Considerations related to dose selection for regulatory animal testing

Selecting dose levels in regulatory toxicology studies is not clearly regulated by OECD guidelines and regional differences exist. Establishing a high dose level or maximum tolerated dose (MTD) that is scientifically justified, ethically sound, and aligned with regulatory expectations is essential to generate meaningful data for human risk assessment while minimizing unnecessary animal distress. Understanding a compound’s pharmacokinetics, mechanism of action, anticipated toxicity profile, and progression of toxicity over time are important components of dose-selection. Accumulation of parent compound or its metabolites due to limited renal excretion may result in excessive toxicity in studies of longer duration We emphasize the role of appropriate preliminary studies in identifying a high dose that induces clear but non-lethal toxic effects. Clinical signs of toxicity can be used for high dose selection, noting that signs indicating pain or severe distress are indicative of an exceedance of an MTD. Hematology and pathology are further important sources of information to establish an MTD. For studies in which the animals are dosed during their growth phase (regulatory studies with a duration ≤ 90days and developmental toxicity studies) reduced bodyweight gain (not above 15%) must be considered. In chronic and carcinogenicity studies body weight differences relative to concurrent controls should be considered for high dose selection. Dose selection should be a multi-disciplinary, team-based approach. Clear written documentation of dose selection is essential for defensible decisions that ultimately contribute to the quality, credibility and regulatory acceptance of toxicological safety assessments.