with suicidal attempt.

8. Distribution and storage • The phosphorothioates (P=S) are more lipophilic than phosphates (P=O). After absorption, both of them are distributed and accumulated in many organs in the body, especially in fatty tissue; fat and liver are the sites where Ops are most concentrated. Other organs, including kidney, glands, and CNS are also targeted. Because they are lipophilic, large amount of OPs are stored extensively in fat and release gradually after apparent recovery from acute poisoning, which explains why the symptoms of OP intoxication can relapse chronically sometimes.

9. Biotransformation • Phosphates are biologically active as acetylcholinesterase (AChE.) inhibitors, whereas phosphorothioates need bioactivation to their phosphate analogues oxon to become biologically active.

10. acetylcholinesterase (AChE.) inhibitors acetylcholinesterase AChE is an enzyme that degrades the neurotransmitter acetylcholine, producing choline and an acetate group. It is mainly found at neuromuscular junctions and cholinergic synapses in the central nervous system,also in red blood cell membranes. Cholinesterase inhibitors — block the function of acetylcholinesterase and thus cause excessive acetylcholine to accumulate . The excess acetylcholine causes neuromuscular paralysis (i.e. interminable muscle contractions) throughout the entire body, leading to death by asphyxiation.

11. Nerve synapse. Toxicants can interfere with neurotransmitter release,stimulation of receptors or the breakdown of acetylcholine. OPS inhibit acetylcholinesterase, producing over-stimulation of the cholinergic systems.

12. Biotransformation of low toxic OPC to active metabolites occurs through five major reactions • oxidative desulfuration of thiophosphate(PS4-xOx3- x = 0, 1, 2, or 3) group, which forms phosphorus compounds; • oxidation of sulfide group, which forms sulfoxides(R-S(=O)-R' ) for sulfones(R-S(=O)(=O)-R' ); • oxidation of amide groups forms N-oxides(R3N→O ) or N-dealkylated compounds; • hydroxylation of alkyl groups forms cyclic phosphate esters(are neurotoxic) or ketones; • various nonoxidative reactions.

13. Enzymes involved in biotransformation of OPC • In reactions of biotransformation of OPC different enzyme systems are involved. Some of them take part in metabolic activation of OPC like Monooxygenases while others can be very important in detoxication reactions and among them are A-esterases, carboxylesterases and glutathione S-transferases. Whether activation or detoxication will be a dominant reaction, largely depends on chemical structure of OPC and its interaction with these enzyme systems. 1. Monooxygenases • Cytochrome P450 • NADPH–cytochrome P450 reductase • Flavin-containing monooxygenase 2. Esterases involved in detoxication of OPC • Phosphoric triester hydrolases • Carboxylesterases

14. Detoxication of organophosphorus • Metabolic detoxication of OPC is mainly done by cleavage of one of the bonds at the phosphorus, which usually forms negatively charged molecule. This negative charge at the phosphorus does not allow OPC to be active as an anticholinesterase agent. Metabolites formed in detoxication reactions are much less potent anticholinesterase agents if at all. They are also hydrosoluble that enables them to be rapidly eliminated via urine. Acyl(RCO-) radical or leaving group usually contains hydroxyl, amino or thiol(-SH) group which easily undergo conjugation reactions and rapid excretion.

15. Example:Biotranformation of Parathion

16. Toxic effects • The first is the acute toxicity is due to the irreversible inhibition of acetylcholinesterase (AChE),which subsequently led to accumulation of acetylcholine at * Muscarinic receptors - in cholinergic receptor cell. *Nicotinic receptors – in skeletal neuromuscular junction and autonomic ganglia * Central Nerves System.

17. Toxic effects • The second effect is arising from single or repeated exposure, is a delayed onset of ataxia, with degeneration of the axon and the myelin in the most distal portion of the longest tracts in both central an peripheral nervous system,which is known as oganophosphate-induced delayed polyneuropathy. Both of these effects are related to chemical structure of OPC that can be largely influenced by metabolism of these compounds that may form potent inhibitors of the enzymes.

18. Symptoms • The presentation of organophosphate poisoning depends upon whether the poisoning is mild, moderate or severe. The symptoms are basically those of excessive acetylcholine activity. • Mild: Small or pinpoint pupils, Painful, blurred vision, Runny nose and eyes, Excess saliva, Eyes look "glassy", Headache, Nausea, Mild muscle weakness, Localised muscle twitching, Mild agitation • Severe: Pinpoint pupils, Confusion and agitation, Convulsions, Copious excess secretions, Cardiac arrhythmias,Collapse, respiratory depression or respiratory arrest, Coma

19. Treatments • Clearing the Airway, Adequate ventilation-consider oxygenation, Remove soiled clothes, Wash contaminated skin to prevent further absorption, Atropine 2mgs every 15 minutes till signs of atropinization are seen (DRY SKIN, DILATED PUPILS), Gastric lavage within an hour followed by activated ,Charcoal administered via nasogastric tube

20. THIS PRESENTATION ARE CITIED OR EDITED FROM • 1. Managing acute organophosphorus pesticide poisoning By Darren M Roberts,1 Cynthia K Aaron2 ) • 2.Toxicokinetic and toxicodynamic aspects of organophosphorus _OP. insecticide poisoning by J.A. Vale • 3. Biotransformation of organophosphorus compounds by Milan Jokanovic • 4. http://kmtc.bernsoft.com/file.php/1/moddata/forum/2/28/ORGANOPHOSPHORUS_POISONING.ppt • 5. http://en.wikipedia.org/wiki/Organophosphorus#Phosphate_esters_and_acids • 6. file:///I:/occupatioal%20health/tox9/presentation/Organophosphorous-Poisoning.htm • 7. http://www.mindfully.org/Pesticide/2003/Organophosphorus-Neurotoxicity1aug03.htm • 8.http://ga.water.usgs.gov/publications/abstracts/ofr00-187cover.gif&imgrefurl=http://ga.water.usgs.gov/publications/abst • 9. Human paraoxonase: A promising approach for pre-treatment • and therapy of organophosphorus poisoning by Daniel Rochua,b, Eric Chabri`ere a,c, Patrick Massona,∗ • 10. Principle of toxicology Course Notes by Paul Héroux • 11. http://en.wikipedia.org/wiki/.... • 12. http://www.sylphium.com/images/sylphium/hydrozylations.gif • 13 http://www.faqs.org/health/images/uchr_02_img0126.jpg • 14 http://thebrain.mcgill.ca/flash/i/i_06/i_06_m/i_06_m_mou/i_06_m_mou_2a.jpg • 15. http://journals.prous.com/journals/dnp/20041704/html/dn170251/images/Spooren_f5.jpg

21. THE END,THANK YOU!