NASA SPECIALIZED CENTER OF RESEARCH

High-energy ionizing radiation (IR) is constantly streaming through space; however, the geomagnetic field around Earth protects us from its harmful effects. Consequently, any journeys into deep space beyond the Earth's magnetosphere (i.e. beyond low earth orbit) would expose traveling astronauts to this highly-penetrating type of radiation. Major sources of ionizing radiation in space include:

• galactic cosmic radiation (GCR) originating from beyond our solar system,

• solar particle events (SPEs) or solar storms,

• radiation trapped in orbit around earth's magnetosphere (Van Allen Belt).

The radiation field in space, unlike that found on Earth, is heterogeneous and predominantly composed of high-energy protons and high-energy, high-charge particles, such as iron, silicon and oxygen ions.

A major goal of the National Aeronautics and Space Administration's (NASA) life-science research program is to enable human exploration of space with risks from space radiation as low as reasonably possible. In a joint effort with the University of Texas Southwestern, the goal of our NASA Specialized Center of Research (NSCOR) is to assess in vivo the risks and molecular characteristics of increased intestinal carcinogenesis following space radiation exposure.

Gastrointestinal (GI) tumors are frequent in the U.S. and colorectal cancer (CRC) is the third most common cancer, accounting for 10% of all cancer deaths. The American Cancer Society estimates that in the year 2010, 142,570 people were diagnosed with colorectal cancer, and 53,194 people died from it (the American Cancer Society). Precancerous lesions are present in about 10% of adults at age 40 (approximately the average age of a typical astronaut) and their incidence increases to ~25% in older adults. Moreover, IR is a known risk factor for colorectal cancer based on studies such as the A-bomb survivor cohort. Therefore, even a modest exposure to space radiation could have a significant effect on health risk estimates for future manned space flights.

Previous studies based on mathematical and statistical modeling have demonstrated an individual having significant probability of developing cancer after a mission to Mars, secondary to chronic radiation exposure. Despite these findings, large uncertainties still exist when making risk projections mainly because there are limited biological data to describe the effects of protons and galactic cosmic rays on mouse or human tissues. Because of these uncertainties, the safety margins have to remain high, limiting how long an astronaut can remain in space. The overarching goal of our proposed studies is to improve the understanding of GI cancer initiation, promotion and progression due to space-type radiation and to contribute to reducing the margin of uncertainty regarding GI cancer following space travel.

The application of scaling factors is probably the only practical approach to human cancer risk estimation for space radiation where the carcinogenic relative biological effectiveness (RBE) of space-type radiation is determined in animal models, and then extrapolated for use in human risk estimation, which is itself derived using epidemiologic risk estimates from terrestrial exposures. Risk modeling is being carried out by Dr. Brenner's team at Columbia University.

Mutations in the adenomatous polyposis coli (APC) gene are involved early in development of both sporadic and familial colon cancer (familial adenomatous polyposis, FAP). Loss of wild-type APC function initiates polyp formation, probably due to cells migrating along the crypt-villus axis continuing to proliferate, rather than differentiate and cease to further divide as happens in healthy tissue. The ApcMin mouse (ApcMin/+), which has a truncation mutation at codon 850, is the most studied of the APC mutants and there is a large literature that has shown its utility as a model for intestinal cancer initiation and prevention studies. Additional mouse models are available for key target genes in colorectal cancer and will also be employed in this program.