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![Bipyridyl Compounds
• Paraquat (most concern)
• Skin sensitizer
• Accumulates in lung and kidney
• High concentration in type II and I /Clara cells
• Toxicity: Redox cycling; superoxide generation and
lipid peroxidation
• Stages of lung destruction; destructive phase;
proliferative phase and intensive fibrosis
• Dexamethasone with PG induction and sodium
salicylate in animals
• Blue stentching pigment added
• Etilogical in Parkinson Disease [Structure similar to
MPP+ and MPTP- Similar to rotenone]
• Some evidence for neurodegeneration to
dopaminergic neurons [dose level not concern to
humans]
DiQuat
No Skin sensitizer; no lung accumulation
Kidneys and eyes- free radical mechanism
Ocular toxicity](https://image.slidesharecdn.com/pesticides-180722160338/75/Pesticides-19-2048.jpg)
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Pesticides
- 1.
- 2. PESTICIDES • Single ormixture of substances • Used from ancient to modern times • Arsenic – herbicide, fumigant • Copper-fungicide, utensils • Nicotine – insecticide • Gerhard Schrader- Father of organophophorous insecticide • Toxicity – mostly non-target species • Dermal, inhalation and oral route
- 3. Regulatory • EPA • FederalInsecticide, Fungicide and Rodenticide Act – Pesticides for use • Federal Food, Drug and Cosmetic Act – allowable residues in human and animal food
- 4. Insecticides • All neurotoxicants •Nontarget species • Organophosphorous • Carbamates • Pyrethroids • Organochlorine • Other and Old New Insecticides • Rotenoids • Nicotine • Neonicotinoids • Formamidines • Avermectins • Phenylpyrozoles • Diamides • Bacillus Thuringiensis • Insect Repellents • DEET • Picaridin
- 5. Organophosphorous Compounds • Phosphorousdouble bonded to oxygen (P=S, phosphorothio) • Sensitive to hydrolysis • Target esterases & Glutathione S-transferases • A –esterases (paraoxanase) • B-esterases (butylcholine) • Acetyl choline esterase (Hallmark of OP toxicity) • Toxicity of ACE inhibition • Overstimulation of cholinergenic receptors (Symptoms, increased sweating, saliva, brochonconstriction, secretion, miosis, increased gastronintestional motility, diarrhea, tremors, muscular twitching, and various central nervous system) • Reactivation slow depends on dimethoxy>diethoxy>>diisopropoxy
- 6. Organophosphorous Toxicity • Treatment •Atropine – dosage important • Oxime (2-PAM) – none or harmful effect • Diazepam to reduce anxiety • Aging is a factor • Biochemical measurements • RBC AChE and Plasma BuChE • P-nitrophenol in urine for parathion or methyl parathion • 3,5,6 trichloropyridinol –chlorpyrifos or methyl chlorpyrifos • DMP, DEP, DMTP and DETP • Toxicity • Intermediate Syndrome – weakness in muscles • Organophosphate induced delayed polyneuropathy • Tingling of hands and feet, progressive muscle weekness, sensory loss, distal sensory motor axonopathy • Classic example – Ginger Jake Paralysis. Tri-ortho-cresyl phosphate (TOCP) • Caused by NEUROPATHY TARGET ESTERASE • Depending on Aging, treatment can promote or prevent the damage Long term – Developmental toxicity in Children
- 7. Carbamates • Derive fromcarbamic acid • Carbaryl – low tox and Aldicarb – high tox • Inhibit AceE and ButE, rapidly reversible • Symptoms, miosis, urination, diarrhea, salivation, muscle fasciculation • Direct inhibitors of AceE, do not require bioactivation • Atropine treatment • Oximes – aggravate the toxicity • Somecase peripheral neuropathy • Aging do not require • Before OP toxicity –carbamate protection • After OP toxicity - promotion
