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BIOLOGICAL EFFECTS of RADIATION DURING STRATOSPHERIC

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					                     June 3-4 2008, Rome




 BIOLOGICAL EFFECTS of
   RADIATION DURING
STRATOSPHERIC FLIGHTS
           Mariano Bizzarri
     Dept. of Experimental Medicine
     University La Sapienza - Roma
On 4 February 1902, Robert Falcon Scott became the first man to go up in a balloon over Antarctica.
It was a modest balloon filled with 226 cubic metres of hydrogen. It rose 243 metres enough for Scott,
who was precariously perched in a basket below the balloon, to see over the edge of the Ross Ice Shelf,
the biggest ice shelf in the world.




                Auguste Piccard




In 1930 he built a balloon to study cosmic rays.
In 1932 he developed a new cabin design for balloons
and in the same year ascended by balloon in a
pressurised gondola to 16,916 mt
In the Man-High II Program, experiments were
conducted to investigate the near-space
environment and its effects on humans
in preparation for spaceflight.




The Strato-Lab Program was designed to conduct aeromedical research on flight
crews, astrophysical investigations, and geophysical observations.
In addition, studies of air pollutants and spectrographic and photographic studies of
the Sun and Venus were conducted.
Major Simons piloted the second Manhigh flight on August 19 - 20, 1957.
He climbed 101,516 feet above the Earth using a 3-million cubic foot balloon.
Simons was the first person to see a sunset and a sunrise from the edge of space
 By 1970, there were over 500 yearly scientific high-altitude manned and unmanned
 balloon launches in the United States.
 These flights were used to study aeronomy, solar physics, astronomy, magnetic fields,
 cosmic dust, biology, and other areas of scientific interest.



1987 Stratospheric balloon, program ODISSEA        Cosmic radiation and lymphocyte
                                                   activation
     Stratospheric balloon, program ODISSEA        Cosmic radiation and lymphocyte
1986 (balloon failure)
                                                   activation
Are balloon-borne experiments
reliable for Microgravity and
Radiation studies?
g values are in fact only minimally reduced in stratospheric flights
A microgravity payload module (MIKROBA) released from a balloon at the
peack attitude was made operational in 1990 and can offer a microgravity
level of 10-3 g (with a free fall duration of 55 sec.)




        This kind of facility is far to reach the expected
           times required by biological experiments
RADIATION EXPOSITION
  in the ATMOSPHERE
COMPOSITION of (primary) COSMIC RADIATION

SOLAR WIND
- visible light
- ultraviolet and infrared radiation
- X-rays and γ-rays (photons)
- Electrons and protons (H+ nuclei) with few keV

SOLAR FLARES
- sudden short-liven light phenomena
- associated with large emissions of charged particles (protons): solar protonic
events (SPE)
- while SPE pose no threat to human beings on the ground on in low-orbit
missions, SPEs constitute a serious risk for planetary missions

GALACTIC COSMIC RAYS (GCR)
- protons (87%)
- α particles (helium nuclei, 12%)
- heavy ions (1%) with Z>2 (C, Fe): HZE particles
The earth’s atmosphere is bombarded
by high-energy particles from our galaxy
(primary cosmic radiation). In the upper
atmospheric layers, these particles react
with air molecules. As a result of nuclear
reactions, a great number of secondary
particles (secondary cosmic radiation) is
formed. Some of these secondary particles
decay again, are absorbed in the atmosphere
or possibly penetrate into the earth. The
radiation fluence generated in this way
is subdivided into three main components:
electrons/photons, hadrons (nuclear components)
and myons (heavy electrons).
The figure shows that the relative dose
fraction at flight altitudes (10 Km) mainly
originates from neutrons (n) and electrons
and photons (e-) with a smaller proton
component (p), whereas myons (µ) and
a small fraction of neutrons mainly
contribute to the dose on the ground level.
The unit of dose is the gray (abbreviated Gy) which represents the absorbtion
of an average of one joule of energy per kilogram of mass in the target
material. This new unit has officially replaced the rad, an older unit (but still
seen a lot in the radiation literature). One gray equals 100 rads. Absorbed
dose was originally measured for x-rays and gamma radiation but has been
extended to describe protons and HZE particles. When used in predicting
biological damage, a further distinction must be made as to the "quality"
of the radiation, in order to evaluate the “biological impact”.
Although the Absorbed Dose of of some radiation may be measured, another
level of consideration must be made before the biological effects of this
radiation can be predicted.

