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DEFINITIONSToxicology -science of poisons -study of poisons, side effects & management Poisons - any agent w/c may cause serious body injury, disease or death Intoxication - toxicity associated with any chemical substance Poisoning - accidental exposure Overdosing - intentional exposure with...

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TOXICOLOGY DEFINITIONS Toxicology -science of poisons -study of poisons, side effects & management Poisons – any agent w/c may cause serious body injury, disease or death Intoxication – toxicity associated with any chemical substance Poisoning – accidental exposure Overdosing – intentional exposure with intent of causing self-harm Branches of Toxicology A. Clinical Toxicology -involve Dx and Tx of poisoning -deal with signs and symptoms of poisoning -medical toxicology B.

Experimental Toxicology -investigation of toxic effects of chemicals -LD50 (median lethal dose) -LC50 (median lethal concentration) -used for inhalational preparations -TLV/TLC (Threshold Limit Value/Concentration) -maximum amount of chemical that is safe for household products.

C. Environmental Toxicology -study of environmental poisons -pesticides, insecticides -water tx: facilities (heavy metals) D. Regulatory Toxicology -toxicity testing to provide the necessary information in order to give safety evaluation -FDA E.

Mechanistic Toxicology -studies the mechanism by which the poison exerts its action.

Classification of Poisons according to Risk Effect 1.

Irritants – cause pain and inflammation and even tissue necrosis upon contact (caustics) -ex. acids, alkalis 2. Neurotics – CNS manifestations and effects 3. Carcinogens – stimulate growth of CA cells -ex. industrial poisons 4. Asphyxiants -ex. gases (methane gas, carbon monoxide; incomplete combustion in cars) -dyspnea (DOB)

5. Lacrimators -excessive flow of tears -ex. organophosphates (pesticides) 6. Sternutators -excessive sneezing -ex. veratrime, capsaicin (from chili) 7. Asthenics -produces muscle weakness 8. Narcotics -produces mental weakness & depression -ex. sedative – hypnotics Biologically active poisons Format: Parent compound → Metabolite 1. Parathion → paraoxon (severe parasympathamimetic) 2. Malathion → malaoxon 3. Imipramine (TCA) →despiramine 4. Amitriptyline → nortryptiline 5. Methamphetamine → p-hydroxylamphetamine (shabu) – most widely abused drug in the Philippines 6. Paracetamol → NAPQI (N-acetylparabenzoquinoneimine) 7. Diquat (paraquat) → free radicals (used as herbicide) (reactive O2 species) Cause: ARDS (Acute Respiratory Distress Syndrome; Pulmonary Fibrosis) 8. Ethylene glycol → oxalic acid (anti-freeze formulation in our batteries) 9. Aspirin → salicylic acid 10. Allopurinol → alloxanthine (used in govt) 11. Codeine → morphine (3-methylmorphine; can be P.O.) 12. Cortisone → hydrocortisone (cortisol) (hydrogenation) 13. Acetohexamide → hydroxyhexamide (sulfonyl urea) 14. Phenylbutazone → oxyphenylbutazone 15. Primidone → phenobarbital (common metabolite) →PEMA (phenyl ethyl malonamide) (major metabolite) Anti-convulsions: long-acting. 16. Diazepam → desmethyldiazepam oxazepam (Serax ®) 17. Digoxin → digoxigenin derivatives 18. Meperidine → normeperidine (remove methyl group) 19. Quinidine → 3-hydroxyquinidine 20. theophylline → caffeine (methylation) (1,3 – dimethylxanthine) (1,3,7 – trimethylxanthine)