- 8. Pyrethroids • Extracts ofchrisanthenum cinerariaefolium • Natural one decomposes under light • Acid moiety, ester bond and alcohol moiety • Modify voltage gated sodium channels • Exits in cis and trans form; cis more toxic than trans • Eg: LD50 trans-resmethirin 8000mg/kg cis 100 mg/kg • Type I and Type II ( Cyano group) • Biotransformation • Hydrolysis of ester – CarE (heptatic and plasma) • Oxidation of alcohol moiety – CytP450 • Type II less sensitive to hydrolysis because of cyano group • Type II- bioactivation by CyP450 • Piperonyl butoxide used as synergist; (inhibits CyP450)
- 9. Type II Pyrethroid •Behavioral arousal, aggressive sparing and tremor • T-Syndrome • Disruption of voltage gated sodium channel • Slow the activation( opening) • Stable hyperexcitable state Type I Pyrethroid • Clonic Seizures and choreoathetosis • CS- Syndrome • Presence of cyano group • Prolongs channel opening • Eventually depolarization • GABA gated chloride channels (ivermectin and phenobarbital prevents) • Calcium ATPase and Ca channels, stimulate PKC • Deltamethrin impregnated beds do not pose problems in children • Occupational paresthesia (tingling) • Topical Vit E • Toxic to fish but not birds
- 10. Organochlorine Compounds • DDTand analogs, cyclodienes and hexachlorocyclohexanes • World over, malaria control • Acute – neurotoxic (moderate than OP) • Chronic – Liver and reproductive system • Isomers (p,p’-DDT strongest) • Stored in adipose; slow biotransformation; excreted in bile, urine and milk • Acute effects - motor unrest, spontaneous muscle movement, abnormal susceptible to fear and other stimuli. fine and course tremors and tonic-clonic convulsions • Hyperesthesia and paresthesia • Mechanism: Sodium channel, Na+ K+ and Ca+ ATPase • Phenytoin and calcium gluconate – in animals • Diazepam and phenobarbital –in humans • Potent inducer of P450cyp2b and CYP3A. • Hepatocarcinogenic in mice and rats; lung tumors and adenoma • Possible human carcinogen • Current alternative dimethoxy pp DDT – Similar effects • Picrotoxin toxin binding site
- 11. Hexachlorocyclohexanes and Cyclodienes • Neurotoxic •Lindane –gamma isomer of BHC • Banned Agri but in shampoo • Convulsions • GABA chloride channel • Phenobarbital and diazepam Mirex and chlordecone • Fire ants and leaf eating insects • Hopewell, VA incident • Tremors • Inhibition of Na, K and Mg ATPases and catecholamine intake • Cholestryamine
- 12. Rotenoids • East AsianDerris Plant • High content rotenone • Toxic to fish; fish capture • Blocks NADH-ubiquinone reductase or complex 1 • Increase cardiac rates and respiration depression • Role in Parkinson Disease Models • Protein inclusions and lewy bodies – rotenone model of PD Nicotine • Alkaloid in tobacco plants • Activates NAChreceptors • Nausea, vomiting, muscle weakness and green tobacco sickness
- 13. Neonicotinoids • Nitromethylene, nitroimineand cyanoimine • Targeted towards insect NAChReceptors Formamidines • Structural similar to norepinephrine • Activates Octopamine dependent adenylate cyclase • (OctP receptors same as adrengenic receptors) • Probable human carcinogen • Bradycardia and hypotension • Yohimbine and adrenoceptor antagonists
- 14. Avermectins • Fungal product •Macrocyclic lactones • Veterinary (antihelminitic and antiparistic) • Humans (intestinal worms, river blindness and lymphatic filariasis) • Activate GABA chloride • Interact with -PGlycoprotein Phenylpyrazole • Block GABA-Cl • Glutamate-activated chloride
- 15. Diamides • Activation ofRyanodine receptors (Ca Receptors) • Muscle contraction Bacillus Thuringiensis • Soil microorganism – produce insecticidal protein • Bt spores contain crystals of Cry and Cyt proteins • Insect ingest, protein toxin in midgut and K+influx; high PH, osmotic lysis
- 16. Insect Repellants DEET • BiotransformCYP450 and excreted in urine/ No strong evidence • Lesions in male rats (alpha-2- globulin) • Similar to nikethamide (convulsant) • Inconclusive BBB transport • Recommended • Children: 10% Adults 30% Picaridin • Biotransform hydroxylation and glucuronidation, and excreted in urine • Olfactory receptors
