Exposure to high levels of space radiation and microgravity are two important concerns which need to be addressed before any long-term manned space mission. There are also reports showing that microgravity, through a synergistic effect, increases the radiation susceptibility of living organisms. Other researchers as well as our team have conducted some experiments on design and fabrication of appropriate radiation shields for spacecrafts. However, due to some cardinal barriers such as weight limitations and extreme inadequacy of current physical shields during extravehicular activity, we strongly believe that the physical shielding alone cannot solve the problem of potential exposure to high levels of radiation in a long-term space mission.
Therefore, over the past several years, we focused on two solutions; radioadaptive response and other biological-based radiation protection methods. Adaptive response, that is the increased radioresistance in cells or living organisms pre-exposed to a low adapting dose and then exposed to a high challenging dose, was firstly proposed by our team in 2003 as an effective method. This novel idea later formed the basis of many space radiation biology projects around the world.
Furthermore, conventional radioprotectors cannot efficiently be used in space due to limitations such as their considerable toxicity and the very narrow time window for their effective use (radioprotectors should be used before or at the time of exposure, while astronauts cannot estimate their doses before a solar particle event). Therefore, we focused on introducing natural radiation mitigators which could be efficiently used several hours after exposure (e.g. when a solar particle event subsides and astronauts are able to estimate their doses). In these experiments, radiation mitigators were introduced by our team which could be used even 24 hours after exposure to high levels of radiation caused by unpredictable sources such as SPEs.
Finally, some of our recent experiments were aimed at finding methods which could lead to boosting the immune system of astronauts during long-term missions. We investigated the effect of RF-EMFs-induced adaptive responses on immune system modulation in a mouse model of hindlimb unloading (HU). Hindlimb unloading rodent model is widely accepted by the scientific community as the model of choice for simulating spaceflight. In this study, serum levels of T helper cytokines were determined in HU mice, RF-EMF treated mice and HU mice pre-exposed to RF-EMF compared to those of untreated controls. The findings of this study will be published soon.
3. Mortazavi SMJ, Ph.D
3
Radiation Protection
Challenges in Space
Three General Guidelines:
• Time (Not Applicable in Space)
• Distance (Not Applicable in
Space)
• Shield (Not Easy in Space due to
Weight Limitations)
6. Mortazavi SMJ, Ph.D
6
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 experience:
9. Mortazavi SMJ, Ph.D
9
“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/
10. Mortazavi SMJ, Ph.D
10
“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/
11. Mortazavi SMJ, Ph.D
11
Therefore, as physical
shielding alone cannot
solve current space
radiation problems, we
focused on:
• Adaptive Response
• Other Biological
Protection Methods
13. Mortazavi SMJ, Ph.D
13
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
14. Mortazavi SMJ, Ph.D
14
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
15. Mortazavi SMJ, Ph.D
15
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
21. Mortazavi SMJ, Ph.D
Two survey meters show dose rates
of 142 and 143 µSv/h on contact
with a bedroom wall
21
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)
Theory
23. Mortazavi SMJ, Ph.D
196 citations recorded by Scopus
Adaptive response in the
residents of High
Background Radiation
Areas (HBRAs)
23
151 citations recorded by WoS (ISI)
344 citations recorded by G Scholar
24. Mortazavi SMJ, Ph.D
24
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!
25. Mortazavi SMJ, Ph.D
25
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.
GCR vs SPE!
27. Mortazavi SMJ, Ph.D
27
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
28. Mortazavi SMJ, Ph.D
28
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.
29. Mortazavi SMJ, Ph.D
29
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!
30. Mortazavi SMJ, Ph.D
30
"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!
31. Mortazavi SMJ, Ph.D
31
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!
32. Mortazavi SMJ, Ph.D
32
“The biological effects of space
radiation, including ARS, are a
significant concern.
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.
