Mutation Research 430 Ž1999.

299–305
www.elsevier.comrlocatermolmut
Community address: www.elsevier.comrlocatermutres

Space radiation effects and microgravity

J. Kiefer ) , H.D. Pross
¨ Leihgesterner Weg 217, D 35392 Giessen, Germany
Strahlenzentrum der Justus-Liebig-UniÕersitat,
Received 7 February 1999; accepted 30 March 1999

Abstract

Humans in space are exposed both to space radiation and microgravity. The question whether radiation effects are
modified by microgravity is an important aspect in risk estimation. No interaction is expected at the molecular level since the
influence of gravity is much smaller than that of thermal motion. Influences might be expected, however, at the cellular and
organ level. For example, changes in immune competence could modify the development of radiogenic cancers. There are
no data so far in this area. The problem of whether intracellular repair of radiation-induced DNA lesions is changed under
microgravity conditions was recently addressed in a number of space experiments. The results are reviewed; they show that
repair processes are not modified by microgravity. q 1999 Elsevier Science B.V. All rights reserved.

Keywords: Space radiation; Microgravity; DNA double strand breaks; Repair

1. Introduction is carcinogenesis. The development of a tumour is

Humans in space are exposed both to radiation
and microgravity. While the adverse effects of the
latter on organ function can to a certain extent be
overcome by suitable countermeasures and training
programmes, it is not clear how they influence fun-
damental physiological processes at the tissue, cellu-
lar and subcellular levels. In the context of the
present discussion, interactions between radiation
damage and microgravity are important. Although
radiation levels in space are considerably higher than
on earth they do not reach doses where deterministic
effects are expected Žwith the possible exception of
very large solar eruptions.. Hence, the main concern
)
Corresponding author. Tel.: q49-641-99-15300; fax: q49-
641-99-15009.
E-mail address: juergen.kiefer@strz.uni-giessen.de ŽJ. Kiefer.
still poorly understood but it is clear that many
stages are involved ŽFig. 1.. The first stage, induc-
tion or initiation, can definitely be caused by radia-
tion while its role in promotion and progression is
unclear. Cellular repair, tissue reactions, and the
immune defence reduce the radiation-related cancer
risk under normal circumstances. If microgravity
interfered with these processes the radiation hazard
in space would be higher than on earth. Interaction
between radiation damage and microgravity is thus
clearly not only of fundamental but also of great
practical relevance.
It is useful to recall that the actual energies in-
volved in gravitational actions are normally small
and depend on the mass of the entities involved.
Influences of gravity changes can only be expected if
they are larger than the thermal energy kT where k
is the Boltzmann constant Ž1.38 = 10y2 3 JrK. and T

0027-5107r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 7 - 5 1 0 7 Ž 9 9 . 0 0 1 4 2 - 6
300 J. Kiefer, H.D. Prossr Mutation Research 430 (1999) 299–305
Fig. 1. Proposed scheme of tumour development after irradiation.
Initiation is clearly increased by radiation while its role in promo-
tion and progression is unknown. Gravity effects may exert influ-
ences at all stages.
is the thermodynamical temperature measured in
Kelvin ŽK.. Under ambient conditions kT is about
4 = 10y2 1 J or 2.6 = 10y2 eV. To compare with
gravitational energies it is assumed that spherical
bodies with radius r and unit density move for just
one radius. Results of such simple calculations are
depicted in Fig. 2. It is obvious that gravity actions
cannot be expected for even big molecules and may
start to be important only with larger cell organelles
such as the nucleus. This is supported by space
experiments where changes in plasma streaming have
been attributed to cytoskeleton stress by the nucleus
w1x. Changes of lymphocyte proliferation and activa-
tion have been reported w2x which seem to demon-
strate microgravity effects on cellular signal trans-
duction. The whole field has recently been the
subject of a comprehensive review w3x. Theoretical
considerations to explain cellular gravity effects can
be found in Refs. w4 and 5x. Non-linear thermody-
namics has shown that even very small changes may
drastically alter the state of a system w6x. All this
does, of course, not prove the existence of micro-
gravity effect but only shows that they are possible
and not at variance with basic physics. The ultimate
demonstration requires very careful experimentation.
2. Experiments on the interaction of radiation and
microgravity
Although it goes without saying that the ex-
tremely complex conditions during a space experi-
ment call for very careful control of all parameters
involved, this obvious principle has not always been
followed and it is thus not surprising that the picture
is not clear. The ‘‘state of the art’’ up to about 1990
was comprehensively discussed by Horneck w7,8x.
This review is updated in Table 1. In most cases, the
biological samples were irradiated on the ground
before the flight but in a few cases on board radia-
tion sources were used which better mimic the real
situation. The interactions are classified as ‘‘ad-
ditive’’ Žneither sensitisation nor protection., ‘‘syn-
ergistic’’ Žincreased radiation effect under micro-
gravity. or ‘‘antagonistic’’ Žreduced radiation effect..
The inspection of the table shows that in about the
same number of cases either additive or synergistic
actions were reported and a clear picture does not
emerge. In only two examples could the experiment
be repeated, namely on the induction of chromoso-
mal aberrations in human lymphocytes w9,10x and on
double strand repair in yeast w17,22x. In both cases, a
potentiation of radiation damage had originally been
reported which could not be confirmed. Protection
by microgravity was only described twice. The first
case involved a short flight while the more recent
investigation was performed under much better con-
ditions on IML-2. The object was the extremely
radioresistant bacterium D. radiodurans which may
behave in an atypical way so that generalisation is
hardly possible.
Synergistic actions may be a cause for concern
and have, therefore, to be considered in more detail.
Before doing so a few general remarks are in place.
Fig. 2. A comparison of thermal and gravitational energies for
bodies of different size with unit density. Plotted is the ratio of
thermal to gravitational energy on the ordinate Žsee text. vs. radius
of spherical bodies.
Table 1
Radiobiological experiments in space: observed interactions between radiation and microgravity in various biological systems Žmodified from Refs. w7 and 8x and updated.
Test system, year Endpoint studied Mission, duration Irradiation Effect References

