A hypothesis on biological protection from space radiation through the use of new therapeutic gases as medical counter measures.

Abstract

Radiation exposure to astronauts could be a significant obstacle for long duration manned space exploration because of current uncertainties regarding the extent of biological effects. Furthermore, concepts for protective shielding also pose a technically challenging issue due to the nature of cosmic radiation and current mass and power constraints with modern exploration technology. The concern regarding exposure to cosmic radiation is biological damage that is associated with increased oxidative stress. It is therefore important and would be enabling to mitigate and/or prevent oxidative stress prior to the development of clinical symptoms and disease. This paper hypothesizes a "systems biology" approach in which a combination of chemical and biological mitigation techniques are used conjunctively. It proposes using new, therapeutic, medical gases as chemical radioprotectors for radical scavenging and as biological signaling molecules for management of the body's response to exposure. From reviewing radiochemistry of water, biological effects of CO, H2, NO, and H2S gas, and mechanisms of radiation biology, it can be concluded that this approach may have therapeutic potential for radiation exposure. Furthermore, it also appears to have similar potential for curtailing the pathogenesis of other diseases in which oxidative stress has been implicated including cardiovascular disease, cancer, chronic inflammatory disease, hypertension, ischemia/reperfusion (IR) injury, acute respiratory distress syndrome, Parkinson's and Alzheimer's disease, cataracts, and aging. We envision applying these therapies through inhalation of gas mixtures or ingestion of water with dissolved gases.

Full text

Page 1

REVIEWOpen Access
A hypothesis on biological protection from space
radiation through the use of new therapeutic
gases as medical counter measures
Michael P Schoenfeld1*, Rafat R Ansari2, Atsunori Nakao3and David Wink4*
Abstract
Radiation exposure to astronauts could be a significant obstacle for long duration manned space exploration
because of current uncertainties regarding the extent of biological effects. Furthermore, concepts for protective
shielding also pose a technically challenging issue due to the nature of cosmic radiation and current mass and
power constraints with modern exploration technology. The concern regarding exposure to cosmic radiation is
biological damage that is associated with increased oxidative stress. It is therefore important and would be
enabling to mitigate and/or prevent oxidative stress prior to the development of clinical symptoms and disease.
This paper hypothesizes a “systems biology” approach in which a combination of chemical and biological
mitigation techniques are used conjunctively. It proposes using new, therapeutic, medical gases as chemical
radioprotectors for radical scavenging and as biological signaling molecules for management of the body’s
response to exposure. From reviewing radiochemistry of water, biological effects of CO, H2, NO, and H2S gas, and
mechanisms of radiation biology, it can be concluded that this approach may have therapeutic potential for
radiation exposure. Furthermore, it also appears to have similar potential for curtailing the pathogenesis of other
diseases in which oxidative stress has been implicated including cardiovascular disease, cancer, chronic
inflammatory disease, hypertension, ischemia/reperfusion (IR) injury, acute respiratory distress syndrome, Parkinson’s
and Alzheimer’s disease, cataracts, and aging. We envision applying these therapies through inhalation of gas
mixtures or ingestion of water with dissolved gases.
Keywords: space radiation, radiolysis, radiochemistry, radiation shielding, therapeutic medical gas, reactive oxygen
species, oxidative stress, countermeasure
The Challenge of Space Radiation
Galactic Cosmic Rays (GCR), solar energetic particles
(SEP), and trapped energetic particles in a planetary
magnetic field are natural sources of radiation in space.
GCRs consist of highly energetic nuclei, predominately
protons and He, but also trace amounts of C, O, Ne, Si,
Ca, and Fe ions. Particle energies can range from 100
MeV to 10 GeV per nucleon [1]. Although the high
charge and energy (HZE) nuclei are in trace amounts,
they are still of concern because they can cause more
damage than protons since they are more highly
ionizing. As well, even though particle fluxes are typi-
cally low, they are chronic and can significantly increase
with solar events [1]. Furthermore, GCRs and SEPs
impinging on shielding material, atmosphere, or surface
of a planet or satellite can produce secondary radiation,
including energetic neutrons, from nuclear fragmenta-
tion of the primary ion and target atoms. This can
introduce an additional component to the radiation field
which makes shielding from HZE quite challenging and
poses one of the principal unknowns in understanding
the HZE effects with human tissue [2]. Furthermore,
while our bodies do possess a natural repair mechanism,
radiation with a high linear energy transfer (LET) rate,
like space radiation, is attributed to be more likely to
cause double strand breaks in DNA that are relatively
more difficult for our natural repair mechanisms to fix
* Correspondence: michael.p.schoenfeld@nasa.gov; wink@mail.nih.gov
1National Aeronautics and Space Administration Marshall Space Flight
Center, Huntsville, Alabama, USA
4National Institute of Health, National Cancer Institute, Radiation Biology
Branch, Bethesda, Maryland, USA
Full list of author information is available at the end of the article
Schoenfeld et al. Medical Gas Research 2012, 2:8
http://www.medicalgasresearch.com/content/2/1/8
MEDICAL GAS
RESEARCH
© 2012 Schoenfeld et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.

