UNITED NATIONSREPORT OF THE
UNITED NATIONSSCIENTIFIC COI\IMITTEE
ON THE
EFFECTS OF ATOMIC RADIATIONNOTE
Throughout this report and its annexes cross-references are denoted by a letter
followed by a number: the Jetter refers to the relevant technical annex (see Tableof Contents) and the number is that of the relevant paragraph. \Vithin each technicalannex, references are made to its individual scientific bibliography by a number
without any preceding letter.
Symbols of United Nations documents are composed of capital letters combined with figures. Mention of such a symbol indicates a reference to a United
Nations document.

ANXEXF

FUNDAMENTAL RADIOBIOLOGYTABLEOF CONTENTS
Paragrapl~sI. DISSIPATIONO F PHYSICAL ENERGY

Introduction-Direct and indirect effects ................. 1
L E T and RBE ....................................... 4
Dose-eff ect relations ..................................
8
Time intensity factor ................................. 12
Inactivation by transmutation of radioactive elements
15......

11. RADIATIONCHEMISTRY ................................. 17
Indirect effects ...................................... 18
Direct effects ........................................ 28
Effect of LET ....................................... 36
Oxygen effect ....................................... 38
After-effects ........................................ 39
Radioprotection ..................................... 42
Restoration ......................................... 48
Present status of the "target" theory ..................... 51

111. BIOCHEMICALEFFECTS.................................. 52

Cellular constituents .................................. 53
Biochemical mechanisms .............................. 59.

I V CYTOLOGICALEFFECTS ..................................
66
Nucleus ............................................ 67
Cytoplasm .......................................... 72

V. BIOLOGICALEFFECTS .................................... 87

Homogeneous cell populations ......................... 88
Differentiating cell populations ......................... 113
Adult organisms ..................................... 120

VI. VARIABLESIN RADIATION EFFECTS

Physiological conditions ............................... 128
Comparative sensitivity of living organisms .............. 138
Adaptation to radiation ............................... 146
Secondary effects ....................................153

V I I. ALTERATIONSOF RADIATION EFFECTS BY FOREIGN AGENTS
Protection .......................................... 159
Sensitization ........................................ 170
Recovery ........................................... 173......................................... 188
VIII. CONCLUSIONS
I. DISSIPATION
OF PHYSICAL ENERGY(Space and time factors)
Iniroduction-Direct atrd indirect effects
1 The effect of radiation is induced by the processes
pf absorption. when the energy of radiation is dissipated
In the irradiated matter .Apart from excitation. the ionization of molecules is believed to be largely responsible
for the initiation of primary chemical reactions There
are at present two major theories of the mechanism of
a d o n of radiations on living organisms : the theories of
direct and indirect action. The first one claims that
effective ionizations take place in key cellular structure
or in their immediate vicinity: the probability that their
a!teration causes cellular damage is dependent on thelr
pological specificity. This has often been called thetarget theory". and. since Dessauer . Crowther. Hol~veck.

.

and Lacassagne . Timofeeff-Ressovsky and Lea. the concept has had the support of many physicists ; it is being
constantly revised to take into account many new fundamental acquisition^?^^^^*^^^*^*^.

2 The "theory of indirect action." on the contrary.
claims that the biologically specific cellular structures arealtered as a result of their chemical reaction with free
radicals formed in irradiated water or other molecdes
not belonging to these stru~tures.~
As with most conflicting theories which have had ardent supporters O? .
both sides (another good e - m p l e is the corpuscular and .;.'
electromagnetic theories of light). it is very .probab@.l ..
that the two are complementary . Indeed. it IS almost&':certain that the same cellular component can beaffec&d_.*' ;in a way which is liable to produce identical b!pL%?$*@$
effects by both mechanism^.^*^^." >lethods have been *%.',! .F).
.... ;;

.

A,&
I.)

.-(

developed in recent years which enable the existence of
unpaired electrons resulting from the ionization process
to be demonstrated not only in crystalline amino acids
and other small molecules, but also in proteins, plant
embryos and other kinds of cells.

3. An attempt will be made to draw a brief picture ofsome fundamental aspects of the problem.
Linear energy trarrsfer (LET) and relative biologicaleffectiveness (RBE) of different kinds of radiation
4. The efficiency of radiation per ionizatiort to inducea particular effect is often found to vary for different
types of radiation. Let us at first consider an event whichis caused by one ionization such as the inactivation of an
enzyme or virus : in the case of small structures in vitro,
the radiation producing a low ion density will be more
effective than that giving a high ion density, becausesome of the ionizations of the latter will be wasted.
On the contrary, a radiation with a ligh density ofionization will be more effective when several ionizations
are simultaneously or in a relatively short time neededin the sensitive structure. Thus, the relative biologicalefectiveness (RBE) of radiations varies with theirlittear energy transfer (LET). This term describes thespatial distribution of the transfer of physical energy
in matter-and accounts for the loss of energy of theradiation, not only through ionizing processes, but also
through other processes such as dissipation of heat or
excitation of atoms. I t is a theoretical implication ofthese facts that some of the primary effects of radiations
take place within a shorter time than that needed forthe processes initiated by ionization or excitation to lose
their initial spatial distribution (perhaps as short as 1
millionth of a second) ; and also that the primary biological receptors of radiation are not themselves homogeneously distributed throughout the cell.'?

5. In mice, the relative biological efficiency (RBB)
increases greatly with ion density, for killing with low
intensity radiation, for shortening of the life-span, forinhibition of tumour growth, and for cataract induction :the increase, however. is smaller when one considers
effects on the gonads (sterilization), on the skin(epilation), on the blood white-cell count, or on the
induction of many chromosome abnormalities in
Dro~ophila.'~*l'*~~Some chromosome abnormalities inTradescantia have a very high incidence with highdensity irradiation.'$ Mutations in micro-organisms andsome in Drosophila are only slightly influenced by the
LET.12

6. Reviews on the subject by Lea1 and Zirkle12 haveshown that much could theoretically be achieved by comparing the effects of ion density. Lea had attempted touse the data available to him at the time, on the decrease
in incidence of chromosome breakage with decreasing
ion density, as an argument for the target theory.
However. it appears from Zirkle's paper that changes
in RBE-for comparable effects are often very difficult
to include in a general theory, because in many instances
the direction of change in RBE is not the same forsimilar effects in different materials and the RBE may
be strongly dependent on conditions of irradiation suchas the oxygen tension. It is at present very difficult tomake definite generalizations.

7. The mode of dissipation of radiation energy insideliving cells is not yet understood, although our knowledge of the physical aspects of energy loss is adequate

and hypotheses on the distribution of free radicals along
the radiation tracks have been suggested. However? it is
not clearly understood how this physical energy becomesapparent in chemical changes sudl as ionization andexcitation. I t might be of interest to use inert structuralmodels or do such experiments as comparing the L E T
for a virus inside and outside the host cells to get a better
picture of the sequence of events. When completely
understood, the use of radiations of different L E T may
lead to precise estimates concerning the size of thebiological structures affected.

Dose-effect relations

8. When a homogeneous substrate is irradiated, the1energy is distributed in an unpredictable way and theprobability of a molecule being hit depends on its concentration and on its volume. The concentration of theintact substrate decreases as radiolysis proceeds, andit can be predicted on theoretical grounds for low density
radiations that, if one ionization suffices to cause theeffect, the expression relating the remaining intact
structures ("survivors") to dosage will be exponential.
When a relatively small number of ionizing events isneeded, the number of responses observed will, however,This
be approximately proportional to the dosage.16-17*18
sort of effect has no threshold-which means that any
dosage, however small, is effective in producing somealteration.

9. On the contrary, if several ionizing events or "hits"
are needed, the response only becomes manifest after acertain dosage has been accumulated in the sensitive
structure: the dose effect curve is thenIn this case there is a threshold which, however, may
only be statistical, as when two identical cellular s-uctures need to be irreversibly altered for the effect tobecome manifest, which is so for recessive lethal mutations in yeasts.1° Other threshold effects appear whenrecovery of the altered structure or replacement of killedcells takes place, as is often the case in multicellularorganisms where many interferences may take place
between the primary physical event and its biologicalexpression.
10. The meaning of the dose-effect relationship isoften difficult to understand because the curve may
change quite dramatically when the conditions of irradiation are altered (aerobic or anaerobic irradiation;change of culture medium) : this difficulty is most likely
to occur when one studies a complex phenomenon likecell death, whose cause may be multiple and not identicalin different ~ i r c t m s t a n c e s . ~ ~11. However, several radiobiological processes are
known to give exponential dose-effect curves under
specific environmental conditions, as in the case of many
lethal effects on viruses and on micr~-organisms.'l*~
Diploid yeast
or mammalian cells2' in tissue
culture have a sigmoid dose-effect curve when s-irradiated. In the case of diploid cells, the sigmoid type of
curve is consistent with a 2 hit process, the exponential
response being explained on the assumption of a single
hit. One of the best present arguments ior the "target"
concept comes from the fact that in the case of small
viruses the "target" size can be estimated with a good
approximation21 and that survival curves of protectedbacteriophage are very similar in vitro and during theyery first minutes of infection.?' These results can beiIexplained on the basis that the primary ionization takes
place inside the sensitive structure. In the case of amutation this is the gene. It is, however, difficult toaccept the concept without modification at the present
time, on account of the possible contribution of diffusable radicals from water or other molecules in theimmediate vicinity of the target. However, it is believedthat radicals only diffuse for distances of about 30X.
As most effects have not been fully expressed when theradiation has ceased to be delivered, there is a timeinterval during which restoratiori may occur, andwhether this takes place or not may alter the doseresponse curve. Very little is known about what happens
during this time: the chain of events may be relatively"simple" in the expression of a point mutation in microorganisms or perhaps even in a mammalian germinal
cell, but it is certainly very complex when the inductionof malignant growths is considered. The number ofmutations in bacteria,21D r ~ s o p h i i aand
. ~ ~perhaps mouse
populations." incremes linearly with radiation up tomoderate dosages, as do certain of the chromosome
aberrations2' and perhaps the induction of leukemia.zs~29
However. the determinations do not extend as low as the
background radiation, and much uncertainty remains atthese low levels, although it is highly probable that thebackground radiation causes some of the mutations
which occur naturally, thus contributing to some extent
to the evolution of living organisms and to their load ofmutational hazards. This nreanr that as far m w e know
at present, biological effects will follow irradiation, however small its amount. It has thus become very importantto establish with great accuracy the shape of the doseeffect curve in the lower dose range. in order to estimate
the contribution of the natural Fahiation for di-fferent
effects. The number of experimental animals needed toobtain a good accuracy increases enormously as the dose
decreases and the response b ~ ~ m smallere sor less
frequent. For human populations, as each individual isimportant, the only reasonable "experimental sample",when small doses are concerned, is the total populationof living human beings. In this case, the only ~ o u n dprocedure is to get a better understanding of the fundamental processes which are occurring. Thk may actually
be the only w a y of anstverirrg some of the basic problems
underlying low dosage irradiation.

given dose is f r a ~ t i o n a t e d .A~ ~change of intensity by afactor of one million does not alter the number of phage
induced in E. C O ~ ~ . K , , . ~In' *contrast,~~
the number of
certain chromosome aberrations in Tradescantla micro- like chromosome exchanges,
spores or Vicia seeds34136
which require the simultaneous occurrence of two breaks-are often highly dependent on the time taken to deliver
the dosage: more exchanges are obtained for higher
intensities. When the duration of irradiation is increased, one reaches a time for.wFch the effectivenessdoes not decrease any more; thls hme is related to thelapse during which the breaks remain open. Hot~ever,this picture is complicated by the fact that the rate ofrejoining depends on respiratory activit~.~'The killingof complex organisms like mammals, being the result of
extremely complex cellular damage, 1s very efficient forhigh intensities but much less so for low ~ n e s . ' " * ~ ~ ~ * ~14. The time during which radiation is delivered becomes very important ~f the system being studied undergoes some change during this time: the radiosensitivityof many cellular processes varies during the mitotic
cycle and one can expect a greater radiation effect if theintensity is high during the most sensitive period of thiscycle. Secondary biological reactions may interfere withthe expression of damage and, if recovery or selection
occur, one can expect a greater effect if the intensity ishigh for the same given dosage. For these reasons,it does not appear justijid.de, unless the ftcndantentd
pathways of radiafion damage are known, to consider
tltat an effect observed after high interzsity irradiation
will necessarily follow the applicatiotl of the same dosage
at low intensity.

Inactivation by transntutatiotr of radioactive elemeltts
15. Certain radioactive substances taken up by theorganisms in specific structures may affect them not only
b!? the radiation they
but also by the fact that theis often accompanied by
mission of theserecoil effects or transmutation into an atom having new
chemical properties. Thus P-32 can be incorporated into
important biological structures like viruses or chomosomes, and in the first case it has been shown that theinactivation due to transmutation of P-32 into S-32 ismore efficient than the one due to the /3 particles beinge ~ n i t t e d . ~ ~It- ' is~ conceivable that strontium could reTime intensity factor
place calcium or magnesium, which are probably structural constituents of chromosomes.4BI t has been claimed
12. The time taken to deliver a given dosage of radiathat
a low calcium environment increases the number oftion can be varied in order to give very high or verq. lowv
spontaneous and induced chromosome breaks in Tradesintelzsities per unit time. A &ange in intensity will notaffect the end result when separate ionizing events con~ a q t i a . " ~I f* ~these~ facts were of general application,
the disintegration of strontium-90 or strontium-89 might
tribute i&ependelttly to the observed effect ; this should
affect cells not o d y by emitting P radiation. but also byhold true for some of the exponentially respondingtransmuting to yttrium, which has new chemical properevents although it is not true for all. On the contrary,ties. Such possibilities will have to be discussed, andin the case of events responding by sigmoid curves, sevthe role of trace amounts of metals and o f &dine
era1 ionizations may be needed almost sinncltaneouly
e a r t h ift intp~rtatttcelllklar structltres shoftld be kflown(this is the case when recovery processes exist) ; here,
before one dismisses its possible intportance biologicd
a given dose becomes less effective if delivered in aeffectsof radionuclides which, apart from emittill9 l a d long interval of time.31n3z.39 However, this is not dx~ays
atio?t, !rave a specigc fzbncti0~.
the case, and for inactivation of both homologous chromosome regions of a diploid cell. it is known that pro16. ~ l t h Cads
~ ~ ~hash not been found by ? d i e
traction of irradiation does not alter the effect.
aulography in the bone marrow cells of rats ~revlously
injected with 200 pc,40 nuclear aberrations have been
13- The physiological conditions of DrosopItila sperm
observed in allium which had been grown in the presence
are very constant for a considerable length of time, andof S1--90,~'and further work on the subject. should be
lt has been found that the induction of mutation byirradiating the males does not vary with the intens~ty done to settle this problem. which is of greatm?ortancein understanding the possible cellular damage. Inducedof irradiation.30 The same is true for the induction of
by radionuclides. Their specific radioactivity lnslde cellumost malformations in the mouse embryo. Howvever, inlar structures as well as their rate of turnover and their. Some cases the severity of malformations is greater i f a

i

I

-

,
a

.

!

,

-

X'

129
-

chemical function may be important in inducing cellular
damage.

11. RADIATIONCHEMISTRY
17. It is only by understanding the mechanisms ofaction of radiations on the different cellular constituentsthat one can hope to understand what is happening in
irradiated cells and also to use these basic findings in the
search for protecting agents. Much useful informationon the chemical effects of radiation has been gathered bysubmitting various chemicals to irradiation in vitro(radiation chemistry) ; however, on account of our very
incomplete knowledge of cellular structure and chemistry: biological constituents should be studied after
irradiation of the living organisms (radiation biochemistry) if one is looking for full understanding of radiobiological processes. Furthermore, as will be pointed
out, specific constituents and not bullc chemical properties should be studied whenever-pcssible. Molecules may
be altered by indirect and direct effects of radiation.
Indirect effects
18. I t is known that the most abundant of all biological constituents is water: it constitutes 70 per cent of
most living cells except for certain plant seeds and may
sometimes constitute more +an 95 per cent, but an unknown proportion of it is bound water ahd constitutes
part of the cellular structures. This has prompted muchresearch into the radiochemistry of water.
Effects of radiation on water and substrates in aqueous~01ution~~~~~
19. I t is usually accepted, although-by no means
demonstrated. that water when chemically pure undergoes ionization and, as a result of this-and of secondary
reactions, the sequence of which is hypothetical-splits
into OH0 (hydroxyl radicals) and H0 (hydrogenatoms), which recombine: in the absence of any impurity, nothing apparently will have happened because
the radicals cannot enter any other reaction. Traces ofH2 and H,O, are thought to be formed during thisprocess. The formation of radicals takes place in the
short time ~f 10-l1 -lo-'? s e ~ . ~ ~20. The existince of OH0 radicals has been demonstrated: certain radiation reactions leading to the polymerization of acrylonitrile can best be explained on thebasis of an OH0 radical mechanism, as also the oxidationof benzene to p h e n ~ l . ~ l * ~ ~21. On the other hand, the existence of free H atoms
is still questioned on account of the high osidizing powerof radiation on substrates in aqueous solutions ; several
mechanisms of radiolysis have been suggested, which
do not make necessary the postulation of the existenceof HGatorns.jl It may be easier to interpret many biochemical reactions of radiation when a better understanding of the radiolysis of water has been achieved.
This should certainly be of great importance for the
logical approach to protection mechanisms. Although
the existence of a free hydrogen atom is doubted bysome, many authors have assumed that it does exist,
and much present thinking is based on this assumption.
I t will make the discussion easier if we tentatively adoptv,
a mechanism involving this radica!
this ~ { e ~ wheneveris suggested. If oxygen is present as it is when a solution is in equilibrium in air, O,HO (perhydrosy radical)(hydrogen peroside) are also formed In addiand H202
tion to H0and OH0.51

22. When the water contains various solutes, these
are the site of chemical reactions due to HG,O H 0 and
O,HO radicals formed in the solution through the radiolysis of water. These radicals have reducing or oxidizing properties and can react with the substrate,oxidizing or reducing it or transforming it in turn toa new free radical. Thus, if many solutes are present,
they may be altered by radicals coming either fromwater or from the other solutes: this last mechanisnl
although not too well studied could very well be of some
importance in very complex systems. When macromolecules are irradiated, the yield of altered molecules perion is usually smaller than expected from what happens
to smaller molecules of similar chemical properties : thisis thought to be due to the fact that bonds, broken inthese structures, are not able to come apart (they areheld together by the other intact bonds in the structure
or cannot come apart by normal diffusion processes) andthe radicals formed presumably recombine. Such a "cageeffect" would be chiefly expected in concentrated solution
and in complex cellular ~tructures.~'
There are probably
also some biologically inert chemical groups whosealteration ~vouldnot impair the biological activity ofsome n~acrom~lecules.~~
23. Although some reduction reactions occur whensubstrates are irradiated. most reactions appear to beo ~ i d a t i v e . ~ From
~ * ~ " experilnental data it is apparent
that a substance is reduced only when it possesses a very
high normal redox potential (greater than 0.9 - 1.0 for
effects of X-rays in the absence of ~ x y g e n ) . ~ 'Nature of the chenrical efects
24. Ionizing radiations may alter inorganic as wellas organic substrates. The following reactions can betaken as examples

Oxidiziftg reactions may be effected by OH0 radicals(a) By simply removing an electron from an ion
Fez' + Fe3+-a reaction used for chemical dosimetry ;(b) By removing an H atom, leaving a radical which
can combine with another ones1
2CH3 COOH + 2C0H2COOH + COOH-CHZ-CH, -COOH ;(c) By substitution of a hydrogen by an OH0 as in
the oxidation of benzene to p h e n 0 1 . ~ * ~ ~ ~25. In a similar manner, small organic molecules likealcohols, aldehydes or acids undergo oxidation, and thelast-named compounds are often d e c a r b o ~ y l a t e d . ~ ~ ~ ~ ~They are also sometimes capable of undergoing polymerization by the formation of a chemical bond possibly
between two radicals as in the second reaction above:
acetic acid is capable of giving succinic and even still
more complex organic acids. Amino-2cids may be osidatively deaminatedIs1and if they have sulfhydq-l groups
these are oxidized to disulfur (S-S)=' and sometimes tosulioside, as in the case of cy~teine.~O*~~
26. Rcdztckg reaciions may be obtained as folloi~~s:(a) O H 0 radicals may act on strongly osidizing
agents (this is the case for iodate and ceric
salts) .51(b) I n certain cases. organic redox indicztors havebeen reversibly bleached in the absence of osygen.62The mechanisms are at present difficult tounderstand on account of the questionable existence of the free H atom.

