IONIZING RADIATION:
SOURCES AND BIOLOGICALEFFECTS
United Nations Scientific Committee
on the Effects of Atomic Radiation
1982 Report to the General Assembly, with annexes

UNITED NATIONSNew York, 1982

NOTE
The report of the Committee without its annexes appears as Official Records of the General Assembly, Thirtyseventh Session, Supplement No. 45 (A/37/45).
The designations employed and the presentation of material in this publication do not imply the expression of
any opinion whatsoever on the part oft he Secretariat of the United Nations concerning the legal status of any country,
territory. city or area, or of its authorities, or concerning the delimitation of its frontiers or boundaries.

UNITED NATIONS PUBLICATION
Sales No. E.82.IX.806300PANNEXJ

Non-stochastic effects of irradiation

CONTENTSParagraphs

Paragraphs

INTRODUCTION ....................... .

1·6

I. BASIC CONCEPTS OF RADIATIONEFFECTS ON CELLS AND TISSUES

7-57

A.
B.
C.
D.
E.

F.
G.

H.

I.

Characteristics of cell survival .....
Response to fractionated irradiation
Irradiation at low dose rate .....•..
Residual injury ................ .
Modifiers of radiation response ... .
Isoeffect formulae .............. .
Cell proliferation and its relationshi~ t? t~e. time of expression of
rad1at1on lllJUry .........•••..••.
Normal tissue kinetics: changes
after irradiation ................ .
Summary ............•.........

II. EFFECTS OF EXTERNAL IRRADIATION ON TISSUES OF EXPERIMENTAL ANIMALS .............. .

7-16
17-24
25-29
30-36
37
38-46

47-51
52-56
57

58-184Skin ......................... .
Gastrointestinal tract ........•...
Cartilage and bone ............. .
Heart ........................ .
Lung ......................... .
F. Liver ......................... .
G. Urinary system ................••
H. Central nervous system .......... .
I.
Endocrine organs ....•...........
J.
Gonads ....................... .
K. The eye ....................... .
L.
Haematopoietic tissues .•.........
M. Immune system ................ .
N. Summary ..................... .

61-79
80-95
96-101
102
103-112113-116
117-129130-140
141-147
148-160
161-168
169-182
183
184

III. EFFECTS OF IONIZING RADIATION ON MAN ................... .

185-242

A.
B.
C.
D.
E.

A.
B.
C.
D.
E.

Skin and mucosa ............... .
Gastrointestinal tract ........... .
Bone and cartilage .............. .
Heart ........................ .
Lung ......................... .

195-202203-207208·212213-214215-218

Liver .......•......•...........
Urinary system ..•.••.....•......
Central nen'ous system .....•..•..
Gonads .......••...............
The eye ....................... .
Haematopoietic system .......... .

219-220221-224225-229230-234
235-237
238-242

IV. EFFECTS OF RADIATION QUALITY .............................. .

243-300

F.
G.
H.
I.

J.
K.

A.
B.

C.
D.
E.
F.
G.
H.

Biophysical aspects ....•......•..
Basic differences in response to photons and high-LET irradiations ....
RBE as a function of neutron energy
Neutron fractionation .......•....
Neutron RBE for normal tissues .. .
Mixtures of neutrons and x rays .. .
Other types of high-LET radiation
Summary ..................... .

V. INTERNAL IRRADIATION BY RADIONUCLIDES ................... .

A.
B.
C.
D.

Dose relationships .............. .
Factors
influencing
biologicaleffects ........................ .
Effects on tissues ............... .
Summary ..................... .

VI. THE ROLE OF VASCULAR AND
LYMPHATIC DAMAGE ........... .

243-247248-257258-260261-263264-296297-298299
300
301-407303-313314-322323-404405-407408-481Morphological changes .•.....•..•
Functional changes ............. .
Endothelial cell sensitivity ....... .
Mechanisms underlying vasculardamage ....................... .
Collagen deposition . ............ .
Changes in lymphatics .......... .
Summary ..................... .

412-415416-449
450-461

VII. SUMMARY ....................... .

482-498

VIII. NEEDS FOR FUTURE RESEARCH

499-506

References ......•........................

Page
634

A.
B.
C.
D.
E.
F.
G.

462-466
467-473474-479480-481571

Introduction
I. The main purpose of this Annex is to review
damage to normal tissues caused by ionizing radiation.
Only the so-called "non-stochastic" effects are
considered, i.e .. those resulting from changes taking
place in large numbers of cells. In its publication 26 the
ICRP suggests that "non-stochastic effects arc those forwhich the severity of an effect varies with the dose andfor which a threshold may therefore occur" [11). In
contrast, "stochastic" effects arc those for which theprobability (rather than the severity) of an effectoccurring is a function of dose. In this Annex effects
such as the induction of cancer, hereditary defects,
tcratogencsis and life shortening arc specifically
excluded.
2. This Annex will therefore review radiation effects
on normal tissues, in animals and in man, in order todetermine the threshold dose levels for non-stochastic
effects. It should be pointed out immediately that thethreshold will depend entirely on the end-point
adopted and on the sensitivity of the measuring
technique. For example. functional changes in sometissues may only be detected after several tens of Gy,
whereas structural abnormalities may be detected after
much smaller doses by using an electron microscope.
The concept of threshold dose presents difficulties
throughout the discussion. Consideration is given toradiation quality, dose rate, fractionation and thevolume of tissue irradiated. In general, permanentrather than transient biochemical changes have beenemphasized.
3. Another important parameter is the time at which aradiation response occurs. In gut. microscopic changes
can easily be detected using histological techniques
after hours or a few days, in skin after a week and inliver the reaction may take months or years to develop.
These differences result in part from the different
cellular proliferation characteristics of the cells
involved. to which some attention is paid. However.
other basic factors (e.g .. genetic, hormonal, nervous) arecertainly involved in the time of onset of late radiation
injury.
4. The precise way in which ionizing radiation causes
cells to lose their reproductive integrity is not understood. There is, however, good evidence pointing to themost sensitive sites being in the region of the cell
nucleus rather than in the cytoplasm. A considerable
body of circumstantial evidence suggests that some partof the chromosome is the primary target [H6], especially
the DNA molecule [H64], but there is also evidence
implying that effects on membranes are involved in the
primary damage [A26]. The two possibilities are notmutually exclusive. However, detailed discussion of
fundamental radiobiology is beyond the scope of thisreport.
5. The topic of this Annex is extremely wide. By nomeans have all aspects been considered, but an attempt
is made to be interpretive rather than to simply compile
available data. The basic premise is that the nonstochastic response of a tissue depends on the level ofcell killing (which is in itself a stochastic process).
Therefore the first chapter is devoted to basic conceptsof cell survival, to the factors influencing tissue
response to fractionation or continuous irradiation andto the empirical formulae proposed to estimate thedoses producing the same level of injury under
different treatment schedules. The second chapter is a572

discussion of radiation effects on individual animal
tissues. The third is a review of data obtained onhumans, mostly derived from radiotherapy results but
including also a small number of radiation accident
reports. The effects of radiation quality are discussed inchapter IV with most emphasis on fast neutrons. A
review of the effects of radionuclidcs introduced into
the body is given in chapter V. Chapter VI is a brief
review of studies of radiation damage to the vascularsystem.
6. Experiments and clinical findings have resulted
from irradiations with photons of differing energies.
Sometimes these have been specified in the originalreports, but often they have not. Also, doses in earlyreports have been quoted in roentgen (R). However,differences in effects due to different photon energies
are considered to be negligible. Moreover, in view of
the uncertainties in estimating the dose in most of theearly work, it is reasonable to assume that 1 Gy is not
significantly different from 100 R.

I.
A.

BASIC CONCEPTS OF RADIATIONEFFECTS ON CELLS AND TISSUESCHARACTERISTICS OF CELL SURVIVAL

7. The relationship between the dose of radiation andthe reduction in cell surviving fraction is a cell survival
curve. Knowledge of survival curves is basic to anunderstanding of "non-stochastic" effects, and theirshape is an indication of how cells will respond to
many small dose fractions or to continuous exposures.
Cell survival is defined as the capacity of the cell toundergo sustained proliferation, a survivor being able
to produce a "clone" or a "colony". Cell survival may
be measured in vivo or in vitro.
8. The effects of radiation arc dependent on the stageof a cell in its mitotic cycle. Basically there is a specificperiod. designated S, during which DNA is synthesized(in proliferating cells). There is a period between
mitosis M and S, which is known as G 1 ; the interval
between S and the next mitosis is known as G2. Almost
the first observable effect of radiation on cells both invivo and in vitro is that they are temporarily prevented
from entering mitosis. This is often referred to as the G 2
block or mitotic delay [El]. For cells in vitro 10 Gy
seems to produce a delay of approximately one cell
cycle in duration. Dcnekamp [Dl] analysed both in situ
and in vitro results covering a wide range of cycle times
and found a similar result for cells in situ, namely, thatin general 10-15 Gy causes a delay of approximately I
cell cycle duration.
9. After irradiation, cell death for most cell types
occurs when the cell attempts to divide. Death does notalways occur at the first division. After low doses ofradiation cells may complete 1, 2 or even 3 divisions
before failing. In some cases, however, cells die in interphase, the most notable example being the lymphocyte.
Schematic examples of survival curves for mammaliancells irradiated with low-LET radiation are shown in
Figure I. No systematic differences have been demonstrated between such curves derived from animal orfrom human cells. For low-LET radiations, such as xrays, gamma rays or electrons, survival curves may becontinuously bending, i.e., effectiveness of the radiation

may increase with increasing dose, or they may become
exponential at large doses, with slope defined as - ~ •0

D 0 (the mean inactivation dose) is the dose required toreduce the surviving fraction by a factor of e on an
exponential curve.
10'

lQC

S (D) = e-kD

where S(D) is the surviving fraction after dose D, andk = l/00\,~
C

13. Various models for describing the shapes of cell
survival curves have been proposed [14, S33]. The
simplest is the single exponential model, fitted by

A population of cells may consist of 2 or more subpopulations, each following an exponential curve. In
this case..-Q/J7.!:u~where a, b. etc. are fractions of the total population.
This model describes a curve with a series of exponential slopes, the initial slope depending on the mostsensitive cells and their proportions [S76]. The multitarget single-hit model is described by
3

S (D) = 1 - (I - e-knD?

DOSE { arbi t.rary wii t~ )Figure I. Diagrammatic representation of a single- and split-dose cell
survival curve. The "shoulder" regionis characterized by the extrapolation
number n or the quasi-thresholddose Dq. D0 Is the dose to reduce
survival to 37°/o on the exponential
part of the curve. The parameters are
related by: iog 8 n
Dq/D 0where kn is the sensitivity of each of n targets, each ofwhich must be hit to kill a cell. This curve has zero
initial slope, a finding which is not supported by the
majority of recent data. A model incorporating a finite
initial slope is the modified multi-target single-hit
curve, is given by=

10. At lower doses the radiation is Jess effective andthere is a shoulder region. Exponential curves may be
extrapolated to determine n or Dq, as shown in Figure
I. The sizes of these parameters indicate the capacity of
the cells to accumulate sublethal damage [E2, Fl]. With
low-LET radiation and for cells in vitro n normallyvaries from 1 to 20 for the majority of cell types. Withhigh-LET radiation, (e.g., neutron or alpha particles) n
and Dq are both smaller, indicating less capacity foraccumulation of sublethal damage. Do is also generally
less for high-LET radiation. Sublethal damage cannormally be repaired in a few hours. This is of great
importance in interpreting dose fractionation and low
dose rate effects.
11. Survival curves have been measured for cells insitu as well as in vitro. The former has been achievedfor cells of bone marrow, small intestine, stomach,colon, testis, cartilage, skin. as well as for a range ofexperimental tumours. In general the values of n and
Dq are greater for tissues in vivo than for cells in vitro.
This is also true when D2-D1 is measured, where D1 andD2 are the single dose and dose in two fractions, respectively, to produce the same level of tissue damage. Since
D2-D1 is analogous to Dq from the cell survival curve,
this means that the cells in organized tissue have agreater capacity to recover from sublethal damage thancells in vitro.

12.

An example of evidence that the gross tissue
response reflects that of its constituent cells is obtained
from a comparison of the LDso in 4 days (gut damage[QI]) with cell survival by counting the number ofsurviving crypts [WI]. It was seen that for a variety ofdifferent types of treatment, different dose rate and
LET, the reduction in the proportion of surviving cells
resulting in 50% death of the mice was the same for all
treatments [Hl].

where ds/do = -k1 for D ..... 0. Thus the initial slope isgiven by -k1. The final slope of the curve is given by-k 0 • where ko = k1 + kn, This model describes a curvewith a finite initial slope, consistent with many experimental findings. A continuously bending survival
curve, which has often been adequately used to describe
survival curve data is:
S (D) = exp - (aD + ~0 2)
where a and ~ are constants. This model also has afinite initial slope but continues to bend. the rate of thechange in slope depending on the values of a and ~-14. It is possible to construct curves with almost any
shape, but is normally not possible to distinguish experimentally between the more realistic models. Nevertheless knowledge of cell survival characteristics at low
dose levels is extremely important in order to extrapolate data from single doses to many dose fractions or
to continuous irradiation.
15. Cell sensitivity to ionizing radiation depends on
the phase of the cell generation cycle. This phenomenon has been widely investigated, mainly in vitro. In
general, cells exhibit a bimodal response during the cell
cycle. in which a peak of resistance appears early in G 1
and another late in S. The greatest sensitivity occurs at
mitosis (and G2) and at the G1-S border. In cell lines
with a short G1 the peak in G1 may not be evident, but
the general features are the same [Sl]. The response of anormal synchronous cell population will thus reflect thedifferent responses of cells in different stages of sensitivity.
16. There are, however, variations from one cell line
to another [SI]. Cell cycle times vary from a few hours(e.g., intestinal mucosa) to many weeks or even months
in some tissues (e.g., lung or kidney). These very long573

cycle times arc due to extended G 1 periods, the otherphases differing less markedly from those in more
rapidly dividing tissues. With high-LET radiations, e.g.,fast neutrons, the nuctuation in sensitivity through thecell cycle is qualitatively similar to that for photons.
However, the extent of the nuctuations is much lesswith high-LET radiation [W2, MI].

8.

RESPONSE TO FRACTIONATED
lRRADIATION

17. When radiation is split into two or more dose
fractions the total dose required to produce a given
level of damage is altered. This is due to a number offactors [W3]: repair of sublethal damage: repair ofpotentially lethal damage; other slower repair
processes: repopulation of surviving cells: reassortmentof cells in their mitotic cycle: and reoxygenation of
hypoxic cells. These factors have been shown to occur
to a different extent in different tissues, so that theeffect of dose fractionation is tissue dependent.
1.

Repair of sublethal damage

J8. Cells are capable of absorbing energy which
results in sublethal damage and only with increasing
dose is this converted to lethal damage. Thus survival
curves may be exponential at large dose levels but.usually have a pronounced shoulder in the low dose
region. This region of relatively inefficient killing is dueto the accumulation of sublethal damage. Sublethal
injury may be repaired in a few hours and repair ismanifest by a return of the shoulder region (D2-D1 orDq) for the second treatment (Figure I [E2]). Thus,
repair of sublethal damage is the operational definitionof repair between two radiation doses. Accumulation ofand recovery from sublethal damage are smaller forcells in vitro than for the cells of many tissues in situ,
possibly owing to the greater intercellular contact
between cells in solid tissues. When cells have beengrown as multicell spheroids in which they are incontact through desmosome-like junctions, the capacityof those cells to accumulate and repair sublethal
damage is also markedly increased [D2]. The extent of
repair of sublethal damage is very large in some tissues,e.g., intestine. skin, lung but much less in others, e.g.,
the haemopoietic system. It may be measured as thedifference between the single dose or two fractions
which produce the same level of injury. i.e., D2-D1.
Values for some tissues arc given in Table 1.

19. As the number of fractions is increased and thedose per fraction decreased, the proportion of dose thatis effective in killing cells. relative to that which is usedin accumulating sublethal damage is decreased. Forvery small doses per fraction, only about one-third of
the dose is effective in some tissues. This means that inthese tissues, to produce the same reaction in an
extended fractionation regime as in a single treatment,
three times more dose must be given.
2.

Repair of potentially lethal damage

20. The technique by which cells are cultured after
irradiation will affect the radiation response. It is
possible to decrease radiation sensitivity by various
means, including delaying plating [P3, H5]. This type of574

repair has been called "repair of potentially lethal
damage" (PLD). It is operationally defined as therepair which takes place after irradiation. depending on
the environmental conditions and usually tested bystimulating cells into division. There is a tendency forcells to exhibit repair of PLD when they arc grown into
crowded conditions so that their number is no longer
increasing. They then develop the capability ofrepairing radiation damage before being called upon todivide. In general this causes an increase in 1)0 of thecell survival curve. The phenomenon has been shown tooccur in tumours [S2] but techniques arc not yet
avail;1ble for demonstrating repair of PLO in normal
tissues. There is, however, no reason why the phenomenon should not occur in normal tissues and it may
play an important role in determining tissue radiation
response. Repair of PLO is normally complete within a
few hours. Repair of chromatid aberrations in testes
and bone marrow has also been observed with a similar
time course [B40].
3.