Page 2

correctly [3]. While a week or month of this radiation at
the dose rates naturally present likely will not have ser-
ious consequences, several year durations in space
could. The traditional paradigm for radiation protection
is to minimize exposure time, maximize distance from
radiation sources, and use shielding to attenuate and
absorb radiation before it can deposit its energy in
humans. In regards to minimizing exposure time, new
propulsive technologies could reduce trip times but have
yet to be developed and would not address the ability to
remain at a location for long durations. It is impractical
to maximize distance from cosmic radiation sources. In
regards to shielding, aspects of attenuation by mass or
deflection by magnetic fields or charge repulsion have
been considered. Due to the phenomena of secondary
radiation, shielding by other matter may require a signif-
icant amount of mass which could be impractical within
current mass constraints in space systems. Due to the
high energy of the space radiation, magnetic field and
charge strengths required for deflection may be cur-
rently impractical because of mass and power con-
straints in modern space systems along with other
system design implications. In short, shielding space
radiation is seemingly quite challenging. However,
advances in biochemistry may reveal some more tools
for radiation protection [2].
Parallels between Radiation Chemistry
of Water & Radiobiology
Radiolysis is the decomposition of water from exposure
to ionizing radiation. Radiation chemistry of water has
been well studied since the onset of nuclear power pro-
duction, as water has been the most often used coolant.
Since mammalian cells are composed of about 80%
water, it seemed natural that there exist similarities
between radiation chemistry of water and radiation biol-
ogy. It is these similarities from which analogues for
radioprotective measures were inspired.
Chain of Events Initiated by Chemically Reactive Species
Radiolysis in nuclear systems causes a chain of events
that ultimately manifest into systematic problems like
corrosion and gas generation. Ionizing radiation creates
chemically reactive radicals H3O+, e-, H+, H, and OH by
ionizing and/or breaking the bonds of water molecules.
These radicals then initiate a chain of chemical reactions
within the water which can result in the formation of
molecular decomposition products such as H2, O2, HO2
and H2O2. BWR recirculation water contains oxygen
and hydrogen peroxide in the concentration range from
100 to 300 ppb, and about 10 ppb of dissolved hydrogen
(less than stoichiometric ratio of 8 to 1) [4]. These oxi-
dizing species alter the water composition and therefore
its electrochemical character which facilitates the
manifestation of problems like corrosion or gas genera-
tion. As such, the nature in which systematic problems
develop can be viewed as stemming from a chain of
events that are initiated by ionization and propagated by
a scheme of chemical reactions with the net result or
outcome depending upon the ensuing chemistry.
This scenario is similar in nature to a biological sys-
tem and the pathogenesis of radiation related ailments
and disease. Ionization of key biological molecules can
lead to chemical reactions which transform these mole-
cules. This alters their biochemical function and can
result in changes of their biochemical properties. Modi-
fication of biochemical properties propagates from a cel-
lular level to organ and systematic changes that
ultimately manifest into clinical symptoms and ailments.
Ionization of the molecules can be initiated both directly
(by radiation) and indirectly (by free radicals and reac-
tive oxygen species (ROS) created by radiolysis). Free
radicals and ROS like O2-,1O2, ·OH, ·OOH, NO· and
H2O2can cause cell injury or death by oxidative stress
[5,6]. Oxidative stress to the cell results from such
things as DNA damage or lipid peroxidation. Disease
can then develop as a direct result of radiation damage
or due to a system impairment caused by radiation
damage such as the case of radiation-induced damage of
chromosomes in lymphocytes compromising the
immune system’s ability to prevent tumor development
[7]. Overall, the greatest risks from radiation exposure
are assumed to be cancer [8], cataracts, and damage to
the central nervous system [9]. Thus the nature of the
problem seems similar to nuclear systems in that sys-
tematic manifestations result from a chain of events
initiated by ionization and propagated, in this case, by
ensuing chemical reactions and biological responses.
Interestingly enough, oxidative stress has been impli-
cated to play a role in the development of other diseases
as well [10,11]. That is, the normal production and
development of a variety of disorders and diseases has
also been associated with an increase of oxidative stress
and inflammation similar to that which would be caused
by exposure to radiation. For example, certain detrimen-
tal effects from space radiation on the dopaminergic sys-
tem are similar to functional changes that occur from
Parkinson’s disease [9], diabetogenic problems associated
with increased C-peptide excretion and insulin resis-
tance [12], as well as constipation due to malfunction of
the intestine. Oxidative stress during space flight can
cause a loss of protein after reductive remodeling of ske-
letal muscle due to undernutrition [13]. Diseases in
which oxidative stress is implicated, and thus which
could also be affected by the countermeasures proposed
in this paper, include cardiovascular disease, cancer [14],
chronic inflammatory disease [15], hypertension [16],
ischemia/reperfusion injury [5], acute respiratory distress
Schoenfeld et al. Medical Gas Research 2012, 2:8
http://www.medicalgasresearch.com/content/2/1/8
Page 2 of 13

