Large SPEs, especially when the shielding is inadequate, not only increase the risk of cancer, but also the possibility of occurrence of acute radiation syndrome (ARS). As physical shielding alone cannot solve current space radiation problems, in 2003 we introduced the adaptive response as an efficient model of biological protection. The development of this model is discussed in our recent publications. A recently published paper, authored by 30 scientists from countries such as US, UK, Russia, and Belgium has confirmed the need for selection of astronauts based on their adaptive response (this paper cites our reports on how AR helps choosing the astronauts for a deep space mission). Moreover, A NASA report published in 2016 has cited our early report on the importance of radioadaptive response in space missions and states that cells can be expected to be exposed to multiple hits of protons before being traversed by an HZE particle. However, substantial evidence showing that SPEs are a real concern, indicate that our proposed model is more applicable and evidence-based. Regarding the risk of infection, change of the virulence (ability to cause disease) of microorganisms and astronauts’ dysregulated immune system, significantly increases the infection risk in deep space missions.

1. Adaptive Response May Reduce Acute Radiation
Syndrome (ARS) and Infection Risk During Long
Term Manned Space Missions and Decrease Post
Mission Cancer Risk
SMJ Mortazavi, Ph.D
Fox Chase Cancer Center
Philadelphia, PA 19111
Email: S.M.Javad.Mortazavi@fccc.edu
1
Disclaimer: Opinions expressed in this presentation are my own professional opinion, and do not
represent those of Fox Chase Cancer Center.
© 2018 SMJ Mortazavi

2. Adaptive Response in NASA Report
• A NASA report entitled “Evidence
Report: Risk of Radiation
Carcinogenesis”(Huff et al., 2016)
that is approved for public release
on April 7, 2016 has cited our 2003
report as well as other reports on
the importance of adaptive
response studies in deep space
missions.
Mortazavi SMJ, Ph.D
2

3. Mortazavi SMJ, Ph.D
3
Adaptive Response in NASA Report

4. • “There have been several studies performed
that indicate an adaptive response to low-dose
ionizing radiation can provide a level of
protection against future exposures
(Bhattacharjee and Ito 2001; Mortazavi et al.
2003; Elmore et al. 2008; Rithidech et al.
2012). This may be particularly important for
understanding risks in the space environment
because the GCR environment is comprised
predominantly of protons, and it is realistic to
expect that cells will be exposed to multiple hits
of protons prior to being traversed by an HZE
particle”.
Mortazavi SMJ, Ph.D
4
Adaptive Response in NASA Report

5. Mortazavi SMJ, Ph.D
5
 A recently published
paper (Oncotarget
Journal), authored by
30 scientists from US,
UK, Russia, Belgium,…
confirms the need for
selection of astronauts
based on their adaptive
response (as we
proposed it in 2003)

6. Mortazavi SMJ, Ph.D
6
"There is a strong evidence of a wide range of adaptive
response among different individuals, suggesting that
medical selection of the candidates based on the in
vitro adaptive response studies is very promising
[108, 186, 188, 189]"
"Countries actively engaged in development of the spaceflight
missions, such as United States and Russia, have well-
established protocols for selection of the potential candidates.
While these selection pipelines differ substantially from one to
another 184, 185], in vitro adaptive response studies is the only
approach widely implemented for the medical selection of the
radioresistant individuals [186, 187]. "

7. Mortazavi SMJ, Ph.D
7

8. Mortazavi SMJ, Ph.D
8
Prof SMJ Mortazavi Prof A Niroomand-Rad Prof J R Cameron
So, what’s the model proposed by
our team?
Our early projects date back to 2003!
Univ W MadisonShiraz Univ Med Sci,
Shiraz, Iran
Georgetown Univ,
Univ W Madison

9. Mortazavi SMJ, Ph.D
9
Radiation Protection Challenges
in Space
Three General Guidelines:
•Time (Generally Not Applicable in Space,
Needs New Technologies for Propulsion
System)
•Distance (Not Applicable in Space,
Inverse Square Law Doesn’t help!)
•Shield (Not Easily Applicable in Space due
to Weight Limitations)

10. Mars Mission as a New Challenge
• “Typical missions to the
International Space Station
last six months.
• A round-trip mission to
Mars could last three years.
Key question:
• Do the effects of being in
space change over time?”
Mortazavi SMJ, Ph.D
10
NASA is taking the first steps on its
Journey to Mars. Artist’s concept,
looking toward Mars.
Credits: NASA
Source:
https://www.nasa.gov/feature/bridging-the-gap-nasa-studies-the-
human-body-in-space-for-one-year-to-extrapolate-for

11. Mortazavi SMJ, Ph.D
11
Our Integrative Radiation Protection
Plan Includes:
Physical Shielding
Adaptive response
(Biological Protection)
Other Biological Protection
Methods

12. Mortazavi SMJ, Ph.D
12
Our Integrative Protection
Plan:
Physical Shielding
Adaptive response
Biological Protection

13. Mortazavi SMJ, Ph.D
13
 Other researchers as well as our
team have conducted some
experiments on design and
fabrication of appropriate
radiation shields for spacecrafts.
 In spite of some advances in this
field, it will be discussed here
that improving the physical
shielding alone cannot solve the
problem of exposure to high
levels of radiation in a long term
space mission.
Our previous and current experiences:

14. Mortazavi SMJ, Ph.D
14
Challenges of Physical Shielding in
Space:
 Weight Limitations
 Extravehicular Activities (Space
Walking)