Slow repair

21. Various types of slow repair have been identified.
Van den Brenk et al. [V2] and Reinhold and Buisman[R3] investigated the response of capillary endothelium
to irradiation. The technique used by both groups wasto stimulate cell proliferation in these otherwise slowly
dividing tissues at various times after treatment. By thismeans these authors observed a repair process with ahair-time of about one week, analogous to repair ofpotentially lethal damage, but taking much longer.
Curtis [Cl], using chromosome abnormalities as theend-point for damage to mouse liver, also observed avery slow removal of damage, manifest by a steadydisappearance of the abnormalities. This type of repair
may also be analogous to a slow repair of PLO,
although McKay et al. [M50] believe that there is no
repair of chromosome damage in liver of Chinese
hamsters. In mouse lung there appear to be two phasesof repair of sublethal damage as measured by anincreasing D2-D1 with time between two fractions, thesecond phase taking about 100 times longer than thefirst [FI 7]. This second phase of slow repair is thought
not to result from cellular proliferation [C31].
4.

Repopulation

22. Following irradiation cells undergo a period of
mitotic delay, after which there may be renewed proliferation. Tissue damage is repaired in this way, often
rendering radiation decreasingly effective as the periodof protraction of the dose is increased. It is known, atleast in some tissues (e.g., skin and intestine) that cellproliferation after irradiation is stimulated by homeostatic control in response to the presence of dying cells
or to products of cell lysis. Two techniques have beenused to estimate compensatory cell proliferation. Where
cell survival can be estimated by a clonal assay(intestine). the survival ratio with various intervals
between dose fractions can be measured. Where clonal
assays arc not available and only gross tissue response
can be assessed, rcpopulation is measured in terms of
the increase in D2-D1 as doses are separated beyond thetime during which sublethal damage is repaired.
However, it is difficult with these techniques to distinguish between repopulation and slow intracellular
repair processes. Long-term changes in proliferation
resulting from irradiation have been reviewed by Beer
[B78].

5.

Rcassortmcnt

23. Since, as described earlier. cell sens1t1v1ty varies
with the mitotic cycle. a dose of radiation will preferentially kill the sensitive cells, leaving mostly those in theresistant phases as survivors. After irradiation theremaining resistant cells are at first delayed and thenmove towards the more sensitive phase. Thus a second
dose will be more effective if given some time after the
first treatment than if given immediately afterwards.
This process is in competition with the repair processes,
all of which render the population less sensitive withtime after a first irradiation. In addition mitotic delay is
not constant for cells at all stages of the cell cycle andthe net effect of irradiation is to cause a temporary
accumulation of cells in the G2 phase. This process adds
to the partial synchrony of the population caused by
preferentially killing the sensitive cells. All theseprocesses combined cause a tissue to express a patternof sensitivity to a second treatment with peaks andtroughs. at times depending on the kinetics of thevarious phenomena. The effect of reassortment
becomes extremely complicated with many fractions orwith irradiation at low dose rates and cannot be
predicted with any certainty.

taken by Lajtha and Oliver [L 1] who assumed that
sub lethal damage would be repaired with a half time of
1.5 hours. If many small fractions are giYen, thesurvival curve becomes shallower and the extrapolation
number is reduced, as illustrated in Figure II. As thedose rate is reduced and treatment time protracted agreater proportion of the dose is innicted as sublethal
damage and is repaired. Ultimately a point is reachedwhere effectively all the sublethal damage is repaired
and there can be no further effect of decreasing thedose rate based on sublethal damage. The limiting slope
is shown by the upper solid line in Figure II. The
magnitude of this dose rate effect will depend on theinherent ability of the cells to repair sublethal damage.
This is a very large effect for many, but not allorganized tissues. In general the effect occurs between
dose rates of about 2 10-3 - I Gy min-1. Outside of these
rates there is little or no further effect attributable torecovery from sublethal damage.

z
0;:~10- 1

6.

Reoxygenation

24. It is well known that hypoxic cells are moreresistant to low-LET radiation than are well oxygenatedcells. The factor by which the dose must be increased to
produce the same level of damage in hypoxic ascompared to well oxygenated conditions is normally
2.5-3. Most experimental tumours and some normal
tissues have been shown to contain hypoxic cells, e.g.,mature cartilage. Radiation will sterilize selectively thewell oxygenated cells. It may also cause a reduction in
respiration and after removal of the dead cells andshrinkage of the tissue, all surviving cells will have agreater proximity to blood vessels. Therefore after
irradiation many of the surviving hypoxic cells become
better oxygenated. a process which has been termed
reoxygenation [T2]. This is extremely important fortumours. However, in most normal tissues, a majorityof cells are well oxygenated and if there is any reoxygenation these tissues will, in a protracted regime ofirradiation. respond as if all their cells were well oxygenated. It is therefore unlikely that hypoxia and reoxygenation are important mechanisms in most normal
tissues.
C.

IRRADIATION AT LOW DOSE RATE

25. It is clear from the above considerations that dose
rate is a very important parameter. This is especiallytrue for low-LET radiation. As the dose rate is reduced
and the time of irradiation is therefore extended, theoverall effectiveness is reduced. This is due to two
separate processes: (a) during the exposure there will
be repair of sublethal damage occurring; (b) if the dose
rate is low enough cellular repopulation can occur.
Both of these repair processes cause the radiation to beless effective. Changes in the distribution of cells along
their mitotic cycle may also be a contributing factor.
The subject has often been reviewed. e.g., by Rajewsky
et al. [R37] and by Hall [H6].
26. The effect of repair of sublethal damage on sensitivity may be dealt with by considering low dose rate asif it were many small fractions. This was the approach......,er

z
;;

;;
er

::,

If'_, 10- 2
_,
"'u

2

4

6

8

10

12

14

[•OSE CGYl

Figure II. Illustration of the dose rate
effect due (a) to repair of sublethal damage and (b) to cell proliferation [HS]27. In addition to repair of sublcthal damage. in
rapidly dividing tissues there may be an effect of proliferation during exposure if the dose rate is sufficiently
low and if exposure time is long compared with thenormal length of the cells' mitotic cycle. Cell death willthen be balanced by cell proliferation causing a further
reduction in biological effect as the dose rate is progressively reduced. There may also be a proliferative stimulation of cells not in the division cycle.
28. The dose rate at which the cell death rate cannot
be balanced by the birth rate is critical, since that is thedose rate above which the tissue will gradually bedestroyed. The critical dose rate is very tissue
dependent. For the rat intestine it is about 4 Gy per day[Q2]. The figure is high because of the high proliferative
capacity of the intestinal mucosa. For the bone marrow
the threshold is about 0.5-1 Gy per day for the erythropoietic system in mice and rats (81]. White cell andplatelet levels in rats are maintained at 0.5 Gy per day[L2] and a steady state of granulocyte precursors
develops. However, it was also shown in the rat that 0.5
Gy per day caused a reduction in the level of lymphoidcells in bone marrow, thymus. spleen and in the blood.
In mice, and particularly in the rabbit and guinea pig, it
was suggested that the threshold steady state dose waslower than 0.5 Gy per day (841]. Testis has a far greater
intrinsic sensitivity. Only if the dose rate is below a few
hundredth of Gy per day [B2] can rats and mice
maintain reproduction for 10 generations or more.
575

Obviously the repair potential for developing sperm
cells is extremely limited.
29. Little is known of the effects of low levels ofcontinuous irradiation on non-stochastic effects in
slowly proliferating tissues. It may be expected thatcritical dose rates will be much lower than for rapidly
proliferating tissues, which seem readily able tocompensate for the damage.

D.

RESIDUAL INJURY

30. The extrapolation from single doses to treatments
extending over years, i.e., over a significant proportionof the recipient's life time, is very difficult to make inthe present state of knowledge. Some information may
be obtained from the data on fractionation, but this is
not generally available for more than 30 fractions andfor treatment times longer than a few weeks. These data
do not answer the questions about long term recovery
potential which are related to the complete repair ofparenchymal cell damage through proliferation; to therole of slow repair in this capacity; to the presence andextent of irreparable damage, for example, to thevascular system, as mentioned in section I I.A. anddiscussed further in chapter VI.
31. Experiments in which a "priming" treatment (asingle dose or a series of doses) is followed some timelater by a test treatment can be of help in answeringsome of these questions. The priming treatment isnormally below tolerance and the "residual" damage ata given time is estimated by the response of the tissue toa further test treatment. The results of Denekamp [D3]and of Brown and Probert (83) in mice, show that by
about 6 months after the priming treatment the tissue
responsible for the early skin damage has almost totally
repaired and only about 10% of the priming dose is"remembered" [D5, FS]. This early reaction is the resultof killing of the basal epidermal cells, so clearly theirrepopulation can restore the tissue to near normal. The
same is true for the rapidly proliferating mucosa(
epithelium of the intestine. Human skin can also almost
fully recover, as assessed by early reactions [H7].
32. Brown and Probert [83] also investigated the endpoint of late deformity in the mouse foot. In theirexperiments 35-40% of the priming dose appears to be"remembered" if assayed for late foot deformity. It wassuggested that different components of the limb were
responsible for late reactions and that for these there
was less repair. The accuracy of the Ellis formula forpartial tolerance (see section I.F.) with time after
treatment was tested in the same set of experiments andfound to give a fairly close prediction of the resultsfrom 1 to 10 months after the priming treatment.
33. Hendry et al. [H8) investigated residual injury
using necrosis of the mouse tail as the end-point. The
results were consistent with those for early skin damage
in that the residual injury in the tail was 10% of the firsttreatment after 6 weeks. However, if a further"priming" treatment was given, the residual injury wasincreased to 35%, at which level it remained for
repeated "priming" treatments, each separated by 6
weeks [H9].
34. Thus it appears that rapidly proliferating systems
can almost fully repair a radiation injury, whereas
576

tissues responsible for late injury have a reduced repair
potential and would, therefore. be expected toaccumulate more damage during protracted irradiation.
The relationship, if any, between the early and late
reactions has been the subject of much debate and is
still not resolved [D5, 133, FS, F6, P4, D6, R35].
35. Residual injury has also been investigated after
neutron irradiation. Hendry et al. [H8], using necrosisof the mouse tail, observed that the residual injury was
greater after a treatment with neutrons than after x rays.
A similar set of experiments was performed on mousefoot skin by Field et al. [F7). In this case both the earlyand late reactions were assessed after test doses given 6
months after the priming irradiations. In general,
residual injury after neutron irradiation was greaterthan after x rays. Skin reaction increased withincreasing priming dose, but was not dependent onwhether this was x rays or neutrons. Residual injury,
manifest as late deformity after x ray priming doses,
was only slightly greater than for early reactions. but
the residual injury measured for the same end-point
after neutron priming doses was larger.
36. An interpretation of these observations is thatrecovery from tissue damage leading to late reactions is
at least partly due to slow repair and that this is absent
with neutrons and possibly other high-LET radiations.
Thus the RBE for late damage might be expected toincrease for protracted irradiations if there were lesslong-term recovery after neutrons than after photons.
Such an observation was made from a skin experimentin which the RBE measured for short overall treatment
times was compared with treatment over 6 months. The
RBE for the latter was about 30% higher [F9]. However,
it is not known whether or not this concept may havegeneral validity.

E.

MODIFIERS OF RADIATION RESPONSE

37. Perhaps the most important modifier of the
response to radiation is oxygen. Its absence protects
cells and tissues by a dose factor of 2.5-3 in comparison
with fully oxygenated cells and tissues. The fact thatsome normal tissues may be partially hypoxic andthereby protected to some extent has already been
discussed (section I. B.6). Drugs which are vasoconstrictors may also protect tissue by causing hypoxia.
Some drugs are radiation protectors, e.g., thesulphydryl compounds such as cysteamine, 2-fl-aminoethylthiouronium (AET) and the compound WR2721.
Other drugs are radiation sensitizers, e.g., many of theanti-cancer agents including the antibiotics, somealkylating agents, sulphydryl-binding agents andantimetabolites. The halogenated pyrimidines such as
BUdR and IUdR are also sensitizers. A rather specialgroup of drugs essentially sensitize only hypoxic cells.
The best known are the nitro-imidazoles and these may
be useful in connection with radiotherapy of cancer.
Heat also sensitizes to radiation with temperatures inexcess of 41 °C, and sensitizing factors of 3 or 4 havebeen reported. These factors will be important forpatients undergoing radiotherapy, although it seems
rather unlikely that the response of whole humanpopulations to irradiation would be significantly
affected by any of these modifying factors. Many ofthese factors are considered in detail in Annex L;
reviews are also to be found in [R50 and P59].

F.

ISOEFFECT FORMULAE

38. Data relating the total dose, number of fractions
and overall treatment time for a given degree of normal
tissue damage are all derived from radiotherapy results
or animal studies aimed at providing useful information for the radiotherapist. lsoeffect formulae to fit
these data have been suggested. Whether or not theseformulae are accurate over the therapy range oftreatment times and number of fractions is the subjectof much debate. It is even more dubious whether these
relationships may be extrapolated beyond the therapy
range, but they can certainly be useful in giving an
indication of the dose required to produce a given levelof damage in long protracted irradiations.
39. In 1918 [K2] the results of experiments on humanskin indicated that radiation was less effective if given
in many fractions. Regaud and Ferraux [R4] confirmed
this observation on skin and also indicated an
improved therapeutic ratio by fractionation. The
subject was further studied in the 1930s, [e.g., R5 andM2]; and it became standard radiotherapy practice totreat in many fractions. A classic paper appeared in
1944, by Strandqvist [S3]. He constructed isoeffectcurves for the cure of skin cancer and for various levelsof damage to skin, i.e.. erythema, dry desquamation,
moist desquamation and necrosis. The total required
dose was plotted against the overall treatment time,
both on logarithmic scale. The topic was further
considered by Cohen [C2] who also published data forskin damage and for tumours. Skin damage was takenfrom McComb and Quimby [M2] and Reisner [R5) for
erythema and from Paterson [P5], Jolles and Mitchell[Jl] and Ellis [E3] for tolerance.
40. It was initially thought that the number offractions was less important than the overall treatment
time. However, this view was changed in the 1960s as
the meaning of repair of sublethal damage became
clearer [FlO]. Ellis [E4], on the basis of Cohen's earlier
publication suggested separating the factors for overall
treatment time T (days) and number of fractions N
giving the empirical formula

For convenience in radiotherapy Orton and Ellis [01)introduced TDF (time dose factor) which is proportional to partial tolerance, but is independent ofspecific values of NSD.
TDFr = N (d IOO)l.538 (T/N)-0169 J0-3
where d is the dose per fraction in Gy.
42. An alternative generalization of the NSD formulais that of the Cumulative Radiation Effect (CRE) [K3]
whereT)-0.11
CREr = N
d N0.65(
where N is the number of fractions given and T is theoverall time for those fractions including the first andlast treatment days. CRE is applicable at less thantolerance, as is the case for TDF. Like NSD, CRE is
also based on human data. Differences between CRE
and TDF have been discussed by Turresson and Notter[T28].
43. Both CRE and TDF have been generalized forlow dose rate continuous irradiation, such as implantbrachytherapy [K48, 014]. Thus CREc = k' r ro.11
where r is the dose per day, T is the overall treatment
time in days, and k' is a normalizing constant between
CREr and CREc or TDFc = k" (r 100)1.35 T 10-3 thesymbols having the same meanings as for CREc.
44. Recently these models have been subjected to
critical testing both clinically and experimentally on pig
skin by Turesson and Notter [T28, T29. TIO]. Attention
was focussed on CRE. In the clinical study there wasgood agreement between CREr and acute skin reactions
for a variety of treatment schedules with different
fractionation and overall treatment times. The
agreement with late reactions was less good. The same
was true for the experimental study with significant
differences between prediction and observation withsmall numbers of large dose fractions. A modified CRE
formula was thus proposed [T28] where
CRE = L(d)(~)-o.ii

d N°· 65

total dose = (NSD) N0.24 T°·I I
where NSD is known as the nominal standard dose; its"units" are designated as the ret. The NSD is a"constant" referring to the maximum single dose whicha particular normal tissue can tolerate in radiotherapy.
It will depend, therefore, to some small degree on thejudgement of the physician. It is not consideredreasonable to extrapolate the Ellis NSD formula to lessthan N = 4 or T = 5 and it is questionable whether or
not the formula holds for very large values of N and T.
In addition, the exponents of N and T will vary, tosome extent, from tissue to tissue. The formula was,however, based on human data.
41. The main limitation of the concept of NSD is thatthe formula is applicable only at the level of normal
tissue "tolerance". Various modifications have been
made to make it possible to apply the formula to levels
of injury lower than tolerance. One of these is theconcept of "partial tolerance" (PT)PT = NSD N/NrnL
where NToL is the number of fractions to give fulltolerance and N is the number actually given. By thismeans PT becomes an additive quantity, unlike NSD.

where L(d) is a correction factor for reactions following
doses per fraction of size d. For early reactions L( d) = 1.
This is also the case for late reactions with d = 2 Gy.
Ford = 10 Gy, L(d) rises to 1.18. Turesson and Notter[T28] also compared the predictions of both CREc andTDFc for low dose rate continuous irradiation at two
dose rates (1.20 and 0.54 Gy h-1). It was observed thatthe normalization constant k was significantly different
from the proposed values and that the irradiation was
more damaging than implied by these formulae.
Turesson and Notter proposed revision in the values ofk' in CRE from 0.80 to 0.57 and in k" in TDF from 2.02
to 1.57. The modifications proposed to both TDF and
CRE require further experimentation.
45. The N factor is related to the number of dose
fractions, and is thought to be primarily influenced byrepair of sublethal damage. As this is usually complete
in a few hours it is theoretically possible to give several
fractions per day without changing the N factor.
Extensive repair of sublethal damage will normally beconsistent with a large N factor, i.e., a large sparing of
fractionation and vice versa. Techniques are not yet
available to determine repair of potentially lethal
damage in normal tissues in situ, but if it occurs, it also
will cause the N factor to be increased.

