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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.

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Biological effects of radiation during stratospheric flights l.jpg

June 3-4 2008, Rome

BIOLOGICAL EFFECTS of RADIATION DURING STRATOSPHERIC FLIGHTS

Mariano Bizzarri

Dept. of Experimental Medicine

University La Sapienza - Roma


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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


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In the Man­High II Program, experiments were

conducted to investigate the near­space

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.


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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


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1987

Stratospheric balloon, program ODISSEA

Cosmicradiation and lymphocyte activation

1986

Stratospheric balloon, program ODISSEA (balloon failure)

Cosmicradiation and lymphocyte activation

By 1970, there were over 500 yearly scientific high­altitude 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.


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Are balloon-borne experiments

reliable for Microgravity and

Radiation studies?


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g values are in fact only minimally reduced in stratospheric flights


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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 10-3g (with a free fall duration of 55 sec.)

This kind of facility is far to reach the expected

times required by biological experiments


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RADIATION EXPOSITION in the ATMOSPHERE


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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


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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).


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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.


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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”.


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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. 


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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.


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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)


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RBE ofdifferent

radiations


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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 ifballoon-borneexposures are limited to a spectrum

significantly modified by the shielding of the remaining atmosphere and by the geomagnetic field


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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)


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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.


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BIOLOGICAL MECHANISMSof INTERACTION


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INFLUENCING FACTORS of RADIATION INJURY

  • Dose rate and fractionation

  • LET

  • Radiation quality (RBE)

  • Temperature

  • Chemical modification

    • Oxygen

    • Radiosensitizing agents

    • Radioprotective agents


Radiation q uality l.jpg

Radiation quality


Survival curve for mammalian cells exposed to high a and low let b r adiation l.jpg

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 c ell in c ell c ycle l.jpg

Radiosensitivity of cell in cell cycle

Relative

Survivability

G1 S G2 G1

M

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.


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Mechanisms of damage at molecular level


Relation b etween let and a ction t ype l.jpg

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


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Biochemical reactions with ionizing radiation

DNA is primary target for cell damage from ionizing radiation


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Types of radiation induced lesions in DNA

Base damage

Single-strand breaks

Double strand breaks


Direct a ction l.jpg

Direct action

Ionizing radiation + RH R- + H+

Bond breaks

OH

I

R – C = NH

imidol (enol)

O

II

R – C = NH2

amide (ketol)

Tautomeric Shifts


Indirect a ction l.jpg

Indirect action

OH-

H

O

H+

Xray

 ray

e-

H

Ho

P+

OHo


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Lifetimes of free radicals

RO2o

HO2o

Ho

OHo

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 o xygen on f ree r adical f ormation l.jpg

Effects of oxygen on free radical formation

Oxygencan 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)


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OTHER EFFECTS


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Effect of radiation on cell Cell kinetics


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RADIATION-INDUCED

DAMAGE in CELL


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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.


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First reports on harmful effects of radiation

  • First radiation-induced skin cancer reported

  • 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 leukemiaamong first radiologists


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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”


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  • 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


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“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


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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


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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

emulsion

BIOSTACK

STRATOSPHERIC BALLOONS

GENETIC and METABOLOMIC ANALYSIS


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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.


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HOW TO STUDYGENETIC and METABOLICALTERATIONS in RADIATIOPN-EXPOSED BIOLOGICAL SAMPLES?HOW TO COPE WITH COMPLEXITY ?


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BIOLOGICAL PROCESSES

NETWORK

genes

proteins

metabolites


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PROTEOMICS

CELL

CULTURE

GENOMICS

CELL CYCLE

APOPTOSIS

DIFFERENTIATION

STRUCTURE

METABOLOMICS

MATHEMATICAL NON-LINEAR MODELLING

of the BIOLOGICAL NETWORK


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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 monitoredand can give important information about the consequences of the genetic modification on the cell.

NMR- basedMETABONOMICS is the technique used to characterize the changes in the metabolome of the cell.


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….thanks


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