The problem is that although two different types of heavy charged particle
may deposit the same average energy in a test sample, living cells and tissues
do not necessarily respond in the same way to these two radiations.

This distinction is made via the concept of Relative Biological Effectiveness
(RBE) which is a measure of how damaging a given type of particle is when
compared to an equivalent dose of x-rays.




Basically, the RBE is determined by comparing the damage of the radiation to
the cells/tissue of interest to that with an equal dose of gammas or x-rays.
For example, the RBE of alpha particles has been determined to be 20
(apparently not very dependent on the energy of these particles). This
means that 1 Gy of alphas is equivalent to 20 Gy of gammas/xrays.

Another way to say this is to use a new unit, the sievert (Sv) which measures
the Dose Equivalent (the old unit is the rem; 1 sievert = 100 rem).

Thus 1 Gy absorbed dose of alpha particles is 20 Sv dose equivalent.

The sievert is the unit used in NASA's radiation limits for humans in
Low Earth Orbit.
The measurement of the clonogenic survival is a first step, to
determinate the influence of a radiation on cells. Photon irradiation
leads in most cases to a shouldered dose-effect curve that can be
described by the linear-quadratic equation




The shoulder that is characterised be the ratio α/β is a measure for the
repair capacity of the cell.
Particle irradiation leads to a reduction in the shoulder with increasing
LET up to pure exponential curves. This is caused by the higher local
ionisation density in the ion track. The resulting higher efficiency of
the ions is described by the relation Dphoton/Dparticle leading to the same
biological effect and is called Relative Biological Effectiveness (RBE)
RBE of different
radiations
Although the potential hazards to living systems from the heavy nucleii
component of galactic cosmic radiation was recognized, very little active
research was conducted until the crews of Apollo 11 and subsequent Apollo
missions reported experiencing a visual light flash phenomenon




Exposure to HZE particles during a spaceflight mission offers several unique
advantages, principally, exposure to the primary spectra modified only by the
interactions in the relatively lightly shielded space vehicle.

It is a matter of debate if balloon-borne exposures are limited to a spectrum
significantly modified by the shielding of the remaining atmosphere and by the
geomagnetic field
The crew of a spacecraft is exposed to secondary cosmic radiation:
while the walls of a spacecraft stop most primary GCR particles,
some can penetrate the wall material.
The resulting interactions yeld secondary particles of the same
nature but weaker in energy, as well as neutrons and X-rays.

On the ground, while certain protons do reach the surface of Earth,
most of the GCR is stopped by the atmosphere: α particles and heavy
ions practically disappear at an altitude of 20,000 m, but HZE particles
can penetrate deeper.

All of these particles collide with the oxigen and nitrogen atoms of
the atmosphere. The resulting interactions give rise to electromagnetic
radiation (γ-rays, neutrons, mesons, electrons)
The high atomic number-high energy particle component (HZE particles) of galactic
cosmic radiation was discovered in 1948 and radiobiologists soon became concerned
as to the effect this new type of ionizing radiation might have upon living systems
exposed to it.

Soon after discovery of the HZE particles, Tobias in 1952 predicted that a visual light
flash sensation could be experienced by individuals exposed to these particles.
There followed direct experimental evidence of the character and effectiveness of HZE
particles.
Chase (1954) describes graying of hair in balloon-borne black mice.
Eugster (1955) demonstrated cellular death by single hits of heavy ions on Artemia Salina
eggs; and similar effects were reported by Brustad (1961) on maize embryos.