511

46. The T factor is more difficult to explain. In
rapidly proliferating tissues it is probably due tocellular repopulation, in which case a power function,such as T(l.11 is unlikely to be universally applicable. In
slowly proliferating tissues T may be due to "slowrepair" for which a power function would be more
appropriate. McKenzie [M75) attempted to derive theCRE formula from a cellular survival model withGompertzian repopulation. The agreement obtainedwith the N factor was good, but T could not be
explained by this model.

G.

CELL PROLIFERATION AND ITSRELATIONSHIP TO THE TIME OF
EXPRESSION OF RADIATION INJURY

47. Cell proliferation is important for two reasons.
Firstly. it is related to the time of death of cells in tissue
and thus to the time after irradiation when damage
becomes apparent. Secondly, it is a mechanism bywhich a tissue is restored to near-normal after irradiation. In addition, radiation can perturb the cell proliferation kinetics of a population, and as the cell kinetics
can influence the response of the cell population to any
further dose of radiation, these mutual interactions areof importance in the response of tissues to single doses
and fractionated irradiation. Changes may take place
many years after irradiation, such as cell death which
has been reported after treatment of the breast region of
female babies for haemangiomas [F44, K36).
48. Most adult normal tissues show no net growthunder normal circumstances but an exact balance ofcell production and cell loss. This may result from very
slow production and slow loss as in lung or kidney. orfrom more rapid production and loss as in mostepithelial tissues. The cell production is determined by
the cell cycle time (intermitotic time Tc) and thefraction of cells in the proliferation cycle (i.e., thegrowth fraction or GF). The cell loss may be by
migration (as occurs in the villus of the intestine) or bydifferentiation and death (as for blood cells formed in
the marrow).
49. In the last two decades, experimental techniques
have been developed to investigate the proliferation
rates of cell populations both in vitro and in vivo. These
include labelling studies with radioactive precursors ofDNA, based on the work of Howard and Pelc [HlO].
The cell cycle time and the growth kinetics of a wide
variety of tissues, both normal and malignant, havesince been studied, in undisturbed growth and also after
injury by various agents, including radiation. Becauseof the difficulties in measuring per cent labelled mitoses
curves in populations which are not in steady state of
growth, continuous labelling by repeated injections oftritiated thymidine (lHTdR) has also proved to be auseful technique [07, H63]. More recently techniques ofcytofluorometry have been introduced. In addition.
some tissues have been studied after radiation injury bycomparing the doses needed to inflict a given level of
injury if two dose fractions are separated by a varying
interval of time (Table 1).
50. In the response of any cell population to a dose ofradiation, there is initially a delay in the progress ofcells around the cell cycle (mitotic delay), which isdependent on the radiation dose administered, the stageof the cycle and the cell cycle time. The cells
578

accumulate in the premitotic G2 phase and are blockedfrom entry into mitosis for some time. The radiation
damage is then expressed in dividing cells as a loss of
their proliferative capacity. Most cells die at one of themitoses subsequent to the radiation-induced mitotic
delay. At high doses ( I0-20 Gy) cells die at the firstpost-irradiation division, but after smaller doses (i.e., afew Gy) many or most cells die at a second or thirddivision. There are a few exceptions to radiation deathoccurring at mitosis, e.g., lymphocytes and germ cells.
which can die during intcrphase without any attempt todivide. For most somatic cells, however, the expressionof radiation damage is delayed until mitosis isattempted. After 10 Gy this may occur within 12 hours
in the intestine, within 4-5 days in skin, and presumably not for many weeks in tissues with very long
turnover times such as liver, lung and kidney [01).
Since most tissues consist of a variety of cells withdifferent proliferation rates, the expression of radiation
damage is likely to occur at different times in the
different cell compartments and be further complicatedby various feedback processes.
51. Organ functions may be impaired either when the
majority of cells have died or else when a critical subpopulation has started to express its damage. For thisreason it has been suggested that radiation damage inmany organs may have a common pathway of
expression in the form of endothelial cell death.
Endothelial cells are generally thought to have a very
long turnover time of 2-4 months as measured bysimple tritiated thymidine uptake studies [T3]; however,it seems likely that this may result from a very small
proportion of the cells ( - 1%) cycling with a cell cycle
time of about 20 hours [H4, K4]. The role of vasculardamage will be discussed more extensively in chapter
VJ.

H.

NORMAL TISSUE KINETICS: CHANGES
AFfER IRRADIATION

52. In normal tissues there is a finely balanced
homeostatic mechanism, such that a significant drop incell numbers below the normal level is compensated byan increased rate of cell production. This increased
production may occur in different ways, e.g., from ashortening of the cell cycle time, as in the small
intestine and skin [07, L3, H 11), or by an extra divisionin the amplification process of cell production, as in thebone marrow or in the small intestine [L4, LS]. Recognition of cell depletion and compensatory proliferation
may take place in most normal tissues.
53. Accelerated proliferation in response to injury canbe very rapid when the injury results in immediate cell
destruction such as from mechanical trauma, incisionor burns caused by caustic chemicals. Shortly after suchinjuries to skin (within 6-48 hours) a wave of DNA
synthesis and cells in mitosis are observed near the siteof cell death.
54. The compensation appears to occur when cell
depletion has been recognized, and since the expressionof radiation damage is usually delayed until a subsequent mitosis, the compensatory proliferation afterradiation injury is also delayed. In skin, for example.
the proliferation kinetics do not alter for at least one
week after either a single dose or the beginning of acourse of repeated doses that will each kill a substantial

proportion of the cells [D3. D7, H 11, 08]. Thus a courseof radiation therapy, as usually administered over a
period of 4-7 weeks. will not induce proliferation until
the second and third weeks as more and more cell
depletion is recognized. More rapidly dividing tissues,
such as intestine, will respond earlier [WS, L6, C3] but
more slowly dividing tissues such as lung, liver. kidney,muscle, nervous tissue and vascular and connective
tissue, are not likely to commence compensatory proliferation in response to cell death until a long time after
irradiation [05]. This has recently been demonstrated inmouse bladder epithelium [S4].

55. The cell cycle time varies enormously in different
normal tissues. It is well known for several rapidly
dividing tissues but little detailed information isavailable for the very slowly dividing tissues [036].
56. The relationship between tissue kinetics andradiation response is of great importance. Recently
Michailowski [M70] has suggested a refinement to theaccepted concepts, on the basis that tissues fall into two
categories. i.e .. types H and F. In type H (hierarchical)
there exists a defined stem cell compartment, differentiating into histologically distinguishable functioning
cells. Radiation-induced tissue damage will result frominadequacy of the mature cell compartment which
depends on the life span of the functional cells. A
similar model has been the accepted view for many
years. In type F (flexible) all cells are thought to becapable of proliferation and specific tissue functions. In
these tissues radiation will lead to a dose-dependent
loss of functional cells through their mitotic death, both
following exposure and during the next phase ofcompensatory proliferation, resulting in accelerated
expression of the radiation damage ("avalanche").
Consequently the more severe damage following larger
doses of radiation is seen earlier than milder reactions
produced with smaller doses. Likely examples of type
H tissue include the epidermis and the intestinal
epithelium. Type F tissues would include the dermis.
endothelium. liver parenchyma. Late reactions in type
F tissues can therefore never be totally excluded andmay be precipitated by some unrelated trauma, such as
infection or mechanical injury. Similar phenomena are
well known in radiotherapy.

I.

SUMMARY

57. Radiation-induced tissue injury of a "nonstochastic" nature is likely to have its origin in the sterilization of a large proportion of the critical cells of thattissue, although these cells may be a small proportion of
the total cells. The consequent injury results from thenatural loss of post-mitotic cells which are not replacedor loss of cells which are stimulated into division. The
characteristics of cell survival are of great importancein this context, particularly at low doses, in gaining an
understanding of the response of tissues to fractionatedor continuous irradiation. Various processes of repair
and repopulation will increase the threshold level ofdose when irradiation is given over a long period orwhen a second period of irradiation is encounteredsome time after an earlier exposure. Attempts to express
these parameters have been made in terms of iso-effectformulae. The timing of tissue injury depends on thecells' natural proliferation characteristics and also on
kinetic changes characteristic of the tissue which result
from the irradiation itself.

II. EFFECTS OF EXTERNAL IRRADIATIONON TISSUES OF EXPERIMENT AL ANIMALS
58. Animal tissues often closely resemble those in man
and respond to irradiation in a similar way. It istherefore of value to consider data on animals. These
have frequently been irradiated with a wide range ofdoses, both in single treatments and in many different
fractionated regimes. From examination of the nonstochastic response of different animal species, cautious
extrapolation to man seems justified and at least will
increase confidence in the extrapolation of data directly
derived from the human [Fll].
59. It was recognized long ago that most cells diefrom radiation damage only when they attempt todivide. The rate of proliferation is therefore an
important determinant of the timing of response toirradiation. Rapidly proliferating tissues exhibit early
responses to irradiation and also reach a peak of injury
sooner than the more slowly proliferating tissues.
Rapidly proliferating tissues are also capable of considerable repair of damage due to cellular repopulation.
which may be important during fractionation or lowdose-rate irradiation. This is in contrast to slowly
proliferating tissues which are less able to repair
damage during irradiation through repopulation.
60.
The tolerance of normal tissues to irradiation isorgan specific. It also varies with the volume which isirradiated, bigger effects occurring in bigger volumes.
Experiments on some organs are limited to specificregions as in grid therapy [B52), but there is little information available on this topic.
A.

SKIN

61. The earliest evidence of the damaging effects ofionizing radiation on tissues came from skin reactions
observed after radiotherapy [SS. M3]. The accessibilityof the skin for observation has subsequently resulted inits being the most studied and documented normal
tissue regarding its response to radiation. Several
important principles may be illustrated by reference toresults of skin damage.
62. After irradiation of the skin there are a variety ofobservable changes [Rl]. There may be several waves oferythema leading to dry desquamation and depilation.
Healing may still occur. For larger doses there may bemoist desquamation and permanent pigmentation.
Blood vessel and connective tissue damage can lead toulceration and necrosis with no epithelialization
possible. Repair from moderate doses often takes placefrom the wound edges and therefore large irradiatedareas produce greater reactions and are slower to heal.
Damaged tissue may be replaced by fibrosis in man, pig
and goat, but not normally in the skin of rodents.
63. The relationship between kinetic parameters andradiation response can readily be demonstrated in skin.
Mouse skin has a cell cycle of 4-5 days for most of thecells of the basal layer and a transit time of 10-15 days
through the superficial 2-3 layers of differentiating cells[H 11 ]. Mitotic activity in mouse skin is totally depressed
2-4 days after 5 Gy (K45]. Desquamation occurs after
20-30 Gy for moderately large areas. at 15-20 days, inagreement with the transit time through the differentiating layers [Hl 1, Fl 1, F12]. Skin which has heen
stimulated before irradiation, e.g., by plucking,develops a reaction earlier, and skin with more super579

ficial layers (pig or man) reacts later. Large doses cause
considerable mitotic delay, followed by extensive cell
death in the basal layer, hut the rate of progression ofcells into the more superficial layers is unchanged, atleast for several days [E6]. Eventually the lack of cell
production results in significant lack of basal layer cells
and this may be the signal for more rapid compensatory
proliferation [Ft l]. The proliferative response is thus
delayed by 1-2 weeks after single large doses or about
20 Gy or after starting multiple small doses of a few Gy.
After surgical or mechanical wounding, however, a
deficit is recognized immediately and proliferation isfaster within 24 hours (R48, Fl 1].
64. The level of cell depletion affects the rate ofcompensatory proliferation and in skin the cell cycle
time can shorten from its normal value of 4-5 days,
down to 2 days after moderate damage, or to 18-24
hours after severe depletion [W4. D7, D8]. This delayedcompensatory response is unusual. The only other formof injury producing a delayed response is that of a deep
thermal burn involving the dermis [W9]. After the initiallag, compensatory proliferation will commence during
a course of daily radiation fractions and presumably
continuous irradiation and in mice can be sufficiently
effective to heal the radiation-induced desquamationeven though daily irradiation at over 10 Gy per week iscontinuing [F13]. Mucosa! or epithelial healing is also
sometimes observed during prolonged clinical radiotherapy.
1.

15-30 DAYSg;: M,.,•<u"' 2·0"'"',.,, 1·5
'"'
Vl

.

;;'!

w

>

l·O
0·5

:;o
Figure Ill. Dose-effect curves for pig skin Irradiated with x rays, obtained from the averagereaction between 15 and 30 days after Irradiation. A score of approximately 0.5 Indicates
the threshold erythema. The number of fractions given and overall treatment time are Indicated In the figure [F1)ation, peaking at about 20 days and healing, according
to the dose, by 30-50 days. Rat feet show a distinct
wave of damage, at higher dose levels, which is not seenin mice. The feet of both rats and mice and the ears ofmice ultimately become deformed after large doses andthe deformity is permanent. In rodents the minimum
single dose to produce a visible reaction is at least 10
Gy.

Single doses

65.

Skin damage has been assessed in animals by
estimating the early or late changes on arbitrary scoringscales or by measuring the survival of individual cells inthe basal layer of the epidermis. Pig skin has been usedin radiobiological studies by several groups. It has
many features in common with man, i.e. colour, thepresence of relatively few hair follicles, sweat glands
and a layer of subcutaneous fat. The gross response of
pig skin qualitatively resembles that of man. The
quantitative study of pig skin was pioneered by Fowler
and his colleagues [Ft OJ. They irradiated a number ofrectangular fields on the nank. The very early erythema
was not scored but the next two waves of erythema anddesquamation were. Long-term damage was assessed by
the degree of induration, which is taken as a measure offibrosis, but more recent studies have improved on thislate end-point (84, WlO]. To establish dose-effectrelationships average reactions were taken over various
time periods and these values related to the dose. An
example is shown in Figure III. The smallest single
dose found to produce an observable effect was about
10 Gy.

