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Strategies for Reducing the Risk of
Radiation for Astronauts in Space
Missions to Mars and Beyond
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.
© 2017 SMJ Mortazavi
Mortazavi SMJ, Ph.D
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Prof SMJ Mortazavi
Prof A Niroomand-Rad
Prof J R Cameron
Mortazavi SMJ, Ph.D
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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)
Mortazavi SMJ, Ph.D
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Our Integrative Radiation
Protection Plan Includes:
Physical Shielding
Adaptive response
(Biological Protection)
Other Biological
Protection
Methods
Mortazavi SMJ, Ph.D
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Our Integrative Protection
Plan:
Physical Shielding
Adaptive response
Biological Protection
Mortazavi SMJ, Ph.D
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 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:
Mortazavi SMJ, Ph.D
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Challenges of Physical Shielding in
Space:
• Weight Limitations
• Extravehicular Activities
Mortazavi SMJ, Ph.D
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Physical shielding is extremely
inadequate during extravehicular
activity (EVA)!
Space Walking!
Mortazavi SMJ, Ph.D
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“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/
Mortazavi SMJ, Ph.D
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“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/
Mortazavi SMJ, Ph.D
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Therefore, as physical
shielding alone cannot
solve current space
radiation problems, we
focused on:
• Adaptive Response
• Other Biological
Protection Methods
Mortazavi SMJ, Ph.D
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Our Integrative Protection
Plan:
Physical Shielding
Adaptive response
Biological Protection
Mortazavi SMJ, Ph.D
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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
Mortazavi SMJ, Ph.D
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 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
Mortazavi SMJ, Ph.D
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 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
Mortazavi SMJ, Ph.D
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2003
Advances in
Space Research
Mortazavi SMJ, Ph.D
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pp. 4299–4302 c
2003 by Universal Academy Press, Inc.
Mortazavi SMJ, Ph.D
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2003
Mortazavi SMJ, Ph.D
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Mortazavi SMJ, Ph.D
Mortazavi et al., Advances in Space Research, Vol 31, No. 6, 1543-1552, 2003
20
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
Mortazavi SMJ, Ph.D
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We didn’t use this novel method but our papers received lots
of citations!
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
Mortazavi SMJ, Ph.D
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 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!
Mortazavi SMJ, Ph.D
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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!
Mortazavi SMJ, Ph.D
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SPEs are a real concern!
Mortazavi SMJ, Ph.D
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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
Mortazavi SMJ, Ph.D
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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.
Mortazavi SMJ, Ph.D
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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!
Mortazavi SMJ, Ph.D
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"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!
Mortazavi SMJ, Ph.D
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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!
Mortazavi SMJ, Ph.D
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 “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.
Mortazavi SMJ, Ph.D
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 “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%
Mortazavi SMJ, Ph.D
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Mortazavi et al. 2003
Mortazavi SMJ, Ph.D
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Dicentrics
1
2
3
4
5
6
Mortazavi SMJ, Ph.D
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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:
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
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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
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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
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Mortazavi SMJ, Ph.D
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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.):
Mortazavi SMJ, Ph.D
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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.):
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
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Mortazavi SMJ, Ph.D
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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:
• 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
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Mortazavi SMJ, Ph.D
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After 8 years (in 2011) without citing the early idea:
Protons
Iron Ions
Mortazavi SMJ, Ph.D
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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
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?
Mortazavi SMJ, Ph.D
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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
Mortazavi SMJ, Ph.D
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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.
Mortazavi SMJ, Ph.D
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 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):
Mortazavi SMJ, Ph.D
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Our Integrative Protection
Plan:
Physical Shielding
Adaptive response
Biological Protection
Mortazavi SMJ, Ph.D
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1. Radiation mitigators vs
traditional radioprotectors!
Mortazavi SMJ, Ph.D
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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
Mortazavi SMJ, Ph.D
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 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
Mortazavi SMJ, Ph.D
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We introduced vitamin
C as an efficient
radiomitigator for deep
space manned missions!
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
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 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
Mortazavi SMJ, Ph.D
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Increased survival
when exposed to:
• Protons?
• Energetic Ions?
DNA damage?
Cancer?