Page 3

syndrome (ARDS) [17], neurodegenerative diseases such
as Parkinson’s disease and Alzheimer’s disease [18,19]
and aging [20].
Radical Scavenging & Antioxidants
The actual chemical reactions that ensue and their by-
products depend upon what the radicals come into con-
tact with. For example, in pure water, radical-radical
interactions lead to the formation of the decomposition
products while radical-decomposition product reactions
lead to the reformation of water. In a nuclear system,
manifestation of system level problems has been cur-
tailed by interfering with the chain of events early on
during the chemical stages through the use of additives
that alter water composition. Whereas some additives
have been found to promote and increase water decom-
position, others have been found to suppress it [21].
This occurs through scavenging in which the additives
preferentially react with the radicals. Scavenging has the
effect of removing reactive species from the system and
thereby reduces their ability to participate in chemical
reactions that cause decomposition. While there are var-
ious additives that preferentially react with decomposi-
tion products, the byproducts of the scavenging reaction
are a factor as well since they are a component of the
water composition. For example, some ionic impurities
scavenge radicals (shown in 1-4) but do so at the
expense of water reformation as the consumed H and
OH radicals are no longer available to react with
decomposition products in the reactions that lead to
water reformation.
OH + Br−→ Br + OH−
(1)
H + Br → Br−+ H+
(2)
H + Cu++→ Br−+ H+
(3)
OH + Cu+→ Cu+++ OH−
However, the use of excess H2in a water system
exposed to radiation provides the initial H radicals for a
chain reaction that promotes water reformation and in
which there is no net consumption of H2in the process
(shown in 5-6).
(4)
H2+ OH → H2O + H
(5)
H + H2O2→ H2O + OH
The ability of H2to suppress total oxidant concentra-
tions in a water system exposed to radiation has long
been recognized by the boiling water reactor (BWR)
community and is referred to as hydrogen water
(6)
chemistry (HWC). The first full-scale HWC test in the
U.S. was performed at Dresden-2 in 1982 and similar
tests have subsequently been carried out in several reac-
tors [4]. In the presence of excess H2, both the water
decomposition and production of O2can be suppressed
through a chain reaction which rapidly reduces the con-
centration of OH and H2O2. In an accelerator applica-
tion, Lillard et al. [22] has shown that this has the effect
of suppressing the Open Circuit Potential (OCP) of the
water (Figure 1) and thereby electrochemically reduces
the driving potential for corrosion.
Similarly, in a biological system, antioxidants have
been seen to protect against oxidative stress and pre-
vent the pathological process of a wide range of dis-
ease [23]. The effect of antioxidants in reducing
oxidative stress can be attributed to their ability to
protect tissues from free radicals [6] hinting towards a
scavenging mechanism. Turner [24] indicates, “A num-
ber of radiosensitizing chemicals and drugs are known.
Some sensitize hypoxic cells, but have little or no
effect on normally aerated cells. Other agents act as
radioprotectors reducing biological effectiveness...which
scavenge free radicals. Still other chemicals modifiers
have little effect on cell killing but substantially
enhance some multistep processes, such as oncogenic
cell transformation.” Thus it appears that antioxidants
act similarly to radical scavengers in nuclear coolant
systems in that they chemically protect against indirect
ionization by preferentially reacting with the reactive
species and thus reducing their ability to cause oxida-
tive stress.
The dependency of the outcome on scavenger type is
also similar to nuclear systems where the effect of the
type of additive can either be to promote water
Figure 1 The effect on OCP of the solution from H2 gas
bubbled into it and the addition of 0.1 M H2O2as measured
by Tungsten/Tungsten-Oxide (ref. electrode) and Platinum
electrodes (vs. saturated calomel electrode SCE) [22].
Schoenfeld et al. Medical Gas Research 2012, 2:8
http://www.medicalgasresearch.com/content/2/1/8
Page 3 of 13

