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