( c ) Coenzyme I (Diphosphopyridine nucleotide)can be reduced by radiation to an abnormal
derivative (probably a dimer of the natural molecule) but only in the presence of a hydrogen
donor like ethanol,a3

27. C o ~ > ~ p lnnrolecrrles,e-~such as enzymes and otherproteins,05 nucleic acids, lipids and polysacharides, arealso altered in aitro as a result of the action of ionizing
radiations; enzjmes and desoxyribonucleic acid (in thecase of the transforming principle of bacteria) may loseI n most cases the nature
their biological pr~perties.O~*~~of the reaction has not been analyzed and cannot be
until we know more about the structure of these macromolecules.
( a ) One of the most sensitive cl~emicalgroups ofproteins is the sulfhydryl group (-SH) : two
adjacent groups are oxidized by OH0 to -S-S
resulting in the loss of biological activity when,
as in some enzymes, this activity is associatedwith the reduced form. S-S bridges also cause
cross-linking reactions between two adjacent

25. In the case of a direct e f i e c t , ' ~the~ ~ ionization
caused by the radiation concerns t5e molectile or structure under study. It is probable that the energy released
in one part of such a nlolecule ti-ill be transferred overh\e whole structure and ionizaticn or excitation phenomena will not necessarily occur ai the point of firstinteraction. If the molecule beco~nesionized, reactive
free radicals may be formed and the existeilce of unpaired electrons has been proved in experiments usingparamagnetic resonance; in the absence of water, theseradicals are found to exist for periods as long as \\-eelis
or months."*s4 In the case of water solutions, the lifeof the radicals is much shorter ( a few minutes). Suchstctdies have also been made in irradiated cells, indicati~l~the existence of free r a d i ~ a l s . ~ * * ~ ~29. Cross-linlcing between macromolecules may occur,
as in polyethylene, probably by the reaction of an ionizedmolecule on a normal one.sa The absence of an electronfrom a chemical bond may make this bond unstable
and cause it to be hydrolyzed or broken, and some ions
may also react with normal molecules causing them tocross link, as in some synthetic polymer^.'^ The absorption of energy from the ionizing radiation does not always result in the esptllsion of an electron: when ionization does not occur, the group of atoms may become
excited for a period perhaps as short as
sec. thus
being rendered 1110re reactive with other molecules and~~is thesusceptible to chemical a l t e r a t i ~ n .Escitation
only process responsible for the alteration of substances
by ultraviolet or visible radiations, and the use of thesetypes of radiations is thus extremely useful in thisrespect.
30. Tlze pltysical state of a proteiir rtwleclrle can bemade to vary, and it has been shown that when an
originally globular protein like pepsin is unfolded at an
air-water interface and is irradiated as a inonomolecularlayer it is much more sensitive than when the "stretched"molecules have been compressed into fibresss

molecule^.^^^^^( b ) Other specific osidation reactions of some macromolecules have been found, including the deamination or decarbosylation of proteins,B0and theosidation of structures containing double bonds:
as in the case of unsaturated fatty acids;66 butlarge dosages have usitally been necessary inorder to make measurements possible.
( c ) Cross linking may occur through the formationof a carbon to carbon linkage as the result of the
combination of two macromolecular free radicals,possibly formed by direct or indirect action."-i'This process has, however, mostly been studied in
artificial high polymers like polyvinylalcohol, but
it is also very likely to take place in cells where thelocal concentration or the orientation of macromolecules relative to each other may be advantageous for such a process, as in chromosomes orduring the formation of other oriented cellular
Distinctioir between direct and indirect efects
structures. There is in fact good evidence for its
occurrence in protein73and in DNA.14
Dilution effect( d ) Some effects of ionizing radiations on complex
31. It is possible to distinguish between direct andmolecules of biological interest have been defiindirect effects in a simple system by increasing the connitely shown to be due to OH0 radicals: this iscentration of the molecules under study. In the case ofso for the inactivation of ribonuclease, carboxyindirect efi'ects, the yield of altered solute molecules
peptidase or the S H enzymes. These effects candecreases with increasing concentration of the s o l ~ t e . ~ ~ ~ ~ ~be duplicated by chemically produced OH0.76I n
I t has thus been calculated that in a 1 per cent solution
the case of bacteriophage SIsi6 or catala~e,'~ of thP enzyme carboxypeptidase, more than 90 per centhowever, it has been suggested that they becomeof the inactivation is indirect; in a 20 per cent solution,
inactivated as a result of a reducing mechanism
only 60 per cent of the effect is indirect.OO
but, on account of the ~roblematicexistence ofindependent H atoms 6 usual conditions of irDesiccation aizd protection
radiation, one can probably not be certain of the
32. One can also obtain information on the relative=act mechanism, since new experiments7' mayimportance of direct and indirect mechanisms by comyet lead to other interpretations. In many cases
paring the yield of a radiation reaction on the samethe mechanism of inactivation has not been
substrate after desiccation, in a completely protected
worked out.
solution and in the absence of any protector. although( e ) The physical chemical properties of these moleit is probable that one will not be able to secure absolute
cules may be altered: the asymmetry of nucleic
protection against indirect effect^.^'of fibrous proteinss0 or of hyaluronic
acidT9may be decreased, possibly but not necesTenlperature c o e h i e n t ssarily as a result of a depolymerization ; the absorption spectrum of these various compounds
33. One can expect, if diffusible free radicals p1ay.a
IS often altered. indicating a chemical alteration
part in the indirect effect. that the contribubon of tbls
of the chromophore group ; ' W e stability of protype of effect could be reduced considerably by freezing
teins and nucleic acids towards heat or otherthe solution.92 This has been experimentally proved.
denaturing agent is usually decreased.1°
However, irradiation of dry substances at differentarise by the oxidizing action of O,HO on organica ~ i d s . " , l ~The~ ~ rate~ ~ ' of inactivation of certain non-SH
enzymes does not appear to depend on the presence ofoxygen, but S H enzymes are far more radiosensitive
when oxygen is present.lo5 Other biolc~gicalmaterials
Oxygen effectsuch as the desoxyribonucleic acid0"68*10zo r bacteriophageT6( a desoxyribonucleoprotein) appear to be inac34. The existence of an oxygen effect (paragraphtivated by ionizing radiations, by mechanisms chiefly38) was considered until recently as a criterion for pdirect effects; however, as the radiosensitivity of dr~ed independent of the presence of oxygen. This is also true
proteins and polymers varies with oxygen t e n s i ~ n , ~ ~ J "for the induction of bacteriophage in E. Coli K12?7J06
But it has been shown that DNA irradiated in the presthis is no longer a good test until more is known about
ence of oxygen is capable of forming hydroperoxides
the mechanism of oxygen effects.
which arise almost certainly from the indirect effect of
35. A major problem in radiobiology is to determine
the perhydroxyl radicals on pyrimidine bases.lo7 Howthe relative contribution of direct and indirect effects3 ever, the excited DNA molecule itself can form similar
and its solution will also be of great help in developing
compounds by reacting with molecular oxygen and thismethods of chemical protection. A first attempt has been
will result in the direct formation of hydroper~xides.'~'made with yeasts; it can be shown that when they are
It has recently been shown that dehydrated proteins
irradiated in the dry and hydrated state the order of(trypsin) also show an oxygen efect when irradiatedmagnitude of both types of effects is very similar.9s with sparsely ionizing radiation ( X or y rays) ; thisHowever, the molecular organization of most structures
may be due to 0,- ions.03(chromosomes, cytoplasmic particles, nucleoli, cell membrane) is hardly understood, nor is the contribution tothese structures of free or bound water and the possi39. I t has often been observed that the molecules
bility of diffusion of the free radicals formed during
under study continue to undergo alteration after theirradiation into or around them. A better understanding
exposure to irradiation has ceased. This is the case forof all these fundamental problems would undoubtedly
the oxidation of tyrosine,loDor for the inactivation of
be of great value.
some proteins,l1° nucleic acids.67bacteriophage,lll othern u c l e ~ p r o t e i n shyaluronic~~~
acid.I9 Pneumococcal DNA
E f e c t of LET
whentestedfortransforming
activity does not appear
36. According to the type of radiation used, yields per
to show any after-effect after irradiation in 1 per cention pair fornled may vary as a result of different LET.
yeast extract.6s
I t has been calculatted for water solutions that radiation
giving high specific ionizations ( a particles, slow neu40. The after-effect seems to be the result of a pritrons. soft electrons) produce high concentrations of H0 * mary process taking place chiefly in the presence of disand OH0 radicals along the ionization track;96 theirsolved oxygen but it may not be sufficient injtself toefficiency per ion pair in water solution will thus beinactivate the molecule. It could be due to the H,Ollll
smaller, \\*hen they are compared to y or x-rays or highor to the organic hydroperoxidesi12 formed in the soluenergy electrons. In the first case, the radicals, beingtion, but other hypotheses have been presented.
more densely distributed in space, will have a higher
41. The case of desoxyribonucleic acid has been theprobability of recombining or neutralizing each other,most studied: many mechanisms-such as the oxidative
and this explains the lower yield of reactions such asformation of labile phosphate l i d s with the sugar rings
the oxidation of tyrosine, the inactivation of the enzymeof the macromolecular chain or the slow unwinding ofcarboxypeptidase or of several viruses when the highthe double helical structure of desoxyribonucleic acidspecific ionizations are used.'"have been po~tulated.~~'~"~J'O
Although H,O, formed
37. These densely ionizing particles form Hz, O,,
in the solution does not appear to be necessary in the
may have a very
case of desosyribonucleic acid,ll"tH20, and presumably HOq as a result of the radiolysis
of H 2 0 2in water. evert in the absence of oxygeri and there
pronounced effect on bacteriophag? S, which becomes
more sensitive to this agent after irradiations; S,, also
are instances where H 2 0 2has been shown to be responbecomes more sensitive to some reducing agent likesible for part at least, of the effect of these particles; it
ascorbic acid.i6 As the after-effect does not appear tohas been estimated that local concentration of H,O,
occur after irradiation in the dry state (in the case of
may reach molarity along the track of a particles.96
DNA)S5 it does appear to be the consequence of an
indirect effect of irradiation. One will not be able to
Oxygen effectestimate
its contribution in irradiated organisms until
38. In aerated water solutions, irradiated with X or :/one knows more about direct and indirect action irz viz~o.
rays, H,O, is fornled, and it is thought that the radical
O,HO (perhydrosyl) is also produced as a result of the
reduction of molecular oxygen by an H 0 atom :51J'7*"00
in these, the radio-oxidation yield of many substrates is
I?r water so1l.t'ton
strikingly increased, sometimes by a factor of 5 to 6. In
42. I n a radiation-induced reaction taking place inthe case of the more densely ionizing particles, as thesewater, the fact that the major part of the effect is ofradicals are formed even in the absence of oxygen, one
indirect origin has iundarnental as well as important~ ~ ~instances,~"finds hardly any oxygen e f f e ~ t . ~In~ some
practical consequences.
new osidation products appear, as when irradiated ala43. Any other solute, reactlng with the free radicals
nine becomes oxidized to pyruvic acidlo' (the latter
fornled at the expense of the water molecules. will
also occurs as a natural oxidation product of alanine
render them less available to the substance under study
through the action of aninoacid osidase) .51 In some degradation reactions of polymetacrylate, oxygen is necand protect it possibly by a competitive r n e ~ h a n i s r n . ~ ~ ~ ~ 'Many organic or inorganic compounds are efficient inessary;s7*102organic hydroperoxides or peracids also
temperatures shows that the direct effect of ionizing
radiation also varies with the temperature, which makes
the use of temperature coefficients more hazardous, butnevertheless useful.82

I

4

:

vitro, amongst these thiourea, aniline, phenol, cysteamine
which is not the natural one and which cannot be restored
and S-2-Aminoand its osydation derivative cysta~nine,~~to an active biological compound by natural processes.63
ethylisothiuroniumOBrOHBr ( S T ) .lls
Coenzyme I is reduced by X or irradiation to an unnatural rroduct only in the presence of alcohol which is
44. Substances capable of reacting with essential
osidised to acetaldehyde :the reaction cannot be reversed
groups of enzymes may, when present during irradiaby enzymatic osidation. The great majority of radiotion, protect the group ; removal of the agent after irradichemical
reactions are apparently irreversible ilr vitro.
ation uncovers an unaltered group and this has been
If a radiation reaction similar to the last one describedshown to be the mechanism in the case of SH enzymes
were to take place itt slivo, natural enzymatic processes
protected in vitro by some SH r e a g e n t ~ . ~ ~ Many*'l~could restore the srcbstrate to its natural state, and the
enzymes are also protected by their substrate,'" theiracetaldehyde
formed could be reduced again to ethanol.
coenzvme or by competitive i n h i b i t ~ r s , ~ ~ probl~l~~*l~~ably &so becaise thh biologically active sites 01 thePresent staftis of the "target" tlzeory
enzyme molecules are maslied by the protector. I t has
51. According to its original meaning given by Crowbeen suggested, furthermore, that the S H group ofther in 1924, a "target" in radiobiology is a sensitive cellcystearnine can protect S H groups of enzymes by beular Structure whose inactivation by One Or several ionicoming linked to them reversibly through s - S bridges.
zations (hits) would result in the observed biological
Similar dissociable complexes can be postulated in othereEects. 131When ionization takes place exclusively in the
instance^.^^^*^'^
sensitive structure (direct effects) the dosage to effect'j- I f organic
originating from irradiatedrelationship has enabled one to calculate a target volume.
molecules are prevented to diffuse from one another, one
1, the case of dry or highly protected small viruses whichfavours their rejoining. This is also a possible mechare inactivated by a single efficient ionization, it has been
anism of radioprotection and it can probably be achieved
their volume and molpossible on this basis toby freezing at low t e i t ~ j e r a t t w e . ~ ~ ~ecular weight and obtain values in agreement with those
46. Reducing the oxygen tension will inhibit thoseobtained by other methods. As water is a major cell coneffects of radiation which are known to be increased instituent, it can be expected that part of the biological efosygen. There are many ways of producing anoxic confect of radiations is of an indirect nature: this raises
new problems as to the applicability of the target hypoditions, including the use of chemicals, such as hydrosulfite, cysteine or ~ y s t e a m i n e , l " ~and*~~of~ more usual
thesis to living cells. If all indirect effects could be suprespiratory inhibitors. I n vivo, many reducing organicpressed, as it is thought they are in dried seeds, there
would be no problem. A t present there is no certain way
substrates which consume the cellular oxygen by way ofof doing this : loading the organism with chemical prothe normal respiratory processes probably also produce
tectors, freezing the cells or reducing the oxygen tension
anoxic c ~ n d i t i o n s . ~I t~ is~ 'difficult~~at present to know
may not do it efficiently because it cannot be foreseen to
the exact contribution of these mechanisms in the case ofwhat extent a chemical protector will reach the cellularcertain protecting agents like cysteine or cysteamine ; itstructure under consideration. and because free radicals
is probable that it varies according to the type of submay remain frozen at or near their site of origin until
strate. the presence of other solutes and the concentrathe cells are thawed for biological assay. Therefore,tion of the different substances.
more kno~vledgeis needed about the relative importanceof
indirect effects and about the distances over which
In the d r y state
free radicals may diffuse before being neutralized o r
47. However, it is possible to protect molecules in the
before reaching the cellular targets. I n order to have a
dry state. I t has been shown that the four first substances
clear-cut criterion which can be observed, the biochemical
listed above, (paragraph 43) when i n c o ~ o r a t e dinto aor biological reactions controlled by the targets should besynthetic polymetacrylate, protect it during irradiation
well defined. Probably, when these conditions are satiseven when in the dry state.5s I n the solid state. no water
be possible to use the target concept as a usefied, it
radicals being present, the protective action is probably
ful analytical tool. JVorIi in this direction is in progress.
due to a transfer of energy through the polymer mole111. BIOCHEMICALEFFECTS
cules to the radioprotector. This would be the mechanismof protection in the case of a direct action of radiation
52. ~h~ seq,4ence of cjze,,zical evellts from the momenton the molecule. The ribonucleic acid of tobacco mosaic
when the cell constituents are subjected to radiation up
virus also appears to be protected against direct
to the time the biological effects become apparent can
by cysteine.lsO
conceivably be discovered with biochemical techniques.
The search for an immediate or initial biochemical event
will thus be the first step in this attempt. Two approaches
Restoration'Ons N d ~ i n gthe effects On
been usedhave
48. Redoration is a process starting in the irradiatedstituents and on biochemical mechanisms.
material, by which the original product can be obtainedwith its normal characteristics.
Cellular constituents
49. Reducing agents when added after irradiation
53. ~h~fordamage to important
have been
to be capable of restoring the full encellular constituents can be done by assaying, as Soon as
zymatic activity of a number of S H enzymes. The respossible after irradiation, the biological or the physicotoration is complete only at very low dosages :as dosageof various cell componenb of m h dchemical1s increased, reversibiity is less and less complete, wh~ch the integrity appears to be important for the econo.my ?£shows that different sites of one molecular species are
the cell. E~~~~~~or nucleic acids can be mamined tn thls
altered with different efficiencie~.~~way, but although high doses have been used no definite
clues have so far been reached. despite the very great
50- Although some compounds are normally oxidized
tonumber of observations. The general conclusionof reduced during normal cellular processes, the radiopoint to the apparent radioresistance of the ma~Orltyof. biological oxidations or reductions may lead to a productseeems133

cellular proteins ;and even sulfhydryl groups, which arevery radiosensitive in dilute solution. 13"134 do not appear
Similarly, esto be considerably dainaged itr vivo.12G*133
sential coeazymes and vitamins do not seem significantly
altered immediately after irradiation.lta This is due tothe fact that only a very small percentage of the constituents are affected unless very high dosages areapplied.126
54. I t must be realized that in such attempts to identif y radiosensitive molecular species by looking for theoxidation of SH groups or changes in molecular asymmetry these molecules are usually considered in bulk, andeven when specific analysis is undertaken, it is often
found, as is the case of coenzyme A, that no alteration
can be detected.l3"hesenegative findings do not exclude the possibility that a small number of molecules of a
type controlling key mechanisms (cell division for esample) or having a particular location may still be altered-but at present, general knowledge about the existenceof such specific molecules is lacking.
55. In the case of genetic constituents (desoxyribonucleoproteins), which presumably constitute a class ofrelatively few molecules each having a very high degreeof biological specifiaty. the alteration of a single unit
would result in some cellular damage which would become expressed at the end of the chain of reactions it
initiated.
56. The question of the radiosensitivity of nudeic
acids in G o seems still to be controversial, althoughevidence indicates that nucleoprotein complexes areprobably dissociated in many tissues as a result of moder~ ~been~~~calculated, on the basis of
ate i r r a d i a t i ~ nI.t~hasin vitro measurements, that a dosage of 100 r could
damage 100 to 200 molecules of DNA in a mammaliancell.137and this figure does not disagree with the data
indicating the stability of p~leumococcusDNA when
~ ~ dosages,
used in these experiirradiated in v i v ~ l thements not being sufficient to cause any significant inact i v a t i ~ n .Thus,~ ~ a very much lower dosage than 1 r
would be theoretically sficient to alter permanently
some genetic constituent in a single cell. In this case,not all cells would have one of their DNA molecules
affected. However, nothing is known on the possible
interactions that intact cells could have on the affected
ones, either by influencing their recovery processes orby competing effectively with them (selection). Knowledge on the behaviour of an affected cell in a normal
population nrould be of great interest to understand low
dosage effects.
57. There is no reason to believe that ribonucleoproteins are not as radiosensitive as the desoxyribonucleaproteins, but very littie is known about the number ofunits of each type which a cell is likely to possess andeven less of the specific reactions they control. Chromosomal ribonucleoproteins could very well be concernedwith the duplication of genetic material in dividing cells,
as suggested by recent work on bacteriophage syntheSiS.138,139,140

