toxicology

• Toxicology


  The study of substances introduced exogenously
• Steps in toxicology

  1. Detect the presence by doing qualitative tests

  2. If positive for detection, measure the concentration of the toxic substance in body fluid using quantitative methods
• 4 major disciplines in toxicology

  • Mechanistic toxicology
  • Descriptive toxicology
  • Forensic toxicology
  • Clinical toxicology
• Mechanistic toxicology


  • Elucidates the cellular and biochemical effects of toxins
  • Provides basis for rational therapy design and development of tests to assess the degree of exposure of poisoned individuals
• Descriptive toxicology


  • Uses results from animal experiments to predict what level of exposure will cause harm in humans
  • aka risk assessment
  • Provides basis for determining whether a substance is beneficial or harmful to man
• Forensic toxicology


  • Concerned with the medico legal consequences of toxin exposure
  • Focus on establishing and validating the analytic performance of the methods used to generate evidence in legal situations including cause of death
• Clinical toxicology


  • Study of interrelationships between toxin exposure and disease states
  • Emphasize not only in diagnostic testing but also therapeutic intervention
• Routes of exposure to toxins

  • Ingestion
  • Inhalation
  • Transdermal absorption
• Oral dosage


  • ED 50 - Effective dose 50
  • TD 50 - Toxic dose 50
  • LD 50 - Lethal dose 50
• Therapeutic index

  Ratio of TD 50 to ED 50
• Acute and chronic toxicity

  • Acute toxicity - Single, short-term exposure
  • Chronic toxicity - Repeated, frequent exposure from extended periods
• Alcohol is a common CNS depressant that can cause disorientation, euphoria, confusion and may progress to unconsciousness, paralysis and even death
• Symptoms of alcohol intoxication begin when the concentration is > 0.05% w/v (>50 mg/dl blood alcohol)
• Ethanol (Grain Alcohol)


  • Most commonly abused drug
  • Most ethanol is converted to acetic acid
  • Methods: enzymatic (AD), GLC and osmometry
  • ↑ in GTT, AST, AST/ALT ratio (>2.0), HDL and mean corpuscular volume
  • Detection limit: 12 hours
  • Toxic blood levels: 250-400 mg/dl
  • Fatal dose: 300-400 ml of pure alcohol consumed in less than one hour
• Methanol


  • Commonly used solvent and a contaminant of homemade liquors
  • Converted first to formaldehyde, then finally to formic acid in the liver
  • Fatal dose: 60-250 ml
• Isopropanol (Rubbing Alcohol)


  • Metabolized to hepatic ADH to acetone
  • Fatal dose: 250 ml
• Ethylene Glycol (1,2 Ethanediol)


  • Common constituent of hydraulic fluid and antifreeze
  • Converted to oxalic acid and glycolic acid
  • Production of final products leads to deposition of calcium oxalate crystals in renal tubules
  • Fatal dose: 100 grams
• Carbon Monoxide (CO)

  • Produced by incomplete combustion of carbon-containing substances like gasoline engines, organic materials in fire and cigarette smoke
  • Colorless, odorless, tasteless gas; very toxic substance
  • Toxic effects are manifested by binding with heme proteins (cytochromes, myoglobin and hemoglobin)
  • Has higher affinity for hemoglobin than does oxygen- impairs oxygen transport by binding to hemoglobin producing carboxyhemoglobin
  • Inhibits cellular respiration and electron transport
  • Net effect: tissue hypoxia
  • Indicator: "cherry-red" color of the face
  • Sample: EDTA whole blood
  • Method: CO-oximetry
  • Toxic level: 20%CO
• Arsenic


  • Component of ant poisons, rodenticides, paint and metal alloys
  • Comicide or suicide agent; common agent of heavy metal poisoning
  • Exposure to this chemical occurs in smelting industries and agriculture
  • Expresses its toxicity by high affinity binding to the thiol groups in proteins
• Cadmium


  • Utilized in electroplating and galvanizing
  • A significant environmental pollutant; pigment in paints and plastics
  • Poisoning can result to ↓ of type 1 epithelial cells in the lung and decreased resistance to bacterial infection
• Lead


  • A component of household paints and a potent enzyme inhibitor
  • Combines with the matrix of bone and can persist in this area for a long time
  • Exposure results to encephalopathy, birth defects and compromised immunity
  • Low-level exposure may cause behavioral changes like hyperactivity and attentional deficit disorder, and also affect intelligence quotient scores (decrease)
  • Toxicity dose: > 0.5 mg/day
  • Fatal dose: 0.5 g
  • CDC cutoff for normal lead in children: < 10 ug/dl
  • Toxic blood levels: > 70ug/dl (definitive lead poisoning
  • Methods: Graphite furnace AAS (children), Inductively coupled plasma emission spectrophotometry (ICPES, anodic stripping voltammetry), Zinc protoporphyrin or free RBC protoporphyrin test
• Mercury


  • Binds with proteins and also an enzyme inhibitor
  • Has the ability to "amalgamate"
  • Small drops of mercury on benchtops and floors can poison the environment in a poorly ventilated room
  • Presence of this substance in blood may result to loss of glomerular integrity
  • Samples for testing: whole blood (organic mercury) and urine (inorganic mercury)
  • Method: Reinsch test
• Amphetamines


  • For treating narcolepsy and attentional deficit disorder
  • ↑ the mental alertness and physical capacity, and has anorectic property
  • Structurally related to dopamine and catecholamines
  • 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') is a derivative of methamphetamine and a popular recreational abused drug
  • Hyperpyrexia (↑ body temp) is a sign of acute intoxication
  • Toxic effects: hypertension
• Zinc protoporphyrin or free RBC protoporphyrin test


