SLP - Toxicometrics_6a11d1feca7197484a18315a2aea81e1

Self-Learning Package Overview

  • Title: Toxicometrics Membrane & Receptor

  • Program: Medical Doctor (MD) Programme

  • Institution: Faculty of Medicine, The National University of Malaysia

  • Author: Dr. Chin Kok Yong, Department of Pharmacology

  • Revision Date: 14/1/2019

Objectives of the Self-Learning Package

At the end of this self-learning package, students should be able to:

  1. Understand the toxic effects of any drug considering individual drug-dose response.

  2. Estimate LD50 (lethal dose for 50% of the population) and understand factors affecting its value.

  3. Define TD50, ED50, LC50, TI (Therapeutic Index), and margin of safety.

  4. Describe the procedures of various toxicity tests.

  5. Identify factors influencing drug toxicity.

Definitions

  • Toxicometry: Quantitative assessment of toxicity from hazardous substances.

  • Toxicity Test: Assessment of adverse effects on humans, animals, or the environment, involving:

    • Acute Toxicity: Short-term exposure effects.

    • Chronic Toxicity: Long-term exposure effects.

    • Specific endpoints include:

      • Cytotoxicity: Damage to cells.

      • Mutagenicity: Changes in genetic material.

      • Carcinogenicity: Cancer-causing potential.

      • Teratogenicity: Causes birth defects.

  • OECD Guidelines: Guidelines provided by the Organization for Economic Co-operation and Development for health effects testing in chemicals.

Animals Used in Toxicity Testing

  • Rodents: Rats, mice, guinea pigs

  • Non-rodents: Dogs, rabbits, cats, monkeys

Types of Toxicity Testing

Acute Test

  • Measures adverse effects after a short time (7-14 days) from a single dose

  • Procedure: OECD Guidelines 420

Subacute Test

  • Assesses repeated doses every day for 28 days.

  • Procedure: OECD Guidelines 407

Subchronic Test

  • Evaluates toxicity through repeated dosing over an extended period (10% of test lifespan).

  • Procedure: OECD Guidelines 408, 409

Chronic Test

  • Explores prolonged exposure effects, lasting usually 12 months.

  • Procedure: OECD Guidelines 452

Carcinogenicity Test

  • Monitors animals for neoplastic lesions during or after various dose exposures, lasting typically 24 months for rats.

  • Procedure: OECD Guidelines 451

Reproductive Test

  • Observes effects of drug exposure before mating or during gestation, including fertility and hormonal changes.

Mutagenicity Test

  • Tests ability to induce genetic mutations (e.g., bacterial reverse mutation test).

  • Procedure: OECD Guidelines 471

Toxicometrics Measurements

Median Lethal Dose (LD50)

  • Dose causing death in 50% of the population.

Median Lethal Concentration (LC50)

  • Concentration causing death in 50% of the population under defined test conditions.

Toxicity Classes

Class

LD50 (mg/kg)

Example

I

< 1

Tetrachlorodibenzo-p-dioxin

II

1-50

Picrotoxin

III

50-500

Phenobarbital

IV

500-5000

Morphine sulfate

V

5000-15000

Ethanol

LD50 Determination

  • LD50 refers to the dose that results in 50% mortality in test animals.

  • In practice, it may not always yield exact values, necessitating alternative calculation methods involving Probits.

Dose-Response Relationship

  • Shape of the dose-response curve indicates drug toxicity. A steeper slope indicates higher toxicity.

Safety Measurement - Therapeutic Index (TI)

  • Definition: A measure of drug safety comparing therapeutic effects (ED50) and toxic effects (TD50).

  • Higher TI indicates greater safety.

  • Example of calculation: TI = LD50 / ED50 or TD50 / ED50.

Therapeutic Window

  • Definition: Range of doses that produces therapeutic responses without significant adverse effects.

  • Some drugs may have narrow or wide therapeutic windows.

Margin of Safety/Safety Ratio

  • Definition: Ratio of TD01 (toxic dose for 1% population) to ED99 (effectiveness for 99% population).

Factors Influencing Toxicity

  • Age: Different susceptibility in children and elderly.

  • Gender: Differences in toxicity susceptibility.

  • Dietary Habits: Nutritional intake influences toxicity response.

  • Smoking & Alcohol: Interactions with toxicants affecting toxicity.

  • Medications: Concurrent medicines may change responses to toxicants.

  • Environmental Chemicals: Polymorphism and environmental chemical influence.

Types of Drug Toxicity

  1. Natural Toxicity: Already existing toxins (e.g., snake venom)

  2. Overdose: High doses of drugs.

  3. Idiosyncratic Effects: Unpredictable due to genetic variations.

  4. Teratogenic Effects: Fetal deformities due to drug exposure.

  5. Mutagenic Effects: DNA alterations.

  6. Carcinogenic Effects: Drug-induced cancer.

  7. Iatrogenic Effects: Illness caused by medical treatment.

  8. Hypersensitivity: Immunological reactions (e.g., rashes).

  9. Addictive Effects: Dependence on drugs.

  10. Adverse Effects: Interactions between drugs.

Toxicity Mechanisms

  • Pharmacological Drug Toxicity: Dose-related general effects.

  • Biochemical Drug Toxicity: Dose-related but can be unpredictable, affecting cellular components.

  • Immunological Drug Toxicity: Unpredictable responses not related to dose.

References

  • Hodgson, E. (2010). A Textbook of Modern Toxicology. 4th Edition, Wiley, New Jersey.

  • Randhawa, M.A. (2009). LD50 Calculation Method. J Ayub Med Coll Abbottabad, 21(3): 184-185.

  • OECD Guidelines for the Testing of Chemicals. OECD Homepage