Baulch, Janet

Borak, Tomas

Britten, Richard

Limoli, Charles L

English

eScholarship - University of California

UC IrvineUC Irvine Previously Published WorksTitleResponse to the Commentary from Bevelacqua et al.Permalinkhttps://escholarship.org/uc/item/92b7b109JournaleNeuro, 7(1)ISSN2373-2822AuthorsLimoli, Charles LBritten, RichardBaulch, Janetet al.Publication Date2020DOI10.1523/eneuro.0439-19.2019Copyright InformationThis work is made available under the terms of a Creative Commons Attribution License, available at https://creativecommons.org/licenses/by/4.0/ Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaCognition and BehaviorComments on “New Concerns for Neurocognitive Function during Deep Space Exposures to Chronic, Low Dose Rate,Neutron Radiation” https://doi.org/10.1523/ENEURO.0329-19.2019Response to the Commentary from Bevelacqua et al.Charles L. Limoli,1 Richard Britten,2 Janet Baulch,1 and Tomas Borak3https://doi.org/10.1523/ENEURO.0439-19.20191Department of Radiation Oncology, University of California, Irvine, Irvine, California 92697, 2Department of RadiationOncology, Eastern Virginia Medical School, Norfolk, Virginia 23501, and 3Department of Environmental andRadiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523Key words: commentary; deep space; response; travelThis response clarifies certain misconceptions publishedin the commentary by Bevelacqua et al. (2019).We are pleased that our article entitled “New concerns forneurocognitive function during deep space exposures tochronic, low dose rate, neutron radiation” (Acharya et al.,2019) has stimulated interesting discussions and differentperspectives on what may or may not be relevant to esti-mating the risks of CNS dysfunction following exposure tothe space radiation environment. Here we provide our re-sponse to the commentary from Bevelacqua et al. (2019).Bevelacqua et al. (2019) stated that there were a fewmajor shortcomings with our approach, and we would like toclarify our stance regarding those statements. The first andperhaps most disconcerting statement was their assertionthat we have ignored “. . .that in a realistic space environ-ment, cells will be exposed to multiple low LET (linear energytransfer) protons before being traversed by intermediate andhigh-LET HZE (high charge and energy) particles.” The au-thors of Acharya et al. (2019) have conducted research atheavy ion particle accelerators around the world for morethan a decade, and the implication that we might be un-aware of the complexities of the radiation fields in space ismisguided (Parihar et al., 2015, 2016, 2018; Lee et al., 2017).During long-term missions into deep space, astronauts willbe exposed to a complex radiation field that includes high LETcomponents from high energy, heavy ions (HZE particles) atlow dose rates of 0.5 mGy/d for long durations. About 20% ofthe dose is delivered with LET 10 keV/m.Particle accelerators are capable of simulating compo-nents of the galactic cosmic radiation (GCR) spectrum. Themain impediment to performing accelerator-based experi-ments, which are designed to simulate exposures to highLET radiations during extended missions in space, is that itis not reasonable to irradiate large numbers of rodents con-tinuously over many months at meaningful and relevantdoses and dose rates. Fast neutrons from nuclear fissioncreate charged particle nuclei in tissues that have an LETranging from 10 to 200 keV/m. We were careful not toimply that the radiation environment in the 252Cf facility is anexact replica of conditions within a spacecraft or habitat indeep space. However, the charged particles generated byneutrons are produced uniformly in small animals with adose-averaged LET that is similar to many of the HZE com-ponents of the GCR and about a factor of two higher thanspace radiation fields resulting from penetrating particlesand nuclear fragmentation downstream of shielding.We disagree with the statement that precision mea-surements of dose rates and radiation quality for themixed fields within this facility are “. . .significantly easierthan determining the dose from a spectrum of protonsand HZE particles of much greater energy.” Complexdosimetry was required for a large facility capable ofexposing 