Animals used in preclinical safety (PCS)

For new chemicals and drugs, the regulatory bodies generally require testing in one rodent and in one non-rodent species. It is important that historical data are available for the species used to interpret findings, in particular to classify findings as treatment-related vs. spontaneous/incidental alterations. The species used are generally as follows:

  • For general toxicity and safety pharmacology testing, usually purpose-bred rodents (especially rats) and purpose-bred non-rodents (especially dogs, sometimes minipigs)
  • For carcinogenicity testing a compound is investigated especially for tumorigenic effects after exposure during most of the lifetime. Non-rodents are generally not used because of their long life expectancy. Carcinogenicity testing is generally done in rodents only, that is in purpose-bred rats and mice, because of their limited lifespan (around 2 years). Instead of normal mice, transgenic mice can be used in 6-month tests, particularly for detecting
    • Genotoxic or nongenotoxic compounds with mice transgenic e.g. for c-Ha-ras. Accepted by FDA and MHLW. Often used
    • Primarily genotoxic compounds with mice transgenic e.g. for p53+/-. Accepted by FDA and MHLW. EMA accepts the test also for non-genotoxic compounds. Can be insensitive
    • Genotoxic or nongenotoxic compounds with exposure by the dermal route with mice transgenic e.g. for rasH2 or the TG.AC mice (v-Ha-ras). The transgene is transcriptionally silent until activated by full-thickness wounding, UV light or specific chemical exposure. The model is contested as being too often positive, though accepted by FDA
  • For reproductive toxicity, generally purpose-bred rats are used as rodents in all three segments, and purpose-bred rabbits as non-rodents for Segment II studies only, both because of their relatively short reproduction time

However, also other species may be used.

  • In particular, pharmacologists like using purpose-bred mice, which are small and require little of the substance to be tested, an advantage at the early stage of research and development. A particular advantage of mice is that they can be made transgenic for investigating many particular issues (in addition to the ones cited above for testing of tumorigenicity)
  • Other species often used in PCS as non-rodents are purpose-bred minipigs
  • For biologics, including vaccines, a responsive species is needed. If only one species is available, testing is limited to that single species. For toxicity testing of vaccine candidates, the species does not have to be pathogenetically responsive, that is, though upon exposure it may have increased specific antibodies against the vaccine candidate, it may not show typical signs of infection
    Non-human primates (NHP) are sometimes needed as responsive species, though now-a-days there is much hesitation regarding their use. Generally speaking, NHP are not always better models than other species, though – in comparison with dogs or minipigs – generally less compound is needed for adequate exposure

In vivo mutagenicity testing can be done in any species mentioned above, particularly when combined with in vivo studies for pharmacological and/or toxicity purposes.

For an overview regarding various species see presentation on Animal species in drug development with emphasis on preclinical safety. Among others, it explains also that overall and despite in vitro and in silico methods, the use of animals will continue with rodents being the important test species in PCS. Minipigs (micropigs) will increasingly serve as alternative non-rodent species to dogs, but currently there is no indication that ferrets or guinea pigs might become further important alternative non-rodent species in general toxicology. Rabbits will continue serving as non-rodent species in reproductive toxicity testing.