Page 4

decomposition or water reformation. One such example
is the effect of oxygen. There appears to be parallels in
the effect of oxygen to promote water decomposition in
a nuclear system and increased radiosensitivity of cells
in the presence of oxygen as shown in Figure 2C[25].
With increased water decomposition, it would be
expected that there would be more ROS produced lead-
ing to increased damage. This is the case as cell survival
decreases under oxic conditions when exposed to X-
and g-rays implying that the indirect effect of radiolysis
byproducts are the most damaging to the cell. This oxy-
gen effect is quantified by the oxygen enhancement
ratio (OER) that reflects the relative increase of radia-
tion dose needed to produce the same biological damage
under hypoxic conditions as opposed to oxic conditions.
Figure 2D[25] includes the effect of hydrogen on water
decomposition and shows that when in excess of ROS
like O2and H2O2, the water reformation process domi-
nates as ROS are quickly scavenged. This raises the
question of what would the effect of H2be on radiosen-
sitivity of cells? Also noteworthy in Figure 2 is the
occurrence of an equilibrium where the amount of
molecular decomposition byproducts from radiolysis
remains constant. This hints at a scenario of two com-
peting processes in which a critical point occurs when a
balance is achieved between water decomposition and
reformation and suggests that radical scavengers can
shift which process dominates. Biological parallels and
implications of this are discussed next.
A Scenario of Competing Processes with a Critical Point &
Natural Repair Mechanisms
Radiolysis of water can be viewed as a scenario of com-
peting processes, water decomposition and reformation,
in which the outcome will depend upon where the pro-
cesses reach a balance or equilibrium. Decomposition
will still occur even in the presence of additives but they
serve to alter the net outcome by affecting the chemical
reactions such that one process becomes more dominat.
This was seen somewhat in Figure 2 and is shown more
explicitly in Figure 3[26] which shows that the equili-
brium point or threshold for which beyond negative
effects manifest can be increased through bolstering the
scavenging capacity and altering the balance such that
the favorable processes are dominant.
In a biological system, it appears to be a similar sce-
nario between biochemical damage and repair processes.
Free radicals and ROS were identified as the root cause
of oxidative stress and while their production is attribu-
ted to exposure to external sources like X-rays, ozone,
cigarette smoke, air pollutants and industrial chemicals
[27], they are also generated naturally during a variety
of energy-generating biochemical reactions and cellular
functions [5]. In fact, the ROS actually serve a necessary
Figure 2 (A)-(D)[25]reflect water decomposition by the concentration of radiolysis byproducts. (B) is an extension of (A) and is air free
pure water. Decomposition ensues until H2in excess of ROS. (C) is effect of dissolved O2in excess of H2to promote decomposition. (D) is effect
of dissolved hydrogen in excess of O2to scavenge. (E) [24] Shows effect of O2as a biological radiosensitizer. N2is also shown which raises the
question of what the effect of H2would be.
Schoenfeld et al. Medical Gas Research 2012, 2:8
http://www.medicalgasresearch.com/content/2/1/8
Page 4 of 13

