Fundamental Concepts of Toxicology
Definition and Scope of Toxicology
- Toxicology: science dealing with the adverse effects of chemicals (natural or synthetic) on living organisms.
- Examines cellular, biochemical, molecular mechanisms; evaluates probability of occurrence.
- A toxicologist assesses nature/mechanisms of toxicity and quantifies risk.
- Whether a substance is poisonous depends on:
- Type of organism exposed
- Amount (dose)
- Route of exposure
- Core dictum (Paracelsus): “All substances are poisons; the right dose differentiates a poison from a remedy.”
Historical Milestones
- Pre-history: use of plant extracts & animal venoms in hunting, warfare, assassination.
- Ebers Papyrus (~1550 BCE): lists poisons like hemlock, opium, lead, copper.
- Bible – Book of Job (6:4): reference to poison arrows.
- Dioscorides (approx. 1st century CE): De Materia Medica; classified ~600 plant/animal/mineral poisons.
- Paracelsus (1493-1541):
- Emphasized experimentation.
- Distinguished therapeutic vs toxic properties by dose.
- Introduced concept of chemical specificity of action.
- 15th century: first documentation of occupational hazards.
- 19th century: rise of experimental toxicology with organic chemistry.
- Mid-1950s: US FDA strengthens toxicology focus.
- Today: International Congress of Toxicology unites societies from all continents.
Major Areas / Branches of Toxicology
- 1. Mechanistic Toxicology
- Identifies cellular/biochemical/molecular mechanisms.
- Crucial for risk extrapolation from animals to humans.
- 2. Descriptive Toxicology
- Toxicity testing to provide safety data for regulation.
- 3. Regulatory Toxicology
- Determines whether risk is low enough for marketing; sets standards for air, water, etc.
- 4. Forensic Toxicology
- Medicolegal aspects; analytical chemistry + toxicology principles.
- 5. Clinical Toxicology
- Diagnosis & treatment of diseases caused by toxic substances.
- 6. Environmental Toxicology
- Impact of pollutants on non-human organisms.
- Sub-field Ecotoxicology: population-level effects within ecosystems.
- 7. Developmental Toxicology / Teratology
- Effects on developing organism before conception → puberty; teratogens cause malformations.
- 8. Reproductive Toxicology
- Adverse effects on male/female reproductive capability.
Fundamental Terminology
- Poison: any agent capable of causing deleterious response.
- Toxin: poisonous substance produced by living organism (plants, animals, fungi, bacteria).
- Toxoid: originally toxic, rendered non-toxic yet antigenic (e.g., vaccines).
- Toxicant: toxic substance produced by or as by-product of human activity.
- Toxemia: toxins/noxious substances from microorganisms circulating in blood.
- Xenobiotic: foreign chemical to organism/environment.
- Endogenous Substance: normally present; e.g., \text{Ca^{2+}} 9-9.5 mg/dL in serum (hypocalcemia < 9, hypercalcemia > 10.5).
Routes of Entry
- Inhalation (pulmonary): gases, vapors, fine aerosols → blood.
- Skin Absorption (percutaneous): liquids/solutions.
- Ingestion (oral): contaminated food/drink.
- Injection: rare occupationally.
Factors Influencing Toxicity
- Dose (how much)
- Duration (how long)
- Frequency (how often)
- Route of exposure
- Species, sex, age, nutritional status, health, genetics, presence of other chemicals (interactions).
- Occupational note: inhalation & dermal absorption dominate workplace exposure.
Toxicity Assessment Process
- Hazard Identification: Does contaminant cause adverse effect? Identify critical effect.
- NOEL (No Observed Effect Level)
- NOAEL (No Observed Adverse Effect Level)
- Dose–Response Evaluation: Quantify relationship; derive toxicity values used in risk characterization.
- Exposure Assessment
- Risk Characterization
- Dose: mass of chemical per body weight \text{mg/kg} (sometimes ppm or \text{mg/kg·day}).
- Administered/Intake dose vs Uptake/Absorbed dose.
Dose–Response Relationships
- Graded (individual): continuous measurable parameters (enzyme activity, weight).
- Quantal (population): all-or-none outcomes (death, tumor). Produces sigmoid curve when % response plotted vs log-dose.
Key Indices (express all doses as \text{mg/kg} unless noted)
- ED_{p}: Effective dose producing specified reversible effect in p\% of population.
- TD_{p}: Toxic dose (irreversible but non-lethal) in p\%.
- LD_{p}: Lethal dose for p\%.
- Therapeutic Margin: TM = LD{50} - ED{50} (units of dose).
- Margin of Safety: MOS = LD{5} - ED{95}.
- Safety Index: SI = \dfrac{LD{5}}{ED{95}}.
- Therapeutic Index: TI = \dfrac{LD{50}}{ED{50}} (dimensionless ratio).
Lethality Metrics
- LD50: dose killing 50 % of test animals.
- LC50: airborne/water concentration killing 50 % (units \text{mg/L} or ppm).
Approximate Acute LD50 examples (oral, rat):
- Ethanol 10 000 mg/kg → very low toxicity
- Sodium chloride 4 000 mg/kg
- Morphine sulfate 900 mg/kg
- Picrotoxin 5 mg/kg
- Nicotine 1 mg/kg
- Dioxin 0.001 mg/kg
- Botulinum toxin 0.00001 mg/kg (“supertoxic”)
Acute vs Chronic Effects
- Acute: rapid onset after single/short exposure (< 3 months). E.g., irritation, flu-like symptoms.
- Chronic: long latency; effects appear after prolonged exposure (cancer, organ damage).
Spectrum of Undesired Effects
- Side/Secondary effects: non-therapeutic outcomes in pharmaceuticals.