58. Still less information is available concerning thepossibility of other cellular constituents playing key
roles; many remain to be discovered and further fundamental research is required.
Bioclre~rrual nrec1io.nistn.r
Energy-fornzing syste~ns
59. More information is available from the study ofintegrated biochemical reaction chains. like those ofglycolysis and respiratioa. when studied at various times
after irradiation. These systems result in the building up
of compounds rich in chemical energy which can be used
for biosynthetic reactions and cellular work. I n radiosensitive organs like bone marrow, spleen and thymus, suchreactions as aerobic phosphoqlations seem already to
be impaired thirty minutes after irradiation by 50 r (effects on mitochondria), but it cannot yet be statedwhether these radiobiological processes are the cause or
the result of other biochemical damag'e."1J42
Syntlzetic nteclzorrisnzs
60. In dividing tissues, the most constant finding is
an inhibition of the synthesis of desoxyribonucleic
In micro-organisms like yeasts, theacid.
homogenity of the population makes experiments moreeasily interpretable: and it has been found that this inhibition is only temporary and that synthesis resumes
after various lengths of time.144In other instances, there
may be a short time-lag before this inhibition occurs.
However, the mechanism of DNA synthesis, although
beginning to be experimentally approached, is not understood. As has already been pointed out, it may be dependent even in normal cells on protein or ribonucleic acidmetabolism; and in bacteriophage it is probably dependent on such metabolism by the host cell. The natureof the initial step of radiation damage remains to be
determined. On the basis of bacteriophage inactivation,it has been suggested that the DNA model, or template.
on which the new molecules are thought to be formed,
has been altered in such a way as to make its reduplication impossible. The temporary inhibition of DNA synthesis may lead to abnormal DN.4 formation and this isperhaps related to the killing of cells and to mutation,
but in what exact manner is not known.
61. So far, the syntheses of ribonucleic acid and proteins and lipids in bulk do not appear to be consistently
impaired by radiation and may even be enhanced, butthese compounds are very complex and their study inbulk form, the manner in which it has mostly been carried out so far, cannot be regarded as adequate. Proteins and RNA, bound to the chromosomes and othernuclear and cytoplasmic structures. are probably very
complex and each fraction should be studied independently.14' This will only become possible, however, whenmore is known about the chemical composition of cellular
structures and when refined analytical procedures areavailable.
62. The inhibition of ittdzcced proteitt syrztltesis in micro-organisms has usually been found to be resistant toradiations, except in the case of hydrogenlyase in E.
C01i.l~~In mammals, a few cases of induced synthesis of
enzymes are known :the tryptophane peroxidase zctivityof rat liver can be increased if the animal is injectedwith large amounts of tryptophane. This process is inhibited by radiations, but this inhibition only becomesapparent after two or three days.lS0However, if tryptophane is not given to the animal, an i~zcreasedactivity ofthe peroxidase during the first few hours after irradiation can be observed, but this increase does not occur inadrenalectomised rats and is therefore due to a secondary~ ~ . ' ~are~ therefore two conadrenal s t i m u l a t i ~ n . ~There~I t hasflictincr mechanisms which have O D D O S ~effects.
furthgrmore been shou~nthat the oiiurrence of infection
in irradiated mammals can be related to an impaired sJnthesis of a,?ttibodiesif irradiation takes place before theinjection of the antigen
this is not necessarily due to the depletion of antibody-forming cells, but
131*1431"13145:'iG*"'9"R."Brmight be related to the inhibition of the induced sy~rthesisof a specific protein, a complex process generally considered to be related to the metabolism of ribonucleic
acid, but which is not understood. The con~pleteprocess
o i immunological response (the sequence of events between the invasion of the organism by an antigen and thesynthesis of a new specified antibody) is also not properly understood and the cells rvhich are concerned are
just beginning to be identified. The process of induced
synthesis is believed to be related to ribonucleic acidmetabolism, and in micro-organisms it is quite sensitive
to U.V. light absorbed by their constituents which affects
the synthesis not only of the new proteins but also ofribonucleic acid.lS3

I

chromosonle and in this case the damage would be visible.
Two types of mechanisms ior chromosoiiles breakage
appear to be possible;35 the first would be the result of
the breaking of weak ionic bonds, the second the rupture
oi stronger covalent bonds. I n the first case; restitution
is possible in the absence of external energy sources ; inthe second, energy of respiratory origin is necessary.
This interpretation is by no way deiinitlve: it is the one
which best fits the present esperimental data, but its
simplicity is obviously a reflection o i our ignorance ofthe over-all n~olecularstructure of chrolllosornes and o ithe dynamic mechanisms of chromosollie function. I t ispresumed that ionization must take place in the gene~tselfor in its immediate vicinity to cause a muration.
69. Less defined damage, making the chromosomes
stick to each other, is also observed; the result of thisstickiness is, as is often also the case for well-definedabberations, an uneven distribution of chromosomes behveen the daughter cells, which affects the process of
Staining abmitosis or the survival of the cells.162*1Bi
normalities of the nucleus have frequently been obseTVed."A168

E f e c t s 012 traltsport mechaninns in the cell njel~tbrane
63. Enzymatic systems at the surface of the cell membrane take a prominent part in the active transport ofmetabolites through the cell membrane,'54 but, although
cell pernleability has often been said to be affected after
irradiati0n,'~"'~9ewcritical cxperiments have been performed. I t has been shown, for instance, that lethal irradiations and still higher dosages have often led to a
70. New techniques have only recently been developed
leak of potassium ions into the medium ; this has been
for mammals, making possible in them the identification
proved in erythrocytes, in muscle but not in liver.15i Simof all the chromosomes in a sufficient number of cells
ilar phenomena. if existing in nerve cells, could be a basis€or the quantitative study of aberrations, which would
for esplaining some of the nervous symptoms of irradilead to the establishment of dose effect relationships ination. Surface mechanisms can be affected in yeasts bymen. Observations of this kind will be extremely laborU.V. light 365 mp. without apparently producing otherious and one cannot expect much information beiore
effects than delaying mitosis ;these surface lesions cause
many competent observers have been trained.
considerable loss in potassium.15s
71. The n~orphologyas well as the number of riiccleoli
64. The loss of small organic molecules like adenosine(small nuclear spherules characterized by their hightriphosphate has been shown to occur from irradiatedcontent of ribonucleic acid) may be altered in mammamicro-organisn~s,'~~and techniques of tissue culture willlian cells.lsO The total cellular volume may increase as
make it possible to establish whether such behavioura result of irradiation, as the volume of the nucleus often
applies also to mammalian cells. I n mammals, it is known
does; the nucleoli may become swollen, fragmented orthat amino acids and other small molecules (taurine for~ a c u o l a t e d . ~The
~ ~ ~precise' ~ ~ function of the nucleoli
instance) are released in the blood stream and ~ r i n e , ' ~ ~ * ' ~in' normal cells is far from completely known, but it
and this might be the result of impaired permeability.
may be related to such diverse processes as cell diSer65. The exact significance of these various biochementiation, protein synthesis and coenzyme synthesis, andical effects is difficult to discuss because our present
their obvious relationship with the chromosomes in many
instances make these organelles of prominent interest
knowledge of the sequence of biochemical mechanisms
for the proper functioning of the cell.lil
taking place in a normal cell and their interrelationshipis still very fragmentary.
EFFECTS
IV. CYTOLOGICAL

72. Nuclear swelling is often accompanied by cytowelling, and giant cells are often observed after
plasmic
tion, cytologists have tried for the last half century toirradiationof micro-organisms as well as of mammalianidentify abnormal cell structures.
cells.17' The fact that the dry weight or total nitrogenilcreases at the same time indicates that many synthetic
Nucleusreactions have not been interrupted. Swelling of cells
67. I n tlze cell nucleus. the most conspicuous damage(or elongation of bacteria) appears to be the result of
is in the chrotnosomes, which are very sensitive and frean impaired cytoplasmic deavage.':3~"'*lT5*1i8*17This
quently grossly altered ; irradiation as low as 25 r or evencellular swelling has often been the basis o i a misinterless is svfficient to induce chromosome aberrations inpretation : many references to the stinaulatiort of growthembryonic nerve cellsi6?or in many plant t i s ~ u e s . ~of~irradiated~ ~ ~ ~ ~organisms can be cited. Actually, as in the
68. Irradiation causes the breakage of chromosomes,
case of seedlings, this is merely the result of the elongawhich probably occurs during exposure; this is followed
tion of non-dividing cells :1i6*xi*lT8
the inhibition of one
by normal or abnormal recombination of the broken
process (cell division) may result in the increase ofends; but these may remain separate. As not only theavailable energy or building blocks for other reactions,.
molecular integrity but also the order of the genes onthus merely shifting one steady state to a n p t h e ~Thethe chromoson~esis important, this damage may lead toenergy of radiation and its random distribubon 1s suchgenetical effects simulating mutations. Point mutatlons
that the chances of obtaining deleterious reactions appear.
are molecular alterations of genes usually not accomgreater than those for specifically removing inhibitory
panied by visible aberrations, and they may perhaps
processes. another logical mechanism by ybch s~lnulaconcern only a very few sub-units (nucleotides) oftion could be explained. Effects of radiation should al-.
however, a point mutation could
genetical material :1s5+36
ways be thoroughly analysed before they can be as:umed,
occur at the point of breakage and reunion of theto be useful to the irradiated subject.
66. I n order to explain the biological effects of radia-

I

j.
f.

ill(2

i.2

13

.

.

73. The cell cytoplasm is known to contain a varietyof particular structures, the exact identity of which has
not yet thoroughly been worked out.lS0
74. Mitochondria are the largest of cellular particles ;they contain most of the enzymes and coenzymes responsible for cellular respiration which release the majorpart of energy used in biochemical reactions ; they also
have important functions in lipid metaboli~m?~'They
have been observed to swell or show abnormal staining
a finding which has
in irradiated spleen ceUs,lsl~lsz~l83
been supported by biochemical evidence (inhibition ofoxidative phosp1~orylation),18~~1S5
If, after irradiation,
the behaviour of the ~ a r i o u s biochemical functions
which are attributed to mitochondria were compared,
it should be possible to draw a consistent picture of theiralterati~ns;~~%nfortunately
the experiments have seldom been carried out in comparable conditions.
75. The following have been described :( a ) An inhibition of respiration and phosphorylations
chiefly in thymus and spleen ; the phosphorylation
processes appear to be more sensitive than respiration.lS4'186.1S7( b ) L4n increase of spleen adenosine-triphosphatasewhich seems to be independent, at least initially,of the inhibition of phosphorylation.ls6(c) -An altered lipid metabolism characterized chiefiy
by an increased synthesis of the phospholipids ofthe liver;188however in spleen and thymus it isslightly lower or remains normal. It must beemphasized, however, that lipid synthesis may
not necessarily be linked to mitochondrial integrity, as suggested by a number of experiments.
189.190,191

76. Thus, the different reactions to radiation of threedifferent mitochondria1 functions do not appear to respond identically. This raises the problem of the identity of the mitochondria performing all these threefunctions. Much better controlled worlc, where several
properties of the same particles are investigated in
identical conditions, could help to solve this important
problem, and radiations could perhaps in this instancebe useful as an analytical tool: the site of lipid metabolism could be a radioresistant type of mitochondrion.
77. It must finally be kept in mind that respiratory
processes appear, as in yeast, to be controlled by nuclearo r cytoplasmic factors ;lg3the latter may or may not be
identical with the cytoplasmic particles carrying the
respiratory enzymes themselves. An alteration o i thesecontrolling mechanisms could very well be the origin oi
late radiation effects on these functions.
78. Microsomes form another class of smaller, cytoplasmic structures organized in a reticulum. as seen by~ ' ~ have
~ ~ ~ a strong affinity
the electron m i c r o s c ~ p e . ~Theyfor basic dyes. a condition which is strikingly augmented
in tissues undergoing differentiation and actively synthesizing protein; in the course of these processes,
ribonucleic acid, chemically related to the desoxyribonucleic acids constituting the nuclear genes, undoubtedly
plays an important part. There does appear to be a functional relationship between microsomes and nucleoli,
but its nature is not understood. These particles are atpresent considered to be the major site of protein~ynthesis.1'~

79. Surprisingly, electron microscopy has not beenmuch used for the study of the structure of the irradiatedcytoplasmic reticulum and the scanty observations so far

performed in the thyroid and in the testes have not revealed any damage to this reticulum.196
80. If the microsomes are considered irom a dynamic
point of view and the cellular functions to which they
are related are studied, several conclusions can betentatively reached.
81. In general, protein sy~thesisdoes not appear to
be impaired immediately after irradiation,lgS and it is,on the contrary, often enhanced : however, this increased
activity is often followed by a depression, as in the caseof the synthesis of the protein moiety o i hemoThis bimodal response to radiation, often
globin.1Di~1s9
found for protein synthesis, makes it difficult to interpret the variations of the serum proteins200in irradiatedanimals where a very complex picture is often obtained
and when the many results available are difficult tocompare on account of different methods and timing of
the experiments.
82. The inhibition of the induced synthesis of tryptophane oxidase and antibodies are perhaps also related tomicrosome activity.150
83. Cholesterol synthesis is also related to the integ~ ' is often enhanced after irrarity of m i c r ~ s o m e s ~anddiation: when it is inhibited as in spleen, this only
becomes apparent after twenty-four hours.97
84. In most cases, the effects of radiation on microsome function probably do not become expressed immediately after irradiation. It will not be possible to understand these late effects until the fundamental facts aboutprotein synthesis and their relation to nuclear activity
are known. Experiments on enucleated unicellular organisms have shown that the nucleus has a definite but
remote control over the cytoplasmic ribonucleoproteins :Ii1 the irradiation of non-nucleated cytoplasm in
the amoeba has shown that at least ultra-violet lightaffects cytoplasmic ribonucleoproteins quite rapidly.'OZ
85. Lysosomes form a type of cellular particle chiefly
studied in liver; they are intermediate in size between
microsomes and mitochondria ;Is0 they are characterized
by a high content of iron and by their association withseveral enzymes like desoxyribonuclease 11, ribonuclease, cathespin, glucuronidase, and acid phosphatase.
As the activity of the first three of these enzymes has
been found to increase in tissue homogenates o r in theit could be
blood stream after irradiation,203*2M~z05~206~~0isuggested that this is a result of damage to the lysosomes ;critical experiments in which enzymes are assayed simultaneously in an irradiated animal might prove this hypothesis. In the case of cathepsin, the increased activity
can be related to the disappearance after irradiation of an
enzyme inhibitor normally present in the blood.-"01208
86. C h l o r ~ p l a s t sthe
, ~ chlorophyl-containing~~~~~~
cytotheplasmic particles of plant cells, and ki~retoson~es,"~particles related to flagella in protozoa, are both endowedwith genetic continuity: this gives to these structures
great theoretical importance. If the speed of multiplicatlon of these structures can be reduced to a greater extent
than that of cell division, one can expect to find that someof the daughter cells have completely lost them. The reverse could also be true, and recent work on moderate!^
irradiated grasshopper testeslg6has shown in the electron
microscope the appearance of supernumerary tail filaments and centrosomes, probably related to the kinetosomes of protozoa. These obsenlations have led theirauthors to an interesting theory of radiation damage
based on the synergistic action of non-specific moleculardisplacements leading to the formation of abnormal

i
,
1

!

s t r u c t ~ r e s . 'Extensive~~
work on irradiated plant cells
has led to the demonstration that the activity of several
enzymes bound to the chloroplasts were altered.?ll

V. BIOLOGICALEFFECTS
87. The effects on homogeneous populations of cells
will be considered first, and then those on complex
organisms.

ing of the critical period in other cell^.?^^*?^^ Also, in eachcell type. although the general course of nitosis is quite
similar, the duration of each phase and sometimes theexact denomination of the stage considered may varyto a considerable extent, which makes exact comparisonsvery difficult.

92. The exact cause of the inhibition of mitotic division is not known. It has been suggested that it is related
to the inhibition of DNA ~ y n t h e s i s * ~which~ ~ ? ' ~occurs
frequently- but some instances where cell division is
Ho~nogeneouscell popt~lations
inihibited with apparently normal DNA metabolism will
88. Cell populations such as micro-organisms, proforce us to reconsider this vie^."^ DNA synthesis, astozoa, unicellular algae, cultures and surviving suspenstatedpreviously, is a complex process; it is perhaps
sions of cells from multicellular organisms like fibroassociated with chromosomal protein'2s or RNA synblasts, bone marrow cells, gametes and certain cancerous
thesis,138of which next to nothing is known. I t has beencells have been extensively studied.1*213*214*'15*217*218
suggested on the other hand that an interference of radiRecent techniques make possible the culture in liquid
ation with the oxido-reduction of sulfhydryl compounds
media of almost any type of mammalian cell
these
known
to occur during cell division^*^^*'^^"^^ might also
cells are capable, in vitro, of forming organized strucbe
one
cause
of its inhibition ; inhibition of mechanisms
tures recalling the original tissue they come from,216
ofcytoplasmiccleavagezz6 or of spindle formationzi
which should be of great value in studying problems of
are
other
plausible
hypotheses.
cellular organizations and in understandig multicellularorganisms. These cell populations have been irradiatedMufatiomin rather comparable conditions, and they have beenshown to react in very similar ways.
93. I t has been stated earlier that cells which do notdie after several divisions are said. to recover. This
89. When fundavtental Properties of the cells such as
statement is very imprecise, because all that is known issurvival, cell multiplication or mitosis, increase in drythat these cells look as if they had recovered. However.
weight, differentiation of non-mature cell types, cellin certain instances although they continue to have amovements, or permeability of the cell membranes arequite normal appearance, they have undergone wttttation.
studied, one can usually describe a comnton pattern ofThese changes have been observed most clearly inreaction to radiation.
bacteria, moulds, and other unicellular autotrophic or
90. O n the other hand, cells performing specialized
heterotrophic organisms ; and very recently, the studies
functions may react to radiation in a specific mannerof cultures of isolated mammalian cells have suggested
related to this function. In multicellular organisms, imthat such mutant forms also =ist amongst the surportant i?zteractions between the different tisslies havev i v o r ~ These. ~ ~ ~mutations are characterized by the factthat the surviving cell as well as most of its descendants
also to be considered.
have been affected in a way which makes them permnutiently incapable of performing some biochemical reMitosis (i.e., cell division)action. If this biochemical reaction (for instance, the91. Cells are rarely killed immediately, but usually die
formation of an essential building block) is necessary
after having attempted division or after having underfor the cell to grow and multiply, the mutation will leadgone one or several divisions. Mitosis itself is interferedto the arrest of growth and multiplication, and finally thewith and is usually delayed, if irradiation happens earlycells will die, if this essential building block is not proenough in the mitotic cycle. This has been examined mostvided in the culture medium. It is believed that there is aelegantly by direct observation on hanging drop prepaperiod of time following irradiation dtiring which therations of neuroblasts from grasshopper embryos.167 process of mrrtation is not fully e~tablished.'~?~~~~.~~~"~~
These experiments have shown the existence of a very
What takes place during this time is not known-but it iscritical stage of cell division during the period when thepossible, at least in the case of ultra-violet irradiation ofchromosomes condense as visible threads and when both
micro-organisms, that the expression of damage depends
the nuclear membrane and nucleolus disappear. Irradiaon the synthesis of some protein. Although this tirnetion before this critical stage usually makes the wholelag gives the possibility of interfering with mutaprocess stop for a duration depending on dosage; afterg e n e s i ~ ? ~ ' * ~ ~subject~ - a which will be discussed more
it has passed this stage, the mitotic events do not appear
thoroughly in another section-it is generally accepted
to be interfered with if dosages are small. It is remarkthat this damage once fzrlly established cannot be r e v e r ~ e dable that, if applied at the right moment before the critby non-genetical processes. I n addition to induced muical period, dosages as small as 8 or 16 rad will delay the
tants
there are always a certain number of spontaneoru
progression of mitosis in this type of cell. These observaones,
which arise in the absence of any added external
tions are essentially similar to the previous analyses on
agents.
fibroblast c ~ l t u r e s ; ~they~ ~ *also~ = fit~ rather well withthe experiments on irradiated gametes of the sea94. Back nzlitation (reverse mutation), the apparent
urchins, where cleavage of the fertilized embryos obreversal of the previous mutation and the evolution fromtained by the conjugation of irradiated gametes (either
dependency to independence of some specific metabohte?
pr both of which have been irradiated) is also delayed,
may occur spontaneously or by irradiation of the mul f irradiation occurs before early prophase in this case.222
tant; apparently there is what could be called a true
If irradiation occurs aftenvards, it is the subsequent
recovery of the cell o r at least of that part of thecleavage which is slowed down. This general picture ofwhich had first been altered.g37However, the spontaneous phenomenon has a small probability of occurring
mitotic delay may be subject to some alteration when
and the process of back mutation, zcnless it could be dzdifferent types of cells are considered; less direct
methods of observation may have led to a different timrected, is not a ~racticalrecovery process.
.
----.:1771178