J. Kiefer, H.D. Prossr Mutation Research 430 (1999) 299–305

32
Human leukocytes 1967 chromosome deletion Gemini 3, 5 h P, 1.8 Gy in flight synergistic w9x
32
Human leukocytes, 1968 chromosome deletion Gemini 11, 72 h P, 2.8 Gy in flight additive w10x
85
E. coli, 1971 phage induction Biosatellite II, 45 h Sr, 17 Gy in flight additive w11x
Lettuce seeds, 1972 chromosome aberration Cosmos 368, 6 days g-rays 100 Gy pre-flight additive w12x
Hydrogenomonas eutrphia, 1972 inactivation Cosmos 368, 6 days g-rays 60 Gy pre-flight additive w12x
Saccharomyces ellipsoides, 1972 inactivation Cosmos 368, 6 days g-rays 1.6 kGy pre-flight additive w12x
85
Drosophila, 1974 larvae mortality Biosatellite II, 45 h Sr, 8 Gy in-flight synergistic w13x
85
Drosophila, 1974 genetic effects in sperm Biosatellite II, 45 h Sr, 1.4 Gy in-flight synergistic w13x
85
Neurospora, 1974 inactivation mutagenesis Biosatellite II, 45 h Sr, 90 Gy in-flight antagonisticradditive w13x
137
Rat, 1978 haemopoetic system Cosmos 690, 22 days Cs, 8 Gy in-flight additive w14x
Lettuce seeds, up to 1982 chromosome aberration Cosmos 782, 19 days g-rays 150 Gy pre-flight synergistic w15x
Lettuce seeds, up to 1982 mutagenesis Salyut 7, 72 days g-rays 100 Gy pre-flight additive w15x
Arabidopsis seeds, up to 1982 mutagenesis SoyuzrSalyut g-rays 300 Gy pre-rpost-flight additiversynergistic w15x
Carausius morosus, 1986 development anomalies Spacelab Dl, 7 days Cosmic HZE particles in flight synergistic w16x
S. cereÕisiae rad 54-3, 1994 DSB repair IML-1, 9 days 80 kV X-rays up to 140 Gy pre-flight synergistic w17x
Deinococcus radiodurans, 1996 DNA repair IML-2, 14 days g-rays, up to 12 kGy pre-flight antagonistic w18,19x
Bacillus subtilis HA 101, 1996 survivalrCFA IML-2, REPAIR, 14 days UV 254 nm, up to 335 Jrm2 pre-flight additive w20,21x
E. coli Br r, 1996 DSB repair IML-2, KINETICS, 14 days X-rays 150 kV, 120 Gy pre-flight additive w20,21x
60
E. coli PQ37, 1996 SOS-system IML-2, KINETICS, 14 days Co g-rays, 300 Gy pre-flight additive w20,21x
Human fibroblasts, 1996 SSB repair IML-2, KINETICS, 14 days X-rays 300 kV, 5r10 Gy pre-flight additive w20,21x
S. cereÕisiae rad 54-3, 1998 DSB repair XRAY 80 kV X-rays up to 140 Gy pre-flight additive w22x
63
S. cereÕisiae rad 54-3, 1998 DSB repair BETARAY Ni b-particles, up to 160 Gy in-flight additive w23x