15. Mortazavi SMJ, Ph.D
15
“For space applications, however,
every kilogram of mass has a
significant impact upon the
mission cost and feasibility.”
http://large.stanford.edu/courses/20
15/ph241/clark1/

16. Mortazavi SMJ, Ph.D
16
“ In fact, shielding is very
difficult in space: the very high
energy of the cosmic rays and the
severe mass constraints in
spaceflight represent a serious
hindrance to effective shielding.”
Marco Durante and Francis A. Cucinotta
Physical basis of radiation protection in space travel
Rev. Mod. Phys. 83, 1245 – Published 8 November 2011
REVIEWS OF
MODERN
PHYSICS

17. Mortazavi SMJ, Ph.D
17
“For space applications, however,
every kilogram of mass has a
significant impact upon the
mission cost and feasibility.”
http://large.stanford.edu/courses/20
15/ph241/clark1/

18. Mortazavi SMJ, Ph.D
18
Physical shielding is extremely
inadequate during extravehicular
activity (EVA)!
Space Walking!

19. Mortazavi SMJ, Ph.D
19
“Examining the different methods
of space radiation shielding, it is
clear that no single good solution
currently exists to adequately
protect astronauts from the
radiation environment of space.”
http://large.stanford.edu/courses/20
15/ph241/clark1/

20. Mortazavi SMJ, Ph.D
20
Therefore, as physical
shielding alone cannot
solve current space
radiation problems, we
focused on:
• Adaptive Response
• Other Biological
Protection Methods

21. NASA’s Twin Study: Genomic Era of Space Travel
• Let’s take a look at NASA’s Twin Study
• “NASA was interested to see what happened to astronaut
Scott Kelly, in space, compared to his identical twin brother,
Mark, who remained on Earth.
• This study propelled NASA into the genomics era of space
travel.
• The Twins Study brought ten research teams from around
the country together to accomplish one goal:
 discover what happens to the human body after spending one year in
space. “
Mortazavi SMJ, Ph.D
21

22. Mortazavi SMJ, Ph.D
22
Incorrect News
Spread By Media
In contrast with lots
of incorrect news, Scott
Kelly's DNA was not
changed after spending
a year in space
Image Credit: NASA

23. Mortazavi SMJ, Ph.D
23
“NASA has a grasp on what
happens to the body after the
standard-duration six-month
missions aboard the
International Space Station, but
Scott Kelly’s one-year mission
is a stepping stone to a three-
year mission to Mars.”
Source:
https://www.nasa.gov/feature/nasa-twins-study-confirms-preliminary-
findings
NASA/Robert Markowitz

24. Mortazavi SMJ, Ph.D
24
NASA reports that "Scott’s
telomeres …actually became
significantly longer in space.
Additionally, a new finding is
that the majority of those
telomeres shortened within two
days of Scott’s return to Earth".
Source: NASA
https://www.nasa.gov/feature/nasa-twins-
study-confirms-preliminary-findings

25. Mortazavi SMJ, Ph.D
25
• It can be postulated that Scott only
needed this protective mechanism
when he was in space, maybe a
natural response to high levels of
space radiation.
• This experiment can support the
theory that at least for long-term
space missions (e.g. Mars missions),
physical shielding alone cannot be
adequate for controlling radiation-
induced stresses.
https://www.ncbi.nlm.nih.gov/pubmed/29358
922
Image Credit: NASA/SOHO

26. Mortazavi SMJ, Ph.D
26
In this light, in a Mars
mission, we need screening
for measuring the
magnitude of
radioadaptation and
selection of the best
candidates.
As discussed in our recent papers
(https://www.ncbi.nlm.nih.gov/pubmed/12971409), adaptive
response not only increases the resistance against high levels
of space radiation but also it can limit factors such as
inflammation which affect gene expression.

27. Mortazavi SMJ, Ph.D
27
Mars vs. ISS Missions
A deep space mission such as a
journey to Mars would be
completely different from ISS
missions!
• No shielding effects of
magnetosphere
• Much longer mission duration
• Urgent EVAs are more likely, so
higher radiation doses are
expected!
• More biological effects?

28. Mortazavi SMJ, Ph.D
28
Our Integrative Protection
Plan:
Physical Shielding
Adaptive response
Biological Protection

29. Mortazavi SMJ, Ph.D
29
Adaptive response, that is
an increased
radioresistance in cells or
organisms exposed to a
high challenging dose after
pre-exposure to a low
adapting dose, can
considerably reduce the
radiation susceptibility of
humans (Olivieri et al.,
1984).
Mortazavi et al. 2003
Adaptive response

30. Mortazavi SMJ, Ph.D
30
• In any irradiated biological
systems, immediate
molecular damage may
increase linearly with the
absorbed dose.
• However, the response to
radiation damage of the
whole biological system is
not linear.
Feinendegen LE
Quantification of Adaptive Protection Following Low-dose
Irradiation.
Health Phys. 2016 Mar;110(3):276-80.
doi: 10.1097/HP.0000000000000431.

31. Mortazavi SMJ, Ph.D
31
What does it mean?
 Our bodies are not passive
observers of the damages
physical and chemical
stressors induce!
 Repair mechanisms!
 Adaptation?
Feinendegen LE
Quantification of Adaptive Protection Following Low-dose
Irradiation.
Health Phys. 2016 Mar;110(3):276-80.
doi: 10.1097/HP.0000000000000431.

