Intro to Toxicology

Overview – Intro to Toxicology

Intro to toxicology provides the foundation for understanding how chemical and physical agents can harm living organisms, particularly through mechanisms like absorption, distribution, metabolism, and excretion. Toxicology is an essential subject in pharmacology, especially for final-year medical students preparing to manage drug safety, overdose scenarios, and drug interactions in clinical practice.

Definition

• Toxicology: The study of the adverse effects of chemical or physical agents on living organisms.
• Toxicity: The ability of a chemical to cause harm.
• Toxicant: Any substance that has toxic properties.
• Toxication: The metabolic activation of a substance into a harmful form.
• Routes of exposure:
  • Inhalation
  • Absorption (e.g., skin, mucosa, conjunctiva, GIT)
  • Ingestion

Pathways to Toxicity

Toxic effects result from a sequence of events that can be interrupted to reduce harm:

A) Delivery

• The extent to which a toxicant reaches its target depends on:
  • Absorption:
    • Molecular size and solubility
    • Capillary porosity (e.g., liver vs blood-brain barrier)
  • Distribution:
    • Lipid/water solubility → affects tissue storage and elimination
    • Membrane transporters → store or extrude toxicants
    • Binding to blood or intracellular proteins (e.g., melanin, metallothionein)
  • Biotransformation:
    • Toxication: Conversion to a harmful form
    • Detoxification: Facilitates excretion
  • Excretion: Relies on cardiovascular and renal integrity

B) Cellular Dysfunction

• Functional disruption leads to tissue or systemic toxicity.

C) Disrepair

• Failure in cellular maintenance → cell death and surrounding tissue damage.

Factors Affecting Toxicity

• Chemical properties: Reactivity, target specificity, clearance
• Dose and duration: Acute vs chronic exposure
• Route of entry: Affects bioavailability and bioactivation
• Metabolism: Determines toxication vs detoxification

Biotransformation

Biotransformation changes a substance’s chemical properties for:

• Excretion (↑ water solubility)
• Bioactivation or toxication (via metabolic enzymes)

Phase I Reactions

• Introduce or expose functional groups
• Mainly via Cytochrome P450 (CYP450) enzymes
  • Found in liver, GI tract, kidneys
  • CYP2D6 is key: metabolizes ~30% of clinical drugs
  • Polymorphic → affects drug metabolism rate (poor/normal/rapid/ultra-rapid)

Phase II Reactions

• Conjugation with polar molecules → ↑ solubility for excretion
• Key conjugation types:
  • Glucuronidation (main focus) – via UDP-GA
  • Glutathione conjugation
  • Acetylation
  • Sulfation
  • Methylation
  • Amino acid conjugation

Factors Influencing Metabolism

Age

• Newborns: No Phase II enzymes, poor renal function → high toxicity risk
• Children (1–8 yrs): Faster metabolism (esp. oxidation)
  • ↑ or ↓ toxicity depending on metabolite type
• Elderly: Slower metabolism → risk of accumulation or inadequate detoxification

Pharmacogenetics

• Genetic polymorphisms affect enzyme activity (e.g., acetylation rate)
  • Slow acetylators: higher peripheral drug levels → ↑ toxicity
  • Fast acetylators: more liver metabolism → ↑ hepatic/renal toxicity
• Aldehyde dehydrogenase variants:
  • Absent/mutated enzyme → acetaldehyde buildup → flushing, nausea

Drug Interactions

Enzyme Inhibition (usually acute)

• Competitive inhibition: Two drugs share or block an enzyme
• Non-competitive inhibition: Irreversible or long-lasting enzyme inhibition

Enzyme Induction (usually chronic)

• ↑ transcription, stability, or translation of metabolic enzymes
• Can reduce drug effectiveness by accelerating clearance

Physiological & Disease States

• Gender: Hormonal differences may alter drug metabolism
• CV status: Influences distribution
• Renal/hepatic function: Affects clearance
• Nutrition: Co-factor availability influences metabolism

Summary – Intro to Toxicology

Intro to toxicology equips medical students with the principles needed to understand how drugs and chemicals can cause harm, influenced by dose, route, metabolism, and genetic factors. Core concepts such as toxication, biotransformation, and enzyme variability underpin clinical pharmacology and patient safety. For a broader context, see our Pharmacology & Toxicology Overview page.