- 17. Herbicides • Capable ofkilling or injuring the plants • Types of herbicides • Preplanting • Preemergent • Postemergent • Contact • Translocated • Relatively Low Acute toxicity except paraquat (contact dermatitis) • Five major class • Chlorophenoxy • Bipyridyl • Chloroacetanilides • Triazines • Phosphomethyl amino acids
- 18. Chlorophenoxy Compounds • 2,4-D;2,4,5 T; and MCPA (different forms of phenoxy acetic acids) • Mimics plant hormone auxin • Produce uncontrollable growth in target plants • Contaminations, TCDD, PCDD • 50: 50 mixture of 2,4-D; 2,4,5 T – Agent Orange (Vietnam War) • Low to acute toxicity; Dogs are more sensitive • Becomes acidic –vomit, moth burning, hypotension, coma • Alkalization of urine and intraven bicarbonate administration • Possible mechanism 1) cell damage 2) Ac-CoA disturbance 3)uncoupling oxidative phosphorylation • Possible Demyleination and degeneration of CNS • Associated with non-Hodgkin lymphoma and soft tissue sarcoma/ no strong evidence • Classified as Group D agent (non classifiable as human carcinogen)
- 19. Bipyridyl Compounds • Paraquat(most concern) • Skin sensitizer • Accumulates in lung and kidney • High concentration in type II and I /Clara cells • Toxicity: Redox cycling; superoxide generation and lipid peroxidation • Stages of lung destruction; destructive phase; proliferative phase and intensive fibrosis • Dexamethasone with PG induction and sodium salicylate in animals • Blue stentching pigment added • Etilogical in Parkinson Disease [Structure similar to MPP+ and MPTP- Similar to rotenone] • Some evidence for neurodegeneration to dopaminergic neurons [dose level not concern to humans] DiQuat No Skin sensitizer; no lung accumulation Kidneys and eyes- free radical mechanism Ocular toxicity
- 20. Chloroacetanilides • Alachlor, Acetochlor,metolachlor and butachlor • Inhibit synthesis of lipids, alcohols, fatty acids and terpenoids • Alachlor – ocular toxicity in Long-Evan Rats – progressive uveal degeneration syndrome • Not observed in mice, dogs or any other rats. • Produce tumors • Basis of weight of evidence – non genotoxic • Probable human carcinogens ( Group B2) • May be species specific • Forms quinone metabolites – radical producers, glutathione scavenger • Current Recommendation for alachlor- likely at high doses but not likely at low doses
- 21. Triazines • Atrazine, simazine,propazine • Inhibition of photosynthesis • Possible clastogenic of atrazine- • Mammary carcinomas in Sprague-dawley rats • Possible endocrine disruption • Atrazine and Simazine (Group 3 by IARC; not classficable to humans) • Atrazine – possible feminization of frogs- endrocine disruption; EPA revisiting
- 22. Phosphonomethyl amino acids Glyphosphate •Inhbition of 5-enol pyruvylshikimate- 3-phosphate • Present only in plants • Group E by EPA( non carcinogen to humans) • Surfactant POEA –possible damage Glufosinate • Inhibit glutamine synthetase • Increase ammonia and glutamine deficiency • dosage at this level not concern to humans • Role of surfactants in toxicity
- 23. Fungicides • Low acutetoxicity to mammals • Oncogenic risk • Banned • Methylmercury – Iraq- grains • HCB – Turkey- black sore, blistering skin, hepatomegaly and immunosupression
- 24. Captan and Folpet •Contains, chlorine, carbon and sulfur • Thiophosgene, a common metabolite • Duodenal tumors in mice • Probable human carcinogens (Category B2) and recently changed to “not likely to be a human carcinogen when used according to label directions” • Resembles thalidoamide
