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Clinical and Forensic Toxicology

Clinical and Forensic Toxicology. Roger L. Bertholf, Ph.D. Associate Professor of Pathology Chief of Clinical Chemistry & Toxicology. Toxicology Disciplines. Industrial Toxicology Toxic exposures in the workplace Product testing Molecular Toxicology Veterinary Toxicology

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Clinical and Forensic Toxicology

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  1. Clinical and Forensic Toxicology Roger L. Bertholf, Ph.D. Associate Professor of Pathology Chief of Clinical Chemistry & Toxicology

  2. Toxicology Disciplines • Industrial Toxicology • Toxic exposures in the workplace • Product testing • Molecular Toxicology • Veterinary Toxicology • Environmental Toxicology • Clinical Toxicology • Forensic Toxicology

  3. Clinical Toxicology • The branch of toxicology that is concerned with human poisoning • Drug overdoses • Pharmaceuticals • Drugs of abuse • Toxic exposures • Environmental • Occupational • Accidental

  4. The Top Ten Poisoning. . . Exposures Deaths • Cleaning Products • Analgesics • Cosmetics • Plants • Cough/Cold Preparations • Hydrocarbons • Bites • Topicals • Foreign Bodies • Chemicals • Antidepressants • Analgesics • Sedative/Hypnotics • Street Drugs • Cardiovascular Drugs • Alcohols • Fumes • Chemicals • Asthma Medications • Cleaning Products

  5. Pharmacokinetics Peak plasma concentration Plasma drug concentration t1/2   Time 

  6. Pharmacokinetics Summary

  7. Pharmacokinetics Summary

  8. Pharmacokinetics Summary

  9. The Autonomic Nervous System Sympathetic (Thoracocolumbar) Norepinephrine Parasympathetic (Craniosacral) Acetylcholine Muscarinic Nicotinic   GI Vascular smooth muscle 1 2 Cardiovascular Smooth muscle Insulin release Gluconeogenesis

  10. Cholinergic Poisoning • Organophosphates, some mushrooms (Group III, clytocybe and inocybe species), betel nuts, pilocarpine, carbachol, acetylcholine • Miosis, vasodilatation, bronchial secretions, bradycardia, increased bowel motility, urination, sweating • Mnemonic: DUMB BELS (Diarrhea, Urination, Miosis, Bradycardia, Bronchorrhea, Emesis, Lacrimation, Salivation) • Atropine + pralidoxamine is antidote • Laboratory monitors AChE activity

  11. Anticholinergic Poisoning • Belladonna, Jimsonweed, antihistamines, phenothiazines, certain mushrooms (Group V), scopolamine, tricylics, OTC sleeping pills • Mnemonic: Red as a beet, dry as a bone, mad as a hatter, hot as a stone, bowel and bladder lose their tone, and the heart runs alone. • Physostigmine is antidote

  12. Sympathetic Poisoning • : vasoconstriction, pupillary dilitation, coronary artery dilitation, decreased bowel motility, bladdar contraction • 1: tachycardia • 2: smooth muscle dilatation, insulin release, lipolysis, renin release, gluconeogenesis (miosis, vasodilatation, bronchodilatation, hyperglycemia, decreased bowel motility, bladder relaxation)

  13. Nicotinic Poisoning • Insecticides, tobacco, black widow spider venom • Tachycardia, hypertension, muscle fasciculations, weakness, paralysis • d-turbocurarine is antidote

  14. Ethanol • Most common (by far) toxic exposure • Often associated with: • Trauma • Loss of consciousness • Other drug exposure • Frequently involves medico-legal interventions

  15. Ethanol Pharmacodynamics Loss of consciousness Staggering gait CNS impairment  Slurred speech Blood alcohol concentration (mg/dL, %) Impaired motor coordination Loss of inhibition 0 0.05 0.10 0.15 0.20 0.25 0.30 0.35

  16. Ethanol distribution Cells 82% H2O Serum 95% H2O EtOH Serum (or plasma) ethanol is 5 – 15% higher than whole blood ethanol

  17. Enzymatic Ethanol Methods • ADH is selective, but not specific for ethanol • Other enzymes that involve NADH can potentially interfere

  18. Non-ethanol Alcohol Poisoning • Alcohol toxicity is primarily related to metabolites • Ethanol  Acetaldehyde  Acetate • Isopropanol  Acetone • Methanol  Formaldehyde  Formic acid • Ethylene Glycol  Oxalate and Hippuric acid • Non-ethanol alcohol exposures can be detected by an increase in the osmol gap

  19. The Osmol Gap Calculated Osmolality:

  20. The Osmol Gap • Colligative properties depend on the number of of dissolved particles • Boiling point • Freezing point • Osmolality is usually determined by freezing point depression • The difference between the calculated and measured osmolality is the Osmol Gap

  21. The Osmol Gap

  22. Osmol Gap Mnemonic Methanol Ethanol Diuretics (glycerol, mannitol, sorbitol) Isopropanol Ethylene glycol

  23. Analgesic Poisoning Exposures Fatalities

  24. Salicylate Poisoning • Toxic symptoms develop at serum concentrations exceeding 250 mg/L • Serum concentrations exceeding 1000 mg/L can be fatal • Symptoms are tinnitus, hyperventilation, respiratory failure, convulsions, coma • Lab results reveal mixed metabolic acidosis/respiratory alkalosis • Acidification of urine enhances elimination

