Normal-Organ Absorbed Dose and Response Assessment in α-Particle Radiopharmaceutical Therapy.

α-particle radiopharmaceutical therapy (α-RPT) is an emerging oncologic modality for treating malignancies, but its clinical development is hindered by limited datasets pairing patient-level dosimetry with prospectively collected toxicity and response endpoints. Additional challenges include radionuclide-specific imaging constraints, radioactive daughter redistribution, suborgan heterogeneity that decouples whole-organ absorbed dose from biologic effect, and uncertainty in relative biological effectiveness modeling. On behalf of the multidisciplinary Radiopharmaceutical Therapy-Tissue Effects in the Clinic committee, we review the literature on normal-organ dose and response assessment in α-RPT and propose a 2-stage framework to guide study design and data collection. Stage I emphasizes whole-organ dosimetry to support early safety characterization and derive preliminary organ toxicity reference levels. Stage II focuses on small-scale dosimetry and heterogeneity to enable more transferable, biologically informed reference levels. We offer practical recommendations for imaging feasibility, dosimetry workflows, toxicity endpoint selection (including delayed effects), and interpretation of dosimetry-toxicity relationships in early-phase trials, with the goal of standardizing data collection and accelerating the development of organ toxicity reference levels in α-RPT.