33. Mortazavi SMJ, Ph.D
33
“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%
36. Mortazavi SMJ, Ph.D
36
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 some
simple tests (needless to say after
exposing blood samples to a low dose and
then to a high dose radiation and
measuring parameters such as
chromosome aberrations, etc.).
Mortazavi et al., Dose Response, 2003
Summary of the hypothesis proposed by our team:
37. Measuring the magnitude of
adaptive response
• For measuring the magnitude of
adaptive response, blood sample of
each candidate will be divided into 4
aliquots; one aliquot will only be
exposed to low dose, one only to high
dose, one to both doses (adapting and
challenge doses) and one will be
remained unexposed.
Mortazavi SMJ, Ph.D
37
38. 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
38
39. 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 high dose + Freq of Dic/Ring in samples only
exposed to low dose - Freq of Dic/Ring in non-exposed
samples.
Mortazavi SMJ, Ph.D
39
40. Mortazavi SMJ, Ph.D
40
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.
Mortazavi et al., Dose Response, 2003
Summary of the hypothesis proposed by our team (cont.):
41. Mortazavi SMJ, Ph.D
41
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.
Mortazavi et al., Dose Response, 2003
Summary of the hypothesis proposed by our team (cont.):
42. Two years after Mortazavi et al. 2003 report, other
scientists 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
42
43. Mortazavi SMJ, Ph.D
43
George et al. 2007:
“This study of adaptive response is very interesting and it is important
that the phenomenon be investigated further.
Four years
later, in
2007:
44. • 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
44
46. Mortazavi SMJ, Ph.D
46
After 8 years (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
47. Mortazavi SMJ, Ph.D
47
• “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.”
After 11 years (in 2014)
without citing the early
idea:
1st Mission
2nd Mission
Methodological
Error?
The Time
Interval Between
AD and CD?
48. Mortazavi SMJ, Ph.D
48
After 13 years (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
49. Mortazavi SMJ, Ph.D
49
After 13 years (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.
50. Mortazavi SMJ, Ph.D
50
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
After 14 years (in
2017):
53. Mortazavi SMJ, Ph.D
53
Conventional radioprotectors
cannot efficiently be used in
space due to 2 basic limitations:
• Their considerable toxicity
• They should be used before
exposure (when astronauts cannot
accurately calculate their doses)
Radioprotectors
54. Mortazavi SMJ, Ph.D
54
In contrast with radioprotectors,
radiation mitigators can efficiently
be used after exposure (e.g. when an
intense solar particle event subsides
and astronauts can estimate their
doses).
Radiation mitigators can be used
even 24 hours after exposure to high
levels of radiation.
Radiomitigators
55. Mortazavi SMJ, Ph.D
55
We introduced vitamin
C as an efficient
radiomitigator for deep
space manned missions!
56. S.M.J. Mortazavi, S. Sharif-Zadeh, H. Mozdarani,
M. Foadi, M. Haghani, E. Sabet. Future role of
vitamin C in radiation mitigation and its possible
applications in manned deep space missions:
Survival study and the measurement of cell
viability Physica Medica, Volume 30, Supplement
1, 2014, Page e97
Mortazavi SMJ, Ph.D
56
Survival Rate in Control group
100%
Animals received only LD50/30,
50%
Received vitamin C
(+radiation):
• 1h, before radiation, 80%
• 1h, after radiation, 55%
• 12h, after radiation, 60%
• 24h, after radiation, 80%
Vit C (400 mg/kg) +
Gamma (LD50/30)
24 h after exposure
Only Gamma
(LD50/30)
30% Increase
57. Mortazavi SMJ, Ph.D
57
Increased survival
when exposed to:
• Protons?
• Energetic Ions?
DNA damage?
Cancer?
Vit C increased the
survival rate 24 h
after exposure to
gamma radiation
62. Mortazavi SMJ, Ph.D
62
SMJ Mortazavi, 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, 11 (2), 2012 DOI:
10.2203/dose-response.12-
010.Mortazavi
RF Gamma (LD 50)
Survival
63. Mortazavi SMJ, Ph.D
63
Our second experiment on another rodent with the same findings!