301
302 J. Kiefer, H.D. Prossr Mutation Research 430 (1999) 299–305
It is obvious that a space experiment differs grossly
from one performed in the home laboratory. This
situation requires very careful planning not only
regarding experimental procedures but also regarding
the logistics of transport and storing. A study under-
taken without ground controls, treated exactly like
the space samples, will never yield meaningful re-
sults. This states a necessary but by no means suffi-
cient condition. A direct comparison in space by
using a reference centrifuge is an important improve-
ment but even under these conditions error sources
cannot be completely excluded since simulated grav-
ity by centrifugal forces is different from the terres-
trial environment. The only answer is ‘‘reproducibil-
ity’’, i.e., repeat experiments which are unfortunately
neither popular with funding agencies nor with the
space agencies who seem sometimes to be more
interested in seemingly spectacular findings — even
if not repeatable — than in scientific solidity. With
regard to radiation safety of astronauts this consti-
tutes not only a scientific but also an ethical issue.
It is very difficult to reconstruct the early experi-
mental conditions on Russian spacecraft and the
reported synergistic effects cannot be properly evalu-
ated. The two others, chromosomal aberrations in
human lymphocytes and DNA double strand break
repair Žto be discussed in more detail below. have
already been mentioned. The first reported synergis-
tic effects could not be confirmed in repeat experi-
ments. This means that the only so far proven case of
synergistic interaction is C. morosus w16x. This is not
a cellular system but a developing multicellular or-
ganism. Its development is impaired by the action of
space particles which were recorded and this effect is
enforced by microgravity. This makes sense since it
is known from studies not involving radiation that
microgravity interferes with embryonic development
w24x. What this means in terms of human radiation
hazard can hardly be said. It is quite clear that at
present, pregnant women will not go into space but
this may be difficult to exclude at later times with
missions of several years duration. This should be
kept in mind.
3. Cellular repair processes and microgravity
It was pointed out above that a direct effect on
enzymatic mechanisms can be excluded on thermo-
dynamical grounds. On the other hand, repair pro-
cesses are under cellular control and may depend on
transcriptional activity. This has so far only been
shown for excision repair of UV damage w25x but
may also exist for other pathways. Cellular
metabolism is under the control of signal transduc-
tion systems which are controlled by environmental
parameters, presumably also by gravity w7x. Modifi-
cations of cellular repair can hence not be excluded
per se. Two groups have recently addressed this
question: Horneck et al. w20,21x in bacteria and hu-
man fibroblasts; and the author et al. w22,23x with the
diploid yeast S. cereÕisiae. This latter object allows
us to tackle the problem in a very straightforward
manner. The special strain used, termed rad54-3, is
temperature-conditional for the repair of DNA dou-
ble strand breaks w26x. It is thus possible to keep the
cells at a low temperature in a metabolically inert
state during all transportation and handling phases
and to start the repair period only in microgravity. A
pilot experiment under non-ideal conditions could be
flown on IML-1 whose results indicated an impair-
ment of repair w17x. The repeat experiment which
was performed under the code-name XRAY on STS-
76 and strictly controlled did not confirm this finding
w22x. No change in repair was found in the experi-
ment BETARAY on STS-84 w23x. Here, the cells
were exposed to radiation only during the flight so
that it was possible to investigate reparability under
irradiation which mimics the real situation in space.
The essence of these two experiments is summarised
as follows.
4. Experimental approaches
Experimental details are given elsewhere w22,23x
so only a short account will be given here. The
diploid mutant rad54-3 of the yeast S. cereÕisiae
was used throughout. Cells were grown on standard
medium supplemented with those components neces-
sary to cover auxotrophic requirements. For the re-
pair experiments the cells were collected on mem-
brane filters and placed on minimal agar Ž1.8% agar,
0.9% NaCl, 0.91% KH 2 PO4 . which in the case of
BETARAY was supplemented with 0.02% of histi-
dine, adenine, leucine, uracil and tryptophan in order
to facilitate recovery. All samples were housed in
 J. Kiefer, H.D. Prossr Mutation Research 430 (1999) 299–305 303

Dosimetry for XRAY was carried out by standard

chemical dosimetry. In the case of BETARAY the
situation was complicated by the fact that the 63 Ni
foil did not meet the required specifications and
showed large inhomogeneities. It was thus necessary
to determine doses for each individual membrane
filter. This was achieved with the aid of a ‘‘Phos-
phorimager’’ calibrated to an ionisation chamber by
low energy X-rays. Nevertheless, there is some un-
certainty in doses but this does not invalidate the
main conclusions.