199. I t has bcen shown in many cases that potas95. Other mutagenic agents (lower ener radiation
like ultra-violet light,z3Smanytoxic compoun s and chemsium leaks out of many irradiated cells like erythroical analogues to normal building b l o ~ k s ) ~are~ d~ ~ ~ c' ~y t e ~ , ~and~ cardiac~ * ~ ~ ~ * ~but
~ not
~ out of liveror kidney,2s1or striated muscle.240
useful in helping to clarify the mechanism of mutations.
Chemical analogues, for instance. compete with normal
100. The entry of glucose or amino acids into cells isbuilding blocks and may often replace them in importantalso dependent on surface enzymes, and it should bemacromolecules like nucleic acids. sometimes preventing
clarified whether an inhibition of these systems might
their reduplication or their normal functioning. Comaffect secondarily synthetic or energy-forming mechaparison of ultra-violet lights of different wavelengths will
nisms. In micro-organisms (E.Coli, yeasts), it is known
indicate which of them is most effective and enables thethat the induced synthesis of many enzymes is not innature of the chemical groups absorbing the energy tohibited by X-rayszs2 for doses which conlpletely arrest
be determined. The use of these agents is of very greatcellmultiplication. which indicates that the inductor subimportance in elucidating the mechanism, not only ofstrates are still capable of penetrating into the cells.
mutation, but also of chromosome breakage and of miHowever, quantitative studies have not been performed.
tosis, which they are capable of d i ~ t u r b i n g . ' ~ ~On the other hand, it has been proved that in similarorganisms (E.Coli) irradiation leads to the diffusion of
96. Genes presumably control the biochemical mechainto the outside medium, as well as
many n~cleotides'~~nisms (many of which are located in the cytoplasm)of potassium, which has already bcen discussed (pararesponsible for producing enzymes or other specificgraph 63).
cellular constituent^.'^' It is possible to ima~linethat, as aresult of irradiation, the block in the reaction chain
101. In mammals, it has been found that when glucose
between gene and enzyme-forming system could occur
is injected under the skin immediately after irradiation,
in some intermediate cytoplarrrtic structure. Ii this strucits entrance into the blood stream is slowed d o ~ n . ~ ~ ~ture is one which, like the chromosomes and the genes
The passage of metabolites from the hypodermal region
they carry, has to reproduce itself at each mitosis in
into the blood capillaries could be a more complex pheorder that each daughter cell be identical to its parents,
nomenon, because it involves the passing of the moleculeand if damage has rendered the reduplication of thethrough an organized tissue. The same applies to theoriginal structure impossible, one will obtain a cytoinhibition of the intestinal absorption of glucose, whichplaslnic ntutation. Nothing much is knoivn about these,is diminished three to six days after total body irradiabut the induction in yeasts of respiratory deficient strainstion in rats. However, in this case the inhibition is acby poisons or radiation and the demonstration that thiscompanied by important cytological
The case
deficiency is not necessarily of nuclear origin, indicates~ ~the barrier separating the eye from the blood stream"55
the existence of heritable cytoplasmic c l ~ a r a c t e r s . ' ~ ~ * ~ofas well as many otherslJ6 have also been studied withsimilar results.

P

97. CrlH $nobility can be stopped by irradiation, but

Cell deatlz

usually very high dosages are needed for such an effect.
Irradiation of spermatozoa2" may result in the loss of
motion, probably as a consequence of the inhibition ofphosphorylation ;='= this causes them to become infertile.
but the dosages are much larger than the ones required
to delay cleavage of the fertilized egg. Nothing specificis known of the effects of radiation on the cellularmigrations IT-hich occur in the developing embryo.
On the other hand, radiation is Icnown to inhibit phagocytosis in mammalian polymorphonuclear white blood
but phagocytosis is a complex phenomenon andthis effect is not necessarily due to the inhibition of
movements. Alterations of cytoplasmic or nuclear movements inside living cells might also give useful indications. but so far their quantitative measurement isdifficult.

102. Irradiated cells die either immediately (i.e., during irradiation) or after a certain delay: in the former
case, much higher dosages are needed, and death can be
attributed to a general denaturation of cellular constituents. Many conflicting results on cell death have appeared in the literature : this can be accounted for by thedifficulty in defining cell death: in micro-organisms, forinstance, death has been defined as the inability to form
visible colonies on agar plates. Furthermore, the primarycause of cellular death may differ from one system toanother, and it is not necessarily unique; any of thecytochemical. biochemical, physiological o r geneticaleffects of radiation so far discussed could each take partin killing the cell. A mutation in a micro-organism leading to the inability to form an essential building block
will be "lethal" otzly in the case where the culture medium
does not contain this substance.

Aleltrbra~rcpheflotrte~iaajzd io)tic equilibria

103. Delayed death of dividing cells occurs after one
or several cellular divisions have taken place,220~'56~z57
and it may often be linked to chromosome damage.2ss
but it could also be due to nutritional or other deficiencies, such as occur in a non-dividing population. Delayed
death is caused by much more specific damage than immediate death, and its study is thus of far greater interest. The doses required for obtaining delayed deathmay be different not only for cells of different species.l
but also for closely related cells such as different strainsof the same bacterial species.25g

9s. The statement frequently made that radiation
alters the cell permeability needs to be specified. The
evchange of inorganic or organic molecules and ions
between cells and their natural environment is a very
complex process, because many substances have to beconcentrated inside the cell aga~nsta concentration gradient, a process which requires energy.15' and inhibitionof permeability could result from the inhibition ofenergy-forming systems. This is the case for K+ orscarbohydrates: in the case of the latter, c o n ~ ~ l eenzvmatic systems. located on the cellular membiane, ha;ebeen described, and it would furthermore not be surprising that this organized structure be upset by radiationas are other patterns of cellular organization.

10-4. Recent experiments on cultures originating fromdifferent single mammalian cells have shon-n a very similar sensitivity ;231this probably results from the fact thatin these abnormal conditions cells undergo relatively

rapid division, whereas in the whole organism thisprocess may be estremcly sloiv and may differ from one
tissue to another. When penetrating radiations are used,
it can be assumed that each cell of an irradiated population receives the same amount ot' radiation. I n an average-sized mammalian cell, submitted to an irradiation of
1 r, severd hundreds of ionizations occur. and the probabiiity of a structure being damaged will depend on several factors, including its size and the radiosensitivity of
its constituent molecules in vivo. I t has been calculated
that 100 r to a mammalian cell nucleus produce 100-200
hits into the DNA: 1.000 r to a bacterium will produce of the order of 5 to 20 direct hits in the DNA alone.
and every radical which might reach the D N A could
damage another molecule.6g Alterations of D N A could
be one cause of late cell~dardeath, but other cellularconstituents are also damaged. It can be shown thatsome cells die while others recover and apparently behave
again like normal ones. This probably results from differences in the distribution of the energy to "critical"
and to less "critical" molecules and it has to be remembered that it is the remaining physiological activity ofeach cell constituent which will determine the final biol o"~ + Aeffect.

Effects olt virtues and I< particles in Para~zecia
105. Radiation effects on such specialized biologicalsystems may at first appear to be out of place in a general survey as this one, aiming at understanding radiation hazards to man. However. these systems are very
closely related to chromosomes (and presumably thegenes they carry) and to many cytoplasmic particles;
they consist of nucleoprotein, and the mechanism bywhich viruses reproduce autocatalytically offers the bestmodel at present available for the study of the reduplication of cellular nucleoproteins. Viruses are very important in radiobiology, because they can be studied bothas chemical entities irz vitro and they can be irradiatedindependently of the cells they multiply in. Bacterial
viruses (bacteriophage)some of the animal viruses and the cytoplasmic K particle of Paran~ecica"~
are desoxyribonucleoprotcins. like the bullc of the chromosomes: plant viruses and some animal viruses areribonucleoproteins, others are desoxyribonucleoproteins.
,2601261

106. Bacterial viruses are the ones most attention has
been paid to, and the following fundamental facts havebeen discovered and have in some cases been confirmed
using other viruses.
107. Ionizing or ultraviolet radiation applied in vivo
or in vitro inactivates them, i.e. interferes with thepossibility of their being self-dztplicafed inside theCel~.?60,263.?62

110. Esperiments like these may have very generalimplications for the understanding of damage and ofrecovery processes talcing place in cells of more complex
organisms and therefore should be vigorously encouraged.

Eflects ool~lysogexic cells
111. Certain types of bacteriophages invade their hostbut do not multiply in the usual way; on the contrary.
they appear to become integrated into the bacterial
desosyribonucleoprotein and thus reduplicate cim~~ltaneously with the bacterial nuclear material without causing any apparent trouble to the cell. However, estrenlely
low dosages of irradiation as well as a variety of otheragents induce the transformation of this "prophage" toa virulent bacteriophage, which will multiply and h d l ylyse the infected
I n certain strains of lysogenic
bacteria, a dosage of 0.1 r may give a measurable induction, and the linearity of the dose-response curve for this"genetic" effect has been demonstrated down to suchWhat
~ J ~characterizes induction is that it
low d o s a g e ~ . ~takes place in almost 100 per cent of lysogenic cells.
whereas mutation only talces place in a small number.
112. Experiments on infected micro-organisms havealso shown that a virus is capable of becoming integrated
into the genetic material of the host and of transducing
some genetic characters from one genetic type of host
~ *not~ ~unlikely~that processes similar
to a n ~ t h e r . l I~t isto bacterial transformation by DNA or to transduction
involving the transfer of genetic material from one typeof cell to another, also exist in mammals. If such phenomena were discovered, directed reversed nztctations
might become possible iiz ~narnnzals.

Differetitiating cell populations
Embryonic developntent
113. Gametes arise from the differentiation of stem
cells, the oogonia or spermatogonia, which takes placein the gonads. This differentiation (oogenesis or spermatogenesis) is a process during which the double genetic
equipment (diploid) existing in the stem cells as well as
in the somatic cells is halved evenly through the complex
process of meiosis to give daughter cells, which willproduce gametes containing only one gene of each kind
(haploid). Fertilization will result in the fusion of theparent nuclei, and the usual diploid number of thesomatic cells is thus obtained.
Irradiation of galiretes
114. W e have seen that when either of the gametes isirradiated, the first cleavage of the fertilized egg isdelayed: if the embryo is then left to develop. thecleavage divisions usually proceed apparently quite
normally up to the blastula stage. However, embryonicdevelopment usually comes to a permanent stop before
the completion of blastulation or during early gastrulation: this is one of the numerous examples of delayed
death.269The fundamental biological situatioll is t!lat
gastrulation is the first stage of development dun%
which cellular differe~ttiatio~roccurs : this process is preceded by a striking increase in the metabolism of rib?nucleic acid (both in the cytoplasm and n u c l ~ ~ l u s ) . 1s
the case in most biological processes where Intense protein synthesis and differentiation is taking
Furthermore, during gastrulation important cellular
movements lead to the formation of three dieerent c d u lar layers which ultimately become organized in tissues

108. F o r certain strains, non-irradiated bacteriophages are capable of growing in bacteria heavily irradiated by X-rays or ultraviolet radiation, indicating veryclearly that the self-duplicating strzlctzrre itself has to beaffected and that the bacteria remain capable of supporting phage m ~ ~ l t i p l i c a t i o n . " ~ * ~109. If the conditions of infection are such that there
are several ultraviolet inactivated bacteriophage per cell.
for certain strains of bacteriophage. the intact parts ofeach virus can recombine into a complete new unit,
which is again capable of duplication (this is called
nttfdtiplicity r e a ~ t i v a t i o n )This. ~ ~ ~is a crude and probably quite inaccurate way of explaining a compIex
mechanism of which little is known. This type of reactlvation has also been described for X-rays.'66
139

and organs. Some of the cells in certain layers are capaof the embryo is the following : irradiation of the motherble of inducing specific differentiation processes inafter fertilization but during the pre-implantation period
others. There is not just a change in the "geographical"
leads to a high incidence of prenatal death : however, therelationship of the cells as a result of these movements,
survivors have very few major abnornlalities :this meansthat only the slightly affected embryos survive. I n conbut their apparent uniformity- up to the stage of the
trast. if irradiation occurs after the embryo is implanted
blastula is lost: this is demonstrated by the fact that thein utero, during the period of organogenesis, death
nuclei lose the general potentialities they had until
then.z71
usually occurs onlv after birth--but it is much less frequent: on the othe; hand, there is a very marked increase
115. The cause of the death of embryos obtained fromofmalformations of the embryo. During early embryonicoocytes fertilized with irradiated sperm appears certainly
development (if irradiation takes place during theto be related to nuclear daniage: the sperm cell contains
formatioil of the neural folds), malformations may oconly very little cytoplasm, and the damage can remain
curin the eyes, brain and medulla but also in the kidney
hldden, as it may do in mutations, over many cellularandliver. Irradiation at a slightly later stage of organogenerations. Cell divisions appear to be blocked as a
genesisgives rise chiefly to abnormalities of the skeleton
result of incomplete fusion of the maternal chromosomesof various types. There appear to be short critical periods
with the abnormal ones of male origin, a situation leadof development during which certain types of abnoring eventually to abnormality and uneven distribution
malities arise with very great frequency.278
of chromosomes between daughter cells.2681z'2.27ss2741275
It is important to notice that thve process of cell division
118. The -act mechanism of
which
these
becomes inhibited at a stage of development where theare all possible in humans, is far from being well undergenetic material is presumed to initiate differentiation.
stood on account of our ignorance of many- importantI f , however, the fusion of the abnormal paternal chromofacts concerning embryonic development, such as thesomes with the normal maternal ones is c o n l ~ l e t e Prel~
nature of i,ductiow (interaction bet~jreenneighbouring
vented (which can be done by using higher dosages oftissues), the cause of morphogerletic movetnents or theradiation), a situation arises where the abnormal nucleus
nature of gertetic expres&on, that is, the mechanism byis eliminated, and in this case an apparerttly nor?tzd which one single cell is capable of becoming differentiembryo will develop if the species studied are capable ofated into a multitude of daughter cells performing aparthenogenetic d e v e l ~ p m e n t . ~This~ ~ ~is"one~ ~exam~~~variety of functions.
ple, amongst others, where dosage-effect relationships
Dosage-efect relatiorlrlzips
appear to be non-linear and even paradoxical : higher
dosage producing less lhal damage than lower Ones.
119. These have been studied in certain cases, and for
The =planation ismechanisms
most bone abnornlalities they have been found to be ofment, secondary to the initial damage to the chromatin
the sigmid fype.~eo
the case of the decreased weightare observed : this damage, however, is probably relatedof the foetus at birth, the dosage relationship is lillear,~sO
in a simple way to the amount of irradiation received.
,d litter size appears to fall ofi logarithmically
A similar paradoxical situation may be found in the
dosage to he gametes.z8~ A constant finding is that aexperimental inductions in the embryo of certain abnorhigher dose not onlyincreases he incidence but also themalities such as m i c r ~ p h t h a l m i aand
~ ~ ~this can be logdegree of malformation and the lengh of the sensitive
ically explained by the existence of some competition
period during which a specific response can be inwith other lesions at higher dosage.
d~ced.'~OIt has been shown that a dose as small as 25 r
116. In the wasp H a b r o b r a c o ~and~ ~ in~ ~silk wormzT7 to the mouse embryo has led to the induction of minor
but nevertheless well defined abnormalities. It is difficult
the reverse situation is possible, and the fusion of aat present to know how such small doses could affectnormal sperm cell with a highly irradiated egg cell may
human embryos, but it can be expected that very minutelead to an androgenic embryo (containing only its
malformations of the brain, which could perhaps not befather's chromatin). Experiments such as this point
detected in experimental animals, will result in someagain to the very important role of radiation damage tokind of psychological disorders. Responses to lower
the cell nucleus. Nuclear damage (genetic) is probably
dosages still could probably be detected if a greater
also responsible for the various forms of abortion or of
number of animals and more refined tests were used.
malformations of offspring born of parents, one or both
The case of leukemia, also believed to be inducible byof which have been irradiated. In this case, the developirradiation of the human embry0,2~'is discussed in detailment of the embryo ceases at some stage of organogein chapter V and annex G.
nesis, sometimes even after birth. However, as different
stages of gavtztogenesis have different radiosensitivities,
Adult orgattis~rrs
one espects to have a different probability of abnormal
offspring when mating occurs at different times after
Difierelltiot.H
irradiati~n.?'~The longer the time lapse before concep120. Some undifferentiated cells are carried on intotion. the smaller the probability of abnormal developthe adult organisms and these stem cells go on differenment, because it has been found that the earlier stages
throughout life: the white blood cells are formed~ ~ ~ ~ tiating' ~are the least sensitive ones, at least in m i ~ e . Within the bone marrow and in the lymphatic tissues (lymph
slight irradiation, development may in many cases pronodes and spleen and other organs). Thc lymphatic
ceed and this will result in more or less dramatic extissues are considered to be of major importance in antipressions of genetic damage visible in the offspring.
body formation. The red blood cells originate from bone
Irradiatioi~after f ertilizatiorl
marrow and during embryonic life from spleen andliver. In rodents, myelopoesis and erythropoiesis con117. If irradiation is given at different stages of emtinue in spleen during adult life, but not in man. This isbrvonic developjnertt, the inhibition of cell division andone of many physiological differences it is essentid not
differentiation and cell death may cause the developto overlook when one transposes the results from esperiment to be either completely or partially stopped. In themental animals to man.
mouse, the pattern of response to irradiation (200 r )140

121. Adult organisms contain other tissues coirtkuoztsly regz;rerating from stem cells, such as epithelia(skin, gut, etc.) or bone: finally there are tissues inwhich fez,cell dkisions take place (liver, kidneys, pancreas, brain, or conjunctive tissue).

mutations or in chromosome damage of non-germinal
cells either as a result of death or loss o i specific cellfunctions.

122. -4s in the case of isolated cells. esperimental evidence points to the particz~larradiosensitivity not o~rlyof
rapidly dividing cells, but also of the e~tlbryonicor stew
cells whirl1 are still due to wtdergo cellrclar diferentiatio~r.'~This can be shown when one observes the survival or the cytological alterations of these cells. The
mature lymphocyte, however, which does not belong toeither of these classes is an exception to this rule; its
great sensitivity to radiation^'^^^*^^ is not well understood but may be related in some way to the fact that thenucleus is surrounded by unusually little cytoplasm
which may diminish spontaneous recovery mechanisms
or to the fact that it is a cell with a very short lifeexpectancy. It is also sensitive to many other stimuli.
The situation is diiTerent from that in the spermatozoon,
whose haploid nudeus plays an important role both incell division and in differentiation processes which do
not occur in the case of the lymphocyte, whose diploidnudeus may be more resistant than the sperm nucleus.