TOXICOLOGY theobromine (3, 7 – dimethylxanthine) 21. acetonitrile → cyanide ≡N 23. chloral hydrate → trichloroctanol (knock-out drops) 24. ethanol → aldehyde → acetic acide (acetaldehyde) 25. methanol → formaldehyde → formic acid (blindness) 26. isopropyl alcohol → acetone 2° alcohol → ketone 27. prednisone → prednisolone 28. benzyl alcohol → benzoic acid (hippuric acid) Acids and Alkalis Acids – coagulation necrosis (eschar formation) Alkalis – liquefaction necrosis A. Acids 1. HCl (muriatic acid in toilet cleaners) -whitish burns 2. H2SO4 (oil of Vitriol) -brown black burns -bloody vomit (ingested) 3. HNO3 (aqua fortis) -yellow burns 4. phenol (carbolic acid) -bleaching/whitish burns B. Bases 1. NaOH (lye, sosa in drain cleaners) 2. KOH (caustic potash) C. Salts 1. NaOCL (Zonrox ®bleach) – Dakin’s solution 2. PbCrO4 (yellow food coloring at a small/minimum concentration) Microbial and Foodborne Toxins 1. Aflatoxin (Aspergillus flavus) -carcinogenic -improper storage *Nagaraya, Lily’s peanut butter 2. Saxitoxin (Dinoflagellates) -red tide, PSP (paralytic shellfish poisoning) 3. Ptomaine (bacterial decay) – spoiled food, milk, dairy products, cheese tyrotoxicon – rotten putrid cheese; cholera-like symptoms 4. Ergot (Claviceps purpurea) – ergotism, ergotoxicosis ; called St. Anthony’s fire -Tx: Tolazoline, Na nitroprusside (HPN)

Exotoxin G(+) -proteinacosus - ↑ virulence - small doses: lethal

Endotoxin G(-) -lipoidal - ↓ virulence - large doses: lethal

Bacterial Endotoxin Test (BET) LAL (Limulus Amelocyte lysate) -blood extract hormone crab (Limulus polyphemus) -react to bacterial endotoxin -gel dot -turbidimetry -chromogenic Exotoxin 1. Botulinum toxin (C. botolinun) -canned goods -neuromuscular poison 2. Tetanospasmin (C. tetani) -tetanus -tetanus toxoid (prohylaxis) – IM -10 yrs (booster shot) 3. Cytotoxin (C. perfringens) -gas gangrene -complications in diabetic px 4. Enterotoxin (S. aureus) -Food poisoning -heat stable -toxic shock syndrome 5. Diphtheria cytotoxin (Corynebacterium diphtheriae) -Chinese-character like -CHON synthesis inhibitors -nerve, heart, kidnes, cells 6. Cholera enterotoxin (V. cholerae) -rice, water, stool 7. Escherichia enterotoxin (E. coli) -ETEC (Enterotoxigenic E. coli) -traveller’s diarrhea -rice, water, stool Endotoxin 1. Typhoid (Salmonella typhi) -raw, uncooled, improperly cooked chicken -typhoid fever -DOC: chlorampenicol (old) ceftriaxone, ciprofloxacin (new) 2. Proteus (Proteus spp.) – UTI

TOXICOLOGY Animal Toxicology / Poisonous Animals ZOOTOXIN 1. Chironex toxin 2. Spingomyelinase D (neurotoxin) 3. Latrotoxin

4. CHlorotoxin (neurotoxin) 5. Apitoxin

6. Hyaluronidase 7. Gila monster venom (neurotoxin)

8. Batrachotoxin

9. Cantharidin

10. Clupeotoxin

11. Scombroid toxin

12.Ciguatoxin

SOURCES -box jellyish -Chironex fleckeri -brown recluse spider -Loxosceles reclusa -black widow spider -Lactrodectus mactans - red, hourglass shape - scorpion - Centuroides sculpturatus -bees & wasps - Apis mellifera -anaphylactic vaccines -snakes -Heloderma sp. -Exenatide (for diabetes) -only poisonous lizard (SW USA, New Mexico) -amphibians -poison dart frog -blistering flies Uses: -aphrodisiac -local irritants Manifestation: blisters -anchovies, herring sardines -sharp metallic taste -abdominal pain, diarrhea -45% fatality -tuna (saurine) -mackerel (gemblid) - confused w/ MSG rxns (chinese restaurant syndrome) -Gambierdiscus toxicus (dinoflagellate) -ingested by coral reef fishes