900 mice and 60 rats simultaneously. The radi-ation field at the exposure location consists of directneutrons from the source as well as albedo neutrons fromthe walls and floor. There is also a component of directphotons emitted from the source and scattered photonsfrom the surrounding shielding. Tissue equivalent propor-tional counters (TEPCs) were used to measure neutrons.A miniature GM (Geiger-Müller) counter and CaF2 ther-moluminescent dosimeters were used to measure pho-tons. Data from the TEPCs provide direct estimates of thedose rate from neutrons around the room as well asReceived October 22, 2019; accepted December 4, 2019; First publishedDecember 17, 2019.The authors declare no competing financial interests.Author contributions: C.L.L., R.B., J.B., and T.B. wrote the paper.This research was supported by National Aeronautics and SpaceAdministration-Johnson Space Center Grants NNX15AI22G andNNX15AK13G.Correspondence should be addressed to Charles L. Limoli at Climoli@uci.edu.https://doi.org/10.1523/ENEURO.0439-19.2019Copyright © 2020 Limoli et al.This is an open-access article distributed under the terms of the CreativeCommons Attribution 4.0 International license, which permits unrestricted use,distribution and reproduction in any medium provided that the original work isproperly attributed.CommentaryJanuary/February 2020, 7(1) ENEURO.0439-19.2019 1–2patterns of energy deposition in volumes of tissue similarto the size of a mammalian cell (i.e., lineal energy). Thesedata encompass all the direct and complex environmentalmodifications to the radiation exposures. Eighty percentof the total dose is from nuclear recoil particles producedby neutron interactions in tissue and 20% is from incidentphotons. Further details regarding the radiation dosimetryof this facility have been published (Borak et al., 2019).The authors correctly point out that the animals in the252Cf facility are not subjected to “multiple low LET pro-tons before being traversed by intermediate and high LETparticles.” They imply that this sequential process of ex-posure can lead to the induction of adaptive responses inspace. However, it must be noted that in our 252Cf facilityanimals are exposed continuously to low LET photonswith intermittent production high LET nuclear recoils.The assertion that this study should have taken intoaccount the possibility of adaptive responses seems mis-guided. Adaptive responses have never been convinc-ingly demonstrated in vivo and are considered by manyradiobiologists to be artifacts of in vitro cell culture (Sowaet al., 2010, 2011). To that end, none of the referencesprovided in the commentary documented conclusive ev-idence regarding the adaptive response in vivo, much lessin the CNS. Further, the idea that functional CNS endpoints such as cognition, behavior, and electrophysiologywould resemble what has been found using in vitro cul-tures of various cancer cell lines is incongruous. Preciselyhow in vitro studies using transformed cancer cells canshed any light on the functionality of an intact brain isunclear. No agency responsible for radiation protectionhas incorporated adaptive response into risk assessmentmodels because this effect is not adequately supported inanimals or humans.We are confused with the authors criticism of this workbased on the premise that “The absorbed dose does notcorrespond to a biological detriment.” The suggestion ofBevelacqua et al. (2019) to introduce International Commis-sion on Radiologic Protection stochastic quality factors orradiation weighting factors is meaningless for neurocognitivefunction. These dose-modifying factors are based on carci-nogenesis in humans with most information derived fromacute exposures. The objectives of investigations at the252Cf facility are to establish dose, dose rate, and radiationquality effects on biological end points that are beyond thereach of other available experimental protocols. It could beargued that these results will provide valuable information forcreating the next generation of dose-modifying factors forradiation risk analysis.One of the primary driving forces for establishing theneutron facility at Colorado State University was to investi-gate dose rate effects, since there is a large and reproduc-ible body of literature demonstrating that lowering the doserate (in cGy/h) provides for the temporal overlap of DNArepair during dose delivery. The end result is that nearly all ofthe adverse effects of exposure to ionizing radiation areameliorated at low dose rates simply due to effective DNArepair. It stands to reason then that at space-relevant doserates similar reductions in adverse effects would be ob-served, which was not the case in the study by Acharya et al.