127. These effects. as well as their possible genetic
origin, are discussed iil chapter V and in annex G.

Mutations in nrulticellular orga~cisnts
123. Genetic mutations are found when gametes orthe cells they originate from have survived irradiation
and undergo f e r t i l i z a t i ~ n . ' ~ ~ J ~123. Many mutations are not lethal, and genetic abnormality of one of the gametes is believed to be thecause of many forms of congenital malformations: inthis case. embryonic development is only very locallyinhibited, and this leads to abnormalities such as harelip, cleft palate, spina bifida or the many deficiencies of
the nervous system like congenital blindness, deafness ormental deficiencies. Hereditary diseases due to well defined biochemical deficiencies are also known to occur inand in a few instances they have been quite
thoroughly anal~sed:in man the missing enzyme hassometimes been identified, as in galactosen~ia?~~
and inphenylpyruvic 01igo~hreniaz87,a form of mental deficiency related to abnormal phenylalanine metabolism.

Mutations in sontatit cells
125. Mutations in somatic cells will affect the lineageo i these cells but will not be carried to the offspring.
These mutations have been shown to talte place at afrequency oi the same order as that found in the germ
cells before meiosis (gonia)2JJ8Wg0.20' and they havebeen found to occur in irradiated tissue culture; suchmutations might play an important part in the determination of malignant growths.

Carciizoge)tesis and other sotnatic efects

VI. VAFSABLESIX UDIATIONEFFECTS

Physiological conditiofts
128. Physiological conditions may vary in many ways
and this can iduence radiation responses.'l129. During cell division (nlitosis and wzeiosis) there
are different phases of radiosensitivity which one has
attempted, not too successfully so far, to link to thedifferent phases of new chromosome formation andnucleic acid synthesis which occur during these events.
The survival of cells, the incidence of mutation and thealterations of chromosomes all undergo striking changes
in radiation response, depending on the stage of thedivision cycle during which the organisms are irradiated,
but it is difficult to generalize as to which is the criticalstage since it can vary from one effect, or from one
organism, to a n ~ t h e r . " ~ * ~ ~ ~ * ~ ~ *130. The induction of abnormalities or the lethal
effect in developing embryos after irradiation of immature gametes of either sex, is strongly dependent on thestage of gametogenesis during which irradiation takes
place. The first meiotic division is the period when it ispossible to induce the greatest number of dominant
the case of the male,lethals in the mouse o o ~ y t e . =In~ ~spermatogonia are the most sensitive and it seems thatthe degeneration occurs during the interphase or the
first prophase following irradiation. The period of greatest sensitivity for various effects induced during embryonic development need not be identical.
131. TIle age o f cells and orgallhnrs may affect theirradiosensitivity: in an aged bacterial szcspettsion, when
the cells have reached their stationary phase, they become less sensitive to radiation;m5 but what is usuallycalled an old culture is simply an "undernourished" onewhich has ceased to divide because the stationary phase
only begins when some nutrient begins to be deficient;modem continuous cultures in media constantly renewed. By means of the chemostat might help to demonstrate whether aging occurs in micro-organisms or cellular suspensions of dividing cells of more complex
organisms. The possibility of aging would exist if thedaughter cells were not identical; and such a condition
would arise if cytoplasmic material endon-ed with genetic
continuity were not distributed evenly between daughter
cells. I t is probable that in aged cultures the radioresistance is greater because the bacteria have stopped
dividing.

126. I t is very probable that the mechanism of m t a tion in higher organisms is very similar to that in microorganisms; and the importance of fundamental studies
in bacteriophage. microbial or fruit-fly genetics is that132. In the case of higher orgafristtts,there is u s u d l ~a great sensitivity during foetal life and the LDso is lessthey enable us to get answers much more rapidly and inthan half that of the adult, and. as has been alreadymuch better defined environmental conditions than can
shown. the type of lesion depends on the time
be hoped for in the case of the higher animals. Tissue
bryonic development during which the radiation Is deculture, which is complex in the case of these organisms,
livered. In certain strains of mice. 200 r on the ninth
may become of primary importance for the study of
day of gestation is 100 per cent lethal: on the tenth
genetical mechanisms in mammalian cells, since suchgreater
twice this dosage is required and after b*!istudies have become possible by culturing isolated mamdosages still are needed. The sensitivl9' conti?ues to de- malian cells in the same way as micro-organisms : mutaat
tlons have been induced in such cultured cells.29z*231 crease until adult life is reached: the LDso Is
for CAFz
forty days and reaches 670 r at 140
Many somatic effects may have their origin in such

--

141

mice.'96~29i~2g8
The sensitivity then remains very constant
up to the last months of life-~vhen it again increases
sharply. A similar pattern of response exists in rats ;'"DrosophilaSoOand birds,301on the other hand, have amuch more constant radiosensitivity throughout theiradult life.
133. These variations of resistance with age may be
due to changes in mitotic rate (there are no divisions ?fsomatic cells in Drosophila) or to changes in metabol~c
activity of different tissues, or to the fact that foetal
tissues are undergoing active differentiation, or because
the recovery processes of the aged cells have become
inefficient.
134. Nutritional a,ld other pltysiological conditiotls.
Starvation of micro-organisms may render them moreresistant, as seen in paragraph 131, but in other mstances, or in reference to other types of effects, they
can become more sensitive: fermentation by yeasts cultivated in a medium poor in ammonium salts is inhibitedby doses which do not affect the same process when thesenutrients are normal.302
135. There are felt? data on the effects of nutritional
conditions on the radiosensitivity of the mammal,
although a certain number of radiation effects concerning adrenal metabolism (weight, ascorbic acid, cholesterol) have the same sensitivity after one or seven days
fasting.303
136. Other conditions: Anaemia apparently renders
mice more sensitive to radiation, as is shown by the lower
LD,, of certain anaemic strains. Exercise, on the otherhand. does not seem to have much effect in mice.304
It is possible, however, that in human populations, undernourishment and strain may affect the recovery
processes.

organisms cannot be compared on exactly the same basis,but it often takes as much as 100,000 r or sometimes
much more to prevent 50 per cent of the organisms ofmany species from developing colonies. and certain protozoa may need more than 300,000 r to kill them.
139. Various factors may explain these difierences.
I n cold blooded animals, either low nletabolic rates or
low cell division rates imply that radiation damage willtake longer to develop; but this will not hold true formicro-organisms, which divide much faster than mammalian cells and resist much higher doses.
140. There may also be varying oxygerr tensions indifferent organisnls which could account for different
radiosensi tivities.
141. In the same species, organisms of different
genetic strains may vary in radiosensitivity to lethal
effects. This has frequently been observed in microorganisms but it holds true also for mammals, where different strains of mice have different LD,0/,0.318~319I t has
also been shown that similar genes in different speciesof Drosophila may mutate at rates which can diEer by
I t has furthermore beena factor as high as 2.236*Q5*316
shown that the f requenq of production of developmental
abnormalities may depend very much on the genetic
strain: in Ea1b.C mice. certain malformations of thespine occur in 100 per cent of animals irradiated with
200 r during the 8th y day of gestation, whereas in the
hybrid (C57XNB) F, no such malformations occur.31i
For practical purposes, tl& ftteans that obsewations obtained frotn one h~mrara~opztlationdo not necessarily
apply to a genetically di8ereizt population.
142. I n some organisms such as adult insects where
no cell divisions take place. one expects, and finds, ahigher radioresistance ;but in this case the gonads, where
cell divisions do take place, appear also to be rather
radioresistant; on the other hand, we have seen thatembryonic cells may be very sensitive,320as in grasshoppers.

137. Oxygen iensioa. The irradiation of water sohtions in the presence of oxygen results in the formationof D,HO radicals, in addition to H 0 and OH0. This
radical could also be formed in vivo. This would explainthat when the oxygerz tension is diniinished, a lower
143. The presence of natural radioprotectors may be
response to irradiation occurs ;305this is true for the
yet another factor: some organisms like insects are
survival ofand of birds,308for certain
known to lave a higher concentration of aminoacids
m ~ t a t i o n s ~but
~ ~not~ ~all,s1o
l l for chromosome damage,s1'(which are fair radioprotectors) in their body fluids.
for various effects on embryonic d e ~ e l o p m e n t ? and~ ~ * ~ ~The~ degree of oxygenation of the tissues should also betaken into c o n s i d e r a t i ~ n . ~ ~ ~for certain biochemical reactions dependent on oxygen.
Chemical metabolites or poisons whose presence in tissues
144. Finally, the number of sets of genes (ploidy)
reduces the oxygen tension may have similar effect.
has
certainly something to do with radiosensitivity, as
Lowering the oxygen tension may reduce the response
has been demonstrated for yeast and certain other microto irradiation by a factor of 3 to 5 in the case of highorganisms, in which diploid strains (containing bvo sets
energy radiation ha&g a low ionizing density (X andof genes) are more resistant than haploid ones (containy rays. fast neutrons); when the oxygen tension is
Not only the number of sets ofing
only one set).32av3?1
increased, these effects are not enhanced, which indicatesthat in air the osygen tension is sufficient for the m ~ x i - genes, but the number of chromosomes and their lengthappear to be important ; the greater their number or themum effect. In the case of the densely ionizing a particles
shorter their length, the more resistant the organisms
or s l o ~ neutrons,t~there is no oxygen effect.305
seem to be. This holds true at least in the case of theplantswhich have been studied in this respect.g2'
Co~r~parative
radioserisitivity of living orgatlisitls
145. Many of these suggestions are mere working
138. When the survival rates after irradiation of difhypotheses and nothing systematic hx ever been done tothe senferent types oforganisms arefind out about these different factors. Work in this direcsitivities are found to vary very widely.314 hfanm-mls tion may lead to theof bener ,vays of proappear to be the most sensitive of all classes of organisms
tection.
and doses able to kill 50 Der cent of animals in thirtv
days (LD,,/,,)
range f;om about 200 rad for thi
Adaptation to radiotiof8
guinea pig to 900 rad for the rat. the best estimate forman being 400 f 100 rad. Cold blooded animals have146. Little is known about the possibilities of organan LD,J,, which can rise to 3,000 r for the triton andisms becoming adapted to radiation: the follo~vingsugperhaps 20,000 r for the snail. Bacteria and other microgestions may ho~veverbe made.

117. Increase in catalase (an enzyme destroying hydrogen peroside and possibly neutralizing other peroxides) in algae from the Bikini area has led to the
hypothesis that this might be the result o i some adaptive
enzymatic processes induced by the unusual amount of
peroside detectable in the sea
1%. Selcctio~tmight be expected to lead, in certain
populations of mised species, to the predominance of themost resistant strain. Furthermore, it is quite conceiv&le that irradiation itself induces a mutation which increases or decreases the radiosensitivity of an originallyhomogeneous population of cells. However, work doneon D r o ~ o p h i l a ?and~ ~ yeasts324does not indicate thatbreeding in a high radiation background leads to theappearance of more resistvlt genes. The U\' irradiationof E Coli B, on the other hand, has selected a small
number of radioresistant mutants (B/r)2z9 occurring innormal cultures as a result of spontaneous mutations withthe rate of about 1 X
mutations per bacterium per
generation ; one would expect that under chronic irradiation one could select this strain to some extent.
149. Tumours have oiten been claimed to becomeradioresistant when treated with X-rays; it is howeverdifficult at present to give any sound explanation forsuch a behaviour ; adaptation of the cells has been given
as one reason3?5,=6,=,a~ but it is d i c u l t to dismiss thefact that the oxygen tension may decrease as a result of
pathologic changes in the blood vessels and that the polyploidy of the tumour cells may enhance their radioresistance.
150. Another possible interpretation is that tumour
cells may become incapable of further cell division itt
vivo, although when cultured they can resume division.
Recent experiments tend to indicate that small dosagesof X-rays (25 r ) to embryonic mice makes them somewhat more resistant to exposure to X-rays during theiradult life; this is however true only for females, themales appearing on the contrary to be adversely afi e ~ t e d . ~This' ~ apparent beneficial effect of low dosesof X-rays on females is compensated by the fact thatthe nunlber of litters they were able to bear fell from 5
for the control to 0.5 for the SO r group; furthermore
the number of young per litter was also greatly reduced-it may therefore be the fact of not bearing offspringwhich is responsible for the increase in life-espectan~y.~~O151. The study of the biology of species living inregions of high natural radioactivity may lead to some
information concerning this problem. However, suchworlc, although it may lead cluite rapidly to definite ideas
conccming tGe beha6our of short lived organisms or to
the identification of pathological symptoms in man, willneed to be carried on over many years or decades for thereactions of humans to such conditions to be understood.
The mechanism of possible changes in these populations
will need to be worked out in the laboratory where
genetic strains as well as experimental conditions can be
accurately controlled.

by higher crop yield, is reported with various contradictory results.33A,""633"Secondary efects
153. One important problem is to know whether irradiation applied to one site oi a cell or organism can
induce an efFect in another part.

154. Such secondary effects can be espected on account of the close physiological relationship behveen the
different cellular organelles. It is known that i i the normal isolated nucleus of an amoeba is put into the irradiated cytoplasn~of another amoeba that had previously
been enucleated, mitosis is inhibited in the reconstitutedamoeba at cytoplasmic dosages only three times thoseIt
producing the same effect in a normal 0rganism.~~7
has also been shown that unspecific chromosome darnage
can be induced in an intact frog oocyte nucleus introduced in the irradiated cytoplasm of another o ~ c y t e ~ ~ ~and ultra violet irradiation of the cytoplasm of the giant
unicellular Acetabtilaria klediterranea induces very
rapidly some cytochemical alterations in the nucleolus
which had been shielded during irradiation (this last
HOWeffect is hardly apparent in the case of
ever, nuclear damage to Acetabularia is also demonstrated if only the nucleus is irradiated. In the course ofexperiment on eggs of Drosophila, the much greater
sensitivity of the nucleus when directly irradiated isevident: it takes much more energy to kill the offspringby irradiating the cytoplasn~of &e egg alone than byirradiating the nucleus :340 the same holds true for attempts to induce chro~nosomedamage by micro-irradiating other parts of the cell.3" Primary nuclear damage
appears to play a prominent role in processes where
nuclear activity is important as in cell division, mutations
or inany lethal effects. However, this does not mean thatthe cytoplasm does not participate in radiation damage.
In some cells where no division occurs, cytoplasmic
processes may become efficiently inhibited: this is thecase of non-nucleated cytoplasnls of Anroeba and Acetabularia which survive for shorter periods than if theya nucleus :20',34%343 In this case, the role of thenucleus could be associated with some repair processes
wl~icl~cannot take place as efficiently in its absence, perhaps on account of the fact that the synthesis of cytoplasmic ribonucleic acid becomes seriously impaired incytoplasm which has been deprived of its nucleus forsome time?"
Peroxide fortnatiorz in irradiated cells

155. One of the possible agents for these secondary
effectscould be organic or other peroxides arising during
irradiation. It has been found that. bone marrow cells
incubated irt vitro produce peroxides when the cells
originate from an irradiated rabbit."' The si,gnificanceof this finding is difficultto understand on account of thefact that many tissues (although not bone marrow) ffom
non-irradiated rabbits also produce peroxides ha v~fro.
152. In certain experiments, the conclusion has been
Not much is known of the effects these ~ e r o s i d e rnlghtsdrawn of the favourable effect of small doses of radiation
have on other cellular populations. It has, however, been("biopositive influence", "stimulating effect") bothdemonstrated that many lysogenic bactena -show a. ~ ~ ~ *diminished~ ~ ~ ~response~ ~ when put in the presence ?I ~ t a l a s efrom =ternal and internal s o ~ r ~ e sHowever,further analysis usually explains this as a consequence(catalase reactivation after U.V. and X i r r a d ~ a ~ o n ) . ~ ' ~of pathologically shifted functional equilibrium, where
Another argument for the formation of peroxides in
one biological function, taken in isolation, may appear
irradiated organisms is that even with small dosages
to be stimulated. Also, the possibility of stimulating the(17,000 r ) to yeasts grown in anaerobiosis. these organinitial stages of plant development and growth, followed
isms synthesize catalase or ~erosidasewhen kept inanaerobiosis, a condition during which they normally
only have traces of the enzymes.340The synthesis of new
enzymes is believed to be induced by peroxides formed
during irradiation.
156. Radiation is also capable of inducing the formation of peroxides outside the cells, and irradiation by
X o r U.V. rays of organic culture media is mutagenic
f o r the bacteria which are cultured aftenvards; theeffect can be prevented by catala~e.~'~157. I t has been found repeatedly that the rtucleic acidnzetabolisna of a carcinoma is temporarily decreased asa result of irradiation of the animal bearing it, although
it had been completely shielded during the irradiation.
It has also been demonstrated that tumours originating from non-irradiated thymus cells can develop i fthese cells are grafted on a totally irradiated host whose
thymus had previously been removed;350 damage (byradiation or other means) or removal of the thyroid
may lead to pituitary cancer.351 No h a 1 explanationof effects of this type can be given ; the first mentioned
could be due to diffusible organic peroxides produced
during irradiation and very small quantities of peroxides
have been found in irradiated mice.352
158. On the other hand, normal regulatory processes
located in the irradiated part of the animal can certainly
be affected: hormonal effects, which are dealt with inchapter V, must be considered.3G3Stimulation of thepituitary as a result of thyroid disfunction is probably
the cause of the pituitary tumour mentioned above (paragraph 157). Tlze exact relationships between lzorntones
and biochemical processes in norinal organisms should
be known to understand many effects of radiation in the
mammal.

VII. ALTERATIONSOF RADIATION EFFECTS BY FOREIGNAGENTS

Protection
159. Protecting agetrts are those whose presence drrring irradiatiorr decreases the response of an organism
to radiation. Man experiments reported earlier (paragraphs 38,42 to 4 ) constitute a basis for finding chemicals capable of protecting living organisms against
radiations. However, our ideas on the mechanisms ofprotection in vivo are often conflicting, for the simple
reason that the fundamental processes of radiobiology
are not understood.