  25. Acetaminophen Poisoning • Toxic symptoms develop at serum concentrations exceeding 100 mg/L • Serum concentrations exceeding 450-500 mg/L result in severe liver damage • Symptoms may not appear until hepatic failure is evident and irreversible • Antidote is N-acetylcysteine

  26. Acetaminophen Metabolism

  27. Carbon Monoxide Poisoning • Can be deliberate or accidental • CO is odorless • CO binds irreversibly to hemoglobin, displacing oxygen • CO-Hb (carboxyhemoglobin) can be measured on a co-oximeter • Different max than O2-Hb (oxyhemoglobin) • Hyperbaric oxygen may be indicated

  28. Metal Poisonings • Iron is most common (particularly in kids) • Ferritin • Deferoxamine is antidote • Arsenic is most notorious • Acute vs. chronic • Inorganic vs. arsine gas • BAL (dimercaprol) is antidote

  29. Metal Poisonings • Lead • Most cases in children exposed to lead paint • Blood lead >10 g/L is considered risk • Monitor with -aminolevulinic acid dehydratase • EDTA is antidote • Mercury • Organic vs. inorganic • Neurotoxic, nephrotoxic, teratogenic

  30. Spot Tests for Metal Poisoning • Reinsch Test: Copper wire turns. . . • Shiny silver: Mercury • Dull black: Arsenic • Shiny black: Bismuth • Dark purple sheen: Antimony • Gutzeit test for arsenic • Acidification produces arsine gas, which discolors silver nitrate paper • Iron reacts with potassium ferricyanide and ferrous sulfate to produce Prussian Blue

  31. Thin Layer Chromatography

  32. TLC Stains • Ninhydrin: 1o or 2o amines (sympathomimetics) • Mercuric Sulfate: barbiturates, glutethimide, phenytoin (white ppt) • Diphenylcarbazone: same as mercuric sulfate (blue or purple spot) • Iodoplatinate: 3o amines • Dragendorf's reagent: methaqualone • UV absorption at 254 nm: benzodiazepines, barbiturates, methaqualone • Fluorescence at 366: Benzodiazepines, quinine, quinidine

  33. Patient consent not required Identity of specimen is presumed Screening result is sufficient for medical decision Results are used for medical evaluation Subject must consent to be tested Identity of specimen must be proved Only confirmed results can be considered positive Results are used for legal action Medical vs. forensic drug testing

  34. Illegal Drug Use in the U.S.(1998 Household Survey) • 13.6 million Americans use illicit drugs • 25 million in 1979 • 8.3% of youths age 12-17 use marijuana • 14.2% in 1979 • 1.8 million Americans use cocaine • 5.7 million in 1985

  35. Types of drugs used

  36. History of workplace drug testing • 1960s – 1970s: The Department of Defense begins testing military personnel for illegal drug use. • 1986: President Reagan establishes the “Federal Drug-Free Workplace”. • 1988: Mandatory Guidelines for Federal Workplace Drug Testing Programs is published in the Federal Register.

  37. The “NIDA” program • NIDA (now SAMHSA) requirements for drug testing were drafted by Research Triangle Institute • The RTI established the National Laboratory Certification Program (NLCP) • Drug testing for federal agencies (DOT, NRC, etc.) must be performed in a NLCP-certified laboratory

  38. Florida Drug-Free Workplace • The Florida HRS (now AHCA) established a drug-free workplace program in 1990 • Specifications for the State of Florida program are similar to federal requirements, but there are notable differences • Employees of Florida Drug-Free Workplace-compliant businesses must be tested in AHCA-licensed laboratories

  39. Low cost Fast Semi-quantitative High sensitivity Low specificity High cost Slow Quantitative High sensitivity High specificity Screening vs. Confirmation

  40. A confirmatory method should . . . • Utilize the most accurate (specific) testing method available • Have sensitivity equal to or better than the screening method • Be economically feasible • Be simple enough to standardize across many laboratories • Produce results that are legally defensible

  41. GC/Mass Spectrometry Detector Injector Ionizer Mass Filter GC Column Data System

  42. Focusing lens From GC + + To MS + Ion volume (or source) (-) Electron impact ionization Power supply Filament e- e- Collector (+)

  43. Direction of current Direction of magnetic field The “Right Hand Rule”

  44. From ion source + To detector Magnetic sector mass spectrometer

  45. From ion source + To detector Quadrupole mass spectrometer

  46. From mass filter e- 104 e- + Ammeter Electron multiplier Negative dynode Positive dynode

  47. Mass spectrum

  48. Full scan time = 1.0 sec (0.002 sec/ion) 0.1s Single ion monitoring (SIM) m/z Time 

  49. Cocaine C17H21NO4 MW=303.35

  50. 82 (base peak) 182 [M-121]+ 303 (M+) 121 [M-31]+ 272

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