Risk of Acute (In-flight) or Late Central Nervous System Effects from Radiation Exposure Evidence Report: Risk of Acute and Late Central Nervous System Effects from Radiation Exposure Human Research Program Space Radiation Program Element Approved for Public Release: April 6, 2016 National Aeronautics and Space Administration Lyndon B. Johnson Space Center Houston, Texas 1 Risk of Acute (In-flight) or Late Central Nervous System Effects from Radiation Exposure CURRENT CONTRIBUTING AUTHORS: Gregory A. Nelson Loma Linda University/ NASA IPA NASA Johnson Space Center, Houston, TX Lisa Simonsen NASA Langley Research Center, Hampton, VA Janice L. Huff Universities Space Research Association, Houston, TX PREVIOUS CONTRIBUTING AUTHORS: Francis A. Cucinotta NASA Johnson Space Center, Houston, TX Janice L. Huff Universities Space Research Association, Houston, TX Myung-Hee Y. Kim Universities Space Research Association, Houston, TX Janapriya Saha Universities Space Research Association, Houston, TX Minli Wang Universities Space Research Association, Houston, TX Frank M. Sulzman Universities Space Research Association, Houston, TX Reference for original report: Human Health and Performance Risks of Space Exploration Missions, (Jancy C. McPhee and John B. Charles, editors), NASA SP-2009- 3405, 2009. Slack KJ, Shea C, Leveton LB, Whitmire AM, Schmidt LL (2009) Risk of Behavioral and Psychiatric Conditions In: McPhee JC, Charles JB (eds) Human Health and Performance Risks of Space Exploration Missions, NASA SP-2009-3405 2 Risk of Acute (In-flight) or Late Central Nervous System Effects from Radiation Exposure TABLE OF CONTENTS: I. PRD RISK TITLE: RISK OF ACUTE (IN-FLIGHT) AND LATE CENTRAL NERVOUS SYSTEM EFFECTS FROM RADIATION EXPOSURE ........................... 5 II. EXECUTIVE SUMMARY ................................................................................................. 5 III. INTRODUCTION ................................................................................................................ 7 A. Description of CNS Risks of Concern to NASA ................................................................... 9 B. Current NASA Permissible Exposure Limits (PELs) .......................................................... 9 IV. EVIDENCE ........................................................................................................................ 10 A. Review of Human Data ......................................................................................................... 10 B. Review of Space Flight Issues .............................................................................................. 11 C. Radiobiology Studies of CNS Risks for Protons, Neutrons and HZE Nuclei .................. 12 1. Overall observations ...................................................................................................... 12 2. Effects in Neuronal Cells and the CNS .......................................................................... 12 a. CNS Structure ............................................................................................................... 12 b. Neurogenesis ................................................................................................................. 14 c. Oxidative Stress ............................................................................................................ 14 d. Neuroinflammation ....................................................................................................... 16 e. Microvascular Changes ................................................................................................. 18 f. Neuronal and Brain Tissue Structural Changes ............................................................ 18 g. Electrophysiology ......................................................................................................... 20 h. Molecular Marker Changes ........................................................................................... 22 i. Loss of Autophagy ......................................................................................................... 25 3. Behavioral Effects .......................................................................................................... 25 a. Overall Observations ..................................................................................................... 25 b. Sensorimotor Tests ........................................................................................................ 26 c. Conditioned Taste Aversion .......................................................................................... 26 d. Operant Conditioning .................................................................................................... 27 e. Learning and Memory ................................................................................................... 28 f. Novel Object Recognition ............................................................................................ 29 g. Tests of Executive Function .......................................................................................... 31 h. Emesis ........................................................................................................................... 33 4. Neurodegenerative Changes .......................................................................................... 34 D. Non-Human Primate Research ............................................................................................ 35 1. Rationale .......................................................................................................................... 35 2. Previous Behavioral Studies with Irradiated Non-Human Primates ............................... 36 E. Future Research Strategies- Recommendations of an Ad-Hoc Panel on CNS Research 40 3 Risk of Acute (In-flight) or Late Central Nervous System Effects from Radiation Exposure V. ADVERSE OUTCOME PATHWAYS AND COMPUTER MODELING FOR ESTIMATION OF CNS RISKS ....................................................................................... 41 A. Adverse Outcome Pathway Frameworks ............................................................................ 41 B. Models Applicable to Radiation-Induced CNS Responses ................................................. 43 VI. RISK IN CONTEXT OF EXPLORATION MISSION OPERATIONAL SCENARIOS 45 A. Projections for Space Missions ............................................................................................ 45 B. Potential for Biological Countermeasures .......................................................................... 46 C. Individual Risk Factors ........................................................................................................ 47 D. Synergistic Effects of Spaceflight ........................................................................................ 48 VII. GAPS ................................................................................................................................... 48 VIII. CONCLUSION ........................................................................................................... 49 IX. REFERENCES ................................................................................................................... 50 X. TEAM .................................................................................................................................. 67 XI. LIST OF ACRONYMS ..................................................................................................... 67 4 Space Radiation CNS Risks I. PRD Risk Title: Risk of Acute (In-flight) and Late Central Nervous System Effects from Radiation Exposure Possible acute and late risks to the central nervous system (CNS) from galactic cosmic rays (GCR) and solar particle events (SPE) are concerns for human exploration of space. Acute CNS risks may include: altered cognitive function, reduced motor function, and behavioral changes, all of which may affect performance and human health. Late CNS risks may include neurological disorders such as Alzheimer’s disease (AD), dementia and premature aging. Although detrimental CNS changes are observed in humans treated with high-dose radiation (e.g., gamma rays and protons) for cancer and are supported by experimental evidence showing neurocognitive and behavioral effects in animal models, the significance of these results on the morbidity to astronauts has not been elucidated. There is a lack of human epidemiology data on which to base CNS risk estimates; therefore, risk projection based on scaling to human data, as done for cancer risk, is not possible for CNS risks. Research specific to the spaceflight environment using animal and cell models must be compiled to quantify the magnitude of CNS changes in order to estimate this risk and to establish validity of the current permissible exposure limits (PELs). In addition, the impact of radiation exposure in combination with individual sensitivity or other space flight factors, as well as assessment of the need for biological/pharmaceutical countermeasures, will be considered after further definition of CNS risk occurs. II. Executive Summary The possible acute and late risks to the CNS from GCR and SPEs are a documented concern for human exploration of our solar system (NAS 1973; NAS-NRC 1996; NCRP 2006; NAS 2008; NRC 2008; NCRP 2014). In the past, the risks to the CNS in adults exposed to low to moderate doses of ionizing radiation (0 to 2 gray (Gy), where 1 Gy