Tx -5% vinegar -wash w/ sea water -steroids

-antivenom -Ca gluconate

13. Holothurin 14. Conotoxin 15. Neurotoxin 16. Tetrodotoxin 17. Maculotoxin

-most common poison from ingested fish -sea cucumbers -contact dermatitis -cone snail -Ixodes ticks -puffer fish -blue-ringed octopus

Plant Toxicology

-barbiturates, IV antivenom -epinephrine (IM) -diphenhydramine

-antivenom

-barbiturates -diazepam (convulsion)

1. Abrin – Rosary pea – “Jequirty bean” 2. Aconitine – Monkshood – Aconitum sp. 3. Atropine – deadly nightshade – Atropa belladona tx: physostigmine 4. Digitalis glycosides: -Digitoxin -Digoxin *Foxglove – Digitalis purpurea; D. lanata 5. Cytisine – Golden chain tree – Laburnum anagyroides 6. Oleandrin – oncrioside – toxic digitalis – Nerium oleander 7. Amygdalin – cyanogenic glycoside – cherry, almonds, pear pits – Prunus spp. 8. Ricin – Ricinus communis – Castor bean (tangan-tangan) 9. Sanguinarine – blood root – Sanguinaria candensis 10. Taxine – Japanese yew – Taxus cuspidata 11. Arecoline – betel nut (nganga) – Areca catechu 12. Brucine, Strychnine –Nux vomica 13. Picrotoxin –fish berries –Anamiria cocculus 14. Myristicin –nutmeg –Myristica fragrans 15. Cicutoxin – water hemlock – Cicula maculata 16. Hemlock – Conium maculatum – Coniine (toxic principle) – Socrates died of hemlock overdosing (intentional) 17. Colchicine – used for gout – Autumn crocus – Colchicum autumnale

TOXICOLOGY 18. Con vallarin –Lily of the Valley –Convalaria majalis 19. Andromedotoxin, Grayanotoxins –Mountain laurel –Kalmia latifolia –Wolff-Parkinson-White Syndrome: –disorder of conduction system of heart; very short PR intervals 20. Lycorine: oxalates – Daffodil – Narcissus sp. 21. Podophyloresin – May apple – Podophyllum peltatum 22. Oxalic acid & Anthraquinones – Rhubarb (Rheum rhabarbarum) – Boston Ivy (Parthenocissus tricuspidata) 23. Urushiol – Poison ivy – Toxicondendron radicans 24. Robitin, Robin – black locust – Robinia pseudoacacia 25. Solanine – Solanum family – Solanum nigrum (black night shade) 26. Veratrine – false hellebore, corn lily – Veratrum viridae 27. Physostigmine – Calabar bean – Physostigma venenosum 28. α – cumanitin – Amanita mushroom – Amanita phalloides 29. Manihotoxin – cassava – Manihot esculenta – cyanogenic glycoside Mushroom Poisoning Toxin Group I. Cyclopeptides: Amanitoxin Pallotoxins -violet vomiting, diarrhea, abdominal pain -failure: kidney & liver -coma --> death -tx: penicillin, silibinine (hepatoprotective agent) II. Gyramitrin ex. Monomethylhydrazine (MMH) - bloating, N/V, diarrhea -liver toxicity -dizzy, lethargic feeling -tx: pyridoxine, methylene blue for methemoglobinemia III. Orellanise -renal damage -N/V, abdominal pain, diarrhea -frequent urination, burning thirst -tx: activated charcoal, hemoperfusion IV. Muscarine -“PSL” symptom – perspiration, salivation, lacrimation -N/V diarrhea -blurred vision