32. Mortazavi SMJ, Ph.D
32
“Brief exposure of a major
part of the body to more than
1 Sv may cause acute
radiation syndrome….”
Source: Radiation Injury
Arthur C. Upton, in Goldman's Cecil Medicine
(Twenty Fourth Edition), 2012
Adaptive response can
prevent ARS.
ARS can threaten the
success of space mission

33. Mortazavi SMJ, Ph.D
33
 The Galactic Cosmic Radiation (GCR) ions originate from
outside our solar system and contain mostly highly energetic
protons and alpha particles, with a small component of high
charge and energy (HZE) nuclei moving at relativistic speeds
and energies.
 About 88% of all GCR particles are hydrogen (protons), 10%
are helium (alpha particles), and the remaining percentage
(~2%) consists of heavier ions.
 In addition to GCR, unpredictable and intermittent solar
particle events (SPEs) can produce large plasma clouds
containing highly energetic protons and some heavy ions that
may cause a rapid surge of radiation both outside and within
a spacecraft.
Space Environment

34. Mortazavi SMJ, Ph.D
34
 Radiation risk from high level cosmic
rays exposure and microgravity are
two important concerns that need to
be addressed prior to a long-term
space mission.
 It has been reported that microgravity
increases the radiation susceptibility
of living organisms by a synergistic
effect.
Mortazavi et al. 2003
Radiation and Microgravity as
Two Main Barriers

35. Mortazavi SMJ, Ph.D
35
2003
Advances in
Space Research

36. Mortazavi SMJ, Ph.D
36
pp. 4299–4302 c
2003 by Universal Academy Press, Inc.

37. Mortazavi SMJ, Ph.D
37
2003

38. Mortazavi SMJ, Ph.D
38

39. Mortazavi SMJ, Ph.D
Mortazavi et al., Advances in Space Research, Vol 31, No. 6, 1543-1552, 2003
39

40. Mortazavi SMJ, Ph.D
Two survey meters show dose rates
of 142 and 143 µSv/h on contact
with a bedroom wall
40
Our proposed theory was
based on the findings of the
1st report on the induction of
adaptive response in the
residents of High Background
Radiation Areas (HBRAs)
Background of our Theory

41. Mortazavi SMJ, Ph.D
41
We didn’t use this novel method but our papers received lots
of citations!

42. Mortazavi SMJ, Ph.D
365 citations recorded by
GoogleScholasr
Adaptive response in the
residents of High
Background Radiation
Areas (HBRAs)
42
202 citations recorded by
Scopus

43. Mortazavi SMJ, Ph.D
43
 We have previously shown that
chronic exposure of humans to
ionizing radiation can lead to
induction of adaptive response
in the majority of participants.
 However, some of the
participants did not show this
phenomenon and even their
lymphocytes became more
sensitive to subsequent high
dose exposures (Synergistic
Effect).
Mortazavi et al. 2003
Inter-individual variabilities!

44. Mortazavi SMJ, Ph.D
44
o Astronauts are chronically exposed to
different levels of galactic cosmic
radiation (GCR).
o If a solar particle event (SPE) occurs,
astronauts may receive doses as high
as 1 Gy in a short time.
o In this light selection of astronauts
with high magnitude of adaptive
response would be critical.
o In this case, astronauts will be
adapted by GCR and when SPE
occurs, they will show a significant
radioresistance.
Mortazavi et al. 2003: GCR vs SPE!

45. Mortazavi SMJ, Ph.D
45
Although NASA report cites our paper,
it looks at AR from a different point of
view:
“…. Cells will be exposed to multiple
hits of protons prior to being traversed
by an HZE particle”
NASA 2016 reprt
Source: Huff, J., Carnell, L., Blattnig, S., Chappell, L., Kerry, G., Lumpkins, S., et al.
(2016). Evidence Report: Risk of Radiation Carcinogenesis. National Aeronautics and
Space Administration (NASA).

46. Mortazavi SMJ, Ph.D
46
NASA 2016 report
Our 2013 report
 Substantial evidence shows
that our proposed
mechanism is more
applicable and evidence-
based!

47. Mortazavi SMJ, Ph.D
47
NASA 2016 report
Our 2013 report
Review of the
supporting
evidence

48. Mortazavi SMJ, Ph.D
48
SPEs are a real concern!

49. Mortazavi SMJ, Ph.D
49
SPEs are a real concern!
“NASA has funded several projects that have provided
evidence for the radiation risk in space. One radiation
concern arises from solar particle event (SPE) radiation,
which is composed of energetic electrons, protons, alpha
particles and heavier particles. SPEs are unpredictable
and the accompanying SPE radiation can place astronauts
at risk of blood cell death, contributing to a weakened
immune system and increased susceptibility to infection”.
Sanzari JK1, Cengel KA1, Wan XS1, Rusek A2, Kennedy AR1.Acute Hematological Effects in Mice Exposed to the Expected Doses,
Dose-rates, and Energies of Solar Particle Event-like Proton Radiation.Life Sci Space Res (Amst). 2014 Jul 1;2:86-91.
PMID: 25202654 PMCID: PMC4155507 DOI: 10.1016/j.lssr.2014.01.003

50. Mortazavi SMJ, Ph.D
50
SPEs are a real concern!
"For future space missions outside of the Earth's
magnetic field, the risk of radiation exposure from
solar particle events (SPEs) during extra-vehicular
activities (EVAs) or in lightly shielded vehicles is a
major concern when designing radiation protection
including determining sufficient shielding
requirements for astronauts and hardware.".
Kim MH1, Hayat MJ, Feiveson AH, Cucinotta FA.Prediction of frequency and exposure level of solar
particle events.Health Phys. 2009 Jul;97(1):68-81. doi: 10.1097/01.HP.0000346799.65001.9c.

