Analyses of cancer incidence and other morbidities in gamma irradiated B6CF1 mice.

Alia Zander,Gayle E Woloschak,Tatjana Paunesku,Roberto Amendola

doi:10.1371/journal.pone.0231510

Abstract

With increasing medical radiation exposures, it is important to understand how different modes of delivery of ionizing radiation as well as total doses of exposure impact health outcomes. Our lab studied the risks associated with ionizing radiation by analyzing the Northwestern University Radiation Archive for animals (NURA). NURA contains detailed data from a series of 10 individual neutron and gamma irradiation experiments conducted on over 50,000 mice. Rigorous statistical testing on control mice from all Janus experiments enabled us to select studies that could be compared to one another and uncover unexpected differences among the controls as well as experimental animals. For controls, mice sham irradiated with 300 fractions died significantly earlier than those with fewer sham fractions and were excluded from the pooled dataset. Using the integrated dataset of gamma irradiated and control mice, we found that fractionation significantly decreased the death hazard for animals dying of lymphomas, tumors, non-tumors, and unknown causes. Gender differences in frequencies of causes of death were identified irrespective of irradiation and dose fractionation, with female mice being at a greater risk for all causes of death, except for lung tumors. Irradiated and control male mice were at a significantly greater risk for lung tumors, the opposite from observations noted in humans. Additionally, we discovered that lymphoma deaths can occur quickly after exposures to high doses of gamma rays. This study systematically cross-compared outcomes of different modes of fractionation evaluated across different Janus experiments and across a wide span of total doses. It demonstrates that protraction modulated survival and disease status differently based on the total dose, cause of death, and sex of an animal. This novel method for analyzing the Janus datasets will lead to insightful new mechanistic hypotheses and research in the fields of radiation biology and protection.

Highlights

Ionizing radiation is an unavoidable risk in daily life and understanding its biological impacts is important for setting radiation protection standards
Because general stress is the only probable cause for the increased death hazard observed in this group of animals and irradiated animals exposed to 300 fractions most likely experienced the same stress, we excluded mice exposed to 300 fractions from our main analysis
By graphing predicted outcomes under varying conditions, we discovered that when the difference between high and low total doses is small (10cGy vs 100cGy), fractionation is the biggest determinate for tumor incidence, with acute exposures resulting in the most tumors (Fig 4D)

Summary

Introduction

Ionizing radiation is an unavoidable risk in daily life and understanding its biological impacts is important for setting radiation protection standards. The major source of data on whole-body human exposures to gamma radiation is the Life Span Study (LSS) cohort that includes over 120,000 survivors of the atomic bombing in 1945 [3,4,5,6]. While these data have been a remarkable resource for epidemiological studies determining risks associated with acute exposures [5, 7,8,9,10,11,12,13], extrapolation of health risks to humans exposed intermittently to lower doses of radiation remains uncertain. This study is a prime example of utilizing archives by analyzing data in a new light to further augment our understanding of radiation biology

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Results

Discussion