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