51. Mortazavi SMJ, Ph.D
51
"Ancedotal reports suggest Amifostine may have
been carried by US astronauts on their trips to the
moon (Hall, 2012), to be used in case of a solar
flare event where astronauts could be exposed to
an estimated total body dose of several Gy".
Kleiman et al. 2017
Doses in SPE!

52. Mortazavi SMJ, Ph.D
52
o “The likelihood that SPE will
produce doses that are above 1
Gy is small, while the occurrence
of doses that can induce
prodromal risks are quite
possible”.
o Wu et al.
Doses in SPE!

53. Mortazavi SMJ, Ph.D
53
High doses of radiation can induce
profound radiation sickness and death.
Lower doses of radiation induce
symptoms that are much milder
physiologically, but that pose
operational risks that are equally
serious.
Both scenarios have the potential to
seriously affect crew health and/or
prevent the completion of mission
objectives”
o Wu et al.

54. Mortazavi SMJ, Ph.D
54
 “Complicating matters is the additional ~
20% probability of short-term solar particle
events (SPEs) during the roughly 400- day
round trip to and from Mars
 This could conceivably impart a relatively
high acute dose of predominantly protons and
light ions within 1 hour or less, significantly
increasing mission total dose equivalent
(TDE)”. Rodman et al., Leukemia, 2016
The Probability of a Solar Particle
Event in Mars Missions
http://www.nature.com/leu/journal/vaop/ncurrent/full/leu2016344a.html
20%

55. Mortazavi SMJ, Ph.D
55
The average Effective dose for 6-
month ISS missions of 80 mSv
(Cucinotta et al., 2008).
Transcontinental pilots receive
annual exposures of about 1 to 5
mSv
F. Cucinotta et al. Space Radiation Risk Limits and
Earth-Moon-Mars Environmental Models, NASA
Lyndon B. Johnson Space Center 2101 NASA
Parkway, Houston, Texas 77058
Mars mission potential dose:
Up to several Gy?

56. Mortazavi SMJ, Ph.D
56

57. Mortazavi SMJ, Ph.D
57
NASA standards limit the additional risk of cancer
death by radiation exposure, not the total lifetime
risk of dying from cancer
• Baseline lifetime risk of death from cancer (non-
smokers) – 16% males, 12% females.
• After Mars Mission (solar max), Astronauts
lifetime risk of death from cancer ~20%.
https://www.nasa.gov/sites/default/files/files/1_NAC_HEO_SMD_Committee_Mars_Radiation_Intro_201
5April7_Final_TAGGED.pdf

58. Mortazavi SMJ, Ph.D
58
Is 4-8% increase in lifetime risk of death from cancer so
high? Comparing the risk with what LNT wrongly
predicts for a chest x-ray!

59. Mortazavi SMJ, Ph.D
59
 “Low doses of ionizing radiation to cells and animals may
induce adaptive responses that reduce the risk of cancer.
 However, there are upper dose thresholds above which
these protective adaptive responses do not occur.”
Mitchel RE1, Burchart P, Wyatt H. Radiat Res. 2008
Dec;170(6):765-75. doi: 10.1667/RR1414.1.
Adaptive response can reduce the risk
of cancer

60. Mortazavi SMJ, Ph.D
60
 In a study on adaptive response in high background radiation
area (HBRA) of Yangjiang, China, gene and protein
expression of receptor for advanced glycation end products
(RAGE) and S100A6 in peripheral blood and sputum in the
inhabitants were determined.
 RAGE and S100A6 expression were significantly reduced in
both gene and protein level in HBRA residents compared to
those of control area.
 Authors concluded that the low expression of RAGE and
S100A6 in HBRA group might be correlated with the adaptive
response and the low mortality of cancer in HBRA.
Adaptive response can reduce the risk
of cancer (cont.)
Zhang SP1, Wu ZZ, Wu YW, Su SB, Tong J.Mechanism study of adaptive response in high
background radiation area of Yangjiang in China.2010 Zhonghua Yu Fang Yi Xue Za Zhi,
Sep;44(9):815-9.

61. • The development of our early model of radioadaptation
as well as the importance of SPEs are discussed in detail
in our recent publications:
1. Bevelacqua JJ, Welsh J, Mortazavi SMJ. Response to ‘An overview
of space medicine’. British Journal of Anaesthesia. 2018
2018/02/01/.
2. 4. Bevelacqua JJ, Mortazavi SMJ. Commentary: Human
Pathophysiological Adaptations to the Space Environment.
Frontiers in Physiology. 2018 2018-January-08;8(1116). English.
3. 5. Mortazavi SMJ, Bevelacqua JJ, Fornalski KW, Welsh J, Doss
M. Comments on "Space: The Final Frontier-Research Relevant to
Mars". Health Phys. 2018 Mar;114(3):344-5. PubMed PMID:
29360711. Pubmed Central PMCID: PMC5784783. Epub
2018/01/24. eng.
Mortazavi SMJ, Ph.D
61