Brain injury studies were attempted by Yagoda and co-workers (1963) and by Haymaker
and co-workers (1970) in balloon-borne mice and monkeys, respectively.
BIOLOGICAL MECHANISMS
    of INTERACTION
      INFLUENCING FACTORS of
         RADIATION INJURY

Dose rate and fractionation
LET
Radiation quality (RBE)
Temperature
Chemical modification
 Oxygen
 Radiosensitizing agents
 Radioprotective agents
Radiation quality
Survival curve for mammalian cells exposed to
     high- (A) and low-LET (B) radiation


                   n

               Dq




           1-1/e            1-1/e
    ,037
                   D0               D0
                                         B
                        A
       Radiosensitivity of cell in cell
                   cycle
Relative
Survivability




                 G1          S           G2       M              G1
Relative survivability of cells irradiated in different phases of the
cell cycle. Synchronised cells in late G2 and in mitosis (M) showed
greatest sensitivity to cell killing.
Mechanisms of damage at molecular
              level
           Relation between LET
              and action type

Direct action is predominant with high LET
  radiation, e.g. alpha particles and neutrons
Indirect action is predominant with low
  LET radiation, e.g. X and gamma rays
Biochemical reactions with ionizing
            radiation




  DNA is primary target for cell damage from
  ionizing radiation
   Types of radiation induced lesions
                in DNA
                 Base damage




Single-strand breaks   Double strand breaks
              Direct action
Ionizing radiation + RH                R- + H+



                               
                   Bond breaks
       OH                           O
       I                            II
   R – C = NH                   R – C = NH2
   imidol (enol)                amide (ketol)
            Tautomeric Shifts
        Indirect action




                  H   OH-
        e-    O        H+
X ray
                  H   Ho
 ray   P+
                      OHo
       Lifetimes of free radicals
               HO2  o                       RO2o

          H             OHo
          o                                            3nm


              OHo                Ho
Because short life of simple free radicals (10-10sec), only
those formed in water column of 2-3 nm around DNA are
able to participate in indirect effect
  Effects of oxygen on free radical formation
Oxygen can modify the reaction by
enabling creation of other free radical
species with greater stability and longer
lifetimes

H0+O2  HO20 (hydroperoxy free radical)

R0+O2 RO20 (organic peroxy free radical)
OTHER EFFECTS
Effect of radiation on cell Cell kinetics
RADIATION-INDUCED
DAMAGE in CELL
ACUTE EFFECTS
The acute, or more immediately-seen effects of radiation can affect the
performance astronauts. These effects include skin-reddening,
vomiting/nausea and dehydration. Other tissue and organ effects are
possible.

LONG TERM EFFECTS
Given that only moderate doses of radiation are encountered (and thus acute
effects are not seen) the long-term effects of radiation become the most
important to consider. The passage of an energetic charged particle through
a cell produces a region of dense ionization along its track. The ionization of
water and other cell components can damage DNA molecules near the particle
path but a "direct" effect is breaks in DNA strands. Single strand breaks
(SSB) are quite common and Double Strand Breaks (DSB) are less common
but both can be repaired by built-in cell mechanisms.
"Clustered" DNA damage, areas where both SSB and DSB occur can lead to cell
death. DSB due to ionizing radiation (especially the high LET radiation found
in space) is an important component of long-term risk .
A more dangerous event may be the non-lethal change of DNA molecules which
may lead to cell proliferation and eventually to malignancy.
          First reports on harmful effects of
• First radiation-induced skin cancer reported
                           radiation
        in 1902
• First radiation-induced leukemia described
        in 1911



                  • 1920s: bone cancer among radium dial
                  painters
                  • 1930s: liver cancer and leukemia due to
                  Throtrast administration
                  • 1940s: excess leukemia among first
                  radiologists
Spatial Agency Reports “gives estimates of the uncertainty in the health
(carcinogenic, mutagenic) risks from HZE particles.
The reason is that there is only ground-based carcinogenesis experiment on
cancer induction in animals.”