-urge to urinate -tx: atropine (prototype anti-muscarinic drug) V. Ibolenic Acid, Muscinol -alcohol intoxication-like symptoms -unable to walk, drunken gnit -confusion -sleep: vivid dream -tx: phycostigmine VI. Caprine (Antabuse ®-like reaction) (Disulfiram ®-like reaction) -hot flushes -metallic taste -tingling sensation -Metronidazole, Cefoperazone, Cefoletan, Cetamandole, Tolbutamide (disulfiram-lik reactions), Griseofulvin (administered w/ fatty meds) -tx: dopamine, NE for hypotension VII. Psilocybin & Psilocin -magic mushrooms -hallucination, euphoria, disembodied experience -tx: diazepam (long-acting benzodiazepine) – Valium ® VIII. Unclassified mushroom poisons -immediate gastric upset w/n 30-90 mins Inorganic poisoning Summary: Group I, II, III – cause extensive cellular damage Group IV, V – affect autonomic system Group VI, VII – affect CNS Group VIII – unclassified Other Inorganic Poisons 1. Beryllium – most toxic metal –respiratory system –lung carcinoma –chronic granuloma 2. Gold – contact dermatitis 3. Barium – xray of radiopaque medium – Baritosis (hoarse, lowered voice, loss of voice) 4. Iodine – Iodism – metallic taste, GI distress, skin weeping and crusting, similar to corrosives –tx: starch (to form iodo-starch complex: non toxic) 5. Silver – Argyria – protein precipitant -tx: NSS (NaCl) --> AgCl 6. Nickel – contact dermatitis – present in fancy jewelries – Nickel HCN 7. Antimony – similar to Arsenic poisoning – cause MI – stable gas w/ acid if heated 8. Magnesium – flaccid paralysis –tx: CaCl2, hemodialysis (↑ serum level) 9. Uranium – some deodorant formulation –granulomas

TOXICOLOGY 10. Cadmium – itai-itai 11. Copper – Wilson’s 12. Aluminum – Shaver’s 13. Mercury – Minamata Clinical Signs and symptoms of Poisoning 1. breath odor a.) sweet, penetrating odor -acetone, isopropanol, salicylates, diabetic ketoacidosis b.) airplane glue -toluene, aromatic hydrocarbons c.) bitter almonds -cyanide (silver polish odor) -cherry poisoning -apricot pits poisoning d.) carrot-like odor – cicutoxin of hemlock e.) disinfectant odor -phenol, cresole f.) foul – bromine, lithium g.) garlic -arsenic, DMSO, parathion, malathion, yellow phosphorus, selenium, tellurium, zinc phosphide h.) pear – chloral hydrate, paraldehyde i.) shoe polish -nitrobenzene poisoning j.) stale tobacco -nicotine k.) alcohol -chico, fruit odor -ethanol l.) urine – ammonia m.) bleach – hypochlorite (NaOCl) n.) coal gas – carbon monoxide o.) mouse urine – coniine p.) burnt rope odor – marijuana (hemp) q.) peanuts – Vacar ® (Pyrinuron rodenticide) r.) rotten egg odor – H2S, disulfiram, NAC s.) wintergreen odor – salicylate (methlysalicylate) 2. Skin appearance a.) acne form – Br, I, Li, steorid b.) black – chloramphenicol, Ag, Bi c.) blue / cyanosis -aniline, opium sulfides, methylene blue, oxalic acid d.) ash gray - phenol (carbolic acid) e.) bronze - As, Arsine gas f.) hirsutism -androgens, corticosteroids, diazoxide -excess hair growth g.) SJS – Stevens-Johnson Syndrome -amoxicillin, carbamazepine, sulfa drugs, erythromycin, phenobarbital, phenylbutazone

h.) alopecia -heavy metal -As, Au, Pb, Li, Hg, Th, Se i.) yellow-brown -Br, Cl, dinitrobenzene, picric acid, TNT (trinitrotoluene), cresol, phenol j.) dry & flushed -ethanol intoxication -antihistamines -anticholinergics k.) boiled lobster -boric acid l.) green -copper m.) keratinization -Th, As n.) jaundice (yellow skin) -liver toxicity -chlorinated HC, As, Au, Fe, P, aniline, hemolytic substance 3. gastric contents (thru endoscopy) a.) blue green -boric acid, Cu Salts, Ni, Iodine + starch complex b.) luminous -phosphorus, arsenic c.) brown -iodine, sulfuric acid (ground coffee) d.) pink - ethenlorugnol (elacidyl ®) 4. Bowel changes a.) black -Bi, charcoal, Fe, Pb, MgO, AgNO3 b.) clay-like -alchol, Ba c.) white -Al(OH)3 d.) blue -boric acid, methylene blue e.) green -indomethacin, Fe, CuS04 f.) red -hemolytic substances 5. Other changes a.) muscle twitching, loss of voice -baritosis, Ba b.) lock-jaw -strychnine c.) violent sneezing -veratrine d.) loose teeth -Hg, Pb, P e.) bleeding gums -As, Hg f.) blister formation -contharidin g.) gumline discoloration -blue: Bi, Pb