- Allergic (Hypersensitivity): immune-mediated; chemical acts as hapten binding endogenous protein → antigen.
- Idiosyncratic: genetically determined abnormal sensitivity/insensitivity.
- Immediate vs Delayed: e.g., carcinogens — tumors after 20-30 years.
- Reversible vs Irreversible:
- Liver injuries often reversible (high regeneration).
- CNS damage, carcinogenesis, teratogenesis often irreversible.
- Local vs Systemic: action at contact site vs distant after absorption.
Chemical Interactions
- Additive: A+B= A+B (effects sum).
- Synergistic: A+B> A+B (greater than sum).
- Potentiation: non-toxic A increases toxicity of B.
- Antagonism: one chemical reduces effect of another.
- Functional, Chemical (inactivation), Dispositional, Receptor antagonism.
Reversibility, Sensitivity & Specific End-Organ Toxicity
- Reversible vs Irreversible effects definition.
- Specific adverse classifications: carcinogen, mutagen, teratogen, reproductive hazard, dermatotoxic, hemotoxic, hepatotoxic, nephrotoxic, neurotoxic, pulmonotoxic.
- Hypersensitivity (hyper-) vs Hyposensitivity (hypo-) to doses.
Pharmacokinetics & Disposition
- ADME: Absorption, Distribution, Metabolism (biotransformation), Excretion.
- Bioaccumulation: uptake rate > elimination rate; problematic for Pb, Hg, PCBs, \text{CCl_4}.
- Elimination routes: kidneys (urine), liver (bile/feces), lungs (exhalation), minor via sweat, milk, hair.
- Detoxification: enzymatic conversion to less harmful metabolites; storage in adipose tissues may delay toxicity.
Immunotoxicology Concepts
- Immunocompetence: capacity to recognize/react to foreign substances.
- Immunosuppression: decreased competence → infections, cancer.
- Immunoenhancement: exaggerated response → hypersensitivity, possible autoimmunity.
- Innate Immunity: physical/biochemical barriers + nonspecific cells.
- Acquired (Adaptive) Immunity: antigen-specific, memory-based.
- Autoimmunity: immune attack against self tissues.
- Antigen: non-self molecule; recognized via antibodies produced by B-cells; small chemicals act as immunogens after haptenation.
- Immunoassays: sensitive analytical methods for trace antigen/antibody detection.
Workplace Hazard Control & Environmental Management
- Basic Principles (Hierarchy): Elimination → Substitution → Engineering Controls → Administrative Controls → PPE.
- Engineering Controls:
- Substitution (e.g., leaded → unleaded gasoline; TCE → kerosene).
- Isolation/Enclosure (sound-proof covers, glove boxes).
- Ventilation: Natural vs Artificial; Local Exhaust (preferred) vs Dilution.
- Administrative Controls: policies, job rotation, rest breaks, health surveillance, training.
- Personal Protective Equipment (PPE): last resort; helmets, safety glasses, gloves, respirators, ear protection, etc.
- Sanitation Measures: potable water, eating areas, vector control, waste treatment, housekeeping, personal hygiene.
Philippine OSH Standards Highlights
- Rule 1070 (Occupational Health & Environmental Control)
- Establishes Threshold Limit Values (TLVs) for chemicals, noise, etc.
- Secretary of Labor reviews/updates with BWC technical committee.
- Rule 1080 (PPE)
- Employer must provide appropriate PPE at no cost; maintain and replace.
- Loss/damage deductions governed by Labor Code (Art 114).
Glossary (Selected)
- Acute toxicity: rapid onset, short course.
- Chronic toxicity: long duration/latency.
- Carcinogen / Oncogenic: cancer-causing.
- Sarcoma / Carcinoma / Leukemia / Lymphoma: cancer types (mesodermal, epithelial, blood, lymphatic).
- Initiator: chemical causing irreversible DNA change; needs promoter for tumor development.
- Promoter: increases tumor incidence after initiation.
- Genotoxic: damages DNA.
- Metastasis: spread of cancer cells.
- Teratogenesis: birth-defect formation.
- Subacute toxicity: effects assessed during first 10 % of normal lifespan with continuous dosing.
- Multistage Model: tumors arise from sequential biological events; contrasts with one-hit hypothesis.
Example Numerical References & Equations
- Blood \text{Ca^{2+}} normal range 9 \text{–} 9.5\,\text{mg/dL}.
- Hypocalcemia
- Therapeutic Index example: if LD{50} = 100\,\text{mg/kg} and ED{50}=10\,\text{mg/kg}, then TI = 10.
- Margin of Safety example: LD{5}=30\,\text{mg/kg}, ED{95}=5\,\text{mg/kg} → MOS = 25\,\text{mg/kg}; SI = 6.
Real-World & Ethical Considerations
- No ethical way to test toxicants in humans ⇒ reliance on animal models (rats, rabbits, dogs, etc.)
- Species differences and extrapolation uncertainty.
- Statistical designs needed; control groups essential.
- Historical industrial disaster: Bhopal, India (methyl isocyanate release) underscores need for rigorous control.
- Vaccines: use toxoids (e.g., botulinum toxoid) conversion from lethal toxin to safe immunogen.
- Occupational exposures influenced by lifestyle (e.g., smoking potentiates asbestos; alcohol impairs hepatic detoxification).
Study Tips / Connections
- Always relate mechanism (mechanistic tox) to observed dose–response (descriptive) for risk assessment.
- Remember the hierarchy of control when answering engineering vs administrative questions.
- Practice converting between LD, ED, TD indices and computing TI, MOS, SI quickly.
- Link immunotoxicology concepts with hypersensitivity/autoimmunity in pathology modules.
- Place historical quotes (Paracelsus) & landmark events to frame essay questions.