Clinical Chem Toxicology

Learning Outcome

  • To understand the general principles of clinical toxicology
  • To understand the impact on human health of selected toxic substances

Key terms & Definitions

^^Toxicology^^ – scientific study of the adverse effects of xenobiotics on biological system

^^Clinical toxicology^^

–focuses on the relationship between xenobiotics and disease states

–includes definitive diagnosis, assessment of immediate and long-term effects and therapeutic intervention

^^Xenobiotics^^

– chemical compounds that are not naturally present in or produced within the organisms, and exert adverse impacts on the living systems & environment

– more often, synthetic chemicals (eg., drugs, pesticides, industrial pollutants)

^^Poisons^^ – exogenous agents that have adverse effects on biological system

–more often, originated from an animal or plant, or is a type of mineral or gas (eg., snake venom, arsenic, lead, carbon monoxide)

^^Toxins^^ –endogenous substances biologically synthesized by living cells or microorganisms that are harmful to cells and tissues

– eg., botulinum toxin from Clostridium botulinum, mycotoxins from fungi

Principles of Clinical Toxicology

  • Routes of exposure
    • “exposure” - concentrations or amount of a substance presented to the individual or amount of toxicant found in specific volumes of air, water or in soil
    • determined by the nature and physical state of the chemical substances
    • a determinant of toxicity
    • 4 major routes
    • inhalation, ingestion, injection, absorption

Inhalation

  • gases, vapours, mists or particulates

  • upon inhalation (entry), chemicals can be exhaled or deposited in the respiratory tract

  • direct contact with tissues in the upper respiratory tract

    • simple irritation to severe tissue destruction
  • diffuse into the blood via the lung-blood interface

    • rapid entry into systemic circulation, distribution to organs that have an affinity for the toxicant
  • example: hydrogen cyanide

    • loss of consciousness, seizures, cardiac dysrhythmias, hypotension; possible death within minutes after exposure
  • factors affecting the inhalation of toxic chemicals

    • concentration of the chemicals in the air
    • solubility of the substances in blood and tissues
    • length & frequency of exposure
    • respiration rate
    • size of toxic particles
    • conditions of the respiratory tract

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Skin/eye absorption

  • Skin (dermal) contact (insecticides)
    • local effect
    • relatively innocuous; redness, mild dermatitis
    • more severe; skin tissue destruction
    • enter systemic circulation
    • many toxic substances can cross the skin barrier & get absorbed into blood circulation
    • produce damage to internal organs
  • factors affecting the skin absorption of toxic chemicals
    • skin conditions
    • damage to the protective layer, e.g., cuts & wounds, allow absorption and deep penetration into dermis
    • nature of the toxic substances
    • inorganic substances
    • water-soluble organic toxicants
    • organic solvents
    • eye contact
    • particularly sensitive to chemicals
    • primary point of contact: cornea
    • severe damage/effects even with short exposure
    • serious eye problems; or causing harmful effects to other body parts
    • e.g., acidic or basic compounds

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Ingestion

  • direct ingestion - inadvertently eating/drinking a chemical
  • indirect ingestion - contaminated food via:
    • intentional application
    • deposition of particulate matter
    • uptake & accumulation from contaminated soil or water
  • non-dietary ingestion - occur intentionally or inadvertently ingestion of soil, dust or chemical residues on surfaces/objects
    • (via hand-to-mouth or object-to-mouth)
  • measurement of dose → the amount of substances that gets into the body in biologically available forms upon ingestion exposure
    • potential dose
    • applied dose
    • internal dose
    • biologically dose
  • factors affecting the absorbance of toxic chemicals from gastrointestinal tract
    • ability to diffuse and cross the cell membranes
    • pH
    • rate of dissolution
    • gastrointestinal motility
    • resistance to degradation

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Injection

  • enter the body if the skin is penetrated or punctured

  • toxic substances circulate in the blood and deposit in target organs

  • toxic effects depend on the nature and lethality of toxicant

  • different injection routes:

    • intravenous injection
    • intramuscular injection
    • intraperitoneal injection
    • intradermal injection
    • subcutaneous injection

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Dose-response relationship - “the dose makes the poison”

