6. DRUG TOXICITY: ACUTE, SUB- ACUTE AND CHRONIC TOXICITY

Introduction

Before a new drug is approved for use in humans, it must be thoroughly tested for safety. This includes both preclinical studies in animals and clinical trials in humans. Toxicity studies are an important part of preclinical evaluation, helping to identify harmful effects, safe dose ranges and target organs that may be affected by the drug.

Preclinical Toxicity Testing

Before a medicine enters human trials, it is tested in animals to understand:

  • How the drug acts on the body (pharmacodynamics)
  • How the body handles the drug (pharmacokinetics)
  • Short-term and long-term toxic effects (toxicology)

These studies help ensure that only drugs with acceptable safety profiles move to human testing.

Types of Toxicity Studies

Toxicity studies are broadly classified into:

  • Acute toxicity studies
  • Sub-acute toxicity studies
  • Chronic toxicity studies
  • Special toxicity studies (carcinogenicity, mutagenicity, teratogenicity)

Acute Toxicity Studies

Acute toxicity refers to harmful effects that occur shortly after a single large dose of a drug.

Key Features

  • Conducted in two animal species — one rodent (e.g., mouse or rat) and one non-rodent (e.g., rabbit or dog).
  • Single, graded doses are given to small groups of animals.
  • One of the routes used must match the intended human route.
  • Animals are observed for behaviour changes, toxicity signs and death.

LD50 Determination

Acute toxicity studies determine the LD50, which is the dose that kills 50% of the test animals.

LD50 is usually measured within 24 hours after drug administration. This value helps estimate the relative safety margin of the drug.

Sub-Acute Toxicity Studies

Sub-acute toxicity develops after repeated administration of a drug for a short duration (weeks).

Study Characteristics

  • Conducted in two different animal species.
  • Drug is administered daily for a duration that reflects intended human use.
  • Helps determine the maximum tolerated dose (MTD).
  • Identifies target organs of toxicity such as liver, kidney or heart.

Monitoring Parameters

  • General behaviour and activity
  • Food and water intake
  • Body weight changes
  • Biochemical tests (liver and kidney function)
  • Haematological tests
  • Histopathological examination of tissues

Chronic Toxicity Studies

Chronic toxicity refers to harmful effects that appear after months of continuous drug administration.

Study Design

  • Drugs are given daily for 6–12 months.
  • Two animal species are used — one rodent and one non-rodent.
  • Monitoring procedures are similar to sub-acute studies but extended for a longer period.

Purpose

  • To detect long-term harmful effects.
  • To identify cumulative toxicity or organ damage that may not appear in short-term studies.
  • To estimate safe doses for long-term human therapy.

Special Toxicity Studies

Some drugs require additional testing to identify specific risks:

1. Carcinogenicity

Tests whether long-term drug use may promote tumour formation.

2. Mutagenicity

Checks whether the drug causes genetic mutations that can lead to inherited defects.

3. Teratogenicity

Determines whether the drug can cause birth defects when taken during pregnancy.

4. Reproductive Toxicity

Assesses effects on fertility, embryo development and reproductive capability.

Detailed Notes:

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