62. Mortazavi SMJ, Ph.D
62
Front Physiol. 2018 Jan 8;8:1116. doi: 10.3389/fphys.2017.01116. eCollection 2017.

63. Mortazavi SMJ, Ph.D
63
British Journal of Anaesthesia, 120 (4): 874e885 (2018)

64. Mortazavi SMJ, Ph.D
64
Mortazavi et al., Health Physics 2018 Mar;114(3):344-345. doi:
10.1097/HP.0000000000000823.

65. Mortazavi SMJ, Ph.D
65
Figure 1. (A) An in vitro adaptive response study
help choosing good candidates for deep manned
space missions. (B) During space mission, the
selected astronauts will be adapted to radiation by
exposure to chronic galactic cosmic radiation
(GCR) and will better tolerate sudden high doses
due to solar particle events (SPE).

66. Mortazavi SMJ, Ph.D
66
A. Different individuals show different
levels of radioadaptation (and some
show no radioadaptation and even
show some kind of synergism; more
adverse biological effects).
B. Candidates for deep space missions
should be screened.
C. The level of the radioadaptation of
each individual can be measured by
ground-based tests (e.g. by exposing
blood samples to a low dose and then
to a high dose radiation and measuring
parameters such as chromosome
aberrations, etc.).
Summary of the hypothesis proposed by our team:
Joseph J. Bevelacqua1 and S.M.J. Mortazavi2*
Front. Physiol., 08 January 2018 |
https://doi.org/10.3389/fphys.2017.01116

67. Measuring the magnitude of
adaptive response
• For measuring the
magnitude of adaptive
response, blood sample of
each candidate should be
divided into 4 aliquots; one
aliquot will only be exposed
to low dose, one only to high
dose, one to both adapting
and challenge doses and one
will be remained unexposed.
Mortazavi SMJ, Ph.D
67
Joseph J. Bevelacqua1 and S.M.J. Mortazavi2*
Front. Physiol., 08 January 2018 |
https://doi.org/10.3389/fphys.2017.01116

68. Measuring the magnitude of
adaptive response
• Therefore, the third aliquots
will be firstly exposed to an
adapting or conditioning low
dose (e.g. a few cGy) and then
they will be irradiated with a
challenging high dose (e.g. 1
Gy). In the next step, the
frequency of dicentrics and
rings will be determined.
Mortazavi SMJ, Ph.D
68
Joseph J. Bevelacqua1 and S.M.J. Mortazavi2*
Front. Physiol., 08 January 2018 |
https://doi.org/10.3389/fphys.2017.01116

69. Measuring the magnitude of adaptive
response
• Then the magnitude of adaptive response (MAR) will be
calculated using this equation:
• MAR = Observed frequency/Expected frequency
While expected frequency can be calculated as:
• Expected frequency =
Freq of Dic/Ring in samples only exposed to low dose +
Freq of Dic/Ring in samples only exposed to high dose –
Freq of Dic/Ring in non-exposed control samples.
Mortazavi SMJ, Ph.D
69

70. Mortazavi SMJ, Ph.D
70
D. The magnitude of radioadaptation of
the candidate can be compared now.
E. Candidates with a high magnitude of
radioadaptation will be good choices for a
deep space mission.
F. During space mission, the selected
astronauts will be adapted to radiation by
chronic galactic cosmic radiation (GCR).
 It’s worth noting that the
magnitude and duration of
solar particle event (SPE) is
currently unpredictable.
Summary of the hypothesis proposed by our team (cont.):
Joseph J. Bevelacqua1 and S.M.J. Mortazavi2*
Front. Physiol., 08 January 2018 |
https://doi.org/10.3389/fphys.2017.01116

71. Mortazavi SMJ, Ph.D
71
G. If a solar particle event occurs it can
deliver potentially large doses of energetic
particles even behind modest spacecraft
shielding.
H. Adaptive response can help the selected
astronauts tolerate these relatively high
levels of radiation.
Summary of the hypothesis proposed by our team (cont.):
Joseph J. Bevelacqua1 and S.M.J. Mortazavi2*
Front. Physiol., 08 January 2018 |
https://doi.org/10.3389/fphys.2017.01116

72. AR & Risk of Infection in Deep
Space Missions
Change of virulence (ability to cause
disease)
Dysregulated Immune System
Increased Risk of Infection
AR can Stimulate the Immune System
and Control the Risk of Infection
Mortazavi SMJ, Ph.D
72

73. Two years after Mortazavi et al. 2003 report, cancer
scientists firstly agreed that adaptive response is a
puzzling issue in space radiobiology
• 2005-Cancer specialist Dr. John
Dicello
• “Cells often react in unexpected ways to radiation, notes Dicello.
For example, there's a puzzling phenomenon known as adaptive
response. Sometimes, when tissue is exposed to damaging
radiation, it not only repairs itself, but also learns to repair itself
better next time. How that works is still being investigated”
• “The damage could be less than the two kinds added together -- or
it could be more! There could, perhaps, be an adaptive response in
which lightweight solar protons stimulate repair processes to help
reduce the effects of the heavy cosmic ray ions. Or something
totally unexpected could happen”.
• Mysterious Cancer http://science.nasa.gov/
Mortazavi SMJ, Ph.D
73

74. Mortazavi SMJ, Ph.D
74
George et al. 2007:
“This study of adaptive response is very interesting and it is important
that the phenomenon be investigated further.
in 2007:

75. • Durante and Manti 2008:
• “Another possibility is that an adaptive response to the space environment takes
place after the first exposure, which may confer the exposed individual an increased
radioresistance. Such a response would be similar to that hypothesized to explain
the apparent lack of adverse health effects in VHBRA and HBRA residents. As
pointed out by Mortazavi et al. (2003), radiobiological studies on these areas may
lead to the identification of the cellular and molecular mechanisms by which
susceptibility to genetic damage and cancer is decreased by chronic radiation
exposure, hence helping the astronaut selection process.”
Mortazavi SMJ, Ph.D
75

76. Mortazavi SMJ, Ph.D
76
In 2011, without citing the early idea:
Protons
Iron Ions

77. Mortazavi SMJ, Ph.D
77
In 2011, without citing the early idea:
o Low dose (10 cGy)
of protons followed
after either 5-15 min
(immediate) or 16-24
h (delayed) by 1 Gy
of iron ions
o Low dose (10 cGy) of
iron ions followed
after either 5-15 min
or 16-24 h by 1 Gy of
protons

78. Mortazavi SMJ, Ph.D
78
• “Moreover, a second spaceflight apparently does not proportionately increase the
yield of aberrations, suggesting a non-additive or even an infra-additive effect,
raising the possibility of a radio-adaptive response in crewmembers (i.e.,
“radiation hormesis”).”
• “Notwithstanding this finding, knowledge of the basic mechanisms specific to
low-dose radiation, to sequential doses of low-dose radiation and to adaptive
responses is still at a rudimentary stage.”
In 2014, without citing the
early idea:
1st Mission
2nd Mission
Methodological
Error?
The Time
Interval Between
AD and CD?

79. Mortazavi SMJ, Ph.D
79
In 2016, without citing the
early idea:
• Effects of mixed-field proton/iron ion irradiations on cellular
adaptive responses were examined by Elmore et al. using an in vitro
HeLa X human fibroblast hybrid cell transformation assay, but
interestingly was only shown to be radioprotective when 10 cGy 1
GeV/n iron ions was delivered prior to 1 Gy of 1 GeV protons, (that
is, the reverse order of our irradiations).
Protons
Iron Ions

80. Mortazavi SMJ, Ph.D
80
In 2016, without citing the
early idea:
• More recently, Buonanno et al. reported significant radioprotection
for chromosomal damage (micronuclei) induction in primary
human fibroblasts exposed to 20 cGy of 50 MeV or 1 GeV protons
followed by 50 cGy of 1 GeV/n iron ions, with the radioprotective
effect persisting for 24 h.

81. Mortazavi SMJ, Ph.D
81
 Space particles have an inevitable impact
on organisms during space missions
 Radio-adaptive response (RAR) is a
critical radiation effect due to both low-
dose background and sudden high-dose
radiation exposure during solar storms.
Chenguang Deng et al. Effect of modeled microgravity on radiation-induced adaptive
response of root growth in Arabidopsis thaliana, Mutation Research/Fundamental and
Molecular Mechanisms of Mutagenesis 2017
And in 2017:

82. Mortazavi SMJ, Ph.D
82
Concluding Remarks:
• Even lower doses of radiation which induce
mild symptoms may cause operational risks
which can affect crew health and/or prevent
the completion of mission goals.
• Physical protection alone cannot solve the key
problem of high levels of space radiation.
• We need effective biological protection
methods.
• Screening can solve the existing problems
(choosing astronauts with a high magnitude of
adaptive response after Ground-based in vitro
examinations)!
• In this case, adaptive Response can reduce
ARS and infection risk during long term
manned space missions and decreases cancer
risk post mission

83. References:
• Huff, J., Carnell, L., Blattnig, S., Chappell, L., Kerry, G., Lumpkins, S., et al. (2016). Evidence Report:
Risk of Radiation Carcinogenesis. National Aeronautics and Space Administration (NASA).
• Bevelacqua JJ, Mortazavi SMJ. Commentary: Human Pathophysiological Adaptations to the Space
Environment. Front Physiol. 2017;8:1116. PubMed PMID: 29358922. Pubmed Central PMCID:
PMC5766677. Epub 2018/01/24. eng.
• Mortazavi H, Baharvand M. Review of common conditions associated with periodontal ligament
widening. Imaging science in dentistry. 2016 Dec;46(4):229-37. PubMed PMID: 28035300. Pubmed
Central PMCID: PMC5192020. Epub 2016/12/31. eng.
• Mortazavi SMJ, Bevelacqua JJ, Fornalski KW, Welsh J, Doss M. Comments on "Space: The Final
Frontier-Research Relevant to Mars". Health Phys. 2018 Mar;114(3):344-5. PubMed PMID:
29360711. Pubmed Central PMCID: PMC5784783. Epub 2018/01/24. eng.
• Bose Girigoswami, K., Ghosh, R. Response to gamma-irradiation in V79 cells conditioned by repeated
treatment with low doses of hydrogen peroxide. Radiat Environ Biophys 44, 131-7, 2005.
• Cao, Y., Xu, Q., Jin, Z.D., Zhou, Z., Nie, J.H., Tong, J. Induction of adaptive response: pre-exposure of
mice to 900 MHz radiofrequency fields reduces hematopoietic damage caused by subsequent
exposure to ionising radiation. Int J Radiat Biol 87, 720-8, 2011.
Mortazavi SMJ, Ph.D
83