Fig. 3. Results of the XRAY experiment: full circles: cells incu-

bated at the repair permissive temperature under microgravity, 5. Results
open circles: cells incubated at the restrictive temperature in orbit,
diamonds: data from the ground experiment performed in parallel.
Full lines are for the experiment in orbit, broken lines for the Fig. 3 summarises the results of XRAY. It is
ground experiment. obvious that there is no difference between samples
exposed to microgravity during the repair period and
those on the ground. Those which were kept on the
reference centrifuges display an erratic behaviour
ESA ‘‘type I’’ containers which contained, in the Ždata not shown. as they show always a clearly
case of BETARAY, the radiation sources consisting lower survival but again with no difference between
of 63 Ni foils of different activities. space and ground samples. This effect which was
In the XRAY experiment the cells were exposed also noted during preliminary test experiments is not
to graded X-ray doses in the home laboratory and yet understood. Similar variations were also seen
transported at 0–48C to Kennedy Space Center. The during BETARAY Ždata not shown.. The outcome of
cells were kept at this temperature until the orbit was XRAY is clearly at variance with our preliminary
reached where samples were placed into 22 and 378C experiment performed on IML-1 w17x.
incubators. After a repair period of 152.5 h the
containers were cooled down to about 08C at which
level they remained until final analysis in the home
laboratory. Here the cells were washed off the filters,
plated on complete medium, and incubated at the
restrictive temperature of 378C for 3–5 days in order
to assess the remaining unrepaired damage.
In the BETARAY experiment the cells were ex-
posed to 63 Ni b-particles only during the repair
period. The activities were chosen in such a way that
during this time Ž121 h. doses between 3 and 180 Gy
were achieved.
In order to assess possible microgravity effects,
parallel samples were also placed in on-board refer-
ence centrifuges under otherwise identical condi-
tions. Furthermore, the whole experiment was dupli-
Fig. 4. Results of the BETARAY experiment: full symbols charac-
cated on the ground at the Kennedy Space Center in terise incubation at the permissive temperature Žcircles: orbit,
an identical experimental configuration Žexcept for squares: ground., open symbols are for incubation at the restric-
microgravity.. tive temperature Žcircles: orbit, squares: ground.
304 J. Kiefer, H.D. Prossr Mutation Research 430 (1999) 299–305
BETARAY simulates radiation influences in space
in a more realistic way since radiation and micro-
gravity act at the same time. Also here ŽFig. 4. no
differences are seen between samples in orbit and on
the ground. It can be concluded that microgravity
does not impair the repair of radiation-induced dou-
ble strand breaks in yeast. Since repair systems are
highly conserved in evolution w27x it may be safe to
assume that this statement is also true for mam-
malian systems. This was in fact also found by
Horneck et al. w20,21x using different approaches.
6. Discussion
The interplay between radiation and microgravity
poses a great potential hazard to humans in space.
The results reviewed above prove at least that cellu-
lar repair of DNA double strand breaks is not im-
paired. This does not mean that microgravity is no
longer an issue when considering radiation hazards
to humans in space, even at the cellular level. The
investigations so far are either based on survival Žthis
paper. or on molecular measurements of DSB rejoin-
ing w20,21x. It is not at all clear whether this proceeds
without errors and whether radiation-induced muta-
tions or transformations are also not altered. They
are considerably more important for long-term risks
than cell killing so that further studies are indicated.
The involvement of systemic factors, e.g., immune
suppression, is virtually unknown. This problem can-
not be studied in in vitro systems and can only be
approached by animal experimentation.
The review of the relevant literature and the
experience with recent space experiments make clear
that utmost care is indicated before an effect found
can be safely attributed to ‘‘space factors’’. To base
such a statement on a single experiment is unscien-
tific since there are so many possible influences
which may have an impact on the final outcome
even when all steps are controlled. This was already
seen by Bender et al. w9,10x where a synergistic
effect of microgravity on radiation-induced chromo-
somal aberrations could not be confirmed and had to
be attributed to unknown statistical fluctuations. Our
own experience with the precursor of the XRAY
experiment w17x underlines this. As pointed out, the
samples were not under strict temperature control
throughout and the originally reported decrease in
repair has to be attributed to this fact. The repetition
under more stringent conditions w22x as well as BE-
TARAY clearly demonstrated that cellular repair is
not impaired.
Acknowledgements
Experiments as described here have to rely on the
assistance of many people. We want to thank the
teams of ESA ŽDrs. Brinckmann and Brillouet.,
NASA KSC and BIONETICS for support and creat-
ing a stimulating working atmosphere. The hardware
was built in the mechanical workshop of our institu-
tion. All members of our group helped with the
preparations and final evaluation. Special technical
assistance was given by Petra Bepler-Kranert, Helga
Schneider and Barbara Baier. It should also be men-
tioned that the transportation of the samples without
outside interference which was crucial for the suc-
cess was made possible by the very helpful co-oper-
ation of Lufthansa. Financial support was provided
by ‘‘Deutsche Agentur fur ¨ Raumfahrtangelegen-
heiten’’ DARA.
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