66. Non-uniform exposures of pig skin have beenreviewed by Wells et al. [W38] and Osanov et al. [013).
It was not possible to produce visible damage with 0.7
MeV beta rays to fields less than J0-2 cm2 with doses up
to 100 Gy, due to sparing by repopulation of hairfollicle cells. With increasing energies of beta rays lessdose was required to produce visible damage. The basal
layer was clearly seen as being the critical cellcomponent. Thus a 1 cm2 field of 15 Gy to the basal
layer was approximately the minimum dose which
produced a visible injury.
67. Rodent skin reactions have been assessed byseveral workers, e.g., [F2, Fl2, 85, L7]. In mice, feetshow a wave of damage starting at 7 days after irradi580

PIG 2154

68. Both in animals and in humans the correlation
between early and late radiation reactions is a matter ofcontroversy. The early reactions of erythema anddesquamation are due primarily to damage to the basal
layer of the epithelium whilst late· damage is more
complex, probably involving damage to endothelial
cells and increased blood vessel permeability. However,
little is known for certain about the processes leading tolater damage. A good correlation between early andlate damage has been seen by some authors [F5, F6,
D6], but others have observed late injury developing
many years after irradiation without corresponding
early reaction [WlO, A2]. More recently [F7], mice feetwere irradiated with graded doses of x rays (or fastneutrons) given once per week for 25 weeks. The
threshold for production of an erythema was 3 Gy per
week, but even after 10 Gy per week for 25 weeks thereaction faded when irradiation ceased. No latedamage was observed with 10 Gy per week to a total
dose of 250 Gy. The result was similar with neutrons up
to 12.5 Gy.
69. A method for estimating survival curves for mouseskin cells was developed by Withers [W4]. The
technique used was to isolate a defined area by heavily
irradiating a moat around it. The small test areas werethen given a series of graded test doses and the dose
which allowed one or more nodules to grow in the testarea was determined. A nodule was assumed to havegrown from a single cell. The usable dose range was
extended by varying the test area but practical considerations limited the applicable dose range to between 8
and 25 Gy. The survival curve obtained had D 0 = 1.35
Gy, similar to many values obtained in vitro. From split
dose experiments the D2-D1 was about 3.5 Gy, and theextrapolation number n was found to be about 12.
Similar experiments by Emery et al. [E7] gave a value of
D2-D1 of 5.7 Gy but a similar value of D0 to that foundby Withers [Wt I]. By comparing the survival curves

with the dose effect curves for skin reaction it can befound that 15 Gy leaves only one cell per mm2 surviving
and produces a very mild skin reaction indeed. After a
few days the skin cell doubling time is reduced to about
22-36 hours [E7, WI 1]. Presumably this rapid repopulation is sufficient to prevent a severe reaction
following this degree of cell killing.
70. If a sufficient area of skin is irradiated, death of
the animal can result. LDso values. calculated at 30 days
for this end-point have been measured in rats. Values in
the range of 44-50 Gy for external irradiation with gosr
beta rays, and 17-30 Gy for x rays have been quoted[A38, A39. S36].

2.

fraction and possibly not until the dose per fraction iszero. However, it is extremely difficult to resolve thesituation at doses less than 2-4 Gy, although this is theimportant region for extrapolation to many small
fractions.
73. An alternative approach which may be made fromsimilar experiments is to derive the ratio of the initial tolinal slope of the survival curve, in order to make theextrapolation from a single dose to an inlinite numberof fractions, excluding the effects of repopulation. The
initial slope determines the effect of giving an inlinitc
number of fractions. The method of analysis is given by
Field et al. [Fl3] who derived a slope ratio of 1 :5 or 1 :6
[F13, Fl 5). This value may be compared with I :3 from
Dutreix et al. [D9].

Fractionation effects

71. When the dose to the skin is fractionated, moreradiation is required to produce a given level of injury.
Fractionation experiments have been performed byvarying the number of fractions, but keeping the overall
treatment time constant to determine the N factor; orby keeping the number of fractions constant todetermine T (see section I.F.).
72. Experiments to determine N have been based on
an experimental design of Dutreix et al. [09). Theseauthors aimed at estimating repair between small doses.
If a single dose D 1 is split into two fractions at total
dose 02 to give the same effect, then D2-D1 is the
additional dose required by splitting the treatment. as
discussed earlier. If each of N fractions is split into two
fractions to a total dose D2N given in the same overall
time as DN in N fractions, then the additional dose per
fraction is given by
D2N - DN
Dr=----N

The experiments of Dutreix et al. (09] indicated that Dr
became zero when the dose per fraction was 3 Gy or
less. This means that fractionating to doses smaller than
3 Gy resulted in no further sparing effect. These results,
however, were subject to considerable statistical uncertainty. Results of some similar animal experiments[FI 5] are summarized in Figure IV. It is seen that D1
becomes small, but does not approach zero at 3 Gy per

74. Douglas and Fowler [Dl0] extended mouse skinexperiments to 64 fractions. All treatments were given
in a total time of 8 days with the advantage that repopulation could be considered negligible during this period[D8]. Their techniques also avoided the use ofanaesthesia. The results indicated that there wasadditional recovery down to the smallest doses given(Ds "" 1.9 Gy) in agreement with Field et al. [F13] but
contradicting Dutreix et al. [09]. From the results
Douglas and Fowler [010] derived a slope ratio of
I :5.5. They also favoured a survival curve with the form

S = exp - (aD + ~0 2)
75. Denekamp and Harris [Dll] measured the slope
ratio in a different way. They gave mice feet a series ofdaily small "priming" doses of 1.5, 2.5 and 3.5 Gy,
respectively, and measured the size of a single large test
dose required to produce a given reaction. The results
were subject to a moderate degree of scatter, but mostof the derived values were in the range of 1: 4 to 1: 7.
The results were found to be inconsistent with themulti-target single-hit curve. which was also theconclusion of Field et al. [F13]. The results of such
experiments may also be compared with the Ellis
formula. The value derived for N between 4 and 30
fractions varied between 0.24 and 0.33 [F13, 012] but
there are indications that the curve relating log total
dose to log number of fractions becomes flatter above
30 fractions [010].
76. The T factor in a rapidly proliferating tissue, suchas the skin, is primarily due to cellular repopulation
between fractions. Vascular autoradiographic studies
have been made of the proliferation of irradiated areasof skin and mucosa. The results generally showed areduction in cycle time both in the irradiated zone andin the border region. indicating healing [H 11, 013, 86,
Yl]. After a long time (up to 1 year) the skin appeared
thinner and the cycle time was slightly elongated [Yl.

3

L8].
>,

!::.
0

. 2

2

4

6

8

10

12

14

0$ (Gy)Figure IV. A plot of the additional dose
per fraction, D,, against the dose per fraction, 0 1 , tor various tissues [F15]77. An alternative method of measuring proliferation
after irradiation is by estimating D2-D1, D2 being thedose given in two fractions and D1 the equivalent single
dose. When two treatments are separated by up to 1 day
the change in D2 is primarily due to suhlethal damage.
Beyond 1 day an extra dose is required to counteract
repopulation. Since the D 0 value for the skin epidermal
cells is known to be approximately 1.35 Gy (W4, E7],
D2-D1 may be interpreted in terms of doubling time.
Various estimates of the doubling times in skin havebeen obtained in this way (Table 2). Several authors
have estimated a value equivalent to 0.3 Gy/day (D3,
FlO, C4]. This value corresponds to a doubling time of581

about J-4 days in experiments covering a wide range ofdose per fraction and intervals between doses from 1 to
5 weeks. Higher dose increments and therefore shorter
doubling times have been estimated by Comas [CS] andby Fowler et al. [F16). Both Withers [W4] and Emery et
al. [E7] used the Withers cloning technique to estimate
the repopulation rate. However, this type of experimentrequires the hair to be plucked before irradiation, which
may initiate a slightly faster rate of proliferation. The
doubling limes estimated in this way were 1-J days.
From human skin, Dutreix et al. [D14] estimated a cell
doubling time of 1-1.5 days from the rate of growth
into irradiated areas.

suddenly lose weight and die. The probable cause ofdeath is dehydration. Round-cell inflammatory infiltration in the submucosa and muscularis are possibly
contributing factors [Pt]. Mice which do not die appear
to recover totally by repopulation of the basal layer.
After 4 weeks surviving animals appear normal. The
syndrome in mouse may be similar to the acuteoesophagitis seen in patients during thoracic irradiation. However, late effects occur in patients, such as
telangiectasia and fibrosis, which arc only observed inanimals after high doses, i.e., greater than 30 Gy in asingle treatment, which is well beyond the LDso for
pulmonary damage.

78. Repopulation during and after multifraction
experiments has been measured using a radiobiological[D8) and a labelling technique [07] in order to estimate
the extent and timing of stimulated repopulation after
irradiation. Daily fractions of 3 Gy of x rays were given
on 4, 9 or 14 occasions. After 4 fractions there seemed
to be little proliferation as judged from the skinreaction experiments and the labelling studies indicatedan extended period of division delay, lasting for
approximately 5 days after the last fraction. There wasa small reduction in doubling time after 9 days but after
14 days proliferation was very rapid with a doublingtime of less than 1 day. This more rapid proliferation
returned to normal in the second week after the end of
the fractionated treatment.

81. The LDso endpoint for damage to the oesophagus
was developed by Phillips and Margolis [P2]. It was
found that in anaesthetized mice the oesophagus isprotected from radiation by hypoxia [Pt, H2]. Whether
or not the oesophagus of man is radiobiologically
hypoxic is not known. In fractionated or low dose rateirradiation the tissue would, in any case. be expected toreoxygenate, so the oxygenated values of LDso will be
more applicable.

79. In conclusion, skin has an enormous capacity torepair radiation damage so that very large doses mustbe given. if the treatment is in many fractions, in orderto produce erythema threshold changes (Table 3).
However, microscopic changes in the finger ridges ofmonkeys have been observed with fractionated doses ofabout 10 Gy [G32]. The two main types of repair are
recovery from sublethal damage and repopulation. The
former is characterized by the N factor in the Ellis
formula, which is in the region of N0.3. Alternatively it
may be described by the slope ratio, which on average
is about 1 :5. Thus on the basis of repair of sublethal
damage alone the single dose may be increased by 5times if given over a very long period. The other repair
process is repopulation of surviving cells. When injury
is manifest, proliferation increases until the populationis restored to normal or near normal. Observations on
mice and on radiotherapy patients substantiate this
view.
B.

GASTROINTESTINAL TRACTI.

Oesophagus

80. The histological changes observed in irradiatedoesophagus are similar in the mouse and rat [Pl, J2,
K5]. More than 20 Gy in a single treatment produce
mitotic death of the cells in the basal layer of theoesophageal epithelium. This is first seen at about J
days after irradiation using a dose which kills about
20% of mice by 8 days. Homsey and Field [H2]observed that this dose caused almost complete loss ofthe basal layer. Between one and two weeks after irradi·
ation the pattern is more mixed with recovery occurring
by repopulation in competition with further
denudation. If the degree of damage to the basal layer
is sufficiently severe the keratinized layers will not be
replaced as they are lost, the underlying tissues will be
exposed and radiation ulcers will result. Death occurs
usually between the second and third weeks. After areduction in food intake, animals become inactive, they582

82. The results of Phillips and Ross [Pl] and of
Homsey and Field [H2] on 3 mouse strains are in good
agreement regarding the LDso, as single dose values areclose to 30 Gy. If the single doses are corrected for
hypoxia. 20 Gy may be appropriate for the fully oxygenated oesophagus. An LDso of 20 Gy has beenmeasured for rats after irradiation of the thorax only,
animals dying between 16 and 30 days [Al9].
83. The repair capacity of the oesophageal epithelium
is very large, values of D2-D1 between 5.5 and 8.5 Gy
having been reported [H2, Pl]. These values might beeven larger if the single doses were not affected byhypoxia. The slope of the isoeffect curve is about 0.4. It
incorporates both N and T in this case as the available
data do not allow separation of the factors. Proliferation of the basal cells is rapid with a cycle time ofabout two days [L9]. However, Phillips and Ross
showed a very small effect of increasing the temporalseparation of two doses of x rays, for which there is no
obvious explanation.
84. Jn summary, the reaction of the oesophagus isunlikely to be a limiting factor with thoracic irradiation, either for single or fractionated treatments.
Oesophageal cells have a considerable ability to recoverfrom sublethal damage and the cellular proliferation ishigh so that the tissue is able to withstand high levels of
single and fractionated irradiations. Animals without
signs of oesophageal reaction may die later from
pulmonary damage.
2.

Abdominal organs

85. Total body acute exposure of 10 Gy or more
results in the gastrointestinal syndrome with deathoccurring between 3 and 10 days later, depending on
species [M74). The characteristic symptoms are nausea,
vomiting and diarrhoea, leading to dehydration,
electrolyte imbalance, loss of weight and infection.
These symptoms are attributable to the depopulation of
the intestinal epithelial lining. Loss of the cells in thecrypts of Lieberkiihn will lead to denudation of the villi
owing to lack of replacement when the cells arenaturally worn off. A close relationship between cell
survival and the probability of death has been
established by Homsey [H 1J who found that therelationship was unaffected by either dose rate orradiation quality. A detailed review of gastrointestinal
response to irradiation is given by Maisin et al. [M43].
86. Any whole-body radiation dose large enough tocause death from gastrointestinal syndrome is larger
than that required to cause death at a later time fromdamage to the hacmopoietic system [H3, 87). TypicalLDso values at 5-8 days for six species range from 8 to
15 Gy [B7]. If the intestine is irradiated in isolation. thedoses must be increased and the animals survive longer.
If less than the whole intestine is irradiated the LDso isfurther increased. Values of 13.2, 18.6 and 17 .7 Gy wereobtained in rats for treatment of the whole abdomen,
front region or back region only [ZSJ. It has been foundthat the small intestine is the most sensitive part of thegastrointestinal tract [87). Apart from lethality studies,
there have been experiments using absorption changes,
protein and fluid loss. electrolyte balance and changes
in the incorporation of DNA precursors [877. G42,
M74, S72, T25, V19].
87. Withers and Elkind [Wt, WSJ developed two
methods of estimating cell survival in irradiated small
intestine by scoring either macrocolonies (visible to thenaked eye) or microcolonies (visible in histologicalsections). From these studies a D 0 of 1.3 Gy and D2-D1
of 4-5 Gy were derived. The value of Do is similar tothat from many other cells and tissues. The value of D2D1 is similar to that derived from LDso experiments andis also similar to values from other organized tissues(see Table 1). The large value of D2-D1 obtained
indicates that the intestine has a very large capacity foraccumulation and repair of sublethal damage. Withers[W12] presented results from which a slope ratio forjejuna( crypt cells of about 3 may be derived.
88. Vatistas and Homsey [V3] measured dose-effectrelationships for the leakage of molecules of plasma
protein size into the intestine. Radioactive PVP wasused and the activity in the faeces was measured. Doses
greater than 2 Gy of x rays produced increased leakage.
The effect is not due to damage to the intestinal
epithelium but to increased blood vessel permeability.
89. A recent quantitative method of assessing changes
in the gut due to irradiation is the measurement of theabsorptive surface [MS]. This is done from histologicalpreparations. A minimum value is seen at about 3 days
after irradiation and the technique can detect single
doses of 3 Gy or greater.
90. With fractionated or low dose rate treatments the
major repair component in the intestine is compensatory cellular proliferation. The natural cell cycle timein intestine is short, and it has a very high capacity for
rapid proliferation. For example, the cycle time may be
shortened to about 7 hours [L3].

produces an initial depopulation of the crypt cells, after
which a new equilibrium develops. The cell number
remains constant but their rate of proliferation is muchincreased. The animals appear to withstand this daily
dose.
93. Maisin et al. [M6) studied the response of mice
given 2 Gy daily to the abdomen. The animals survived
this treatment up to the maximum total dose given,
which was 60 Gy in 6 weeks. Compensation took theform of a reduced cell cycle time and an increase in thesize of the stem cell compartment. The villi were.
however, reduced to about 70% of normal and thenumber of cells per villus to about 60% of normal. The
animals could not tolerate 3.5 Gy given daily.
94. In contrast to small intestine, far less is known
about the responses of stomach or large bowel to irradiation. Changes in the characteristics of gastric emptying
have been detected with single doses as small as 0.5 Gy[T27], but these changes are transient. Absorptionchanges [015] and effects on gastric acid and bioelectric
potentials were noted above 1.3 Gy [V20]. Gastricmucosa has typical survival curve characteristics (C32].
New methods to assess large bowel response are justbecoming available [I-165).
95. In conclusion, it is clear that the gut can withstandvery large daily doses of radiation. All the studies
mentioned have concentrated on the early forms ofradiation injury but other major problems may arise
later and very little information exists on late damage
to the intestine. Quantitation of fibrosis and of changes
in bowel habits are being attempted in several laboratories but no dose-response curves have yet been
published.
C.

CARTILAGE AND BONE

96. A growing long bone consists of an ossified shaft.
the diaphysis, having metaphyses with an epiphysial
growth cartilage at each end. The effect of irradiation isto reduce the growth potential, by sterilizing the stem
cells in the epiphyses. The result is that the bone
becomes permanently stunted. The phenomenon istherefore especially important in the young where
growth is most active.
97. Kember [K6] developed a technique for estimatingcell survival parameters for cells of growing cartilage inthe tibia of young rats. He derived a D 0 value of 1.65
Gy and an extrapolation number of 6 [K 1]. Although
the technique did not allow very precise measurements.
these values of Do and n were similar to those obtainedfor other types of cell.

91. Sato et al. [S32) observed numbers of cells in
crypts and villi of mice where the trunks only hadreceived 10 Gy x rays. The results confirmed the highdegree of compensatory feedback and proliferation in
the crypts. The timing of onset of this compensation
varies with normal cell cycle time and tissue structure,
being fastest in the jejunum and somewhat slower instomach and colon (for a review see [DI)).