5

capable of decreasing the intracellular oxygen tension
can be expected to afford protection against direct o r indirect effects which are oxygen dependent ;35i ( d ) finally,a protector might conceivably give more chemical stability to a macromolecule and favour the rejoining of brokenbonds or divert energy from it. I t is, however, at presentvery difficult to choose between any of these possibilities.
162. Very many experiments have been performed,
very many chemicals have been tested and many effects
have been found susceptible of a certain amount o iprotection.
163. The sunn'val of unicellular and multicellularorganisms have been quite considerably increased by theuse of various agents. SH and allrirro reagents (cysteine,
cystearnine or cystamine, glutathione) or the methyl
derivative, methionine, as well as thiourea have beenused successfully on micro-organisms a l d mammals.
Very similar possibilities have been found with
S-2-aminoethylisothiuronium . Br . HBr (AET)U8
which is less toxic and may thus be used in many mammals, including monkeys and dogs.359AS far as is known,
there have been no attempts to use this compound inman. Further analysis has shown that at neutral p H arearrangement of the A E T to guanidine form occurred,
so that the effective compound was 2-mercaptoethylguanidine hydrobromide (MEG) .360
35513s6*358

164. These protecting agents appear to have greater
efficiency in promoting recovery processes rather thanin preventing the initial damage observed: this is moststriking in the case of the white blood cells and of themetabolism of spleen nucleic acid which seem to follow
a similar pattern of response.s01
165. The nutnber of chrornosonre a b e r r a t i o t 1 3 ~ ~ ~ ~ ~ ~ *and in some instances the number of ~nutatiortsn8 have also been reduced when similar protective
agents were used during irradiation. Successful experiments on plant cells have been reported. but cysteine does
not reduce chromoson~eaberrations in mousealthough nucleic acid integrity does appear to be proin the same organ.
tected by thiourea or cysteamineSBG
I n Drosopitila, however, and in micro-organisms, mutations have not so far responded to the protective actionof cysteine or ~ y s t e a m i n e .In~ ~micro-organisms~
a protective action probably exists, but it is often difficult tointerpret the experiments because increased survival asa result of protection could lead to an enhanced opportunity for a mutation to become e~pressed."~367*3a8.3e9160. The idea of protecting organisms against radiations arose about a decade ago, as a result of the discovery of the indirect nature of radiation effects ondilute solutions. However, as stated earlier, it is verymuch doubted at present whether effects of radiation onorganisms necessarily occur through indirect mechanisms, I t can furthermore be expected that the relative
contribution of direct and indirect mechanisms will vary
for different biological effects and in each case the possibility of protection may thus be different.3s5~S58~S58

166. These agents have in common the properties o ihaving an amino-group and a sulfur atom (which often
is in the form of a sulfhydryl group) and both these are
believed to be important.370However, they can act independently because many amines are also found to besatisfactory protectors in the absence of a sulfhydryl,
and a sulfhydryl group alone may be efficient in someinStanceS.370~371.~~
I t has often been suggested that thesulfhydryl group decreases the intra-cellular oxygen
tension and this has been found to be the case in few
living systems protected with cysteine or cy~tearnine.~'~161. There are many possible ways by which radiation damage might be diminished: ( a ) loading the organism with chemicals capable of reacting with HO, OH0,
and O,HO radicals may divert these from reacting with
important cellular constituents; ( b ) protecting agents
could also act by covering the sensitive site of cell constituents, and this type of mechanism could be operative
both for direct and indirect effects(ch) all agents

167. Many other agents have been used with a varying
degree of success and the mechanism of action of someof these does seem to be dependent on the decrease ofcellular oxygen, as in the case of the protection of micro~ ~ certain number o iorganisms with h y d r o s ~ l f i t e .hnatural metabolites (succinate, glucose, alcohol) haveprotecting properties in a few instances, probably by
consuming the cellular oxygen in the course of theirnormal enzymatic ~xidation.~'%oxia can arso be ODtained with a certain number of drugs like morphine
which depress the respiratory centres : in that case aprotecting effect is also found.3i3 Cyanide, a strong inhibitor of respiratory enzymes, has been found to be an
efficient protector of mice, although it would tend toincrease the intr2cellular tension of oxygen.374On theother hand, seeds irradiated in its presence show agreater mutation rate when it is used in low concentrations, but a smaller one when the concentration is increased.3T5However, in these conditions an increased
number of chromosome breakages is observed.376

3 parwhich appear later are also temporaT and dispIav -pent recovery. In irradiated mammalj. bone mar;o\~andgonads can recover at the expense of the sun.iving cells
which multiply and repopulate thesebut permanent damage, leading for instr?nce to iore
rapid aging,to an increased radiosensitivity or to the developmentof cancer, may have been established,

171. The lapse of time existing befiveen irradiationand the biological expression of the primaT damage:
gives an opportunity of preventing the developmat or
the lesion or of enhancing the spontaneous
processes.
165. I t is not clear at present to what extent the pro175. Recovery agents are those which are efiective
tection is complete, because although damage is not lethal
when given after irradiation. Various methods for proit may well be present and only become apparent at amoting the recovery of irradiated organisms have beenlater stage. It has been shown that rats, protected during
described and can roughly be classified into two groups :irradiation, develop a large number of tumours ;3"J78*176. (a) Those whose object i s to destroy some i)tter3is~sB0 these might have developed in the non-protected
before the damage is definitively
mediate co~~zpol~rzd
animals had they lived, as in the case of mutations inestablished : as in the phtorestoration of a great number
micro-organisms; and it is difficult to know if the priof effects of ultra-violet light,388*388the cafa/ae restoramary events of induction of cancer have or have not beenof lysogenic bacteria treated with ultra-vi~letlight3"
diminished. Nothing much is known on the protection
or, in one instance, the effects of X-rays.387 The first ofagainst other late damage or against the early aging ofthese processes, in the case of ultra-violet irradiated batirradiated organisms.
teriophage is only possible if illumination takes place In
169. Protecting agents are much less efficient in thethe presence of extracts of normal bacteria; the second~ ~ "seens (paracase of alpha rays or n e ~ t r o n s . ~ ~ ~ *wasappears to lead to the destruction ofgraph 37) in these cases reduction of the oxygen tension
formed during irradiation.
is not expected to have any effect.
177. Restoration achieved in some instances by coolingor heating the irradiated cellssmmay inhibit the esPression of injury before it is definitively established but
none of these mechanisms is properly
170. Radiosensitizing agents have been used in cancer
therapy, but the fundamental aspects of sensitization
178. ( b ) Those whose object is to re@ce a da*rpged
are certainly much less known than in those in the caseto m?crocompound or cell. The provision ofof protection. There are a few instances of enhanced
organisms which have lost the capacity of syntheslzIng
reactions to irradiation in the course of in vitro experithem could be considered as one possible mechanismm e n t ~but, ~these~ ~ are not at present susceptible to applirecovery; recovery is however only apparent, because
cation ifa vivo. It has, for instance, been shown that thethe fundamental damage has not been
oxidation of ferrous sulfate by X-rays is enhanced in
179. True recovery would depend on the p ~ ~ s i b i l i t ~the presence of various alcohols or of benzene.
of replacing the damaged molecules or cells by "On171. As a result of the systematic study of many
ifradiated ones. Experiments on bacterial transforma'chemicals, it has been found that s y n k a ~ i t , ~a~derivatlons or on genetic recombinations in micro-organisms
tive of vitamin K, increases the radiation induced mitotic
have shown that it is possible to control some alteration
inhibition in chick fibroblasts cultured in vitro; this efEectof them genetic characters. The mechanisms of thewas carried on in the absence of synkavit for several
greater radioresistance of diploidwith haploid
generations; and if rats are treated with the compound
cells may well have their origin in closely related me&before irradiation their mortality is increased. Synkavit
anisms. O n these grounds, the use of intact des05~ribOis also capable of increasing the permanent regression
nucleic acid to replace the irradiated compound insldethe
after irradiation of experimental tumours in the rat or
chrpmosome becomes a possibility. One successful -of cancer in man. All that is known about the mechanism
periment of saving ultra-violet irradiated salmonellaof action of this agent is that it becomes concentrated inwith intact D N A has been reported.389
the tumour as compared to the other tissues and that in
180. It is possible to replace whole cell populations
tissue cultures its eEect can be abolished by guanosine;
irradiated animals and thus promote their survival ;ofthis may indicate some interference with nucleic acid
this can be done by injecting intact bone rnzrro\v
metabolism. If one increases the oxygen tension of tua non-irradiated donor into the circulation of a lethally
mours where it is usually low, one increases their radioirradiated one. This type of experiment was .at firstsensitivity, a finding which has proved to be useful inperformed as a consequence of the demonstration
cancer therapy.38s
the death incidence of mice firas considerably decreased
the172. I t is not known to what extent natural radiowhen hematopoietic organs (like bone marro\v
sensitizers might accumulate during certain steps ofhind limb, spleen or liver) are shielded during irradiato benormal metabolic processes and thus alter the radiotion. Bone marrow injections have sincesensitivity.
successful in dogs, hamsters, ~ n o n k e ~ s .Only
3 ~ ~ ti'Sues
containing cells capable of forming gran.locfles
polymorphonuclear white blood cells), red blood
cellular173. When organisms are irradiated, many processes,
or platelets are capable of this activity. These
inhibited at first, recover. The synthesis of desoxyribosuspensions are effective in preventing acute death
nucleic acid is often decreased immediately after irradiX or y rays but apparently death caused by neutrons
ation, but only temporarily ; other biochemical effects
is much more difficult to1S1. As a result of injected bone marrow, the blood
cells and platelets tend to reach normal values again! theweight of the body, of the thymus and spleen increases
2nd immunological defence which had disappeared also
becomes functional again. However, many of the lesions
caused by radiation are not diminished after bone marrow injection: the greying of hair is not influenced andthe fertility of gametes is not restored,SoStumours develop with greater frequency in protected or parabiotic
animalSJ9G,S07,3D8 and the normal life-expectancy of theanimal remains decreased.394 All these facts seem todemonstrate that only acute death has been prevented
by the graft.

185. Experiments on cell transfer have been madein attempts to replace leukemic cells, which can be
destroyed by high dosages of irradiation, by normal
marrow tissue with the hope of preventing further development of leukemia Experiments performed on mice
have shown that such a treatment is capable of increasing
considerably the survival time of experimental leukemic
mice.406One such attempt is now being made in a caseof human leukemia.
186. The multiplication of donor cells in the irradiatedhost has unquestionably been established; however, thisdoes not necessarily exclude a possible effect o i subcellular fractions. The idea of the possible recovery
capaaty of bone marrow or spleen nucleoproteins was
put fonvard a few years ago but was later abandoned on
the ground that a small number of intact cells were present in the fractions injected407 I t is, however, not possible at present to exclude the possibility that sub-cellular
fractions do play a role in these recovery phenomena
and, on account of the tremendous importance of proving
or disproving this hypothesis, both for fundamental andapplied purposes, worlc on the biological activity of
nucleoproteins in normal or irradiated mammals is ofgreat interest and should certainly be very actively
pursued.
187. It will probably become possible to enhancesimilar recovery processes in human beings, but this zuillcertainly require a much better understanding of immunological processes and of interactions between cellular populations before it becomes a reality.

182. Important immunological problems are brought
up by such experiments as they were in the case of thefirst blood transfusions: it is well known that mammals
are only able to accept definitively grafts from subjects
belonging to the same genetic strains (iso!ogous grafts).
For instance, one has known for a long tlme that grafts
from one human being to another (homologous grafts)
are usually eliminated rather rapidly. as in the case ofskin grafts ; this is also the case when grafts are madebetween different species of animals like rats and mice(heterologous grafts). This incompatibility originatesfrom the fact that mammals possess imlnunologicaldefence mechanisms which make them synthesize newantibodies to any foreign protein entering their blood
circulation. However, it has been found that the immunological response of mammals is strongly inhibited in thedays following total body irradiation, and in these circumstances both homologous grafts (from other strainsof mice) and heterologous grafts (from rats) of bone
VIII. C o x c ~ t . s ~ o x smarrow are capable of saving lethally irradiated mice.
188. Radiobiology has certainly made great headway
Cells of the donor animal have been characterized in thewithin the last fifteen years. It has had, like cancer
receptor animal by specific genetical or imnrnunologicalresearch, strong governmental support in many countries,
identification ;3s0J99and the repopulation of the myeloid
and both these aspects of medicine have the common
and of the lymphoid tissue has been demonstrated. In
feature that litany cellular mechanisn~sappear to be
the case of heterologous grafting of thymus tissue fromsimultaneously concerned. This is why effects of radiarats into irradiated mice, the cells appear at first to betion are as diverse as are cellular functions. The visible
exclusively of rat origin but the later appearance of andamage will probably depend on which particular mechagglutination reaction with specific mouse antisera inanism is most sensitive at the time of irradiation. on its
dicates that thymus cells of mouse origin may be rerelative importance to the over-all economy of the cellcovering."00
and on the possible interference of other less damaged
153. The survival of the animals injected with boneprocesses. Mutations, carcinogenesis, and the inhibition
marrow becomes, however, dangerously compromisedof mitotic activities, of cellular differentiation and ofafter a certain time, because, whether homologous or
immunological processes. to name but a few examples
heterologous grafts are used, the incompatibility betweenof radiation damage, affect extremely complex cellularthese and the 'cells from the receptor animals reappears.
mechanisms, which, despite the efforts of many able
The discussion has arisen as to whether the recovered
scientists, remain one of the most provocative challenges.
cells from the irradiated organisms are again able toI t thus becomes vital, if effects of radiation are to besynthesize antibodies against the injected cells or
understood and possibly prevented. that the functio~~ing
whether these are making antibodies against the cells ofof normal cells and the organization of cellular populathe irradiatedtions be knotvn. Radiobioloe-v is not a science in itself;
184. There have been recent attempts to stimulate
it is but an applied scienceu;nd it rests entirely on ourbone marrow regeneration. It has been showll that alknowledge of the great principles of biology whichkosyglycerols obtained from bone marrow, as well as
cannot be studied independently of one another. The
some of their derivates, stimulate the white blood cells
understanding of some aspects may at times progresscounts of patients irradiated for therapeutic purposes:
more rapidly than that of others, but in the long run all
this increase seems to concern the neutrophil polynorthese have to be integrated iilto one harmonious picture.
phonuclears and has also a beneficial effect on the platelet
The problein is not merely to push forward the study
count.'03 I t has also been found that the bactericidal
of genetics or of carcinogenesis, because it is obvious
properties of the blood serum mere diminished in irradithat these problems are dependent on most othcr aspects
ated rats ; this could be due to 2 loss of properdin, preof cell physiology. Our ignorance of fundamental biology
sumably a natural non-specific antibody. Treatment of(taken in its widest possible sense) is undoubtedly thethese animals with a fraction from serum rich inmajor factor limiting our understanding o i radiation
properdin appears to increase the s u r \ ; i ~ a l . ~ ~ ' ~ ~ ~ ~effects on man.

1. Lea, D. E., Actions of radiatio~rson living cells,
Muller, H. J., J. Genet. 40, 1-66 (1910).
Cambridge Univ. Press, 1946.
Kaufmann, B. P., Cold Spring Harbor S?m2. Pollard. E.. A. Buzzell, C. Jeffreys, F. Forro, Arch.
posium 9, 82-92 ( 1931).
Eioch. Bioph. 33, 9-21 (1951).
Lea, D. E., op. cit. ref. 1. p. 147.
3. Alesander, P., Ad~laarrcesi r ~Radiobiology, p. 8, Ed.
Auerbach. R., Nature 177.574 (1956).
by Hevesy, Forssberg and Abbatt, Oliver andSas, K., Genetics 2j. 41-68 (1940).
Boyd. Edinburgh and London ( 1956).
Wolff. Sh., and H. E.Luippold, Progress in Radio4. Bacq, 2. M., P. Alesander, Prijlcipes de Racliobiologjl, pp. 217-221. Ed. by AQitchell,Holrnes andbiologie, Sciences et Lettres, Liege, p. 59 (1955:).
Smith, Oliver and Boyd, Edinburgh and London
5. Zimmer, K. G., Acta Radiologica 46, 595-602(1955).
(1956).
6. Blan, M.. K. Altenburg, Anna1 der Physik 12,
Duplan. J. F., H. &Iarcovitch, UN document A/
315 (1923).
AC.S2/G/I<. 16/Add.l.
7. ~esshuer,F., Zschr. Physik 12,3S (1923).
3Iarcovitch, H.. Nature 174, 796-797 (1953).
8. Dale, W. M., Modertz Trends in Radiatiorz B ~ G Lea. D. E.. op. cit. ref. 1. p. 227.
chemistry in Actions chimiques et biochinliqzces
Goldfeder, A., G. E. Clarke. Radiation Res. 7, 318.
des radiations, Ed. by Haissinsky, hlasson: Paris
Abstr. 51 (1957).
(1955).
41. Patt. H. &I., A. bl. Brues, Radiation Biology, Vol.
9. Lebedinsky, A. V., Proc. Internat. Coni. Peaceful
I: pp. 919-958, Ed. by Hollaender. h'lcGraw Hill
Uses of Atomic Energy 11, 7-24, United Nations(1954).
(1956).
42.
Stearner,
S. P., Amer. J. Roentg. Rad. Therap.. 65,
10. Meissel, M. N., Proc. Internat. Conf. Peaceful265-271 (1951).
Uses of Atomic Energy 11, 227-243, United
43. Stearner, S. P., Amer. J. Roentg. Rad. Therap. 65,
Nations ( 1956).
272-276 ( 1951) .
11. Rheinberg, S. A., Vest. rentg. radiol. (Moshva)
44. Hershey, A. D., Pul. D. Kamen, J. W. Kennedy,
NO. 5, 3-10 (1955).
H. Gest, J. Gen. Physiol., 34, 305-319 (1951).
12. Zirkle, R. E:, ~ a d i a t i o nBiology. Ed. by HollaenStent, G.: and C. R. Fuerst, J. Gen. Physidl. 38,
45.
der, Vol. I, pp. 315-350, McGraw Hill (1953).
441(1955).
13. Kirby-Smith, J. S., C. W. Sheppard, D. L. Craig,
46. Mazia. D.. and G. Blumenthal, Proc. Nat. Acad.
Radiobiology Symposizcnz 1954, pp. 262-264. Ed.
Sci. U.S. 40,521-527 (1954).
by Bacq and Alexandcs, Butterworth, London(1955).
47. Stefiensen. D., Proc. Nat. Acad. Sci. U.S. 41. 155160 (1955).
14. Storer, J. B., I). S. Harris, J. E. Furchner. W. 11.
Langham, Rad. Research 6, 188-288 ( 1957).
48. Steffensen, D., Genetics 42, 239-252 (1957).
15. Bacq. Z. M., P. Alesander, op. cit. ref. 4, p. 96.
39. Odell. T. T., and A. C. Upton, Acta Haematol, 14,291-293 (1955).
16. Lea, D. E., op. cit. ref. 1, p. 72.
50. hloutinho de Oliveira, M.. M. T. Cabral. Portug.
17. Fano, U. Radiation Biology, Ed. by Hollaender,
Acta Biol. Ser. A. 4,297-311 (1955), Chem. Abstr.
Vol. I, p. 123, McGraw I-Iill (1954).
50,
101955 (1956).
18. Atwood, K. C., and A. Norman, Proc. Nat. Ac.
51. Lefort, M., in Actions ckinriqtres et biologiques desSci. U.S. 35. 696-709 (1949).
radiations, Ed. by Haissinslcy, Masson, Paris,
19. Zirkle, R. E., C. A. Tobias; Arch. Biochem. andpp. 95-204 (1955).
Biophys. 47, 282-306 ( 1953).
32.
Dainton,F. S.. Progress i ~ Radiobiology,ip. xix,20. Hollaender, A., and G. E. Stapleton, Proc. Internat.
Ed. by Mitchell. Holmes and Smith. Oliver andConf. Peaceful Uses of Atomic Energy. 11, 311Boyd. Edinburgh and London (1955).
314. United Nations (1956).
53.
Lea, D. E.. Brit. J. Radiol., Suppl. 1, p. 59 (1947).
21. Latarjet. R.. Rev. Canad. Biol. 5,9-47 (1946).
54.
Franck.
J., R. Platzman. Radiation Biology, Vol. I ,22. Latarjet. R.. The nature of virus nzuItiplicatioa.
p. 246. Ed. by Hollaender, PIIcGraw Hill ( 1954).
Cambridge Univ. Press, pp. 173-193 (1953).
55. Alesander, P.. Personal communication (1957)
23. Latarjet, R.. et R. Ephrussi, C. R. Acad. Sci., Paris,
229, 306-308 (1949).
56. Bacq. Z. M., P. Alesander, op. cit. ref. 4, p. 131.
24. Puck, T. T., and P. I. htarcus, J. Exp. &/led.103,
57. Lefort, hl.. op. cit. ref. 51. p. 162.
653 (1956).
58. Stein. G., and J. Weiss. J. Chem. Soc., 3265 (1951).
25. hIuller. H.. J., Radiatiorr Biology, Ed. by Hollaen59. Dale, W. M., op. cit. ref. 8, p. 219.
der. Vol. I, pp. 475-626, McGraw Hill (1954) ;and
60. Bacq. Z. M. and P. Alexander, op. cit. ref- 4. P.
UN docun~entA/AC.S2/G/R.58/Anne-u I.
146.
26. Russell, W. L., Bull. of Atom. Scientists 12, No. 1
61.
Whitclier.
S. L., Natunviss. 39, 450 (1952).
(1956).
63. Lefort, M., op. cit. ref. 51. p. 161.
27. Muller. H. J., op. cit. ref. 25. p. 181.
63. SwaIIow, A. J.. Progrcss in R o d i o b i o k 7 ~PP.
~ 31728. Court-Brown. W. M. and R. Doll, Lez'kaemia
323, Ed. by hlitchell, Holmes and Srr_llth.
aplastic anaernia irr patients irradiated for ankylosand Boyd, Edinburgh and London ( 1 9 ~ ~ ) ing spondilitis. H.M. Stationery Office, London(1957) : UN document A/AC.82/G/R.105.
64. Barron. E. S. G., Ph. Johnson, Rad- Res- 290302 (1956).
29. Lewis. E. B., Science 152, 965-972 (1957).
5 7