(2019). It is also important to keep in mind that a criticaldifference between the study by Acharya et al. (2019) andthe references cited by Bevelacqua et al. (2019) is that wedid not investigate putative carcinogenic end points in cul-tured cells. Dose rate effects can be expected to play arelatively minor role in a largely postmitotic organ such as thebrain, especially when considering the multifaceted func-tions that characterize the CNS. At the low doses and doserates used in Acharya et al. (2019) radiation effects are notlikely the result of cell killing, but rather an accumulation ofdamage to networks of cells that adversely impact neu-rotransmission.Regardless of the mechanism, findings from the studyby Acharya et al. (2019) demonstrated significant impair-ments in the brain under the stated irradiation conditions,with no evidence for attenuation by adaptive and/or DNArepair processes over the protracted exposure time. De-spite our disagreements with the commentary proffered,we hope these discussions can help the National Aero-nautics and Space Administration and other agenciesproperly evaluate the CNS risks associated with exposureto the deep space radiation environment (Limoli, 2017).ReferencesAcharya MM, Baulch JE, Klein PM, Baddour AAD, Apodaca LA,Kramar EA, Alikhani L, Garcia C Jr, Angulo MC, Batra RS, FallgrenCM, Borak TB, Stark CEL, Wood MA, Britten RA, Soltesz I, LimoliCL (2019) New concerns for neurocognitive function during deepspace exposures to chronic, low dose rate, neutron radiation.eNeuro 6:ENEURO.0094-19.2019.Bevelacqua JJ, Welsh J, Mortazavi SMJ (2019) Comments on “newconcerns for neurocognitive function during deep space expo-sures to chronic, low dose rate, neutron radiation”. eNeuro6:ENEURO.0329-19.2019.Borak TB, Heilbronn LH, Krumland N, Weil MM (2019) Design anddosimetry of a facility to study health effects following exposuresto fission neutrons at low dose rates for long durations. Int J RadiatBiol. Advance online publication. Retrieved November 14, 2019.doi: 10.1080/09553002.2019.1688884.Lee SH, Dudok B, Parihar VK, Jung KM, Zöldi M, Kang YJ, MarosoM, Alexander AL, Nelson GA, Piomelli D, Katona I, Limoli CL,Soltesz I (2017) Neurophysiology of space travel: energetic solarparticles cause cell type-specific plasticity of neurotransmission.Brain Struct Funct 222:2345–2357.Limoli CL (2017) Deep-space deal breaker. Sci Am 316:54–59.Parihar VK, Allen B, Tran KK, Macaraeg TG, Chu EM, Kwok SF,Chmielewski NN, Craver BM, Baulch JE, Acharya MM, CucinottaFA, Limoli CL (2015) What happens to your brain on the way toMars. Sci Adv 1:e1400256.Parihar VK, Allen BD, Caressi C, Kwok S, Chu E, Tran KK,Chmielewski NN, Giedzinski E, Acharya MM, Britten RA, BaulchJE, Limoli CL (2016) Cosmic radiation exposure and persistentcognitive dysfunction. Sci Rep 6:34774.Parihar VK, Maroso M, Syage A, Allen BD, Angulo MC, Soltesz I,Limoli CL (2018) Persistent nature of alterations in cognition andneuronal circuit excitability after exposure to simulated cosmicradiation in mice. Exp Neurol 305:44–55.Sowa MB, Goetz W, Baulch JE, Pyles DN, Dziegielewski J, Yovino S,Snyder AR, de Toledo SM, Azzam EI, Morgan WF (2010) Lack ofevidence for low-LET radiation induced bystander response innormal human fibroblasts and colon carcinoma cells. Int J RadiatBiol 86:102–113.Sowa MB, Goetz W, Baulch JE, Lewis AJ, Morgan WF (2011) Noevidence for a low linear energy transfer adaptive response inirradiated RKO cells. Radiat Prot Dosimetry 143:311–314.Commentary 2 of 2January/February 2020, 7(1) ENEURO.0439-19.2019 eNeuro.org

Response to the Commentary from Bevelacqua et al.

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Response to the Commentary from Bevelacqua et al.

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