98. Stunting of growth of bones has been investigatedby various workers. Early measurements by Bisgard
and Hunt (88] indicated that in rabbits more than 3 Gy
was required to cause measurable stunting. In a reviewof the older literature, Wells [W14) quoted values
between 1 and 5 Gy for the threshold doses to cause
stunting in various animals. In his own experiments on
mouse tibia, Wells [Wl4) found a threshold of about 2
Gy and a 10% reduction caused by 4 Gy. On average
1o/o stunting was caused by 0.33 Gy.

92. The potential for compensatory proliferation
makes the intestine relatively unresponsive tofractionated or low dose rate treatments. Studies on rats
[Q2, UO, W13} indicate that irradiation at 4 Gy per day

99. Dixon [DIS] performed similar experiments on thetails of 7-day old rats. The technique used allowed very
accurate results and no threshold was observed. In
these experiments 1% stunting was caused by approxi583

mately 0.2 Gy. By varying the oxygen concentration
breathed by the rats, Dixon [DIS] concluded that theepiphyseal stem cells were uniformly slightly hypoxic:
the sensitivity was increased by about I 0% when pureoxygen was breathed.

the alveoli together with desquamative and consolidative changes and cellular inliltration. The walls of thealveoli become thickened. Late changes include further
thickening of the reticulum and condensation resulting
in atclcctasis, librosis and loss of respiratory function.

100. The effects of dose fractionation were examinedby Dixon [D5] on rats. Considerable dose sparing due
to recovery from sublethal damage was observed. D2D1 increased with increasing dose to a maximum valueof about 4 Gy. Kember [Kl] using the clonal assay,
obtained a value for D2-D1 of 3.5 Gy. These values are
similar to those found with other tissues (Table 1).

105. The epithelium of the air passages. the hyaline
cartilage and muscle appear to be relatively resistantand are not considered to be limiting components in theradiation response of the respiratory organs. However,other factors which tend to complicate the pathologic
picture are: obstruction to air passages; infections andinflammatory
reactions;capillary
permeabilitychanges: and haematologic changes.

101. In summary. growing cartilage appears to be oneof the more sensitive tissues. The threshold dose forcausing permanent stunting of bone growth is small or
perhaps non-existent. The rate of stunting per Gy ingrowing rodents may be 3-5%.
D.

HEART

102. The response of the heart to ionizing radiation
has been the subject of few investigations, but there islittle doubt of its radiation resistance. After moderate
doses only histological techniques have revealedchanges. Kurohara and Casarett [K5] noted degenerative changes in the rat myocardium after 24 Gy in asingle treatment. At 28 days there was a loss of striationand granularity in the cytoplasm of myocardial cells.
Fajardo and Steward [F35] showed identical pathology
in rabbit and man: 20 Gy caused death of 4% of rabbits
between 70 and 150 days after irradiation from injury
to the pericardium or myocardium and often withcongestive heart failure. The histological results
indicate that the primary damage is to the capillary
endothelium often leading to loss of capillary function.
Insufficient microcirculation leads to fibrosis.
E.

LUNG

103. The lung is a highly differentiated and complex
tissue in which the capacity for cellular proliferationand hence restoration of the normal structure is poor.
Therefore this tissue cannot easily restore function afterlarge parenchymal losses. On the other hand, the respiratory system has a large reserve capacity which cancompensate for losses in functioning parenchyma sothat even after loss of an entire lung the other is usuallyadequate for respiratory requirements. It may thus beexpected that pulmonary function is an insensitive
index by which to measure the effects of irradiation up
to doses which become life threatening. As a result,dose-effect relationships based on physiologicalchanges tend to assume "all or none" threshold characteristics.
104. The pathological changes in irradiated lung havebeen described by various authors [K5. J3. P6, V4, M7,
A20]. Changes tend to be patchy and are dosedependent although not strongly. They occur in threephases. Microscopically, little effect is seen in the lirstdays after irradiation, after which and for the lirstmonth or so, damage to the epithelial cells of the alveoli
may appear, associated with librin-rich exudation.
After low doses, although they may be sufficiently large
to cause late changes, these early sequelae are veryslight or even totally absent. Between 3 weeks andlasting for several months radiation pneumonitis isseen; it is characterized by fibrin-rich membranes lining
584

106. The most important constituent of lungconnective tissue is collagen [C28]. This has been often
studied as a measure of lung librosis, both microscopically and biochemically [K46, C29, D50, 040, Ll 1).
However. if the hemithorax of mice is irradiated,changes in relative collagen content occur much later
than the time of death when both lungs are irradiated[K46, Ll 1]. The indications are therefore that thepulmonary syndrome in mice leading to death as
described above, results primarily from pneumonitis
and its complications and not from fibrosis. Changes inelastin [F53] have also been reported.
107. Physiological studies have been performed ondogs, rats and mice by various authors [MB. S6, T4, T5,
T6]. With doses greater than 10 Gy in a single dose or
30 Gy fractionated over 8 weeks there was a decrease in
the diffusion of carbon monoxide. suggesting an alveolocapillary block and consistent with the histologicallyobserved thickening of the alveolar walls. After dosesof this magnitude or greater. a reduction in a variety oflung function parameters followed.
108. In general it appears that the time course ofradiation-induced changes in lung is relatively
independent of species. In all species the latent period
for the onset of acute radiation pneumonitis is 1 to 3
months, similar to that in man. Also the doses required
to cause measurable changes in physiology are similar
to or greater than doses to kill animals from pulmonary
insufliciency, i.e., greater than 10 Gy in a single
treatment.
109. Following irradiation with single doses of x raysof approximately 12 Gy or higher (or equivalent
fractionated doses) animals die from acute pneumonitis
between about 3 and 7 months after irradiation. After
lower doses, surviving animals may develop long-termchanges leading to pulmonary fibrosis [T31]. Radiopneumonitis is thought to result primarily from direct
effects on parenchymal cells with secondary damage tothe vascular connective tissue. Fibrosis is thought to bea consequence primarily of damage to capillaries withsecondary effects on the parenchyma [A20, K5. P6,
M7]. Van den Brenk [V4] suggested that the primarytarget cells are the type II alveolar cells which produce
surfactant, a lipoprotein preventing adhesion andcollapse of the alveoli on expiration. A reduction insurfactant would lead to an unbalance of osmotic andhydrostatic pressures resulting in accumulation of
Ouids in the alveoli. a characteristic of radiation
pneumonitis which however could also result fromdamage to blood vessels. Various studies of the functionof type II cells have been made. Total lung lipids, total
phospholipids. lipid turnover and surface tension haveall been measured, but the results do not yield a clear
picture [S69, 040, P38, P39, P40, M76, 041).

110. Perhaps the most sens1t1ve end-point forassessing damage to lung in experimental animals is theprobability of survival late after irradiation. Phillips
and Margolis [P2] observed that mice die from lungdamage from about 80 days after irradiation and thatno further deaths occur beyond 160 days. They
estimated the LDso at 160 days for a variety oftreatment regimes with x rays. The mice died withobvious signs of respiratory failure, the lungs were wet,indicating vascular leakage. This was also indicated byisotope studies [H52]. Bacterial infections were rare andthe main damage was to the alveoli. Field et al. [FI 7]
reported very similar results to those of Wara et al.
[W15]. They may be summarized as follows: the LDso inmice is 12-14 Gy. depending on the strain. There is amarked effect of fractionation of x rays, such that data
are fitted by N0.39 up to 8 fractions and N0,25 from 8 to
32 fractions (Figure V). Repair of sublethal damage

IIUIISER OF FRACTIOUS (li)Figure V. lsoeffect curves of total dose versus numberof fractions for lung L0 50 • The upper curve Is for x rays
and the lower curve for neutrons. All data are corrected for an overall effective treatment tlme of 1 day[F17]

between two fractions occurs in a few hours as is thecase for other cells and tissues [F3]. If Jung damage is
examined by the method of Dutreix et al. [D9]. it is seenthat repair of sublethal damage is considerable, perhaps
greater than for other tissues. When the slope ratio is
calculated for Jung the ratio is very similar to values
derived for skin with a ratio of 1 : 7 [Fl 5].
111. With a constant number of fractions and avariable time between them, the T factor for lung may
be derived. Two experimental series [Wl 5, F12] showedthat T0,07 was a good fit to the data. This is smaller thanthat for skin owing to lack of repopulation in lung.
Field and Homsey [F8] showed that for neutrons there
was no further effect of extending the treatment time
beyond an hour, i.e .. after repair of sublethal damage.
Since repopulation is thought to be similar after x rays
and fast neutrons, a slow repair process was suggested
as the explanation for the x-ray result which is absent
after neutrons. Repopulation between fractions has
been excluded as the explanation by labelling experiments [C31] leaving slow repair as the explanation for
the T factor.
112. In summary, lung is a highly complex organ
comprising more than 40 cell types. The pathologicalchanges following irradiation have been described, but
the primary target or targets remain uncertain. Damage
to type I I cells or vascular damage are considered
generally to account for the changes in elastic

properties. pneumonitis and fibrosis that occur. Lung isa relatively sensitive tissue. probably because it Jacks
the rapid proliferative ability. However, lung has alarge capacity for repair of sublethal damage whichenables it to tolerate a high level of fractionated orpresumably continuous irradiation.

F.

LIVER

113. The liver performs a variety of essentialfunctions. Its cells are normally not actively dividing
and, therefore, radiation damage caused by moderate
doses can only be demonstrated late after irradiation.
As a result there has been a long debate as to whether
liver is a radioresistant organ or not (see [L31] fordetails of post irradiation changes). Irradiation of thewhole liver in laboratory animals is exceptionallydifficult without causing severe damage to other more
rapidly proliferating organs such as the intestine. irradiation of which can lead to early death. The liver has avery large reserve capacity and is able to maintainapparently normal function despite a large part of it
having been damaged. In addition, the hepatocytes
have an extraordinary capacity for regeneration.
Should part of the liver be injured these cells willrapidly proliferate to maintain hepatic function.
114. The literature contains few animal experimentson liver and most of these are confined to studies ofrepopulation and regeneration. Results obtained also
appear to be highly variable (see review [L12]) and it
has been suggested that this is due to variations in thestate of liver cells at the time of irradiation or subsequently. Any liver disturbance which elicits a proliferation response may seriously increase the reaction toirradiation, and most experiments have been performedin this way.
115. A technique for measuring liver damage wasdevised by Weinbren et al. [Wl 6] in which latent
damage was unmasked by stimulating the liver into
division either by surgical removal of part of the organ
or by using damaging chemicals, e.g.. carbon tetrachloride. These experiments involved irradiation of
two-thirds of the liver of rats (on exteriorization) to 50
Gy in a single dose. Major changes were not noticed
unlesspartialhepatectomywassubsequently
performed. Kinzie et al. [K7] reported fairly minorchanges in rat liver after single doses of 15 Gy andDettmer et al. [D16] showed very slight changes after
total liver irradiation with 10 Gy but severe after 25 Gy.
De Mignard et al. [D17] measured only a transientchange in rats after 6 Gy, which had returned to normal
by 6 weeks. Damage to the microsomal drug metabolizing enzyme system in the rat has been observed, but
only after high doses of 7.5 Gy given daily. [Y3, Nl2].
Verga and Cali [VS] irradiated rats with 0.5 Gy per day
for a total of 33 Gy before an abnormality wasobserved, i.e. hypertrophia of Kupfer cells. When 3 Gy
per day for a total of 60 Gy was given to rats there wasno reduction in the effect of detoxification.
116. Thus. liver is a slowly proliferating organ. but its
cells can be stimulated into division by injury(including that from radiation) and thereby unmask
latent radiation damage. Single doses of x rays of morethan 10 Gy are needed for demonstrable permanentchanges and this dose may be increased by a factor of
3-6 by extended fractionation.
585

G.

URINARY SYSTEM

117. Under normal circumstances there is little cellproliferation and except for large radiation· doses theeffects of irradiation occur late. These late effects
include proteinuria, hypertension and reduction in
kidney function. It is possible to measure various
aspects of kidney function, e.g., glomerular filtration
rate (GFR), effective renal plasma now (ERPF} andtubular resorption rate (TMrA11).
118. Human and animal kidneys show similar histopathological changes resulting from irradiation. Thesechanges are reported to occur to varying degrees and atvarying times but can be summarized as degeneration,
necrosis or atrophy of the tubular epithelium; increased
interstitial connective tissue; thickening of basement
membranes; hyalinization of connective tissue;
replacement fibrosis; degeneration necrosis; swelling or
proliferation of endothelial cells; intimal vascular
thickening; thickening of vessel walls and narrowing oflumina; degeneration, necrosis, or atrophy and scarringof glomeruli. Similar changes were described after
irradiation of dog kidney by fast protons [F36), A
detailed review of the kidney pathology after irradiation has been made by Mostoli and Berdjis [M9).
119. It is by no means clear whether vascular orparenchymal damage in kidney is the more important.
However, it is known that blood vessels become moresensitive to irradiation in conditions of hypertension[A3). Animal experiments on kidneys have in general
led to wide differences in interpretation. There is noconsensus on the degree, extent or time of onset andprogression of specific changes and considerable
disagreement has resulted in interpreting the histological findings {M9).
120. The dog has been used by various experimenters.
In some cases whole-body irradiation has been given,
sometimes only the kidneys or one kidney has beentreated and sometimes one kidney is removed and theother irradiated. Doses of 20 Gy or less cause profoundchanges. Mendelsohn and Caceres [MIO] performed
unilateral nephrectomy, allowed 15 weeks for compensatory hypertrophy of the remaining kidney andirradiated over 13 days. Kidney function tests indicatedthat tubular function was the most sensitive index but
the authors suggested that the ultimate effect was
through vascular damage.
121. Pospisil and Zaruba [P7] and Zaruba [Zl]measured kidney changes after whole body irradiationand found some with 6 Gy, but concluded that they
were through indirect effect rather than direct damage
to the kidney. Maier and Casarett [Ml 1) irradiated dogs
with a range of doses from 5 Gy. Physiological changes
were measured during a 6 months period after irradiation. It was found that 5 Gy produced very littlechange but 10 Gy produced morphological andfunctional modifications at 6 months. In the neonate
3.3 Gy did produce changes in renal function later inlife [L32].
122. In pigs, Hopewell and Berry [H12) measured
physiological changes and observed thresholds for
reduced function after approximately 10 Gy in a single
dose or 40 Gy in 30 fractions in 6 weeks.
123. Rabbit kidney may be rather radioresistant [M9)but Caldwell et al. [C7J reported LDso values at 6
months of 18 Gy in a single dose or 57 Gy in 24
fractions.
586

124. Effects in rats have been studied by Bennet et al.
[BlOJ and Lamson et al. [L13] who observed hypertension with doses as low as 5 Gy. Hypertension wasobserved even if only one kidney was irradiated [W17).
Berdjis [B 11) observed nephrosclerosis 1 year after 9 Gy
to rat kidneys which was reduced but not eliminated if
the rats had been given S Gy whole-body irradiation.
KUrcher and Schulz [KS) observed functional andenzymatic changes if both kidneys were given 10 Gy,
which were reversible if 011 ly 1 kidney was irradiated.
Chauser et al. [CS) measured ERPF and collagendeposition at 18 weeks after irradiation of 1 kidney
only in rat; 10 Gy had no effect on function and caused
a very small increase in collagen; 20 Gy caused renal
failure between 16 and 18 weeks, but the rats appeared
normal.
125. Many authors irradiated mice over the wholebody and estimated kidney changes. These occur at
fairly low doses of about 5 Gy, but as stated previously,
may not be direct effects on the kidney [B12, GI, C9).
Irradiation of only the kidneys by Glatstein {G2)demonstrated a threshold dose for impairment of renal
blood now of less than 10 Gy. Phillips and Ross [P8]estimated the LDso to be 13 Gy at 16 months by unilateral nephrectomy and irradiation after hypertrophy of
the remaining kidney. The threshold dose to cause
death in these experiments was about 8 Gy. Donaldson
et al. [018] measured the inhibition of compensatory
renal growth after unilateral nephrectomy in weaning
mice. In this case the threshold for a permanent effectwas 10-15 Gy. Geraci et al. [G3] measured decrease in
kidney weight at 6 months and observed a threshold of
about 10 Gy x rays and 7 Gy neutrons. Dogs irradiatedwith two doses of 3.5 Gy of fast protons and kept aliveby shielding part of the bone marrow, showed a varietyof changes after 6 months, including a decrease in
secretary activity, protcinurea, hypertony and bloodchanges [NlO]. Threshold doses from single doseexperiments are summarized in Table 4.
126. Fractionation experiments have been performedon mouse kidney by Phillips and Ross [PS] and by
Glatstein [G4] and on pigs by Hopewell and Wiernik[H13). All series showed a marked reduction in theeffect of irradiation with increasing fractionation.
Recovery from sublethal damage was perhaps evengreater than with skin but less than for lung [P8]. In
general the Ellis formula provides a reasonable
description of the fractionation effects on kidney.
127. The late foetal or neonatal kidney has beenshown to be more sensitive than in the adult. For
example, mice irradiated at birth showed far more intercapillary glomerulosclerosis than if irradiated at 12, 23
or 53 days of age [Gl]. Guttman showed that 4.5 Gygiven to mice at birth caused significant changes in theglomeruli followed by deposition of collagen.
Phemestcr et al. [P29] observed beagle dogs which hadreceived 2.7-4.4 Gy either at 55 days in utero or at 2days old. The animals subsequently died with chronic
renal failure.
128. Very few studies on the response of the urinary
bladder to irradiation have been performed. However,recently a functional assay for damage to the mouse
bladder has been developed [S73] and it has shown thatbeyond 5 months after single doses of irradiation thethreshold for detectable changes is 15 Gy. Damage wasto the epithelium with a loss of the specialized
polyploid surface cells. Fibroses became apparent after
one year. Compensatory proliferation occurred only
when loss of function became apparent [S74].

