Scoping review maps rodent safety data for therapeutic radiopharmaceuticals

Therapeutic radiopharmaceuticals deliver radiation directly to targets such as tumors, and their growing role in translational cancer research has made nonclinical safety testing a central step in their development. Yet the rodent studies that underpin these safety assessments have rarely been examined as a whole. A scoping review now published in EJNMMI Research set out to characterize how pathology-related endpoints are actually used in rodent studies of therapeutic radionuclides and radiopharmaceuticals, and to identify the reporting gaps that make cross-study interpretation difficult.

The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidance. The authors searched PubMed for in vivo rodent studies of therapeutic radionuclides or radiopharmaceuticals that reported clinical pathology and/or histopathology endpoints. Data were charted descriptively, with emphasis on study characteristics, endpoint selection, organ evaluation, observation period, and pathology-informed interpretation. In total, seventy-five studies were included.

The results reveal a fragmented evidence base. Clinical pathology was reported in 68 of the 75 studies and histopathology in 51, but only 29 studies reported hematology, blood chemistry, and histopathology together. That means fewer than half of the reviewed rodent studies combined all three major pathology-related assessment streams, limiting how completely safety signals could be evaluated across the field.

Within hematology, white blood cell (WBC) and platelet counts were the most frequently reported parameters, a pattern consistent with the hematologic suppression that radiation-delivering drugs can produce. The kidneys themselves emerged as the most commonly examined organs and the most frequent sites of reported lesions. Specific renal findings included tubular epithelial karyomegaly, glomerulosclerosis, tubular dilatation, and interstitial fibrosis, a set of changes pointing to recurring renal injury in these models.

Observation periods ranged from 4 days to 52 weeks, and the review found that these durations varied widely both within and across radionuclide groups.

Tolerability reporting proved equally inconsistent. The activity ranges associated with intolerance varied widely across radionuclides and study designs, and for several radionuclides the review found no extractable or clearly defined activity levels associated with intolerance. Without defined intolerable activity levels, comparing dose-limiting toxicity across different radiopharmaceutical platforms becomes substantially harder.

The authors concluded that nonclinical safety studies of therapeutic radiopharmaceuticals show recurring patterns of hematologic suppression and renal injury, but that substantial heterogeneity in endpoint selection, organ evaluation, follow-up design, and tolerability reporting limited cross-study interpretability. In other words, the safety signals themselves are recognizable, but the way studies are designed and reported makes it difficult to synthesize them reliably.

As a response to these gaps, the mapped evidence supports a more explicit minimum reporting framework covering clinical pathology, histopathology, organ selection, follow-up duration, and pathology-based tolerability assessment in therapeutic radiopharmaceutical development. Such a framework would aim to make future rodent safety studies more interpretable and more directly comparable across radionuclides and study designs.

The review is an open-access article published on 14 October 2026, and it is presented as an early-shared, peer-reviewed accepted version that is citable and carries a permanent DOI, subject to further edits before the final Version of Record. As a scoping review, it maps and describes existing rodent studies rather than generating new experimental safety data, and its findings describe the reporting landscape of the included literature rather than establishing efficacy or clinical outcomes for any therapeutic radiopharmaceutical.

Subject of Research: Nonclinical safety endpoints and reporting gaps in rodent studies of therapeutic radiopharmaceuticals

Article Title: Nonclinical safety assessment for therapeutic radiopharmaceutical development: a scoping review of rodent studies

Article References: Shin, J. I., Baik, J. Y., Choi, Y., Lee, E. S., Lee, Y. J., & Kim, K. I. (2026). Nonclinical safety assessment for therapeutic radiopharmaceutical development: a scoping review of rodent studies. EJNMMI Research. https://doi.org/10.1186/s13550-026-01527-4

Image Credits: AI Generated

DOI: 10.1186/s13550-026-01527-4

Keywords: therapeutic radiopharmaceuticals, scoping review, rodent studies, nonclinical safety, clinical pathology, histopathology, hematology, kidney injury, PRISMA-ScR, reporting framework, radionuclides, EJNMMI Research