Carcinogenesis following space radiation exposures is considered the primary impediment to human space exploration. Calculating the actual risks confronted by spaceflight crews is complicated by our limited understanding of the carcinogenic effects of high charge, high energy (HZE) ions—a radiation type for which no human exposure data exists. The current NASA model to calculate cancer risk from space radiation exposures is built largely upon epidemiological data from the survivors of the Hiroshima and Nagasaki atomic bombings, a cohort of individuals exposed predominantly to γ-rays. This dissertation examines some of the assumptions underpinning the current NASA model used to assess space radiation cancer risk.
Through a genetics approach using carcinogenesis data from a mouse model of population diversity, we find that not only is the spectrum of tumors induced by accelerator produced HZE ions similar to the spectra of spontaneous and γ ray-induced tumors, but that the QTL controlling susceptibilities often overlap between groups. This overlap indicates shared tumorigenesis mechanisms between γ-ray and HZE ion exposures and supports the use of human epidemiological data from γ-ray exposures to predict cancer risk from galactic cosmic rays.
Permissible exposure limits for astronauts are based on the risk of death from cancer rather than cancer incidence. Because the incidence to mortality conversion used in current risk calculations is based on mortality from background cancers in the U.S. population, there is an assumption that radiogenic tumors are no more lethal than spontaneous tumors. We find that malignancy, as measured by metastases endpoints, is comparable for spontaneous tumors and tumor induced following HZE ion or γ-ray exposures.
To efficiently utilize the vast genetic resources produced in this study, cataractogenesis endpoints are characterized and QTL mapping is performed. The progression of radiation-induced ocular changes is followed by dilated slit lamp biomicroscopy, with each mouse being examined up to seven times post-irradiation. Progressive, radiation-associated lens changes are noted in both HZE ion and γ-ray exposed populations. QTL controlling latencies for radiation-induced cataracts are identified and overlap in susceptibility loci are observed for mice exposed to HZE ion and γ-ray radiation.
Finally, because sufficiently powered lifetime carcinogenesis studies have not been previously undertaken in highly recombinant outbred mouse populations, many of the QTL presented here are novel. QTL are described for 11 tumor histotypes, radiation-induced cataractogenesis, and neurobehavioral endpoints. For tumor incidence, 51 QTL are presented with an average confidence interval of 3.4 megabases and effect sizes averaging 3.7% (range: 0.75 - 7.46%). Commonly for these endpoints, the genetic architecture of the phenotypic variance is complex with multiple QTL individually explaining only a small proportion of the total variance. Although loci with moderate effects on the phenotype were most common, 11 large effect QTL are described for 7 tumor histotypes, with effect sizes greater than 5%.
The results presented in this dissertation indicate that cancer risks following space radiation exposures are largely determined by genetic background and can be calculated based on epidemiologic data from terrestrial radiation exposures. Therefore, the subpopulations at increased risk for radiation-induced tumors on Earth are likely to substantially overlap with subpopulations at increased risk in the space radiation environment. These findings support the assumptions underlying the current model used by NASA to estimate fatal cancer risks from space radiation exposures. Additionally, this work indicates that individualized cancer risk assessment may be warranted to mitigate cancer and health risks from space radiation exposures. (Abstract shortened by ProQuest.)
|Advisor:||Weil, Michael M., VandeWoude, Sue|
|Commitee:||Kamstock, Debra, Olver, Christine, Thamm, Doug|
|School:||Colorado State University|
|Department:||Microbiology, Immunology, and Pathology|
|School Location:||United States -- Colorado|
|Source:||DAI-B 78/05(E), Dissertation Abstracts International|
|Subjects:||Toxicology, Surgery, Pathology, Bioinformatics|
|Keywords:||Carcinogenesis, Genomic mapping, High-energy ions, Quantitative trait loci, Radiation|
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