Acute rodent toxicity and genotoxicity screening

Aim: To assess tolerability, acute toxicity profile and in vivo genotoxic potential of the test item after single dose administration (various routes available) to rodents.

Background information: Toxicological testing generally demands using high doses of the test item to maximize the detection potential of the experimental system. When assessing the in vivo toxicological profile of a test item, this will be usually limited by animal tolerability. For new unstudied test items, the information gained from single dose administration studies allows determining its’ dose limiting toxicity profile and aids in stablishing an adequate dose-range for follow-up repeated dose toxicity studies.

The presence of genotoxic activity in a candidate drug is considered an important liability, for being considered associated to the risk of acting as a human carcinogen and/or mutagen. If present  under in vivo experimental conditions, it will seriously condition the viability of the candidate drug.

In this screening format assay, animals are administered different single dose levels of the test item to determine the “highest non-lethal dose” or the “lowest lethal dose”. At the same time, a peripheral blood sample is obtained and analyzed, by flow cytometry, to determine the frequency of peripheral blood micronucleated reticulocytes (MNRET). Micronuclei are small chromatin containing bodies that represent fragments of chromosomes or whole chromosomes, whose formation is increased by the exposure to clastogenic or aneugenic agents.

Animal species: mice (rats on request)

Compound requirement: 1 g for mice (recomended species)

Turnaround time: 3 weeks

Experimental procedure

  • 2 males + 2 females/group, administered test item or formulation vehicle
  • Route of administration: as per clinical use
  • 72 hours observation period for clinical signs and mortality
  • Necropsy and macroscopic observation of organs at term
  • Micronucleus assessment (optional)
  • 48 hours post-administration peripheral blood sampling
  • Blood samples processed and analyzed by flow cytometry

Delivered results 

  • Determination of “highest non-lethal” and/or “lowest lethal” dose
  • Observation of clinical signs and target organs of toxicity
  • Assessment of in vivo genotoxic potential (MNRET ‰)