  Useful to assess blood concentration of lead
• Mercury


  • Binds with proteins and also an enzyme inhibitor
  • Has the ability to "amalgamate" (mix or merge with other substances)
  • Small drops of mercury on benchtops and floors can poison the environment in a poorly ventilated room
  • Presence of this substance in blood may result to loss of glomerular integrity
• Samples for testing


  Whole blood (organic mercury) and urine (inorganic mercury)
• Method


  Reinsch test
• Amphetamines


  • Used to treat narcolepsy and attentional deficit disorder
  • Increases mental alertness and physical capacity, and has anorectic property
  • Structurally related to dopamine and catecholamines
  • 3,4-methylenedioxymethamphetamine (MDMA or 'ecstasy') is a derivative of methamphetamine and a popular recreational abused drug
  • Hyperpyrexia (increased body temp) is a sign of acute intoxication
  • Toxic effects: hypertension, cardiac arrhythmias and convulsions, pancytopenia
• Anabolic Steroids


  • Chemically associated with the male hormone testosterone (dihydrotestosterone and testosterone)
  • Improves athletic performance by increasing muscle mass
  • Toxic effects: Chronic hepatitis, atherosclerosis, abnormal platelet aggregation and cardiomegaly
• Cannabinoids


  • Naturally occurring cannabinoids are marijuana and hashish
  • Tetrahydrocannabinol (THC) is the most potent, competent or the psychoactive substance of marijuana
  • THC is associated with impairment of short term memory and intellectual functions
  • After a single use, THC-COOH can be detected in urine for 3-5 days; up to 4 weeks for chronic user
  • Urinary metabolite: 11-nor-delta tetrahydrocannabinol (THC-COOH)
  • Physiologic effects: reddening of the conjunctiva and tachycardia
• Cocaine (Crack)


  • An alkaloid salt that can be taken directly (insufflation of IV) or by inhalation
  • Derived from coca plant (Erythroxylon) and used as additive to some foods
  • Potent CNS stimulant that elicits a sense of excitement and euphoria; increases physical activity
  • Easily pass the placenta and mammary glands
  • Classically has not been considered as an addictive drug
  • Prozac is used to inhibit the action of this illicit drug
  • Single use; Can be detected in urine for up to 3 days; up to 20 days for chronic users
  • Toxic effects: hypertension, arrhythmias, seizures and myocardial infarction
  • Urine metabolite: benzoylecgonine (sensitive and specific indicator)
• Opiates


  • Capable of analgesia, sedation and anesthesia
  • Derived chemically from opium poppy
  • Naturally occurring substances: Opium, morphine and codeine
  • Chemically modified form of opiates: Heroin, hydromorphone (Dilaudid) and oxycodone (Percodan)
  • Common synthetic opiates: meperidine (Demerol), methadone (Dolophine), propoxyphene (Darvon), pentazocine (Talwin) and fentanyl (Sublimaze)
  • Heroin is highly addictive; morphine is a powerful analgesic; codeine is antitussive
  • Morphine binds to mu-receptors in the limbic system (CNS) producing analgesic effect
  • Morphine and meperidine increase liver and pancreatic enzymes
  • Methadone is a nonbicyclic drug that binds with morphine in the brain
  • Darvon overdose combine with alcohol is a major cause of drug-related death
  • Morphine and codeine are substances commonly tested
  • Major metabolites: N-acetylmorphine (heroin) and morphine
  • Antagonist for opiate overdose: naloxone (narcan)
  • Toxic effects: respiratory acidosis, myoglobinuria and cardiopulmonary failure
• Therapeutic Drug Monitoring (TDM)


  • Involves the analysis, assessment and evaluation of circulating concentrations of drugs in serum, plasma or whole blood
  • A quantitative procedure performed for drugs with a narrow therapeutic index
  • Ensures that a given drug produces maximal therapeutic benefit and minimal side effects
  • Allows for the safe use of drugs that would otherwise be potentially toxic
  • Most drugs have a half-life independent of their concentrations
  • Only the free fraction of the drugs can interact with the site of action and result in a biologic response
  • Mixed Function Oxidase (MFO) system is the biochemical pathway responsible for the greatest portion of drug metabolism
• Indications for TDM


  • The consequences of overdosing and underdosing are serious
  • There is a small difference between a therapeutic and toxic dose
  • There is a poor relationship between the dose of drug and circulating concentrations but a good correlation between circulating concentrations and therapeutic and toxic effects
  • There is a change in the patient's physiologic state that may unpredictably affect circulating drug concentrations
  • A drug interaction is or may be occurring
  • Helps in monitoring patient compliance
• Routes of Administration


  1. Circulatory system

  2. Intravenous route (100% bioavailability)

  3. Oral administration (should achieve 0.7 bioavailability fraction)

  4. Other routes: Intramuscular, Subcutaneous, Inhalation, Suppository, Transcutaneous
• Pharmacological Parameters

  • Absorption
  • Distribution
  • Excretion
  • Metabolism
  • Liberation
• Absorption of Drugs


  • Therapeutic dose must be optimally attained
  • Most drugs are absorbed by passive diffusion
  • Absorption in the intestine
  • Absorption of capsules, tablets, and liquid solutions
• Factors Affecting Absorption


  • Changes in intestinal movement
  • pH
  • Inflammation
  • Presence of food or other drugs
• Distribution


  • Body tissues
  • Distribution space
• Excretion


  • The rate at which a particular drug is cleared from the circulation
  • 2 Excreted forms
  • 2 Excretion routes