TOXICOLOGY -black: Hg, As Chemical Tests 1. Bellstein -halogens -VR: green plane due to formation of copper hallide -cannot detect flourine 2. Benzoldt Gumming Test -acetone -VR: indigotine (indigo casemine) 3. Bromine water - aniline - VR: flesh ppt. (tribroaniline) 4. Brown ring test -nitrities, nitrates -VR: brown ring at the interface -false positive: bromine + iodine 5. Lieben’s iodoforom -methanol (vs. ethanol) -VR: formation of yelow ppt. (Ch3Cl) 6. Marquis ______ - commonly abused drugs -ecstacy – dark purple/ black coloration -amphetamine & methamphetamine -orange to brown coloration -propoxyphene: dark purple/black coloration -heroin & opiates: pink to purple -aspirin: red coloration 7. Marsh test -arsenic -VR: mirror-like ppt. soluble in NaOCl -false positive: Sb (mirror-like ppt but insoluble in NaOCl) 8. Reinsch -VR: dark coating on strip -heavy meatals: Sb, As, Bi, TC, sulfides VR: silver coating (Hg: needs confirmation via AAS) 9. Modified Duguenois -marijuana -VR: red coloration in TLC plate -tetrahyrdrocannabinols (THC) 10. Nessler’s test -Potassium Mercuric Iodide (component) -Chloroform (vs. chloral hydrate) -VR: yellow ppt. (iodoform) -also a test for ammonia 11. Phenylisocyanide test -nitrobenzene -if added with ChCl3 --> aniline (very irritating odor) 12. KI test -mercury -VR: orange ppt. w/c dissolves in excess KI (Valser’s rgt: orange solution) 13. Scerer -phosphorus -VR: black ppt. on paper strip (-) several black spots

14. Mitscherlich -phosphorus -VR: phosphorescence 15. Picrate test -HCN (prussic acid) -VR: yellow to brick red ppt. 16. Schonbien-Pagenstecher Test -VR: blue to bluish-green in guiac upper paper 17. Tollen’s test -reducing substances -VR: silver mirror 18. Xanthogenate -CS2 -VR: evolution of H2S gas (rotten egg odor) 19. AAS -heavy metals (ppt: CHONS) Medical Toxicology 1. Salicylates (salicylism) -tachypnea, hyperventilation (CO2 is exhaled, ↓ carbonic acid in the body --> respiratotry alkalosis --> metabolic acidosis (severe) -in children with viral infection: Roye’s syndrome -tx: glucose (for CNS hypoglycemia) vit. K or fresh frozen plasma (bleeding) urinary alkalinization – NaHCO3 hemodialysis 2. Acetaminophen / Paracetamol -major toxic metablite: NAPQI -hepatotoxicity (10-15g/day) -tx: NAC (Fluimucil ®) – replenish gluthathione 3. Chloramphenicol -gray baby syndrome -GI disturbance -anorexia -hypotension -cyanosis -due to absence of enzymes for glucoronidation -tx: activated charcoal, hemoperfusion 4. Vancomycin -red-man syndrome (used for) -clindomycin -induced pseudomembranous colitis 5. Digoxin -Digitalis spp. -heart, CNS, GI -hypokalemia, hypomagnesemia, hypercalcemia -tx: Digibind, Gigoxin Immune Fab, Cholestyramine -syrup of pecac (emetic) 6. Succinylcholine & Pancuronium Bromide -malignant & hyperthermia (DOC: Dantrolene) -tx: epinephrine – for anciphylaxis -: neostigmine – increase Ach 7. methylxanthine -caffeine, theophylline, theobromine -tx: oral activated charcoal