129. In conclusion. a wide range or physiologicalmeasurements and histological changes have beenreported for kidney. Data for threshold doses arc
relatively consistent between experimenters and for
different species and are in the range 5-12 Gy. Withextended fractionation these threshold doses would be
increased by a factor of at least 3. Kidney is considerably more sensitive around the time of birth.

other tissue end-points. showing that the spinal cordhas a relatively large capacity for accumulation andrepair of sublethal damage. In both rat experiments theeffect of varying the time between fractions was tested.
There was initially no effect on LDso of increasing thetime separation, until 8-16 weeks (VI] or about 5 weeks[W6]. Both studies suggest that there is no slow repair inthe spinal cord, but delayed repopulation. The repopulation gave a time factor of about T(l.03 and the dose
fractionation an N factor of approximately ND.4.

H. CENTRALNERVOUSSYSTEM
130. Effects of radiation on the nervous system werecomprehensively reviewed by the Committee in 1969
[U4]. The main findings were that the central nervous
system is very sensitive whilst developing. Transientfunctional and behavioural changes can occur inanimals with doses greater than 0.5 Gy and in somecases ionizing radiation can be detected at levels of a
few tens of mGy. but there is no evidence of permanent
injury at these dose levels. It was noted that workers
exposed for many years within the recommended limits
did not develop any consequence of note. This topic
was reviewed by Maisin [M71]. It was pointed out [U4]that for permanent injury the nervous system of theadult was less sensitive than some other tissues andorgans. During the subsequent years no new data havesignificantly altered these views. Additional information has been obtained. particularly on the role ofthe vascular system in the pathogenesis of radiationinduced neurological syndromes, although its exact roleremains unclear since the vascular changes occurred
more than one year after irradiation [R49].
1.

Spinal cord131. Irradiation of the spinal cord in animals and inman may result in myelopathy whose probability andtime of onset are dose dependent. In some cases thetime of onset both in rats and mice has been found to
be inversely related to the dose of irradiation [ClO. GS].
However. other experimenters observed after about 100
days acute ataxia and paralysis the probability of which
was dose dependent (W6, V6]. In these experiments
only a short segment of the cord was irradiated.
132. At the dose levels required to produce such lateparalysis after irradiation of the cervical cord, necrosis
was restricted to the white matter. but small haemorrhages were observed scattered throughout both thegrey and white matter.
133. Using rats. White and Homsey [W6] found thatno paralysis occurred with single doses of less than 20
Gy. Yan der Kogel [V7], also using rats. found that
doses above 17 Gy caused paralysis. In these experiments paralysis occurring within 6 months was attributed to necrosis of white matter, i.e., neurologicaldamage, whereas vascular injury appeared to cause
later paralysis at 12-18 months at slightly lower doselevels. In mice, Geraci et al. [GS] observed a thresholdof about 12.5 Gy x rays and Goffinet et al. [G6]observed only a small effect with the lowest dose usedof 20 Gy.
134. The effects of dose fractionation on the spinal
cord were carefully investigated by van dcr Kogel (V8]and by White and Homsey [W6] on rats and by Geraci
et al. [G7] and Goffinet et al. [G6] on mice. In all cases
the dose to provide myelitis increased more rapidly
with increasing the number of fractions than for most135. Goffinet et al. [G6] also tested the effects ofirradiating different lengths of cord. They found thatthe tolerance for a single dose was reduced by about
20% when the irradiated length of mouse cord wasincreased from 6 mm to 12 mm.
2.

Brain

136. Ncuro-physiological methods to enable detectionof effects of irradiation to the brain [L14] indicate thatin some respects it is radiation sensitive. For example,
Minamisawa et al. measured changes in evoked potentials recorded from the visual cortex of rabbits onphotic stimulation and showed that this function
gradually decreased over the lifetime of the animal after
single doses of 1-3 Gy or 3-30 Gy fractionated [M44,
M45, M72]. However, in general the organ wasconsidered to be fairly radiation resistant. Doses
greater than about 20 Gy are required to produce
morphological changes and the latent period is shorter
with increasing dose [Z2].
137. Russell, Wilson and Tansley [R6] investigated the
response of rabbit brain. They estimated the minimal
single dose to produce delayed necrosis to be between
20 and 24 Gy. Hopewell and Wright [Hl4] measured
the latent period between irradiation and death in rats.
In normal animals irradiated with 10 Gy to the head
there was no weight loss. no neurological symptoms
and their life span was not different from controls.
However, 20 Gy did cause weight loss and the life span
was reduced. Histologically there were three types ofchange: the earliest changes were in the subependymal
plate, a region of mitotically active cells found aroundthe anterior of the lateral ventricles; large areas of
necrosis were observed later, mainly in the whitematter: vascular lesions in particular hyaline thickening. fibrinoid necrosis of vessel walls and microaneurysms occurred still later.
138. The cells of the subependymal plate are the stem
cells for neuroglia of the white substance [Ll 5]. After
irradiation with photons the number of these cells isdepressed but recovers for doses of 10 Gy or less. With
15 Gy of photons there is total destruction of thesubependymal layer [Cll]. Even 5.5 Gy cause apersistent change in the glial cell balance [R52). With
fast neutrons there appears to be no recovery after
doses as small as 1 Gy [Cll].
139. Irradiation of rabbits with 1.5 Gy produced adecrease in intracranial pressure, while 10 Gy caused atransient increase in intracranial pressure persisting for
2 days [L26, L27].
140. An increasing amount of data supports the viewthat structural damage to neurones can occur after
relatively low doses [A21, Vl4). Fast protons (50-645
MeV) [K33) and gamma rays in the range 1-6 Gy
produced degeneration in the rat brain cortex between587

1 and 12 months after irradiation, leading to neuraldestruction. Al 12 months after 2-4 Gy, 25-40% of theexternal granular layer of rat brain cortex was irreversibly altered. These degenerative changes wereincreasing with an increasing period of observation
after irradiation, indicating that the nervous tissue
cannot simply be regarded as radioresislant.
I.

ENDOCRINE ORGANS

most mammalian cell types, although the D 0 of 19 Gy
was rather higher than usually observed. indicating thatthyroid cells could be rather more resistant than most
[C22].
145. The thyroid is, in conclusion. a non-proliferating
tissue in which radiation effects occur after many years.
10 Gy x rays in a single external treatment is required tocause signs of malfunction or a 50% reduction inepithelial cells.

1. Thyroid
2.

141. The parenchymal cells of the thyroid arc notnormally actively dividing and therefore do not exhibit
early radiation-induced mitotic cell death. After dosesof 50-100 Gy from 131J intcrphase death occurs, detectable during the second week after irradiation [W43). At
later times there is no further radiation-induced cell
death. However there is progressive atrophy of theparenchyma resulting in hypothyroidism [W44], due toprolonged impairment of cellular reproductive
capacity, as demonstrated by reduced response togoitrogenic stimulation. Early radionecrosis of thegland, which is lhe result of damage to the fine vasculature, may appear but requires massive doses, well inexcess of those which produce late changes resulting
from damage to the epithelial cells. The pathogenesis of
the thyroid changes associated with the development ofhypothyroidism appears to involve primarily patchy
degeneration and fibrosis of the fine vasculature andinterfollicular stroma and secondarily degeneration of
the follicular epithelium. In some of the less affected
regions there may be hyperplastic reactions resulting inatrophic nodular structures containing little colloid[Rl].
142. The time of onset of the late hypothyroidism isdose related, occurring earlier with larger doses. Using
adult dogs, Michaelson et al. [M12) showed radiationinduced primary hypothyroidism occurring 3-4 years
later with a threshold of about 10 Gy in a single dose.
At these times the animals showed signs of thyroid
malfunction, such as decreased activity, coarsening
hair, increasing obesity and reduced body temperature.
The uptake of131J by the thyroid was also reduced. The
authors suggested that this radiation-induced chronic
thyroiditis may involve an autoimmune mechanism
through leakage of thyroglobulin and microsomal
material, both of which have been shown to be
antigenic.
143. Techniques to estimate epithelial cell survival
have been developed. These are based on the fact thatapplication of a goitrogenic stimulus, e.g., methylthiouracil, prevents hormone iodination and leads to a
reduction in blood hormone level. As a result thyrotropic hormone level (TSH) is raised and the thyroid
gland increases its weight by 3-5 times over a period of
about a month. This weight increase is reduced byirradiation. With a single dose of 10 Gy the response isreduced by about 500/o [M13]. Clearly the thyroid has alarge reserve capacity. Not only can it tolerate a considerable loss of material, but it will also produce
relatively more T3 hormone at the expense of T4, theformer being by far more effective.
144. A transplantation technique was recently
developed to assess thyroid cell survival. Irradiation
was performed either in situ or in vitro after preparation of a cell suspension. In both cases the parametersof cell survival were found to be within the range for
588

Pituitary146. In the adult the pituitary is regarded as a radioresistant organ. lls suppression results in a fall ofgonadotrophin and in reduced function of otherendocrine organs such as the thyroid and the adrenals[S34]. However, a fall in growth hormone may result
from damage to the hypothalamus, as has beenreported after -radiotherapy, particularly in children[K52]. In the adult animal, very large doses of approximately 300 Gy are required to ablate the pituitary [Rl].
In immature animals the organ is far more sensitive, forexample, whole-body irradiation of 1 Gy caused weightloss in squirrels and 6 Gy caused stunting of growth in
2-day old rats [M46].
3.

Adrenals147. Evaluation of the response of the adrenals toirradiation is complicated. The adrenal responds to thestress from irradiation by an increase in weight andhormone production. It is therefore difficult to assess
direct effects on the gland. As with the pituitary, theorgan is resistant in the adult, but in immature animals
it appears to be more sensitive. Six Gy to calves caused
significant hypertrophy [R31] and 4 Gy to young rats
prevented weight gain [W39]. Older animals are moreresistant, although 9 Gy to rats caused medullary
venous thrombosis and atrophy of the gland. In all theabove experiments the animals died from intestinal
injury a few days after irradiation and therefore theeffects on the adrenals may not have been permanent,
as was shown in experiments in which rats lived longer[S34]. Permanent changes to the adrenals require dosesof 20 lo 30 Gy [EIS].

J.

GONADS
1.

Testis148. Irradiation of the testes produces sterility, which
may be permanent or temporary depending on the doselevels and dose rates employed. An understanding of
the effects of irradiation on the testis requires aknowledge of the development of mature sperm fromthe testicular stem cells. The accepted model for thisprocess is that described by Oakberg [02, 03, 04)
which has recently been re-examined by Meistrich et al.
[M14]. The basic stem cell is an undifferentiated type A
spermatogonium designated Ais which has an LDso of
2-3 Gy [05, ES, M42] and cycle times ranging from 2-9days (04, H15]. The developing spermatogonium ismost sensitive when it is in the differentiated stages A 1
to B. There also exists an intermediate stage, designatedAat, with intermediate sensitivity between the stem cells
Ais and the differentiated spermatogonia. Progressionof differentiation continues through spermatocytes,
spermatids to spermatozoa, the resistance to irradiation

increasing with further differentiation. The full cycle
takes about 6 weeks in a mouse and about 10 \l}eeks inman. Biochemical changes due to irradiation with xrays or protons have been investigated [S38, F37]. The
topic has recently been reviewed by Kondratenko[K32].

effect on sperm production below 0.0017 Gy/day, but
0.0034 Gy/day to a total of 7.5 Gy led to oligospermia.
Giving 0.0017 Gy per day plus a single treatment of
0.42 Gy three times per year caused a still greater effectand after 2.5 years the ability for fertilization was lost,
although recovery took place.

149. From this description, it is clear that small doses
will induce temporary sterility by killing the sensitive
differentiating sperrnatogonia. Larger doses may also
deplete the type Aa1 spermatogonia without inducing
permanent sterility, since the stem cells are moreresistant. If the stem cell compartment is seriously
depicted, it will be initially restored by cell proliferation, after which it will begin to differentiate andultimately produce sperm. About 20% of the normal
spermatozoa count is required for conception.

154. The hormonal secrctory function of the testis is
far more resistant to irradiation than spermatogenesis
since 0.25-0.5 Gy/day to a total of 50--100 Gy in 25
weeks causes no reduction in secretory function [R.32].

150. Radiation doses to induce sterility have beenmeasured by various workers. In mice, the Russells [R 7.
R8) observed recovery after single doses of 6 Gy andlater after 10 Gy. but mutations were produced in thesurvivors. In rats, Shaver [S7, S8] measured single
threshold doses of 5 Gy in adult and 3 Gy in immature
animals. Erickson observed a threshold of about 4 Gyin the rat [E19]. In rabbits, single doses greater than 9.5
Gy were required [Cl 2) and in bulls 8 Gy produced
only reversible injury and not permanent sterility. Withdogs, Casarett and Eddy [C13] demonstrated that evenafter 20 Gy some recovery occurred. [n man single
doses of about 5 Gy would appear to be around thethreshold level [L16].
151. The response of the testis to fractionated and low
dose rate radiation is different from most other tissues.
The evidence suggests that there is no "dose sparing" by
protracting the treatment as is normally the case but
fractionated treatments may actually be more effective
for a given total dose. Brown et al. (813) reported that
continuous irradiation at 0.02 Gy/day to rats and miceallowed reproduction for at least 10 generations
although there was some evidence of life shortening[Dl 9]. At dose rates slightly greater than 0.02 Gy/day,sterilization ultimately resulted. However, Stadler and
Gowen [S9, SlOJ reported maintenance of the germ line
in mice irradiated for 11 successive generations withdaily doses ofup to 0.03 Gy/day. A total dose of 15 Gy
was accumulated without causing reduction in reproductivity or a change in the sex ratio. Oakberg and
Clark (06. 07. 08] reported a threshold of about 0.13
Gy/day in mice. Total doses accumulated at 0.014
Gy/day to 3 Gy caused the spermatogonial population
to reach a new equilibrium ratio of 80% of the control.
152. Casarett and Eddy [C13] compared the effects ofsingle and fractionated irradiation of testis in dogs
using whole-body irradiation. Treatment at 0.03
Gy/day to a total of 3.75 Gy caused a greater degree of
irreversible depression in sperm production than did asingle exposure of 3.75 Gy. When 4.75 Gy was given at
0.03 Gy/day. all dogs became permanently aspermic.
With life-long irradiation, 0.0012 Gy/day causes nodeleterious effects, but 0.006 Gy/day ultimately caused
permanent aspermia and sterility if total doses greaterthan 10 Gy were given. It is possible that recruitment ofcells from an otherwise resting and resistant population
into a more sensitive phase may be primarily responsible for this unusual and important effect of dose
fractionation.
153. Fedorova and colleagues [F39, F40) irradiateddogs for 6 years at varying dose rates. There was no155. In summary. irradiation of the testes causes
temporary sterility and with larger doses sterility may
become permanent. The testis is unlike other normal
tissues in that repair of sublethal damage does notoccur. Moreover, fractionated or continuous irradiation
renders the tissue more rather than less sensitive. In
mice continuous life-long irradiation between 0.02 and0.13 Gy/day is reported to cause permanent sterility. In
dogs, the figure is lower, 0.006 Gy/day being sufficient
but 0.0012 Gy/day insufficient to cause sterility.
2.

