Animal Toxicity Studies

Definition, scope & objectives

• Toxicology — the study of the adverse effects of substances on living organisms; a toxicity study (also called hyperpharmacology) is an ethically necessary stage of drug development, run alongside pharmacological and pharmacokinetic evaluation, to deliver a safe and efficacious drug.
• Two arms — toxicodynamics (the toxic effect/mechanism on the organism, analogue of pharmacodynamics) and toxicokinetics (the pharmacokinetics of a drug under circumstances that produce toxicity).
• Species rule — because of species-to-species variation in response, ≥2 species are always preferred; all protocols must be reviewed and approved by an Institutional Animal Ethics Committee (IAEC) before the experiment.
• Objectives — identify toxic substances before clinical use; characterise the drug effect qualitatively (target organs) and quantitatively (plasma/tissue level at which effects are/are not seen); define cumulative toxicity (not predicted by single doses); guide safe dose selection for later studies; and derive dose descriptors — MLD, LD₅₀, MTD, ED₅₀ — to compute the therapeutic index (TI = LD₅₀/ED₅₀).
• GLP & records — large-set-up toxicity testing must follow Good Laboratory Practice (GLP), qualified staff, calibrated instruments and SOPs; documentation is the single most important element — protocol approval, raw data, reports, histology slides and paraffin blocks are preserved — a minimum of 5 years after marketing.