TOXICOLOGY -β blockers: for tachycardia 8. Lithium -for manic and bipolar disorders -GI upset, fire lava tremors (S/Sx) -tx: NSS, infusion, osmotic diuretics, hemodialysis 9. anti-depressants a.) TCA – anticholinergic b.) SSRI – milder TOA - agitation, drowsiness, confusion -tx: oral activated charcoal BDZ – for seizures ex. Diazepam (Vallium®) 10. Isomazid -NIV, sluured speech, seizure, lactic acidosis -tx: NaHCO3 11 β- blockers – “-olol” -bronchoconstriction *Nadolol *Sotalol *Timolol *Propranolol *non-selective 12. Calcium Channel blockers - “-dipines” -pulmoary edema (Verapamil) -tx: glucagon, CaCl2 13. Potassium - ↑K : hyperkalemia -S/Sx: cardiac irritability, peripheral weakness, systole -tx: CaCl2 (antagonize cardiac effects) glucose + insulin – shift K+ intracellularly SPS (sodium polystyrene sulfonate) cation exchange resis hemodialysis AntidoteS 1. Physiologic antidotes -acts on different sites or receptors -produce opposite effect of poison -atropine: organophosphate -physostigmine: atropine 2. Chemical antidotes -changing the chemical nature/structure of the poison -Na thiosulfate: cyanide -converts cyanide to SCN-Na Calcium edetate (NaEDTA) -chelation of metals 3. Mechanical antidote a.) gastric lavage -CI: hydrocarbon distillates corrosives convulsions b.) emesis -syrup of ipecac -apomorphine (for systemic) -CI: < 6 months of age HC distillates corrosive

unconscious/coma c. catharsis -saline cathartics -castor oil -CI: corrosive d. whole bowel irrigation -used for poorly absorbed drugs -slow-released reparation -body packers e. alteration of urine pH -acidic drug – urinary alkalinization: NaHCO3

-basic drug – urinary acidification: NH4Cl f. adsorption -activated charcoal -ineffective: alcohol, HC distillates, corrosives, metals 4. Extracorporeal Methods a. hemodialysis: -indications: acid-base disturbance electrolyte imbalance intensive care patients overhydration uremia b. hemoperfusion – cannot correct fluid electrolyte imbalance - for highly bound toxins *px w/ decreased mental status 1. *50 mL – 50 L dextrose (adults) *1 ml/Kg (children) *hypoglycemia 2. thiamine 100 mg IV push -for Wernicke-Korsakoff 3. Naloxone 0.4-2mg IV push -opiod ingestion Antidotes 1. Acetylcysteine 2. Amyl nitrite KA: amyl nitrite, NA nitrite, NA thiosulfate 3. Atropine 4. Benztropine

5. Benzylpenicillin 6. Ca gluconate

7. Ca disodium EDTA 8. dantrolene

9. Deferoxamine (Desferral®) 10. diazepam 11. dicobalt edetate

Indications Paracetamol, CCl4 cyanide

cholinergic syndrome dystonia (sustained muscle contractions) – neurological + movement disorder amanita phalloides poisoning hydrofluoric acid, fluorides, hyperkalemia, hypermagnesemia lead malignant hyperthermia, neuroleptic malignant syndrome iron seizures, convulsions CN-, acrylonitrile

TOXICOLOGY 12. digoxin antibody fragment/Digibind 13. dimercaprol 14. ethanol 15. flumazenil 16. Polinic acid/leucovorin

17. glucagon 18. isoprenaline

19. methylene blue 20. Methionine - converted to glutathione in liver 21. naloxone, naltrexone 22. neostigmine 23. oxygen 24. penicillamine 25. phenzolamine 26. phytomenadione (vit. K) 27. pralidoxime 28. procyclidine 29. protamine sulfate 30. prussian blue 31. pyridoxine 32. Na nitrate, Na thiosulfate

digoxin, oleandrin arsenic, gold, copper, inorganic Hg, lead methanol, ethylene glycol benzodiapine folid acid antagonist: methotrexate, trimethopri...