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
- 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
- mainly affects brain and heart
- complications
- heart attack
- convulsion
- memory impairment
- permanent brain damage
- coma
- death
- 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
- 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
\