Furthermore “quantitative designs of appropriate countermeasures, such as
shielding, and biological or biochemical schemes to reduce the damage from
HZE particles are very rudimentary”.

The NASA Strategy Report “recommended a comprehensive research
program to determine the risks from different types and energies of HZE
particles and from high-energy protons for a number of biological end points”
HIGHER PRIORITY

- assessing the carcinogenic risk
- effects on central nervous system (CNS) of exposure to GCR
- how to extrapolate experimental data from rodents to humans

LOW-PRIORITY RECOMMENDATIONS

-estimate the effects of chronic exposure to GCR on fertility and cataract
formation
- to determine whether drugs could be used to protect against the effects
of exposure to GCR
- to assess whether biological response to GCR depend only on the Linear
Energy Transfer (LET) or on the values of the atomic number and energy
separately
“DUE TO ITS EXTENSIVE ENERGY SPECTRUM AND
HETEROGENEOUS COMPOSITION, COSMIC RADIATION IS
DIFFICULT TO REPRODUCE ON THE GROUND.
ACCELERATORS CAN ONLY GENERATE RADIATION OF A
FIXED NATURE AND ENERGY.
THIS DIFFICULTY IS ENHANCED AS COSMIC RADIATION AND
WEIGHTLESSNESS MAY HAVE COMBINED EFFECTS.
SIMULATION OF THESE TWO FACTORS IS CURRENTLY
IMPOSSIBLE TECHNOLOGICALLY”




H. PLANEL, 2004
The major facility for these experiments is the Alternating Gradient
Synchroton (AGS) at Brookhaven National Laboratory but it is available
for only two to four weeks per year.


At the present rate of progress it would take 20 or more years to
complete the high-priority experiments recommended in the
Stategy Report
HENCE, NEW FACILITIES and NEWER METHODOLOGICAL
APPROACHES ARE NEEDED I N ORDER TO ENSURE A
RELIABLE UNDERSTANDING of THE BIOLOGICAL EFFECTS
RELATED to HZE PARTICLES and GCR


                              GCR


                                                stratosphere

                                heavy ions


                                     biological layer

                          BIOSTACK           emulsion


STRATOSPHERIC BALLOONS

              GENETIC and METABOLOMIC ANALYSIS
The new 120-metre-diameter ballloons will make possible long
duration experiments in biological fields, enabling studies and
performances until now never reached.


This balloon should fly for about 100 days (with relative costs)
at an altitude of 40/50.000 m.


Unlike the conventional balloons, the new balloons are sealed to
keep the helium at high pressure and their volume constant.
    HOW TO STUDY
GENETIC and METABOLIC
    ALTERATIONS in
 RADIATIOPN-EXPOSED
 BIOLOGICAL SAMPLES?
  HOW TO COPE WITH
     COMPLEXITY ?
BIOLOGICAL                 NETWORK
PROCESSES




              genes



              proteins


             metabolites
                                          PROTEOMICS

     CELL
    CULTURE            GENOMICS




  CELL CYCLE
   APOPTOSIS
DIFFERENTIATION
   STRUCTURE



                                    METABOLOMICS




      MATHEMATICAL NON-LINEAR MODELLING
      of the BIOLOGICAL NETWORK
    Determination of the biological system metabolites
   defines its metabolome, in other words its metabolic
fingerprint, which allows us to identify and to dynamically
  follow its growth and/or its responses to environmental
                         conditions.
 The changes in metabolite levels due to altered gene
 expression can be monitored and can give important
  information about the consequences of the genetic
               modification on the cell.


NMR- based METABONOMICS is the technique used to
characterize the changes in the metabolome of the cell.
….thanks