Page 5

function as signaling molecules that critically modulate
the activation of the immune system and thus partici-
pate in antibacterial defense [28]. Thus, neutralization of
all free radicals would not be desirable. Oxidative stress
occurs when there is an imbalance between antioxidants
and ROS and free radicals [29] such as when ROS con-
centrations increase due to radiation exposure generat-
ing them by ionization. Chopping [3] observes, “The cell
is protected by different DNA repair mechanisms which
try to restore the damage. We don’t know the details,
except when the repair goes wrong (e.g. a replacement
of a lost nucleotide by a ‘wrong” base pair, etc.)... The
cell contains natural radical scavengers. As long as they
are in excess of the radiolysis products, the DNA may
be protected. When the products exceed the amount of
scavengers, radiation damage and cancer induction may
occur. In principle, there could thus be a threshold dose
for radiation damage, at which the free radicals formed
exceed the capacity of scavenging. The scavenging capa-
city may differ from individual to individual depending
on his/her physical condition.” Experimental investiga-
tions regarding long-duration space flights in particular
clearly showed increased oxidative stress markers and a
reduction in antioxidants after these flights [30,7]. Ken-
nedy et al. [31] demonstrated that exposure to space
radiation may compromise the capacity of the host anti-
oxidant defense system and that this adverse biological
effect can be prevented, at least partially, by dietary sup-
plementation with agents expected to have effects on
antioxidant activities. Interestingly and similarly so, the
radiation resistance of the bacteria Deinococcus radio-
durans that can grow under chronic g radiation (50 Gy/
hr) or recover from acute doses greater than 10 kGy has
been attributed to the role of antioxidants in mitigating
the extent of oxidative damage [32-34]. Thus there
appear to be similarities between the nuclear and biolo-
gical systems in how use of scavengers can enhance and
bolster the favorable process thereby increasing the nat-
ural radiation resistance of the system. Chopping [3]
points out that several radiation protection agents are
known and probably function as scavengers for the pro-
ducts of water radiolysis. However, the oxygen effect to
promote ROS production isn’t seen for the higher LET
a radiation where the OER is 1, as opposed to 3 as for
the case of X-rays, implying that direct damage such as
double strand DNA breaks becomes the more dominant
type of damage process for higher LET radiation. There-
fore, for the high LET space radiation, scavenging alone
may not be an effective mitigation approach. Thus, we
envision a strategy that interrupts the chain of events
leading to biological disease during the chemical and
biological stages. In particular, we propose a strategy
that (1) bolsters antioxidant capacity (2) supports nat-
ural repair processes and (3) manages biological
response to radiation insult. This approach could have a
great effect for increasing the threshold tolerance for
radiation damage before it propagates into systematic
symptoms, disease and ailments.
Radiation protection by a conjunctive
bio-chemical approach
Over the course of the last century, a wealth of knowl-
edge has been accumulated on the effect of radiation on
biological systems. Areas spanning in scope from DNA
damage up to changes in physiology have received
extensive study. To date, biology studies of radiation
damage have largely focused on components of DNA
repair systems such ataxia telangiectasia mutated gene
(ATM). More recently, however, it has been found that
modification of key molecular targets can protect tissue
from radiation induced fibrosis in mice exposed to
doses up to 25 Gy [35,36]. It has also been found that
changes in APOE (Apolipoprotein E) genotype dramati-
cally influences survival following Total Body Irradiation
(TBI) in murine models. These results imply that modi-
fication of key molecular targets to induce biological
changes in the host can protect tissue from radiation
damage. Turner [24] notes that, “for carcinogensis or
Figure 3 Relative contribution of the water decomposition
process is associated with boric acid concentration measured
in milli-molar on the abscissa. System scavenging capacity or
relative contribution of the water reformation process is associated
with the initial amount of dissolved H2measured in micro-molar
concentrations (each curve). Manifestation of negative systematic
effects is reflected by the amount of water decomposition from
radiolysis as reflected by H2gas generation rates measured in
micro-molar concentrations per minute on the ordinate. Figure
illustrates that the addition of dissolved H2increases the scavenging
capacity of the water therefore increasing the threshold and
delaying the onset of when decomposition becomes the dominant
process [26].
Schoenfeld et al. Medical Gas Research 2012, 2:8
http://www.medicalgasresearch.com/content/2/1/8
Page 5 of 13