No Observed Adverse Effect Level (NOAEL)
The highest dose of a compound at which no adverse effects are observed in preclinical toxicology studies. NOAEL is a critical parameter for calculating the safe starting dose in first-in-human clinical trials, typically using a safety factor to convert from animal to human equivalent doses.
Technical Context
NOAEL is determined from the highest dose group in preclinical toxicology studies that shows no statistically or biologically significant increase in adverse findings compared to control. The NOAEL is used to calculate the human equivalent dose (HED) using allometric scaling (body surface area adjustment: HED = animal NOAEL × (animal Km / human Km), where Km = body weight/body surface area). The maximum recommended starting dose (MRSD) for first-in-human trials is typically 1/10th of the HED from the most sensitive species (applying a 10-fold safety factor). For peptides with species-specific pharmacology (e.g. human-specific receptor binding), the NOAEL from pharmacologically relevant species is prioritised. Additional safety factors may be applied for: irreversible toxicity, steep dose-response curves, or novel mechanisms.