Ovary

156. The most sensitive and critical component in thefemale reproductive system is the germ cell. In theovary all cells in the oogonial stages progress to the
oocytes in the embryo. Soon after birth all oocytes arein the resting phase with no further cell division and in
the adult there are no stem cells but a finite number offollicles. These have been graded into categories related
to their degree of maturity. In some species. e.g., mice,
rats and rabbits, the primordial oocyte is more radiosensitive than the later stages of oocyte maturation [07].
Such differences in sensitivity with stage of development have not, however, been observed in guinea
pig. pig or cattle [E9. ElO] or the trend in sensitivity isreversed, as in the monkey [814].
157. There are great interspecies differences in thesensitivity of the ovary to irradiation. In mice 0.1 Gy ina single treatment was sufficient to destroy 50% of theprimordial follicles [09) and 1 Gy produced permanentsterility [R9]. Rat ovary is less sensitive, about 0.7 Gybeing required to destroy 50% of the primordial follicles[MIS], and more than 8 Gy to produce sterility [K9]. In
monkey, the oocyte is little affected by 10 Gy [814) andthe minimum sterilizing dose is about 20 Gy [815]. With
the marmoset. more than 6 Gy is required to kill half
the oocytes [L16]. Erickson has shown that the doses tokill half the oocytes in pigs and cows are 5 and 9 Gy,
respectively. Single doses of 4 Gy or two doses of 3 Gyeach. separated by 55 days, had little effect on the germ
cell or follicular count. no effect in the production ofovarian abnormalities. and no change in fertility or
quality of offspring [E 11 ]. These differences inradiation sensitivity of ovarian follicles between species
are discussed in chapter V of Annex I. They may simply
reflect the existence of a sensitive stage, which may or
may not be irradiated during the development of these
species.
158. Andersen and Rosenblatt [A4] studied fertility
after single or fractionated irradiation of female
beagles. A single dose of 3 Gy had no noticeable effect,but 7.5 Gy given at 0.5 Gy per week caused total sterilization. Many authors (82, S9, SlO. G8, G9] reported
maintenance of the germ line in mice given continuous
irradiation for 11 successive generations with daily
doses of less than 0.03 Gy. Mice accumulated 15 Gy at589

these low dose rates, apparently without harm and withnormal reproductivity and sex ratio, although at 0.02
Gy/day there was a progressive reduction in litter size
[82].

159. The developing oocyte is more sensitive. Afollicular ovaries and sterilization were produced byfractionated irradiations of 0.1 Gy/day to a total of 2
Gy in 2-4 day old dogs and 2.7 Gy in foetal monkeys[A5. A6]. In another experiment [A 7], doses of 0.115 Gy
given twice weekly to a total of 2 Gy severely damaged
the ovaries of eight out of nine foetal bonnet monkeys
and reduced follicle counts to less than 25% of normal,
without causing damage to any other organ.
160. In conclusion, although there are considerable
differences in sensitivity between species, the adultovary is generally more resistant than the testis because
the oogonial stages have progressed to the moreresistant oocyte by the time of birth. However, theovaries in foetal animals are severely damaged by much
lower doses than those required to cause serious
changes to the adult ovary. Fractionated treatments to a
total of 2 Gy cause severe damage to the developing
ovary in dog and monkey.
K.

THE EYE

161. The eye is generally considered to be one of themore sensitive organs to irradiation. Damage to any
part of the eye may occur, but for long term effects themost sensitive structure is thought to be the lens. Here,clinically significant progressive or irreversible changes
can occur well into maturity, by radiation doses whichevoke only transient reactions in other ocular structures, such as the cornea and conjunctiva.
162. Detectable changes in the normally transparent
lens may vary from tiny flecks to almost complete
opacification resulting in total blindness. Cataracts aremost usually associated with old age or with abnormal
metabolic disorder. chronic ocular infection, or trauma.
The lens consists largely of fibre cells and is covered
with an epithelium anteriorly. Dividing cells are limited
to the anterior equatorial region, and the progeny ofthese dividing cells migrate posteriorly and thencentrally to form the Jens fibres. Cell division continues
throughout life, and so the lens may be regarded as aself-renewing tissue. However, it is a cellular systemthat has no blood supply and no mechanism for cell
removal. If dividing cells are injured by radiation. theresulting abnormal fibres are not removed from the lensbut migrate toward the posterior pole and, because they
are not translucent, they constitute the beginning of acataract.
163. Many of the cells in the central portion of thelens are capable of proliferation but are in the restingstage G 0 [G10]. These cells may be stimulated into
division, for example by injury. According to Bateman
and Berdjic [B 16), cataractogenesis can proceed either
by germinal zone epithelial damage or by metabolic
deficit of cortical fibres. They suggest that the former
predominates at low radiation doses and the latter athigher doses.
164. Work on establishing the threshold doses inanimals seems to fall into two groups. In all animals,
including man, there is a finite probability of devel·
oping lens opacities during a life-time. In some laboratory animals this probability is very high. The
590

threshold dose in these cases is defined as the dose tosignificantly increase the probability of opacification.
The values obtained are very low indeed, ranging froma few hundredths of Gy depending on the type ofdamage [e.g .. B16, U2].
165. In other animals, including man, the naturalprobability is very low. It was shown by Focht et al.
[F18] that in this case increasing the dose causes a
reduction in the latent period. In this type of response
the threshold is much higher. for example, single dosesof 5 Gy in mice at I year [R I OJ. more than 3 Gy m
rabbits at 4 years. and 5 Gy in rats at 2 years [U2].
166. Protons ranging from 25-645 MeV produced
qualitatively similar effects to photons, at the same doselevels, independent of proton energy. The inverse
relationship between dose and latent period wasconfirmed and it was shown that the probability of
causing opacities decreased with decreasing dose rateor by giving the treatment in 2 fractions [K30, K31].
167. As with many other tissues, damage to the lens is
reduced by protraction of irradiation. In experiments totest the time-dose relationships, mice were irradiatedwith 14 different schedules and followed for cataractous changes [Sll]. The effects of number of fractions
and overall treatment time were not separated and theslope of the "Strandqvist" isoeffect formula was calculated as 0.3. An analysis of earlier work [KlO]. also on
mice, gave a similar figure. However. Merriam andFocht [M 16] derived a factor of 0.17 from studies on rat
and on man which represents a more pessimistic viewof the sparing by fractionation.
168. It could be concluded that a minimum of 3-5 Gy
are required to produce significant opacities in animals
which are normally not prone to cataract development,
as is the case for man. But in animals who are especiallyprone, very much lower doses increase the incidence.
More dose is required when fractionated, but the dose
sparing may be rather less than in other tissues.

L.

HAEMATOPOIETIC TISSUES

169. Changes in all the elements of the haemopoietic
tissues are observed after fairly low doses of radiationfrom the circulating blood cells, to bone marrow,spleen, thymus and lymph nodes (see [PlO] and [M51]for reviews). These tissues have been extensively
studied, partly because some elements are very radiosensitive and partly because relatively easy quantitative
end-points are available.
170. Changes in peripheral blood counts have been
well documented in both man and experimental
animals (Figure VI). A differential count is considered
to be a useful biological dosimeter in man but is toovariable from animal to animal to be a good quantitative assay in rodents. In man, if the lymphocyte countfalls below 1200 within 24-48 hours. the prognosis isserious and if it falls below 300. the patient is almost
certain to die [021, G30, A22].
171. Early experimental studies were mainly on organ
weight loss and cellularity. After 4 Gy in mice there is ameasurable weight loss in spleen, lymph nodes andthymus. The organs reach a minimum weight at 2-4
days. but are restored to normal at 2 weeks [B 17). In thebone marrow cell depletion is maximal at 3-4 days
[B 17] but later haemorrhage masks the hypocellularity

;: 100

•-

•
X
0
•

•\

z

0

~

~ 60

.

0:

!!:

IU

f ,o

•,
'\,

unidentifiable on morphological criteria, although thesuggestion has been made that it resembles a small
lymphocyte [Y2). Survival of haemopoietic stem cells
has been studied by a variety of tests. These include
quantitative transplantation of bone marrow cells into
lethally irradiated hosts with the subsequent assay ofhost survival [M 18, S 12). spleen colonies in the host for
the estimation of colony-forming units (CFU) [D. M19 .
B19], cell culture techniques [S35) or incorporation of
59fe to test for erythropoiesis [Cl4, Hl6]. Other tests
include the response to exogenous crythroprotein inpolycythaemic mice [J4), to endogenous erythroprotcin
in fasted and re-fed mice [PI 1), or scoring of granulocytes [H 17]. Comparisons of functional assays of
haemopoietic stem cells have been made [H54].

ERYTHROCYTESPLATELETS
GRANULOCYTESLYMPHOCY1ES\ ~-----.
-..........x-._

X

Figure VI. Peripheral blood counts of rats following 5 Gy
whole-body radiation [D21][F19. Nl]. Temporary changes in weight of these organs
may be caused by very small doses, and as little as 0.4
Gy can be detected [K 11, M 17]. Changes in the bonemarrow architecture (in excess of 20 Gy) cause
permanent hypocellularity of the bone marrow,probably due to fibrosis [K 12, K 13. Fl 9, S70].
172. Much effort has been directed towards the studyof lethality from whole-body irradiation at 20-30 days
caused by bone marrow depletion and resultant
haemorrhage (from lack of platelets) and infection(from Jack of lymphocytes and phagocytic cells). Table
5 shows some lethality results for a range of animal
species. There appears to be a tendency towards lower
LDso values (higher radiosensitivity) in the larger
species (Figure VII), but this may be partly a result of
infestations with intestinal parasites [H6].
16,

12

•
0-01

10

()-1

Body weigh!

100

100C

(r,g)

Figure VII. LD 50 for bone marrow depletion as a function of animal weight [HG, B7]173. If partial body irradiation is performed the LDso
increases. In rats the LDso at 30 days was 11.5, 15.3 and16 Gy for irradiation of the whole abdomen, front
region and back region respectively [25). LDso was also
shown to be related to the average area of individual
endothelial cells from the aorta of different species[S37]. In mice it was 7.7. 14.7, 11.6 or 18.0 for irradiation of whole body, head, trunk or lower body, respectively [S71]. When mice were given 5 Gy of x rays either
whole body or to the lower body, trunk or head only,
the changes in leukocyte or platelet count were essentially similar. Loss of cells was greater, however, after
whole-body than partial-body treatment [K47].
174. Among the more quantitative assays are thosewhich test for the pluripotential stem cell, from which
all blood cells are believed to derive. This cell is

175. Belousova [B43] estimated the sensitivities ofcertain cells of the haemopoietic organs: 1-2 days after
4 Gy, depletion of lymphoid organs is at a maximum
and 2 days after 7 Gy the same is true for bone marrow.
All these studies indicate that the haemopoietic "stemcell" is a rather radiosensitive cell [S40, S41] with a Do
of 0.6-1.1 Gy and an extrapolation number of 1.2-2.7.
A correction for various technical differences and forradiation quality brings most of the Do estimates into
the narrow range of 0.65-0.7 Gy [L18]. The bonemarrow stem cell is therefore more sensitive than mostother cell types.
176. If irradiation is not administered to the whole
body, stem cells can migrate from unirradiated bonemarrow and repopulate the irradiated areas [H63, Rl l,
N2, S42, P27].
177. Fractionation studies have shown that the bonemarrow has a rather small capacity to repair sublethal
damage, consistent with the low values of extrapolation
number (1.2-2.7) [TI). Mole [M20] has even demonstrated an increased sensitivity with fractionation,
which he attributes to recruitment of resting cells into
the cell cycle.
178. When continuous irradiation is used there
appears to be no sparing effect over the first 10-20 days
[J5] with 2.4 Gy given as a single dose in 5 minutes or at
0.01 Gy/hour over 10 days, giving a similar reductionof CFU's to 40% of normal. However, a steady state ofrepopulation is then established, so that 38 Gy given
over 160 days also depletes the CFU's to about 40% of
normal. Fedotova [F42] observed mice given 0.025
Gy/hour showing a progressive reduction in stem cells
up to 80 Gy. A similar but smaller reduction was foundwith 0.054 Gy/hour up to 60 Gy [M47, M48]. Theseexperiments show that dose rate is of greater importance than the total dose. and this is due to compensatory proliferation.
179. Studies by Porteous and Lajtha [Pl 2) at approximately 0.5 Gy/day showed a fall in CFU's to 10% by 20
days. with a rise by day 30 in spite of continued irradiation. The work of Lamerton and his colleagues [B 1.
L5] established that the erythropoietic system in rodents
could tolerate continuous irradiation at 0.8-1 Gy/day.
Other blood components are rather more sensitive but
could tolerate 0.5 Gy/day [B1, LS, M49].
180. Differences in bone marrow response have been
noted with different species. It was shown by Belousova
that for mice irradiated at 0.5 Gy/day, after two weeks
the level of bone marrow lymphoid cells sharply
decreased. This was also the case for spleen andthymus. Granulocytes also decreased and after a total591

of 40 Gy the number of erythroid cells also decreased.
In rabbits and guinea pigs the same dose rate led to thedevelopment of a subacute form of radiation sickness
with death occurring due to bone marrow failure at 45
Gy with rabbits and 20 Gy with guinea pigs (U43].
181. Very few late effects have been observed, apartfrom those reported after doses of 20-100 Gy given
locally to a single limb [K 12, K 13) which are the resultof local fibrosis. Late damage has been observed in theerythroid precursors in the rat bone marrow after 1.7
Gy, with an exponential return to normal. the half-life
being 30 weeks (011). After doses higher than 40 Gy
marrow undergoes delayed or lasting aplasia due todamage to the stroma. Recovery can only be effected bytransplantation of healthy marrow into the marrowcavity [W44).
182. In summary. cells of the haemopoietic tissues.
and in particular lymphocytes and bone marrow stem
cells, appear to be very radiosensitive but they have aremarkable regenerative capacity and can showcomplete recovery, if the animal survives the initial
cellular depopulation.
M.

III.

EFFECTS OF IONIZING RADIATION
ON MANIMMUNE SYSTEM

183. An important effect of irradiation is impairmentof the immune response. This may result in a decreased
resistance to pathogens. development of auto-immune
disorders and possibly increased probability ofneoplasia. It is beyond the scope of this Annex to
discuss changes in the immune response in detail. The
topic was reviewed in the UNSCEAR 1972 report [US].
in which it was concluded that decreased resistance toimmune challenge resulted from irradiation with morethan approximately 2 Gy of photon irradiation.
although short-term changes can be detected at lower
doses. The radiosensitivity of immunologicallycompetent cells have been reviewed by Anderson andWarner [A25] who concentrated on early changes. andmore recently by Doria [041) who points out the lack ofknowledge to account satisfactorily for the changes in
the immune system following irradiation. This is particularly true since the introduction of the network
theory of the immune system [J25, U6]. Bazin (B80] has
recently reviewed the effects of irradiation on subsequent infection. with emphasis on the gastrointestinal
tract. A range of late changes in the immune systemhave been studied by Sado et al. [S47] on mice. They
were unable to detect any significant effects up to 4.5
Gy x rays although all the immunological indices usedshowed changes at early times. Sado [S48] noted thepaucity of studies of late effects, but also pointed outthat in general few late changes have been observed inanimals or humans surviving whole-body irradiation.
N.

SUMMARY

184. The time at which radiation damage is maximal
depends on the normal and post-irradiation proliferation kinetics of each tissue. Rapidly proliferating
tissues such as the bone marrow exhibit the damage
soon after treatment. Slowly proliferating tissues suchas the connective and the vascular do not show serious
changes until months or years after irradiation. With
acute single exposures the bone marrow is a mostcritical tissue. For animals of similar size to man the
LDso is 2-3 Gy and there is no evidence that the human
response would be very different. However, the bone592

marrow, as many other tissues, is capable of considerable repopulation between close fractions or during
low dose rate continuous irradiation. Observations on
mice indicate that daily treatment with 5% of the LDso
dose can he tolerated for extended periods. Extrapolating to large animals, this would be 0.1 Gy/day. At
this continuous dose level, the tissue likely to be themost affected is the testis or. in young females, theovary. Continuous exposure to 0.006 Gy/day sterilized
male dogs but 0.0012 Gy/clay had no effect. Mousetestis is rather more resistant. 0.02 Gy/day being thelowest figure reported to cause permanent sterility. The
pituitary is sensitive in the very young, 1 Gy causing
weight loss in the squirrel. Doses of 2-5 Gy cause lens
opacities if given in a single treatment, but more than
10 Gy are needed if the treatment is fractionated. Other
tissue's are more resistant and have significant repair
capabilities so that they arc able to tolerate still larger
doses if fractionated or given continuously. Table 6
summarizes approximate values for threshold doses inexperimental animals.