84. • Cejas, P., Casado, E., Belda-Iniesta, C., et al. Implications of oxidative stress and cell membrane lipid
peroxidation in human cancer (Spain). Cancer Causes Control 15, 707-19, 2004.
• Crucian, B., Stowe, R., Quiriarte, H., Pierson, D., Sams, C. Monocyte phenotype and cytokine
production profiles are dysregulated by short-duration spaceflight. Aviat Space Environ Med 82, 857-
62, 2011.
• Crucian, B.E., Stowe, R.P., Pierson, D.L., Sams, C.F. Immune system dysregulation following short-
vs long-duration spaceflight. Aviat Space Environ Med 79, 835-43, 2008.
• Day, T.K., Zeng, G., Hooker, A.M., Bhat, M., Turner, D.R., Sykes, P.J. Extremely low doses of X-
radiation can induce adaptive responses in mouse prostate. Dose Response 5, 315-22, 2007.
• Dimova, E.G., Bryant, P.E., Chankova, S.G. Adaptive response: some underlying mechanisms and
open questions. Genet. Mol. Biol. 31, 396-408, 2008.
• Durante, M., and Cucinotta, F. A. (2011). Physical basis of radiation protection in space travel. Rev.
Mod. Phys. 83:1245. doi: 10.1103/RevModPhys.83.1245
• Durante, M., George, K., Gialanella, G., Grossi, G., La Tessa, C., Manti, L., et al. (2005). Cytogenetic
effects of high-energy iron ions: dependence on shielding thickness and material. Radiat. Res. 164,
571–576. doi: 10.1667/RR3362.1
• Durante, M., Snigiryova, G., Akaeva, E., Bogomazova, A., Druzhinin, S., Fedorenko, B., et al. (2003).
Chromosome aberration dosimetry in cosmonauts after single or multiple space flights. Cytogenet.
Genome Res. 103, 40–46. doi: 10.1159/000076288
• Esmekaya, M.A., Ozer, C., Seyhan, N. 900 MHz pulse-modulated radiofrequency radiation induces
oxidative stress on heart, lung, testis and liver tissues. Gen Physiol Biophys 30, 84-9, 2011.
• Feinendegen, L.E., Bond, V.P., Sondhaus, C.A., Altman, K.I. Cellular signal adaptation with damage
control at low doses versus the predominance of DNA damage at high doses. C R Acad Sci III 322,
245-51, 1999.
Mortazavi SMJ, Ph.D
84

85. • Feinendegen, L.E., Bond, V.P., Sondhaus, C.A., Muehlensiepen, H. Radiation effects induced by
low doses in complex tissue and their relation to cellular adaptive responses. Mutat Res 358,
199-205, 1996.
• Goldberg, Z., Lehnert, B.E. Radiation-induced effects in unirradiated cells: a review and
implications in cancer. Int J Oncol 21, 337-49, 2002.
• Gridley, D.S., Slater, J.M., Luo-Owen, X., et al. Spaceflight effects on T lymphocyte distribution,
function and gene expression. J Appl Physiol 106, 194-202, 2009.
• Hattori, S. Current status and perspectives of research on radiation hormesis in Japan. Chin
Med J (Engl) 107, 420-4, 1994.
• Jiang, B., Nie, J., Zhou, Z., Zhang, J., Tong, J., Cao, Y. Adaptive response in mice exposed to
900 MHz radiofrequency fields: primary DNA damage. PLoS One 7, e32040, 2012.
• Jiang, B., Zong, C., Zhao, H., Ji, Y., Tong, J., Cao, Y. Induction of adaptive response in mice
exposed to 900MHz radiofrequency fields: Application of micronucleus assay. Mutat Res 751,
127-9, 2013.
• Jin, Z., Zong, C., Jiang, B., Zhou, Z., Tong, J., Cao, Y. The effect of combined exposure of 900
MHz radiofrequency fields and doxorubicin in HL-60 cells. PLoS One 7, e46102, 2012.
• Liu, S.Z., Jin, S.Z., Liu, X.D. Radiation-induced bystander effect in immune response. Biomed
Environ Sci 17, 40-6, 2004.
• Liu, S.Z., Liu, W.H., Sun, J.B. Radiation hormesis: its expression in the immune system. Health
Phys 52, 579-83, 1987.
• Makinodan, T., James, S.J. T cell potentiation by low dose ionizing radiation: possible
mechanisms. Health Phys 59, 29-34, 1990.
Mortazavi SMJ, Ph.D
85

