Acute and late effects of combined internal and external radiation exposures on the hematopoietic system

Abstract

Purpose: Incidents, such as nuclear facility accidents and the release of a ‘dirty bomb’, might result in not only external irradiation of personnel, but additional internal exposures through concomitant inhalation and/or ingestion of radioactive particulates. The purpose of this study was to define the impact of such a combination of radiation injuries on the hematopoietic niche.

Material and methods: To assess changes in the murine hematopoietic system, we used a combined exposure of total body irradiation (TBI, 6 Gy) followed immediately by an internal (intraperitoneal) administration of 100 µCi of soluble ¹³⁷Cs. We then evaluated acute survival in combined versus single modality exposure groups, as well as assessing hematopoietic function at 12 and 26 week time points.

Results: Acutely, the combination of external and internal exposures led to an unexpected delay in excretion of ¹³⁷Cs, increasing the absorbed dose in the combined exposure group and leading to mortality from an acute hematopoietic syndrome. At 12 weeks, all exposure paradigms resulted in decreased numbers of phenotypic hematopoietic stem cells (HSCs), particularly the short-term HSCs (ST-HSC); long-term HSCs (LT-HSC) were depleted only in the internal and combined exposure groups. At 26 weeks, there was significant anemia in both the TBI alone and combined exposure groups. There were decreased numbers in both the LT- and ST-HSCs and decreased functionality, as measured by competitive repopulation, was seen in all radiation groups, with the greatest effects seen in the internal and combined exposure groups.

Conclusions: Our data indicate that a combined injury of sublethal external irradiation with internal contamination induces significant and persistent changes in the hematopoietic system, as may have been predicted from the literature and our own group’s findings. However, a novel observation was that the combined exposure led to an alteration in the excretion kinetics of the internal contamination, increasing the acute effects beyond those anticipated. As a result, we believe that a combined exposure poses a unique challenge to the medical community during both the acute and, possibly, delayed recovery stages.

Keywords:

• Hematopoiesis
• combined radiation injury
• internal contamination
• bone marrow late effects

Acknowledgments

The authors would like to thank the following: Eric Hernady (Williams laboratory), for performing the irradiations, and his subsequent in vivo work and data collection alongside Olga Bromberg (Calvi laboratory); Joe St. Martin (Radiation Safety) for his assistance collecting the internal dosimetry readings; and Dr. Bruce Fenton for his assistance in developing and executing the image analysis. Finally, we thank Dr. Michael Stabin, Vanderbilt University, for his assistance in calculating the absorbed dose from the internal contamination.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

These studies were supported by National Institutes of Health, NIAID grants, [5 U19 AI091036] and [U01 AI107276].

Notes on contributors

Laura M. Calvi

Laura M. Calvi, MD, lead author, is a Professor in the Departments of Medicine, Neurosurgery, and Pharmacology and Physiology at the University of Rochester Medical Center and a member of the Wilmot Cancer Institute.

Benjamin J. Frisch

Benjamin J. Frisch, PhD, is a Research Assistant Professor in the Department of Medicine at the University of Rochester Medical Center.

Paul D. Kingsley

Paul D. Kingsley, PhD, is a Research Assistant Professor in the Department of Pediatrics, Hematology and Oncology at the University of Rochester Medical Center.

Anne D. Koniski

Anne D. Koniski, MA, is a Senior Technical Associate in the Department of Pediatrics, Hematology and Oncology at the University of Rochester Medical Center.

Tanzy M. Love

Tanzy M. Love, PhD, is an Associate Professor in Biostatistics and Computational Biology at the University of Rochester Medical Center and a member of the Wilmot Cancer Institute.

Jacqueline P. Williams

Jacqueline P. Williams, PhD, FASTRO, first senior author, is a Professor in Environmental Medicine and Radiation Oncology at the University of Rochester Medical Center and a member of the Wilmot Cancer Institute.

James Palis

James Palis, MD, second senior author, is a Professor of Pediatrics, Hematology and Oncology and of Biomedical Genetics at the University of Rochester Medical Center and a member of the Wilmot Cancer Institute.