Barron, E. S. G.. Radiation Biology, Vol. I , pp.
283-314, E d by Hollaender, McGraw Hill (1954).
Bacq, Z. M. and P. Alexander, op. cit. ref. 4, p. 171
and p. 181.
Davison, P. F., B. E. Conway and J. A. V. Butler,
Progr. Bioph. and Bioph. Chem. 4, 148-220( 1954).
Ephrussi-Taylor H., R. Latarjet, Bioch., Bioph.
Acta 16. 183-197 (1955).
Guild. W. R., Radiation Res. 7, 320, Abstract 55(1957).
Errera, M., E f e t s biologiques des radiatiomA c t i o ~biochi~riqrtes-in~
Protoplastrtatologia, Ed.
by Weber and Heilbrunn, S~ringerverlag,Vienna,p. 105 (1957).
Bacq. Z. M., and P.Alexander, o f . cit. ref. 4, p.
156.
Alexander, P., and A. Charlesby, J. Polym. Sci. 23,
355-375 (1957).
Alexander, P., M. Fox, K. A. Stacey, D. Rosen,
Nature 178,846-849 (1956).
Kaplan. R. W., Naturwiss. 42,466-467 (1955).
Collinson, E., F. S. Dainton, B. Holmes, Nature
165,267 ( 1950),
Alper, T., Radiobiology Sytttposiz~m1954, pp. 3945, Ed. by B a q and Alexander, Buttenvorth, London (1955).
Ebert, M., Personal communication ( 1957).
Forssberg, A., Nature 159, 308 (1947).
Schoenberd. M. D., R. E. Brook, J. J. Hall, H.
Schneiderman. Personal communication ( 1950).
80. Bacq, Z. M.. P. Alexander, op. cit. ref. 4, p. 171.
81. Dale, W. M., op. cit. ref. 8, p. 223.
82. Pollard. E. C., W. R. Guild, F. Hutchinson and
R B. Setlow. Adv. Biophys. and Biophysic. Chem.
5, 72-108 (1955).
83. Gordy, W., Proc. Nat. Acad. Sci. U.S. 41, 983(1955).
84. Fairbanks. A. J., Radiation Res. 7, 314, Abstract
42 (1957).
85. Zimmer. K. G., L. A. Ehrenberg, Stralllender,
103,3-15 (1957).
86. Charlesby, A., ~ a t u r 171,e 167 (1953).
87. Franck, J., R. Platzman. op. cif. ref. 54, pp. 231253.
88. Mazia. D., and G . Blumenthal, Proc- Nat. licad.
SC. U.S. 34, 328-336.
89. Bacq, Z. M., and P.Alexander, o f . cif. ref. 4. p. 60.
90. Dale, W. M.. Ionizing radiation and cell ntetabolist~t,Ciba Foundation Sympos., p. 26 Cl~urchill,
London ( 1956).
91. Lea, D. E., op. cit. ref. 1. p. 108.
92. Setlow, R. B., and B. Doyle, Arch. Bioch. Bioph.
46,46 (1953).
93. Alexander, P., Radiation Res. 6. 653 (1957).
94. Alexander. P., D. Tons, J. Polylner Sci. 12, 343(1956).
95. Hutchinson, F., Rad. Res. j, 483, Abstract 47(1956).
96. Gray, J. H.. Brit. J. Radiol. 26, 609 (1953).
97. Bacq, Z. 11.and P. Alexander, op. cit. ref. 4 . pp.
361-401.
98. Hewitt. H. B.. and J. Read, Brit. J. Radiol. 23,
416-423 (1950).

Gray. L. H.. Acta Radiol. 41, 63-83 (1954).
Errera, At.. o f . cif. ref. 70, p. 187.
Johnson, G. R. A., G. Stein and J. Weiss, Science
114,412 (1951).
Alexander. P., and 14. Fox, Trans. Farad. Soc. 50,
605 (1954).
Loiseleur. J.. and R. Latarjet. Bull. Soc. Chim.
Biol. 24, 172 ( 1942).
Lefort, M., op. cit. ref. 51, p. 200.
Bacq, Z. h3.. and P. Alexander, op. cit. ref. 4, p.
178.
hfarcovitch, I-I., Ann. Inst. Past. 90, 458-481(1956).
Scholes, G.. J. Weiss, C. M. Wheeler, Nature 178,
157 (1956).
Ekert, B.. and R. htonier, Ann. Inst. Past. 92, 556558 (1957).
Loiseleur. J., and M. Sauvage, C. R. Acad. Sci.
Paris 237,204 (1953).
Anderson, R. S., Brit. J. Radiol. 27.65 (1954).
Alper, T., Brit. J. Radiol. 27, 50 (1954).
Latarjet, R., Ciba Foundation Sympos. on lottizittg
radiatiotz and cell nzetabolistn, pp. 275-308
Churchill, London (1956).
Errera, bl. Cold ~ p r i nHarbori
S~mpos.12, 60(1947).
Errera, M., o f . cit. ref. 70, p. 107.
Scholes, G.. and J. Weiss, Progress irt Radiobiology, pp. 93-104, Ed. by Mitchell, Holmes andSmith. Oliver and Boyd, Edinburgh and London(1955).
116. Conway, B. E.. Nature, 173, 579-581 (1954).
117. Dale, W. Af.. Biochem. J. 36, 80 (1942).
118. Hollaender. A., and G. E. Stapleton, Ionizing radiation and cell nzetabolism, Ciba Foundation Sympos., pp. 120-139 Churchill, London (1956).
119. Barron, E. S. G., S. Dickman, J. -4. Muntz and
T. S. Singer, J. Gen. Physiol. 32, 537 (1949).
120. Doherty, G. D., Fed. Proc. 11 (Part I ) , 35 (1952).
121. Dale, W. I[., Bioch. J. 34, 1367 (1940).
122. Dale, W. M., Bioch. J. 36, 80 (1942).
123. Gray, L. H., Brit. Med. Bull. 4. 11 (1946-47).
124. Eldjarn, L., and A. Pihl, Progress itz Radiobiology,
p. 249, Ed. by Mitchell, Holmes and Smith. Oliverand Boyd, Edinburgh and London (1955).
125. Littman, F. E., E. At. Carr, J. K. Claus. Science
12.5. 737-738 (1957).
126. Errera, M., op,ref. 70.
127. Bacq, Z. M., alld P. Alexander, op. tit. ref. 4,
p. 384.
128. Hollaender. A., and G. E. Stapleton, Physiol. Rev.
33,77 (1953).
129. Gray, L. H.. Progt.essilr Radiobiology, pp. 267-278.
Ed. by Mitchell. Holmes and Smith, Oliver andBoyd. Edinburgh and London (1955).
130. Ginoza, W., and A. Norman. Nature 179, 520-521( 1957).
131. Meissel, 34. N.. O p . tit. ref. 10, p. 227.
132. Graevskii. E. Y., L. I. Korchak, Doldad. Akad.
Nauk SSSR 102,939 (1955).
133. Meissel. M. S.. op. cit. ref. 10, p. 230.
134. Cherez, E.. Klin. Woch. 3 4 , 9 5 9 8 (1956).
135. B a q . Z. M.. and P. Alexander. op. cit. ref. 4.
p. 303.

148

136. Drew, R. hl., Rad. Res. 3, 116-120 (1955).
137. Butler, J. A. V., Rad. Res. 4, 20-32 (1956).
138. Volkin. E., and I. Astrachan, Virology 2, 149-161( 1956).
139. Buiton, K., Bioch. J. 61, 473-483 (1955).
140. Hershey, A. D., and N.E. hlelechen, Virology 3,
207 (1957).
141. Errera, &I., op. cit. ref. 70, p. 33 and p. 175.
142. Meissel, M. N., op. cit, ref. 10, p. 236.
143. Ameida, A. B., and F. G. Sherman, J. Cell. Comp.
Physiol. 44, 333-334 (1954).
144. Errera, M., op. cit. ref. 70, pp. 109, 128, 140, 171.
145. Lebedinsky, A. V., op. cit, ref. 9, p. 17.
146. Pigalyev, I. A., Proc. Int. Conf. Peaceful Uses ofAtom. En., 11, 80-87, United Nations (1956).
147. Gaude, G., and J. Coursaget, Proc. Int. Conf.
Peaceful-Uses of Atom, En., 11, 169-174, United
Nations ( 1956).
148. Taliaferro, W. H.. and L. G. Taliaferro, J.
Immunol. 66, 181-212 (1950).
149. Taliaferro, W. H., and L. G. Taliaferro, J. Infect.
Disease 99, 109-128 (1956).
150. Gros. Ch., G. P. Talwar, J. Coursaget, Bull. Soc.
Chim. Biol. 36, 1569-1580 (1955).
151. Thompson, J. F., and E. T. Mikuta, Proc. Soc.
Exp. Biol. Med. 85,29-32 ( 1954).
152. Bacq, Z. &I., Personal communication ( 1957).
153. Errera, M., op. cii. ref. 70, p. 85.
154. Rothstein. A., Profophnwtologia, 2, E 4, Ed. byWeber and Heilbrunn, Springerverlag, Vienna( 1954).
155. Bacq, Z. M., and P. Alexander, op. cit. ref. 4, p. 300
and p. 334.
156. Lebedinsky, A. V.. op. cit. ref. 9, p. 22.
157. Errera, M., op. cit. ref. 70, p. 66.
158. Bruce, A. K., J. Gen. Physiol., 41, 693 (1958).
159. Billen, D., B. L. Strehler, G. E. Stapleton, E. Brigham, Arch. Bioch. Bioph. 43, 1-10 (1953).
160. Kay, R. E.. S. C. Early. C. Entenman, Rad. Res. 6,
98-109 (1957).
161. ~ i l l i a m s C.
, .Ivl., G. &I. Krise, D. R. Anderson,
R 31.Dowben, Rad. Res. 7, 176-183 ( 1957).
162. Carlson. J. G., N. G. Harrington, Rad. Res., 1,491,
Abstr. 13 (1954).
163. Catcheside, D. G., Adv. in Genet. 2. 271-358(1345).
164. Kaufman. B. P.. Radiation Biology. Vol. I, pp.
627-711, Ed. by Hollaender, McGraw Hill (1954).
165. Benzer, S., Tlze Chernical Basis of Heredity, pp.
70-93, Ed. by iV. D. IVIcElro and B. Glass, John
Hopkins Press, Baltimore ( 1 h 7 ) .
166. Demerec, bI., Cold Spring Harbor Symp. 21,
113-121 (1956).
167. Carlson, J. G. '~odiationBiology, Vol. I, pp. 763S24. Ed. by Hollaender, McGraw Hill (1954).
168. Meissel, M. N., and V. A. Sondak, Dokl. Akad.
Nauk SSSR., 105, No. 6 (1955).
169. Sherer, E., D. Ringelb, Strahlenther. 90, 41-52( 1954).
170. Errera, M.,op. cit. ref. 70, p. 173.
171. Brachet, J., Biochemical Cytology, Acad. Press(1957).

172. Bloom, M. A,, Histopatlzology of irradiation fromexterjzal atld internal sozcrces, McGraw Hill
( 1948).
173. Klein. G.. and A. Forssberg, Esp. Cell. Res. 6,
211-220 (1954).
174. Klein. G., and -4. Forssberg, Esp. Cell. Res. 6,
480-197 ( 1954).
175. Reinberg, S. A., Klin. Med. (MosLxa), 34, 3-5( 1956).
176. Moutschen, J., 2. M. Bacq, A. Heme, Experientia
12,314-315 (1956).
177. Puck, T. T., and H. W. Fischer, J. Exp. Med. 104,427-434 (1956).
178. Puck, T. T., and H. W. Fischer, J. Exp. Med. 104,613 (1956).
179. Meissel, M. N., op. cit. ref. 10, p. 229.
180. De Duve, C., and J. Berthet, Int. Rev. Cytol. 3,
225-276 (1954).
181. Sherer, E., ~trahlenther.99, 230 (1956).
182. Sherer, E., and E. Stolle, Strahlenther. 93,317-320( 1954).
183. Sherer, E., and D. Ringelb, Strahlenther. 90, 3 4 4(1953).
184. Van BekLum, D. W., Bioch. Bioph. Act. 16, 437438 (1955).
185. Van Bekkum, D. W., Ionizi?rg radiatiotrs andcell metabolism, Ciba Foundation Symp. 77-91
Churchill. London (1956).
186. Potter. R. L., and F: H. Bethel, Fed. Proc. 11,270( 1952).
187. Ord, M. G., and L. A. Stocken, Brit. J. Radiol. 28,
279-282 (1955).
188. Chevallier, A., C. Burg, Radiobiology Sjwzposirrnz
1954, pp. 1-25, Ed. by Bacq and Alexander, Butterworth, London ( 1955).
189. Errera, M.,op. cit. ref. 70, pp. 70-74.
190. Popjak, G., and A. Tietz, Eioch. J. 60, 147-155(1955).
191. Popjak, G., and A. Tietz. Bioch. J. 60, 155-165(1955).
192. Kennedv. E. P., and A. Lehninger. Phosphorous~ e t a b o i i s t ~Ed.
t . by W. D. McElroy and B. Glass,
Baltimore, Vol. 11, pp. 253-281 (1952).
193. Ephrussi, B., Nucleocytoplos~itic relations i n nzicroorga~riswzs.Oxford (1953).
194. Palade, G. E., Enzymes, Units of Biological Structure a d Fzmctiojr, .\cad. Press, pp. 185-215( 1956).
195. Palade. G. E., and P. Siekevitz, J. Biol. and Bioch.
Cytol. 2, 171-198 (1956).
196. Tahnlisiul. Th.. and R. L. Devine, Personal cornmunication (1956).
197. Richmond. D. E., K. I. Altman, K. Salomon, J.
Biol. Chem. 190. 817-823 (1951).
198. Errera, ?!I., op. cit. ref. 70, pp. 74-91.
199. Nizet, A., S. Lambert, 2. bl. Bacq, A. Heme! Aick
Int. Physiol. 62, 129-131 (1954).
200. Ord, M.G., and L. A. Stocken, Physiol- Rev.33~
356-386 (1953).
201. Cornatzer, W. E., J. P. Darison, 0-D- E n ~ ~ ~ s ~ ~C. Simonson, Rad. Res. 1, 546-550 (19j4).
649202. Skreb, Y..and M. Errera. ESP. Cell- Res.
656 (1957).

203. Komlessar, 0. D., K. I. Altman, L. H. Hempelmann, Arch. Bioch. Bioph. 52, 362 (1954).
204. Kourlessar. 0. D., K. I. Altman, L. H. Hempelmann, Arch. Bioch. Bioph. 54, 355 (1955).
205. Okada, S., E. R. Gordon, R. King, L. H. Hempelmann, Arch. Bioch. Bioph. 70, 469-476 (1957).
206. Goutier-Pirotte. M., Bioph. Bioch. Act. 22. 396399, (1956) ; and UN document A/AC.82/G/R.3.
207. Feinstein. R. N.. and J. C. Ballin, Proc. SOC.Esp.
Biol. Med. 53, 6-10 (1953).
Feder. Proc. 11,
208. Ballin. J. C.. and R . .
184 (1952).
209. Rhoades, M. M., Cold Spring Harbor Sympos. 11,
202-207 ( 1946).
210. Lwoff, A., Syrnpos. CNRS, Uttitks bbiologiques
doukes de continuitk gttaktiqzte Paris (1936). +211. Sissakian, N. M., Proc. Internat. Conf. PeacefulUses of Atomic Energy 11, pp. 248-255, United
Nations (1956).
212. Lesley, J. W., and XI. M. Lesley, Genetics 41, 575588 (1956).
213. Hollaender, A. (Ed.), Radiatioa Biology, McGraw
Hill (1954).
214. Errera, bl., Ann. Soc. Sci. Med. Nat., Brussels, 5,
65 (1951).
215. Sparrow, A. H.. and F. Forro, Ann. Rev. Nucl.
SU. 3,339-368 (1953).
216. Moscona, A., Proc. Nat. Acad. Sci. U.S., 43, 184194 (1957).
217. Meissel. M. N.. T. M. Kondrateva, Ii. N. Emelyanov, Dokl. Akad. Nauk SSSR 81, No. 6 (1951).
218. Ivanitckaya, A. F., Dold. Akad. Nauk SSSR 110,978-981 ( 1956).
219. Gaulden, M. E., M. Nix, J. Moshmant J. Cell.
Comp. Phys. 41,451 (1953).
220. Spear, F. G., Brit. Med. Bull. 4, 2 (1946-1947).
221. Mayer, E., Tab. Biol. 19, 237 (1939).
222. Ilenshaw. P. S., Am. J. Roentg. Rad. Ther. 43,
899 (1940).
223. Errera. M., op. cit. ref. 70, p. 167.
224. Gaulden. M. E., Abstr. Genet. Soc. -her., Genetics 41, 645 (1956).
225. Bloch, D. P., and G. C. Goodman, J. Biol. Bioph.
Chem. 1, 17-28 (1955).
226. Deering, R. A., and R. B. Setlow, Science 126,397(1957).
227. Sparrow, A. H., Ann. N.Y. A c Sci. 51. 1508
(1951).
228. Gonzales, E. L., and E. S. G. Barron, Bioph. Bioch.
Acta 19,425 (1956).
229. Rapkine, L., J. Chim. Phys. 34, 137 (1938).
230. Stem, H., Science 124. 1292 ( 1956).
231. Puck, Th. T.,~ a d i a t i ~Re;.
n 7,
Abstr.
( 1957).
. and R. Latarjet, Cold Spring Harbor
232. ~ e m e i e cIf.,
Sympos. 9, 38-56 (1947).
233. witkin. E.. Cold spring Harbor Sympos. 21, 123140 ( 1956).
234. Liining, K. G.. and B. Hannerz, Hereditas 43, 549(1957) and U N document A/AC.82/G/FL174.
235. Baker, W. K., and E. von Halle, J. Cell. Comp.
Physiol. 45, Suppl. 2, 299-307 (1955).

i in stein.

444,

236. Liining, K. G., and S. Jonsson, UN document
A/AC.82/G/R.69.
237. Giles. N. H., Brookhaven Sympos. on Biol. 8. 103125 (1955).
238. Swanson, C. P., and L. J. Stadler, Radiation Biology, Vol. 11, pp. 249-281, Ed. by Hollaender,
McGraw Hill (1955).
239. Hemmerly, J., and M. Demerec, Cancer Res.
Suppl.
- - 3, 69-75 ( 1955).
240. Novick, A.. Brookhaven Symp. on Biol. 8,201-216(1955).
241. Suskind, S. R, Chemical Basis of Heredity, Ed. by
W. D. IiicElroy and B. Glass, John Hopkins
Press, Baltimore (1957).
242. Nanncy, D. L., in Chernical Basis of Heredity, pp.
134-166, Ed. by W. D. McElroy and B. Glass,John Hopkins Press, Baltimore (1957).
243. Kanazir, D.. and I f . Errera, Bioch. Bioph. Acta 16,
198-202 (1955).
244. Evans, T., J. C. Slaughter, E. P. Little, G. Failla,
Radiobiol. 39, 663-680 (1942).
245. Hiramatsu. H., and T. Okamoto, U N document.4/.4C.82/G/R.63, para. 12.
246. hfaizel, ?if., J. Physiol. 11-3,59-89 (1951).
247. Sheppard. C. W., and hi. Steward, Fed. P r o c 10,
125 (1951).
248. Sheppard. C. W., and M. Steward, J. Cell. Comp.
Physiol. Suppl. 2, 188-215 ( 1952).
249. W i d e , JV.-s., and C. w.' ~ h e p ~ a r dProc.
.
SOC.
Esp. Biol. Med. 88,249-253 (1955).
250. Coons, J. hi., L. E. Ellinwood and J. E. Wilson,
Fed. Proc. 14, 329 (1955).
251. Denson, J. R., E. J. Gray, J. L. Gray, F. J. Herbert. J. T. Tew, H. Jensen, Proc. Exp. Biol. Med.
22,707-711 (1953).
232. Baron, L. S.. S. Spiegelman. H. Quastler. J. Gen.
Physiol. 36,631-641 (1953).
253. Loureau-Pitres. M.. Ark. Kerni. 7. 211-223(1954).
254. Detrick, L. P., I-I. C. Upham, D. Highly. V. Debley,
T. J. Haley, Rad. Res. 2,483-489 (1955).
255. Kiselev, P. N., and P. A. Buzini, Vest. rentg.
radiol. (Moskva) No. 5, 17-26 (1955).
256. Lasnitzki, I., Brit. J. Radiol. 16, 61 (1943).
257. Lasnitzlci. I., Brit. J. Radiol. 16, 137 (1943).
258. Carlson, J. G., op, cit. ref. 167, p. 804.
259. Witkin. E. M.. Proc. Nat. Ac. Sci. U.S. 32, 59( 1946).
260. ~ u r i a ,S.
. E.. in Radiotion Biology, Vol. 11, pp.
333-364. Ed. bv Hollaender. McGraw Hill ( 1955 ).
261. Pollard, E. C., The physics of virtues, Academic
Press ( 1953).
262. sonneborn, T. M., Proc. 9th Inteutz. Congr. Getret.
Caryologia, Suppl. pp. 307-325 ( 1953).
263. Labaw, L. W.. V. M. Mosley, R. R. Wyckofi. J.
Bact. 65,330-336 (1953).
261. Cheever. F. S.. slid L. W. Smith, Fed. Proc. 14,459 (1955).
365. Luria, S. E.. and R. Dulbecco, Genetics 34. 93-125(1949).
366. Watson. J. D., Genetics 33, 633 (1948).
267. Lwoff, A.. Lysogeny 17,269-337 ( 1953).
268. Zinder, N. D., and J. Lederberg, J. Bact. 64, 679699 (1952).