Vit C increased the
survival rate 24 h
after exposure to
gamma radiation
Mortazavi SMJ, Ph.D
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Mortazavi SMJ, Ph.D
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2. RF-Induced Increased
Survival
The first report on the RF-induced adaptive
response
Mortazavi SMJ, Ph.D
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Mitomycin CRF
Micronuclei
Mortazavi SMJ, Ph.D
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RF Gamma (LD 50)
Survival
Mortazavi SMJ, Ph.D
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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
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
Mortazavi SMJ, Ph.D
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Mortazavi SMJ, Ph.D
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3. Infection Prevention in Deep
Space Missions
Mortazavi SMJ, Ph.D
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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
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?
Mortazavi SMJ, Ph.D
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Mortazavi SMJ, Ph.D
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 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
Mortazavi SMJ, Ph.D
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RF
E. coli injection
Survival
Mortazavi SMJ, Ph.D
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RF Gamma (LD 50)
Survival
Mortazavi SMJ, Ph.D
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Mortazavi SMJ, Ph.D
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4. Boosting the Immune System
in Immunosuppressed
Laboratory Animals
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
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).
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.”
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).
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.
Adaptive
Response in
Space
Research
• Different
methods that
can be used for
reducing the
risk of
radiation
during deep
space missions
Mortazavi SMJ, Ph.D
79
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Mortazavi SMJ, Ph.D
85

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Strategies for reducing the risk of radiation for astronauts in space missions to mars and beyond

  • 1. Strategies for Reducing the Risk of Radiation for Astronauts in Space Missions to Mars and Beyond 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. © 2017 SMJ Mortazavi
  • 2. Mortazavi SMJ, Ph.D 2 Prof SMJ Mortazavi Prof A Niroomand-Rad Prof J R Cameron
  • 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)
  • 4. Mortazavi SMJ, Ph.D 4 Our Integrative Radiation Protection Plan Includes: Physical Shielding Adaptive response (Biological Protection) Other Biological Protection Methods
  • 5. Mortazavi SMJ, Ph.D 5 Our Integrative Protection Plan: Physical Shielding Adaptive response Biological Protection
  • 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:
  • 7. Mortazavi SMJ, Ph.D 7 Challenges of Physical Shielding in Space: • Weight Limitations • Extravehicular Activities
  • 8. Mortazavi SMJ, Ph.D 8 Physical shielding is extremely inadequate during extravehicular activity (EVA)! Space Walking!
  • 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
  • 12. Mortazavi SMJ, Ph.D 12 Our Integrative Protection Plan: Physical Shielding Adaptive response Biological Protection
  • 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
  • 17. Mortazavi SMJ, Ph.D 17 pp. 4299–4302 c 2003 by Universal Academy Press, Inc.
  • 20. Mortazavi SMJ, Ph.D Mortazavi et al., Advances in Space Research, Vol 31, No. 6, 1543-1552, 2003 20
  • 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
  • 22. Mortazavi SMJ, Ph.D 22 We didn’t use this novel method but our papers received lots of citations!
  • 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!
  • 26. Mortazavi SMJ, Ph.D 26 SPEs are a real concern!
  • 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
  • 45. Mortazavi SMJ, Ph.D 45 After 8 years (in 2011) without citing the early idea: Protons Iron Ions
  • 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):
  • 51. Mortazavi SMJ, Ph.D 51 Our Integrative Protection Plan: Physical Shielding Adaptive response Biological Protection
  • 52. Mortazavi SMJ, Ph.D 52 1. Radiation mitigators vs traditional radioprotectors!
  • 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
  • 59. Mortazavi SMJ, Ph.D 59 2. RF-Induced Increased Survival
  • 60. The first report on the RF-induced adaptive response Mortazavi SMJ, Ph.D 60 Mitomycin CRF Micronuclei
  • 61. Mortazavi SMJ, Ph.D 61 RF Gamma (LD 50) Survival
  • 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
  • 65. Mortazavi SMJ, Ph.D 65 3. Infection Prevention in Deep Space Missions
  • 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
  • 70. Mortazavi SMJ, Ph.D 70 RF E. coli injection Survival
  • 71. Mortazavi SMJ, Ph.D 71 RF Gamma (LD 50) Survival
  • 73. Mortazavi SMJ, Ph.D 73 4. Boosting the Immune System in Immunosuppressed Laboratory Animals
  • 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.
  • 79. Adaptive Response in Space Research • Different methods that can be used for reducing the risk of radiation during deep space missions Mortazavi SMJ, Ph.D 79
  • 80. References: • 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. • 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. • 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 80
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