86. • Marnett, L.J., Riggins, J.N., West, J.D. Endogenous generation of reactive oxidants and
electrophiles and their reactions with DNA and protein. J Clin Invest 111, 583-93, 2003.
• Maynard, S., Schurman, S.H., Harboe, C., de Souza-Pinto, N.C., Bohr, V.A. Base excision repair of
oxidative DNA damage and association with cancer and aging. Carcinogenesis 30, 2-10, 2009.
• Mitchel, R.E. The dose window for radiation-induced protective adaptive responses. Dose
Response 8, 192-208, 2010.
• Mortazavi, S., Cameron, J., Niroomand-Rad, A. The life saving role of radioadaptive responses in
long-term interplanetary space journeys. Elsevier, pp. 266-7, 2005.
• Mortazavi, S., Mosleh-Shirazi, M., Tavassoli, A., et al. A comparative study on the increased
radioresistance to lethal doses of gamma rays after exposure to microwave radiation and oral
intake of flaxseed oil. Iranian Journal of Radiation Research 9, 9-14, 2011a.
• Mortazavi, S.M., Cameron, J.R., Niroomand-rad, A. Adaptive response studies may help choose
astronauts for long-term space travel. Adv Space Res 31, 1543-51, 2003.
• Mortazavi, S.M.J. Window Theory in Non-Ionizing Radiation-Induced Adaptive Responses. , . .
Dose Response in press, 2013.
• Mortazavi, S.M.J., Mosleh-Shirazi, M.A., Tavassoli, A.R., et al. A comparative study on the
increased radioresistance to lethal doses of gamma rays after exposure to microwave radiation
and oral intake of flaxseed oil. Iranian Journal of Radiation Research 9, 9-14, 2011b.
• Mortazavi, S.M.J., Mosleh-Shirazi, M.A., Tavassoli, A.R., et al. Increased Radioresistance to
Lethal Doses of Gamma Rays in Mice and Rats after Exposure to Microwave Radiation Emitted
by a GSM Mobile Phone Simulator. Dose Response in press, 2012a.
Mortazavi SMJ, Ph.D
86

87. • Mortazavi, S.M.J., Motamedifar, M., Namdari, G., Taheri, M. Pre-exposure to Radiofrequency
Radiations Emitted from a GSM Mobile Phone Increases Resistance to a Bacterial Infection in BALB/c
Mice. Journal of Biomedical Physics and Engineering in press, 2012b.
• Mortazavi, S.M.J., Motamedifar, M., Namdari, G., Taheri, M., Mortazavi, A.R. Counterbalancing
immunosuppression-induced infections during long-term stay of humans in space. Journal of Medical
Hypotheses and Ideas 7, 8–10, 2013.
• Mortazavi SMJ. Space radiobiology and the new era of induced radioresistance: Should traditional
concepts be moved to science history museums? Technology and Health Care. 2013 in press.
• Murray, D., Allalunis-Turner, M., Weinfeld, M. VIIIth International Workshop on Radiation Damage to
DNA. Int J Radiat Biol 81, 327-37, 2005.
• Olivieri, G., Bodycote, J., Wolff, S. Adaptive response of human lymphocytes to low concentrations of
radioactive thymidine. Science 223, 594-7, 1984.
• Ozgur, E., Guler, G., Seyhan, N. Mobile phone radiation-induced free radical damage in the liver is
inhibited by the antioxidants N-acetyl cysteine and epigallocatechin-gallate. Int J Radiat Biol 86, 935-
45, 2010.
• Plews, M., Simon, S.L., Boreham, D.R., et al. A radiation-induced adaptive response prolongs the
survival of prion-infected mice. Free Radic Biol Med 49, 1417-21, 2010.
• Samson, L., Cairns, J. A new pathway for DNA repair in Escherichia coli. 1977.
• Sannino, A., Sarti, M., Reddy, S.B., Prihoda, T.J., Scarfì, M.R. Induction of adaptive response in human
blood lymphocytes exposed to radiofrequency radiation. Radiation research 171, 735-42, 2009a.
• Sannino, A., Sarti, M., Reddy, S.B., Prihoda, T.J., Vijayalaxmi, Scarfi, M.R. Induction of adaptive
response in human blood lymphocytes exposed to radiofrequency radiation. Radiat Res 171, 735-42,
2009b.
Mortazavi SMJ, Ph.D
87

88. • Sannino, A., Zeni, O., Sarti, M., et al. Induction of adaptive response in human blood
lymphocytes exposed to 900 MHz radiofrequency fields: Influence of cell cycle. Int J Radiat
Biol, 2011.
• Scott, B.R., Walker, D.M., Tesfaigzi, Y., Schollnberger, H., Walker, V. Mechanistic basis for
nonlinear dose-response relationships for low-dose radiation-induced stochastic effects.
Nonlinearity Biol Toxicol Med 1, 93-122, 2003.
• Stowe, R.P., Sams, C.F., Pierson, D.L. Adrenocortical and immune responses following short-
and long-duration spaceflight. Aviat Space Environ Med 82, 627-34, 2011.
• Tapio, S., Jacob, V. Radioadaptive response revisited. Radiat Environ Biophys 46, 1-12, 2007.
• UNSCEAR. SOURCES AND EFFECTS OF IONIZING RADIATION, UNSCEAR 1994 Report to
the General Assembly, with Scientific Annexes. United Nations Scientific Committee on the
Effects of Atomic Radiation, 1994
• Yan, G., Hua, Z., Du, G., Chen, J. Adaptive response of Bacillus sp. F26 to hydrogen peroxide
and menadione. Curr Microbiol 52, 238-42, 2006.
• Zdrojewicz, Z., Strzelczyk, J.J. Radon treatment controversy. Dose Response 4, 106-18, 2006.
• Zeni, O., Sannino, A., Romeo, S., et al. Induction of an adaptive response in human blood
lymphocytes exposed to radiofrequency fields: Influence of the universal mobile
telecommunication system (UMTS) signal and the specific absorption rate. Mutat Res, 2012.
• Zhou, Y., Ni, H., Li, M., et al. Effect of solar particle event radiation and hindlimb suspension on
gastrointestinal tract bacterial translocation and immune activation. PLoS One 7, e44329, 2012.
Mortazavi SMJ, Ph.D
88

89. Thank you
Mortazavi SMJ, Ph.D
89