269. Dalcq, A., and S. Simon, Protoplasma 14, 497(1932).
270. ~ r a c h e t ,J., Embryelogie Chimique, Desoer(Liige) and Masson (Paris) (1915).
271. King, Th. J.? and R. Briggs, Cold Spring Harbor
Symp. 21,271-290 (1956).
272. Muller, H. J., ~ a d i i t i o n~ i o l o Vol.
~ ~ ,I, pp. 351473, Ed. by Hollaender. hlcGraw Hill ( 1954).
273. Russell. W. L., Radiation Biology, ~ o l I,
. pp.
825-859, Ed. by Hollaender, McGraw Hill (1954).
274. Hertwig, O., Arch. Mikroskop. Anat. ~ n t w i c k lungsmech. 82 (11), 1-63 (1913).
275. Hertwig, P.. Zschr. indukt. Abstamm. Vererbungslehre 17,254-261 (1917).
276. Whiting. A. R., ~ e n e t i &35, 139 (1950).
277. Astaurov, B. L., Zhur. Obshchei Biol. 8, 421(1947).
278. Russell, L. B. and W. L. Russell, Progress inRadiobiology,pp. 187-192,Ed. byMitchell. Holmes
and Smith. Oliver and Boyd, Edinburgh and London (1955).
279. Russell, L. B., Radiotion Biology, Vol. I, pp. 861918, Ed. by Hollaender, McGram Hill (1954).
280. Russell, L. B., op. cit. ref. 279, pp. 904, 905 and907.
281. Snell, G. D., J. Exp. Zool. 65,421-441 (1933).
282. Stewart, A.. J. Webb, D. Giles and D. Hewitt,
Lancet 2,447 ( 1956).
283. Wakabayashi. M., and F. Kawamura, U N document A/AC.82/G/R.43.
284. Tsuzuki. &I., UN document A/AC.82/G/R.4.
285. Auerbach, R., Nature, 179, 725-727 (1957).
286. Welshom. W. J., and W. L. Russell, Proc. Nat.
Ac. Sci. U.S. 43,608 ( 1957).
287. Fruton, J. S., and S. Simmons, General Biochenristry, Wiey, p. 732 ( 1953).
288. Kaldcar, H. &I., Science 125, 105 (1957).
289. i us sell. L. B., and hl. H. hlajor, Genetics 36, 621(1952).
290. R u s s d , L. B., and M. H. Major, Genetics 42,161175 (1957).
291. Naville, B., Dissertation Zurich (1955), UN document A/-4C.82/G/R.27.
292. Pudc~ T- T-, P. I. Marcus and S- J. Ciecciura,
J. Exp. lled. 103,273-284 (1956).
, c.,Quart. Rev. Biol. 22,253-282 (1947).
293. ~ i e s eA.
294. Errera. M..op. cit. ref. 70, pp. 165-168.
295. Stapleton. G. E., Ann. N.Y. Ac. Sci. 59, 604-618(1955).
296. Patt. H. M.. and A. M. Brues, op. cit. ref. 41, p.
932.
297. Sacher, G. A., Science 125, 1039-1040 (1957).
298. Kohn, H. I., and R. F. Kallman, Science 124, 1078
( 1956).
299. Hursh. J. B., and G. Cassarett, Personal communication (1955).
300. B ~ u t e r R.
, C.. and L. W. Tuttle, Radiat. Res. 7,
303, Abstr. 14 ( 1957).
301. Patt. H. M., and A. M. Brues, op. cit. ref. 41,
p. 933.
302. Sherman. F. G., Experientia 8, 429-431 (1952).
303. Nims. L. F., and J. L. Geisselsoder. Rad. Res. 5,
58-64 (1956).
304. Smith, F., L. and \V. W. Smith, Am. J. Physiol.
165, 662 (1951).

305. Bacq, Z. &I., and P. Alexander, op. cit. ref. 4, pp.
263-275.
306. Jhwdy, A. H., L. R. Bennett; S. M. Chastain,
Radiology 55, 879-885 (1950).
307. Stender. H. S-. and T.Hornykienrytsch, Katurwiss.
lob, 32-34 (1955).
308. Stearner, S: p h . , . ~ J.
. B. Christian, A. M. Brues,
Am. J. Physiol. 176,455-460 (19j4).
309. ~ u s s ~ lL.
l ,B., M. H. Major, ~ e n e i c 38,
s 687-688( 1953).
310. ~ollaender,A., W. K. Baker. E. H. Anderson.
Cold Spring Harbor Symp. 16, 315-326 (1951).
311. Baker, W. K., Brookhaven Symp. Biol. 8, 191-200(1955).
312. Giles, N. H.. Radiation Biology, Vol. I, pp. 713761, Ed. by Hollaender, McGraw Hill (1954).
313. Russell, L. B., W. L. Russell and M. H. Major,
Anat. Rec. 111,455 (1951).
314. Bacq, Z. &IvI.,
and P. Al=ander, op. cit. ref. 4, pp.
276-285.
315. Timofeeff Ressovsky, N.W., Biol. Zentralblatt 52,
168-476 (1932).
316. Lefhre, G. J., Genetics 40, 374-387 (1955).
317. Russell, L. B., op. cit. ref. 279, p. 907.
318. Kohn, H. I., and R. F. Kallman, Rad. Res. 6. 329332 (1957).
319. Grahn, D., and K. F. Hamilton, Genetics 42, 189198 (1957).
320. Bacq. Z. >I., and P. Alexander, op. cit. ref. 4,
p. 282.
321. See Anncx H.
322. Sparrow, A. H., Science 118, 697-698 (1953).
323. Blinks, L. R., J. Cell. Comp. Physiol. 39, Suppl. 2,
11 (1952).
324. Welch, G. P., Personal communication ( 1957).
325. Brues, A. M., Adv. Canc. Res. 2, 190 (1954).
326. Windholz, F., Radiology 48,398 (1947).
327. Glucksmann, A., Brit. J. Radiol. 25, 38 (1952).
328. ~149 (1957).
~ R., and~ J.h Wolff,, Rad. Res. 7, 462, Abstr.
329. ~ i t t ~ iw.,
~ h G.
, H W ~ G.~ schube,-t,,
Progressin
Radiobiology, pp. 381-385, Ed. by Mitchell,
Holmes and Smith, Oliver and Boyd, Edinburghand London ( 1955).
330. Stadler, J.. Gowen. J. W.. Abstr. Genet. Soc.
Amer. ; Genet. 42, 398 (1957).
331. Stoklasa. I., I. Penkava, Biologic des Rodiums undder radioaktiven Elemente, Berlin ( 1932).
332. Lorenz. E.. J. Nat. Canc. Inst. 15, 1049 (1955).
333. Vlasyuk. P. A.. Tracer Ele~wetits.Publ. Acad. Sci.
Latv. SSR, p. 95 (1955).
334. Johnson, E., Plant Physiol. 23,544 (1948).
335. Granhall, I., L. Ehrenberg, Botan. Notiser 2, 155(1953).
336. Kuzin, A. &I.. Proc. Intern. Conf. Peaceful Usesof Atomic Energy 12, p. 149, United Xations( 1956).
337. Ord, M. J., and J. F. Danielli. J. Gen. Physiol. 39.
29-37 ( 1956).
338. Duryee, W. R.. J. Nat. Canc. Inst. 10, 735-796( 1949).
339. Errera. &I., F. vanderhaeghe, Exp. Cell. Res. 13,
1-10 (1957).
340. Ulrich, H., Nature, 42, 468 (1955).
341. Zirckle. R. E., and W. Bloom, Savlce 117, 487493 (1953).

151342. Bacq, Z. M., F. Vanderhaeghe, J. Lamblon,
M. Errera and A. Herve, Exp. Cell. Res. 12, 639648 (1957).
343. Mazia, D.. and H. Hirshfield, Exp. Cell. Res. 2,
38-72 ( 1951) .
Wilbur,344. Bernheim, F., A. Ottolellghi and K.
Rad. Res. 4, 132-138 (1956).
345. Latarjet, R.. and L. R. Caldas, J. Gen. Physiol. 35,
455-470 (1955).
346. Sels, J.. and H. Chantrenne, Personal communication (1957).
347. Stone, R. S., 0. Wyss, F. Haas, Proc. Nat. Acad.
Sci. U S 33,59 ( 1947).
348. Ahlstrom. L. H., H. von Euler, G. Hevesy, Ark.
Kemi. 1 9 (13), 16 (1935).
349. Kuzin, -4.M., and E. V. Budilova, Dokl. Akad.
Nauk SSSR 91, 1183 (1953).
350. Kaplan, H. S., W. H. Carnes, M. B. Brown, B. B.
Hirsh, Cancer Res. 16, 422-436 (1956).
351. Furth, J., Recent Progr. in Horm. Res. 11, 221249 (1955).
352. Horgan, V. J.. and J. St. L. Philpot, Radiobiology
Symposium 1954, pp. 26-29, Ed. b Bacq andAlexander, Butterworth, London ( 19 5).
353. Lebedinsky, A. V., op. cit. ref. 9, p. 17.
354. Gray. L. H., Nature 179, 991-994 (1957).
355. Patt, H., Physiol. Rev. 33, 35-76 (1953).
356. Bacq, 2. M., and P. Alexander, op. cit. ref. 4, pp.
61,84, 361.
357. Eldjam. L., and A. Pihl, J. Biol. Chem. 223, 341352 (1956).
358. Bond. V. P.. and E. P. Cronkitej Annual Rev.
Physiol. 19,299-328 ( 1957).
359- Crouch, B. G-JR. R- Overmany Science(1957).
360- Doherty, D. G.9 Re Shapira, T. W. McKinley, "01ogy Division Annual Informal Meeting ORNL,
Abstr. 10 (1957).
361. Bacq, Z. M., and P. Alexander. op. cit. ref. 4,
p. 392.
362. Mikaelsen, K., Exp. Cell. Res. 8, 400-403 (1955).
363. Devik. F., Brit..J. Radiol. 27. 481484 (1956).
Struckerman,
364. Hbhne* G. He, H. A- Kunkel*
Naturwiss. 42,491492 (1955).
365. Limperos, G., and W. A. Mosher, Amer. J. Roentgenol. 63, 691-700 (1950).
366. Gros. C., P. Mandel, J. Rodesh, C. R. Ac. Sci. Paris236.2010 (1953).
367. Riley, H. P., Amer. J. Bot. 42, 765-769 (1955).
368. Wolff, S., H. E. Luippold, Saence 122, 231( 1955).
369- Hollaender, A*. R. F. Kimball. Nature 177, 726730 (1956).
370. Bacq. Z. M.. and. Alexander, op. cit. ref. 4, p. 376.
371. Hagen, V. Chern. Abstr. 50,15662 (1956).
372. Hagen. V.. Chem. Abstr. 50, 15671 (1956).
373. Kahn. J. B. Jr., Proc. Soc. Esp. Biol. Med. 78,486(1951).
374. Herve. A., and Z. M. Bacq, C. R. Soc. Biol. 143,
881 and 1158 (1949).
375. D'Amato. F.. and A. Gustafsson. Hereditas 34,
181-192 (1948).
376. Mikaelsen. K.. Proc. Nat. Acad. Sci. U.S. 40, 171178 (1954).

Y

1259

377. Maisin, J., P. Maldague. A. DunjiC, H. Maisin.
Progress in Radiobiology, pp. 463-467, Ed. by
Mitchell, Holmes and Smith. Oliver and Boyd,
Edinburgh and London (1955).
378. Kaplan, H. S., J. Nat. Canc. Inst. 13, 185 (1952).
379. Kaplan, H. S., J. Nat. Canc. Inst. 14, 303 (1953).
380. Meeuwissen, D. J. and h4. Brucer, Nature 179,
201-202 (1957).
381. Forssberg. A., and N. Nybom, Physiologia Plantarum 6, 78 (1953).
382. Pate, H. M.. J. W. Clark. H. Vogel. Proc. Soc. Exp.
Biol. Med. 84, 189-193 (1953).
383. Lefort, M., op. cit. ref. 51, p. 141.
384. Mitchell, J. S., Radiobiology Symposium 1954, pp.
170-193. Ed. by Bacq and Alexander, Buttenvorth,
London (1955).
385- Gray, L. H., A. D. Conger, M. Ebert, S. Homsey,
0. C. Scott, Brit. J. Radio]. 26,638 (1953).
386- Dulbecco. R, Radiation Biology, Vole 11, PF- 455486, Ed. by Hollaender, h4cGraw Hill (1955).
387. atiletif, B., C.R. Acad. Sa., Paris, 238, 1541-1542(1954).
388. Errera, M., op. cit. ref. 70, p. 195.
389. Kanazir. D., (in press).
390. Barnes, D. W. H.. and J. F. Loutit, Ciba Foundation Symp. on Iotrizing Radiation and Cell Metabolism, pp. 140-160 Churchill. London (1956).
391. Congdon, C. C., Progress in Henratology (inpress).
392. Duplan, J. F., C. R Soc. Biol. 150,949-951 (1956).
393. Comsa, J., and Ch. M. Gros, Fortschr. Geb. R-tgenstr. 85, 274-281 (1956).
394. Cole, L. J.. P. C. Nowell, M. E. Ellis, J. Nat. Can.
Inst. 17,433-445 (1956).
395. ~~ J. G., L. bJ. GIe, H.~ N. Stolan,~
Radiat. Res. 7, 462, Abstr. 147 (1957).
396. Brecher, G., E. P. Cronkite, J. H. Peers, J. Nat.
Canc. Inst. 14,159 (1953).
R' T' Bi*ammer' M. Sbeiderl397. FinertyJ J.
and A. P. Cunningham, J. Nat. Canc. Inst. 14, 149(1953).
398. Binhammer, R. T.,J. C. Finerty. M. Schneider,
A. W. P. Cunningham, Rad. Res. 6, 339-348(1957).
399. Makinodan, T., Proc. Soc. Exp. Biol. Med. 92,
174-179 (1956).
400. Urso, I., N. Gengozian, C. C. Congdon, Radiat.
Res. 7,457, Abstr. 135 (1957).
401. Van Bekkurn, D. W., Radiat. Res. 7, 458, Abstr.
137 (1957).
402. Lengerova, A., Cesk. Biol. (Praha) 7,230 (1958).
403. Brohult, A., Advarrces in Radiobiology, pp. 241247, Ed. by Hevesy. Forssberg and Abbatt, Oliverand Boyd, Edinburgh and London (1956).
404. Pillemer, L., Blum, L., Lipow, I. H.. Ross, 0. A..
Todd, E. W., and Wardlaw, A. C.. Science 120,279-285 ( 1954).
405. Strond, A. N., Brues. A. M., Summers, M. M.,
J. Nat. Canc. Inst. 15, 1109-1123 (1955).
406. Barnes, D. W. H., M. J. Corps. J. F. Loutit, F. E.
Neal. Brit. Med. J. 2, 626 (1956).
107. Cole, L. J., and A I . E. Ellis, Cancer Res. 14, 738744 ( 1954).

152~

Appendix

LIST O F SCIENTIFIC EXPERTS
The scientific experts who have taken part in the preparation of the report while attending Committee sessions
as members of national delegations are listed below. The Committee must also express its appreciation to the many
individual scientists not directly connected with national delegations whose voluntary co-operation and good willcontributed in no small measure to the preparation of the report.
ARGENTINA:
Dr. C. Nuiiez (Representative)
Dr. D. J . Beninson
Professor E. Favret
Dr. N. Nussis
Dr. J. A. Olarte
AUSTRALIA:
Dr. C. F. Eddy (Representative-first
Mr. D. J . Stevens (Representative)
Dr. A. R W. Wilson

Dr. A. Halawani (Representative)
Dr. H. T. Daw

session)BELGIUM:
Professor Z. Bacq (Representative)
Mr. R. Boulenger
Dr. M. Errera
Professor F. Twisselman
BRAZIL:
Professor C. Chagas (Repesetrtative)
Dr. B. Gross
Professor N. Libanio
Professor C. Pavan
Father F. X. Roser, S.J.
CANADA:
Dr. E. A, Watkinson (Representative)
Dr. R. K . Appleyard
Dr. P. M. Bird
Dr. W. E. Gnunmitt
Dr. Colin Hunter
Dr. G. H. Josie
Dr. C. A. Mawson
Dr. H. B. Newcombe
Dr. F. D. Sowby
CZECHOSLOVAKIA:
Professor F. Hertik (Representative)
Professor F. BEhounek
Dr. M. HaSek
Dr. L. Novik
Professor V. Sobek
Dr. I. Ulehla
Dr. V. Zelenf

Professor L. Bugnard (Representative)
Dr. A. Allisy
Dr. J. Coursaget
Dr. H. Jammet
Dr. J. Labeyrie
Dr. J. Lejeune

INDIA:
Dr. V. R. Khanolkar (Representative)
Dr. A. R. Gopal-Ayengar
Dr. A. S. Rao
JAPAN :

Dr. M. Tsuzuki (Representative)
Dr. Y. Hiyama
Dr. D. Moriwaki
Dr. K. Murati
Dr. M. Nakaidzumi
Mr. S. Ohta
Dr. N. Saito
Dr. E. Tajima
MEXICO:
Dr. M. Martinez Baez (Representative)
Dr. F. A. Andrade
Dr. H. Zalce

Professor R. M. Sievert (Representative)
Dr. B. A. A. Aler
Dr. R. G. Bjarnerstedt
Professor G. Bonnier
Professor T. 0. Caspersson
Professor C. A. T. Gustafsson
Dr. A. G. A. Nelson* Now in the United Arab Republic.

UNIONOF SOVIETSOCIALISTREPUBLICS:
Professor A. V. Lebedinsky (Representative)
Professor K. K. Aglintsev
Professor B. M. Isaev
Professor P. M. Kireev
Professor A. N. KraevsLy
Professor A. bZ. Kuzin

UNITEDKXNGDOM
OF GREATBRITAINAND
NORTHERNIRELAND
Professor W. V. Mayneord (Represetltativefirst session)
Dr. E. E. Pochin (Represelztative)
Dr. T. C . Carter
Mr. A. C. Chamberlain
Dr. W. G. Marley
Mr. N. G. Stewart

Dr. Shields Warren (Represe~rtative)
Professor G. W. Beadle
Dr. A. M. Brues
Professor J. Crow
Professor Th. Dobzhansky
Dr. C. L. Dunham
Mr. Merril Eisenbud
Professor Sterling Emerson
Professor G. Failla
Dr. J. H. Harley
Dr. J. S. Laughlin
Professor J. V. Nee1
Dr. M. Zelle