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
\