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

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

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

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

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