  • evaluating clinical effects based on the amount of exposure
  • dose
    • total amount of chemical absorbed during an exposure
    • a consistent mathematical and biologically plausible correlation between the number of individuals responding and a given dose over an exposure period
    • depending on the chemical concentration and duration of exposure
  • expressed in terms of the quantity administered:
    • quantity per unit mass (or weight) → mg/kg
    • quantity per unit area of skin surface → mg/cm2
    • volume of substances in air per unit volume of air → ppm or mg/m3
  • Important terms used in toxicology to express dose-response relationships:
    • TD50 - predicted dose that would produce a toxic response in 50% of the population
    • LD50 - predicted dose that would result in death in 50% of the population
    • ED50 - predicted dose that would be effective or have a therapeutic benefit in 50% of the population
  • an increase in the toxic response as the dose increased
  • not all individuals display a toxic response at the same dose
  • factors affecting toxic response:
    • duration and frequency of exposure
    • routes of exposure
    • interspecies & intraspecies variation
    • environmental factors
    • chemical combinations

Alcohols - Ethanol

  • exposure is common
  • excessive consumption → ethanol toxicity →acute/chronic
  • ethanol-related disorders - consistently one of the top ten causes of hospital admissions
  • occurs from the ingestion of large amount of alcoholic beverages & non-beverage ethanol

Acute alcohol intoxication causes several metabolic alterations:

  • hypoglycemia
  • lactic acidosis
  • hypokalemia
  • hypomagnesemia
  • hypoalbuminemia
  • hypocalcemia
  • hypophosphatemia

Pathophysiological consequences of chronic ethanol consumption:

  • 50g of ethanol per day ~10 years
  • liver → accumulation of lipids in hepatocytes → alcoholic hepatitis → toxic form of hepatitis/liver cirrhosis

Mechanism:

Ethanol → Acetaldehyde → Acetate → Acetaldehyde adducts

  • ↑concentration of aldehyde
    • cross blood-brain barrier
    • mediate most of the CNS effects of ethanol
  • ↑ circulating level of acetaldehyde
    • form acetaldehyde adducts
    • inflammation & cellular in alcoholic liver diseases

Carbon Monoxide

  • colourless, odourless & tasteless gas
  • produced by incomplete combustion of carbon-containing substances
  • primary sources: improperly ventilated furnaces, incomplete burning of various fuels, internal combustion engines

Signs & symptoms

  • low to moderate level of CO poisoning
    • headache
    • fatigue
    • shortness of breath
    • nausea
    • dizziness
  • high level of CO poisoning
    • mental confusion
    • vomiting
    • loss of muscular coordination
    • loss of consciousness
    • death
  • severity of CO poisoning - CO level & duration of exposure

Pathophysiology of CO poisoning

  • CO binds to haemoglobin → carboxyhaemoglobin (COHb)
  • affinity for haemoglobin is 200-225 times greater than for O2
    • exposure to CO leads to a decrease in oxyhaemoglobin concentration
    • decrease in the amount of O2 released to tissues
      • hypoxia
  • mainly affects brain and heart
  • complications
    • heart attack
    • convulsion
    • memory impairment
    • permanent brain damage
    • coma
    • death

Metal - Lead

  • naturally found in the crust of Earth
  • common sources of exposure:
    • lead-acid batteries
    • contaminated drinking water from lead pipes/pipes joined with lead solder
    • lead-based paint/products with lead-containing paint
    • art & craft
    • cosmetics
    • traditional medicine
  • symptoms in YOUNG CHILDREN
    • behavioural changes
    • learning difficulty
    • developmental delay
    • problem with hearing/hearing loss
    • irritability
    • loss of appetite
    • weight loss
    • fatigue
  • symptoms in ADULTS
    • hypertension
    • kidney damage
    • abdominal pain & constipation
    • pain, numbness or tingling of the extremities
    • headache & memory loss
    • anemia
    • miscarriage, stillbirth or premature birth
    • lower birth weight

Pathophysiology

  • exposure can be via any route, i.e., ingestion & inhalation
  • varies in gastrointestinal absorption
    • infants>children>adults
  • absorbed lead binds to many macromolecules in high affinity
  • distributed to brain,kidneys, liver, & bone
  • mainly stored in the teeth and bone, and accumulated over time
  • eliminated via renal filtration, at a slow rate

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