RF
0
100%
53.3%
SMJ Mortazavi, 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, 11 (2), 2012 DOI: 10.2203/dose-
response.12-010.Mortazavi
66. Mortazavi SMJ, Ph.D
66
Infection Prevention in Deep Space Missions
In two studies funded by NASA, it
was shown that key factors such as
microgravity and radiation could
change the behavior of bacterial
communities.
In addition, immune system is highly
sensitive to stressors such as radiation
in space flight
Thus, solar and galactic radiation
along with microgravity increase the
risk of infection during long-term
stay of human in space.
Microgravity Radiation
Altered behavior
of Microorganisms
67. Mortazavi SMJ, Ph.D
67
Infection Prevention in Deep Space Missions
Thus, solar and
galactic radiation
along with
microgravity
increase the risk of
infection during
long-term stay of
human in space.
Galactic radiation
Infection Risk
Solar radiation
Microgravity
Intervention?
69. Mortazavi SMJ, Ph.D
69
The immune system is highly
sensitive to different stressors
exist during space flight.
Mortazavi et al. have shown that
exposure to radiofrequency
radiation (RF) increased the
survival rate of laboratory
animals (56% in pre-exposed
animals vs 20% in non-exposed
animals) after i.p. injection of E.
coli bacteria.
Immune System and Radiation
74. Mortazavi SMJ, Ph.D
74
Over the past several years we
have conducted some experiments
on boosting the immune system
by pre-exposure to either ionizing,
or non-ionizing radiation. The
data currently are unpublished.
The findings of these experiments
generally support the importance
of the biological protection in
long term manned space missions.
Our Unpublished Data:
RF
HU Rodents
T helper Cytokines
75. Mortazavi SMJ, Ph.D
75
Boosting the Immune System in
Immunosuppressed Laboratory Animals
In our previous experiment we had used mice with normal
immune system but some scientists criticized our work for
not using immunosuppressed mice.
Their rationale was this point that the immune system of
astronauts in a long-term space mission can be affected by
different stresses such as microgravity and higher levels of
radiation.
Therefore, we designed a new study to investigate the effect
of RF-EMFs-induced adaptive responses on immune system
modulation in a mouse model of hindlimb unloading (HU).
76. Mortazavi SMJ, Ph.D
76
“Mortazavi et al. [42] described exactly the same above experimental
protocol, ….. RF + E. coli may have important clinical implications
in treating bacterial infections and, for decreasing the risk of
infection in immunosuppressed irradiated individuals: the authors
have not mentioned the use of immune-suppressed animals for the
experiments in both publications.”
77. Mortazavi SMJ, Ph.D
77
Boosting the Immune System in
Immunosuppressed Laboratory Animals
We used hindlimb unloading rodent model that
is widely accepted by the scientific community
as the model of choice for simulating
spaceflight.
Serum levels of T helper cytokines were
determined in HU mice, RF-EMF treated mice
and HU mice pre-exposed to RF-EMF
compared to those of untreated controls.
Th-related cytokines measured were Th1 (IFN-
γ, TNF-α, IL-2), Th2 (IL-4, IL-5, IL-6, IL-10
and IL-13), Th17 (IL-17A, IL-17F, IL-21),
Th9 (IL-9) and Th22 (IL-22).
78. Mortazavi SMJ, Ph.D
78
Boosting the Immune System in
Immunosuppressed Laboratory Animals (cont.)
Mice were exposed to 2450 MHz RF-EMF
with a SAR level of 0.478W.kg-1for 12 h per
day on 3 successive days and serum cytokine
levels were determined by multiplex
cytometric bead-based assay.
Our findings may help space research
scientists maintain the immune system
balance in long-term manned space missions
in the future.
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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.
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