- 25. Dithiocarbamates • Maneb (Mn);Ziram and Zineb (Zn); and mancozeb (Mn and Zn) • Thiram without any metal moiety • Ethylenethiourea (ETU) common metabolite • Thyroid tumors – inhibition of T4 and T3- thyroid hypertrophy • Liver tumors in mice; developmental and teratogenicity in rats • Hind limb paralysis (Carbondisulfide – Ethylene bisthiocyanate-sulfide EBIS) Maneb – associated with Parkinson Maneb with paraquat –potentiation –MPTP –dopaminergic DTC resembles disulfuram – known to increase acetaldehyde levels
- 26. Chlorothalonil • Highly toxicin intraperitoneal and inhalation route • Eye lesions in rabbit and dermal irritation Benzimidazoles • Inhibit microtubule assembly – chromosomal aberrations • Contact dermatitis • Liver, testes, bone marrow and gastrointestional tract • Affect male reproductive system in animals
- 27. Inorganic and organometal •Copper Sulfate • Bordeaux mixture (copper sulfate and calcium hydroxide) • Tributyltin • Antifouling agent • Adverse effect to oyster –banned in 2008 • Triphenyltin • Reproductive toxicity and endocrine disruption Organic mercury removed
- 28. Rotenticides • Effective when •In small dose • No bait shyness • Non-suspious • Species-specific
- 29. Fluoroacetic acid • Alias(Compound 1080 or Sodium Fluoroacetate) • Inhibits krebs cycle and aconitase (Fluorocitrate) • Potent chelator of calcium ions • CNS (agitation, convulsion and coma) and Heart toxicity (ventricular tachycardia, hypotension and fibrillation) • Antidote: glycerol monoacetate (monoacetin) • Procainamide (cardiac arrhythmia) and barbiturates (Seizure)
- 30. Thiourea • ANTU • Toxicityto lung • Edema in subepithelial spaces of aleveolar wall • Binds to lung macromolecules • Human poisonings • Chloralase and ANTU • Impurity - B-naphthylamine – bladder cancer
- 31. Anticoagulants • Spoiled sweetclover silage – hemorrhagic disorder – bishydroxycoumarin (dicoumarol) • Warfarin • Inhibition of Vitamin K epoxide reductase • Antagonize – Vitamin K- prevent clotting factor synthesis (Factor, II, VII, IX AND X) • Rats became resistant and second generation anticoagulants • Superwarfarins Brodifacuom and difenacoum • Indane 1, 3-diones derivaties (dophacinone and chlorophacinone) • Increased blood half-life
- 32. Norbormide • Selective torats • Vasoconstrition • Zinc Phosphide • Phosphine gas • Necrosis of GI and Cyto C oxidase inhibition • Aluminium phosphide • GI, CV and electrolytic imbalance Thallium Sulfate and Arsenic alopecia (hairloss) Strychnine seeds of nux-vomica Antagonize glycine (inhibitory aminoacid) potent convulsant Red Squill (Sea Onion) CV and CNS Pyriminil –withdrawn- Complex I INHIBITION - diabetogenic
- 33. Fumigants • Methyl Bromide •Concern for ozone depletion • Long lasting neuropsychiatric disorders and neurotoxicity • Acute: respiratory, GI and neurologic • Conjugation with GSH • Positive in several genotoxic test • Forestomach carcinoma and pituatry adenoma • IARC group 3 (not classificable as human carcinogen) • Chloropicrin added for pungent smell
- 34. 1,3 Dichloropropene • Irritant •Redness and necrosis of skin • Mercapturic acid – major metabolite • Epichlorohydrin – stabilizing agent
- 35. Metam-Sodium • MITC isthe active product and CS2 • Bladder, kidney and liver • Allergic dermatitis • Irritant, buring of eyes, nose and throat • Alternative of methyl bromide
- 36. Sulfur Compounds • ElementalSulfur – ancient pesticide – grapes and tomato • Too acidic to certain crops • Humans (dermatitis) and cerebrocortical necrosis (cattles) –H2S • Sulfurdioxide (grapes) • Fumigant, antimicrobial, high water soluble and food additive • Sulfuryl fluoride • Structural and storage • Neurotoxicity and microvacuolation in various brains
- 37. No longer inUS • CS2 – neurotoxic • CCl4 – hepatotoxicant • 1,2,dibromo-3-chloropropoane – male reproductive toxicant • Ethylene dibromide – carcinogen