185.
The effects of ionizing radiation on humantissues were first noticed by the early radiation
pioneers. The first publication was in the .. German
Medical Weekly" in 1896 by a victim, an engineer. lessthan 6 months after Roentgen's discovery. A year or
two later the dose required to produce dermatitis was
being used to check the output of x-ray tubes. The early
workers were unaware of the need for radiation
protection and at least 336 fatalities were attributed toradiation exposure. Of these, 251 died as a result of skincancer and 56 of blood dyscrasias, e.g., anaemia andleukaemia [H 18). When the importance of radiation
protection was realized, the incidence of deliberate
whole body exposure in humans fell sharply and mostof the later information has been obtained from atomic
bomb survivors, accidents with portable radiation
sources, accidents in atomic energy establishments andpatients treated with total-body irradiation. In some ofthese groups, treatments with pharmacological agents
could alter the picture of radiation-induced changes.
186. Three different phases of injury are distinguishable in man as in other mammals. These are bothdose and time related. After very high doses. damage tothe central nervous system occurs which can be lethal
within two days. After lower whole-body doses, deathfrom gastrointestinal damage can occur between 1-2
weeks. Still lower doses may allow recovery from thegastrointestinal damage but death may result later fromdamage to various tissues. mainly to the bone marrow.
A summqry of the symptoms and injuries from
Hiroshima and Nagasaki casualties is given in Table 7(016].
187. For whole-body exposure the threshold dose
appears to be between 1 and 2 Gy for clinicalsymptoms. The LDso is uncertain but probably within
the range of 3 10 5 Gy [L 17, B18). 1f the exposure is only
to a part of the body, the reactions may be much
reduced. This is due to the regenerative capacity of stem
cells from shielded areas (bone marrow) such that thelevel of dysfunction before repopulation is not sufficiently severe to cause death (e.g., by dehydration in thegastrointestinal syndrome). Partial-body exposure has
been considered by Gregoriev and others who, on amodel basis, demonstrated that the dose may be
increased as much as a factor of 5 to produce a given
effect, depending on the dose distribution [G3 l, D37.
D38].
188. Since the present document deals with localized
exposure. it will consider only the results derived fromradiotherapy. In radiotherapy of cancer normal tissues
are unavoidably included in the treatment volume andit is the damaging effects on these tissues that limits thedose which can be tolerated. For each cancer site, atolerance dose for a limited volume of normal tissue
has been established empirically from years of practice.
This dose is usually defined as the dose that willproduce a small but detectable incidence of serious
complications resulting from the radiation effect on thenormal tissue. Each clinician has a slightly different
level of morbidity that he considers acceptable, but
often 5% of serious corn plications is consideredreasonable. It should be emphasized that this tolerance
dose is not the same as a threshold dose because it isconcerned with serious long-term complications which
may significantly alter the quality or duration of thepatient's life. Transient early damage, or detectable but
non-life-threatening damage are notnormally
considered to be dose limiting in radiotherapy.
Threshold doses for a range of tissues are likely to be in
the same hierarchy of sensitivity as serious complications although at lower dose levels.

whereas those with a low mitotic index showed a low"radiosensitivity" (i.e., little early damage or delayed
expression of damage). Since radiation damage ismainly expressed nt mitosis this concept of tissue sensitivity relates more to time of expression than to the dosethat will cause a particular level of cell survival or aparticular level of tissue dysfunction (see paragraph59).
193. Rubin and Casarett [RIJ have assessed their own
clinical experiences and performed a major review ofthe literature. Their findings are summarized in Table 8
and Figure VII I. where the injury scored at 5 years andthe threshold doses suggested as likely to give 1-5% or
25-50% complications is shown as an example. The
amount of tissue included in the beam is also given.
These data are also plotted in Figure VIII in order ofincreasing radiation resistance both in terms of actual
dose administered, normally as 10 Gy per week at 2 Gy
per day, and in terms of the Nominal Standard Dose in
ret [E4].
mi •::o

,..,

l6C!

CJS

I)

JOJC•)JO"'Boatman~,,..
0...,.
UM

T«<«
Brent (p1,1Mul)

Gro•-, w11bcr
Cr~-.1111 bone
~dnry
l.&ap

Inn

189. Defining a threshold dose depends on themethod of assaying the damage. Some tissues canwithstand a high degree of cell depletion with no grosschange: an example is the skin, for which the dose to
produce signs of desquamation is equivalent to cell
survival of about 0.1 % on the basis of cell survival
estimates (see paragraph 69). With a surviving fraction
between 10% and 1% there is no gross visible damage,although changes are detectable histologically. The
severity of damage that can be tolerated in a tissue ororgan depends on a number of factors including: thelevel of cell depletion that causes tissue malfunctions:the time of expression of damage; the repair andrecovery capacity of the tissue: the volume included in
the field: the total dose administered: and the overall
time and number of fractions into which the dose is
subdivided.
190. Much clinical practice involves daily fractionation on 5 days per week with approximately 2 Gy perday, i.e., 10 Gy per week. In the following paragraphs
this will be referred to as conventional fractionation
treatment. In some cases the dose given will be
converted to the Nominal Standard Dose (ret)according to the Ellis formula (see section I.F).
191. Nowadays. most treatments are given with supervoltage radiation, e.g., from a 4-20 MeV linear accelerator or from 60Co source, both of which deposit theirmaximum dose several millimetres below the bodysurface, resulting in sparing of the skin. Treatments
prior to 1950 utilized lower energy machines which
deposited the maximum dose at the skin surface.
Treatment planning has also progressed so that eachdaily fraction may be administered as 3-6 subfractions
through different portals in order to maximize dose in
the tumour and spread dose to the normal tissues.
192. In 1906, Bergonie and Tribondeau proposed
their "law" relating radiosensitivity to the proliferation
activity. Tissues with a high mitotic index showed ahigh "radiosensitivity" (i.e.. severe early damage)

an

us>

u,o ,,.,.

t--+-------------t
1--1

u,,

1110 2no ,,~ »>0sooo
XIUtOIOOISiOlDO

1----1t--------1
t---4

t----Ct----tt--1
t--1~------

t----<-----

1.J,npb node'

Hean
Stom.ad,l#ltt1Iil'.IC'

Colon
Thy1,ciid

Pnu.iury
CNStcotd)-------------_.

•-+··..··· ·-t,............................... -··········-·-·!
.....................................................

ur,·n,

si.,nOnlmucou
Onorhag1a~tTUf&b11d

U111'W')· bl:adJcr
8to.tt bdvfl)
Qipillarie:,L)mpN1k1
J-btutt bon-c
J.b111!ror11bsx

r,,
Lu

Llrctns
Adrrr~hPuaa1\'qJZU.

..... -----1 ---------•

i----1-------1................................. i.........................,..................... ··i·- -- - ----- -------i--------------~- - - -- - - - - - -------1.,..............................
.................,......................

,.........................,,......... .

l"lcrv,l········••··I

JilrJ11;-l)t·······I

Arttcv!ar c:att tl~ r

Figure VIII. Acceptable doses In radiotherapy. Both thetotal doses (conventional radiotherapy treatment) anddoses in ret are given. The definition of ·acceptable" Is the
personal view of the authors [R1]194. Table 8 shows that there is a wide variation of
acceptable doses from one tissue to another, theacceptable dose in radiotherapy being that for whichside effects are reversible. This may result from adifference in inherent cellular radiosensitivity or may
depend on critical levels of survival for limited subpopulations of cells. Some tissues react because of a
primary response of the parenchymal cells. e.g., testisand ovary. Other tissues react by a delayed depletion ofparenchymal cells, which may either be a late primary
response to radiation or a secondary response tovascular damage resulting in a loss of nutrient supply.
A third form of tissue failure results from radiationinduced fibrosis. The threshold doses are below the
1-5% acceptable doses. Both Figure VI 11 and Table 8
are summaries of the personal views of the authors [R 1J
and the doses quoted would vary somewhat if compiled
by other radiotherapists, although for the purposes ofthis Annex the differences may not he considered large.
Specific normal tissues are discussed in more detailbelow.
593

A.

SKIN AND MUCOSA

195. Because the skin and the buccal mucosa arc so
readily accessible and because the early radiation
sources delivered their maximum dose at the surface,these tissues have been more widely studied than any
others in the body. Most of the clinical concepts offractionation were originally based on clinical observations of skin reactions.
196. The threshold dose for the production of skinerythema is 6-8 Gy in a single treatment for fields
greater than about 5 cm2. This dose may cause atransient reaction a day or two after exposure withblood vessel congestion and subcutaneous oedema but
without gross effect on the epidermis. The initial
erythema may increase during the first week, but will
fade after about to days. It is followed by the mainerythematous reaction which reaches a maximum after
about 2 weeks and lasts from 20 to 30 days. This
reaction does involve the dermis and may. for larger
doses, be followed by dry or moist desquamation oreven necrosis. There may be several waves of reaction.
With fractionated radiation the tolerance dose for theskin is considered to be 6-7 Gy/30F/6w (per 30
fractions given in 6 weeks).

However, these are temporary or reversible changes of
no serious consequence. It is common practice inradiotherapy for skin to receive 50-60 Gy in 30F over 6
weeks without severe consequences [F54]. However, ina study of functional changes in the skin of occupationally exposed workers, using capillary microscopic
techniques, Leny et al. [L33) showed microscopic alterations of the capillaries without changes in the structureof the dermis after 10-30 Gy exposure during 8-25
years. Small fields have also been irradiated in experimental clinical studies of human skin prior to using
neutrons in radiotherapy [M4, K29]. Dose-response
curves for human skin are shown in Figure IX. The
threshold single dose for x rays is about 7 Gy [Jl 7).

2•0

0

;::
u

;'5

I·~

DOSE
S"•GL<
/

.

"'

:/ <

'.

i•
197. The early phase of desquamation has usually
healed by the end of a 6-week course of therapy bycompensatory regeneration of the basal layer which is
initiated when the skin function begins to fail. This
compensation can even produce new cells more rapidly
than they are being killed so that healing may occur
before radiotherapy treatment is ended.
198. Late injury to the skin appears to result fromdamage to the tissue elements in the dermis, rather thanthe epidermis. It occurs at months to years after irradiation and can take several forms. Deep fibrosis andcontraction of irradiated areas occurs with an increased
deposition of collagen in a thick mat-like network.
Progressive occlusion of blood vessels is seen. which
may gradually lead to an undernourished atrophic
epithelium with a greatly increased susceptibility to any
external trauma. Cold, heat, friction or bruising canthen lead to reversible or irreversible breakdown oftissue, in the worst instances resulting in ulceration andnecrosis. Other late changes are depigmentation,
depilation and telangiectasia. The term poikilodermia isalso used to describe atrophy, telangiectasia and dislocation of pigment.
199. The degree of skin reaction and the tolerance
dose are known to be influenced by a number ofbiological variables. including the age of the patient,
the hormonal status, and the anatomical location [RIJ.
These factors may produce their effects as a result ofdifferences in the thickness of the epidermis in different
regions, the degree of friction to which it is normally
exposed and thence the underlying cell proliferation
kinetics. Anoxia of the skin is known to give radioprotection, whether it results from local pressure or fromanaemia [R1]. Skin which has been recently grafted ismore radiosensitive than normal but a successful graft
gradually returns towards the sensitivity of undisturbed
skin [R1].
200. The tolerance dose differs for different skinappendages, as was recognized by Borek [820). Detectable changes can be seen after 3-5 Gy to hair follicles
when temporary depilation results and histologicalchanges have been reported after 1-2 Gy [RIJ.
594

10

20

30

~o

so

DOS£ (Gy)Figure IX. Dose-effect curves for human skin Irradiatedwith x rays, obtained from overage reaction between 5
and 80 days after treatment. A score of 1 represents a
feint erythema. Each symbol represents a patient [F14]201. The volume of tissue irradiated is critical, thedamage being greater for greater areas or volumes.
Cohen [C2] has reviewed this subject and suggests thatthe isoeffect dose is proportional to L-3, where Lis theaverage diameter oflhe irradiated field. Penetration of
the radiation is also of great importance. For ~ rays,
which do not penetrate through all the layers of theskin, less injury is produced with better recovery thanfor more penetrating radiation [013). This result has
been confirmed by analysis of data resulting fromoccupational exposure [B44].
202. The relationships between total dose, number offractions and total treatment time were considered in
section I.F. These were mainly derived from data on
skin and subcutaneous connective tissues, but theextrapolation to very large numbers of fractions oververy long times is still the subject of some argument.
8.

GASTROINTESTINAL TRACT

203. Damage to the intestinal tract leads to many
acute and chronic symptoms ranging from diarrhoea
and dyspepsia to u leer, strictures and obstructions
which can be life-threatening. There are, however, fairly
wide variations in the radiosensitivity of the different
parts of the gastrointestinal tract, the stomach. small
intestine and colon being the most sensitive [F54].
204. The stomach will tolerate doses up to 40 Gy withconventional radiotherapy fractionation. Beyond this,the risk of ulceration or perforation increases rapidly
with dose. This was discovered in a tragic series of treatments at the Walter Reed Hospital 40 years ago [A8,H 19] where about one-quarter of 61 patients receiving
45-54 Gy developed ulcers, some with perforation.

205. The small intestine is also a radiosensitive organ
commonly showing acute mucosa! reactions after 30 Gy
given in 3-4 weeks. These reactions are however reversible even after doses of 40 Gy. Higher doses than thiswill lead to chronic damage in the form of obstructions,constrictions and adhesions, unless a rest period is
introduced during therapy to allow repopulation totake place. The incidence of intestinal complications ismuch higher after surgery if adhesions are alreadypresent, because these prevent the mobility of theintestine, which usually spares any region fromaccumulating the total dose. Gastrointestinal complications are much reduced by protracting the irradiation
procedure [N 13).
206. The colon has a similar or slightly lower radiosensitivity but because it is not mobile it is more likely
to be exposed to the full dose. Early damage resulting
in diarrhoea occurs at 1-2 months but this is not a goodpredictor of late damage due to fibrosis and vascular
injury [Rl2].
207. The rectum is considerably more resistant thanother portions of the gastrointestinal tract. althoughepithelial denudation causes transient symptoms after
30-40 Gy of fractionated treatments [R 12]. The
oesophagus is also a more radioresistant portion of thegastrointestinal tract and can withstand doses of 60 Gy.
After higher doses fibrosis causes stricture which canlead to painful or even disastrous obstructions. Aftermuch lower doses of 20-30 Gy fractionated over 2-3
weeks, epithelial denudation leads to clinical symptomsof burning and dysphagia, but these are transient andrecovery is rapid.
C.

BONE AND CARTILAGE

208. Growing bone and cartilage are known to bemuch more sensitive to radiation than are these same
tissues in the adult. A considerable body of data exists
from children treated for abdominal tumours or fortumours of the limbs. In both situations growing
cartilage and bones exposed to radiation show a dosedependent retardation or even cessation of growth.
Such growth disturbances were recognized in the 1930s[022, S13] and 1940s [Sl4). There are many descriptionsof deformity of the spine caused by unequal irradiationof the vertebrae so that one side of each vertebral body
grows more than the other, resulting in scoliosis.
Varying degrees of radiologic change are observed in
the vertebrae, depending upon the dose and the age ofthe child [N3]. Ten Gy (given in 6 daily doses/week)
produced mild radiographic changes in a young
patient, whilst 12-20 Gy produced moderate to severechanges in most of the children aged 0-6 years at irradiation. The younger the child, the more severe the degreeof growth deformity. When fractionation results [T8]
are transformed to NSD value it is found that theapproximate threshold for producing detectablechanges varies with age, being about 300 ret between 0
and 1 year, 800 ret at 1-2 years, and 1000 ret beyond 2
years.
209. Similar conclusions were drawn from 44 children
treated with megavoltage radiation, using conventional
fractionation, compared with 15 OOO normal unirradiated children [P13]. Changes in both the sitting andstanding heights were observed. In children treatedwith less than 25 Gy, there were differences, but veryslight. Those treated with more than 35 Gy showed
greater differences. The maximum depression of growth

was seen in children whose bones were in active growthat the time of irradiation, i.e .. up to the age of 6 years
and during puberty (see also [G33, R36)).
210. Mature cartilage is known to be much moreresistant to radiation damage and the doses to produce
necrosis are high. For example. it has been noted thatthe elastic cartilage of the pinna will tolerate 60-65 Gy
in 6-8 weeks of daily fractions. The tolerance levels forhyaline cartilage arc similar. Laryngeal cartilage will
tolerate 65-70 Gy over 2-8 weeks or more than 70 Gy
in a more prolonged pattern of dosage over 10-12
weeks [B21]. With shorter overall treatment times there
can be a marked increase in the incidence of necrosis asreported by Fletcher and Klein [F20] when they
increased their dose from 48.5 to 55 Gy given in 20
fractions over 4 weeks.
211. In bone. the dose to produce necrosis is difficult
to determine because the absorbed dose is dependent
on the mineral content and changes markedly with theenergy of the incident radiation [S15]. For 50 keV
photons the local absorption in bone is 5 times that inwater, at 200-5000 keV it is similar to that in water, andat higher energy it again becomes greater than water.
Thus the doses quoted to produce osteonecrosis in theold literature may be in error by a significant amount.
depending on the circumstances [Pl4]. At the higher
energies used in modern radiotherapy bone necrosis israre.
212. In general adult bone is considered to be fairly
radioresistant, but it becomes susceptible to trauma andinfection after irradiation and has a poor regenerative
capacity. Osteonecrosis of the mandible occurs after
irradiation of buccal tumours, but this is almost always
associated with a break in the overlying mucosa,
allowing infection to commence. Radionecrosis may
occur between 2 months and 15 years after therapy[S16]: it is related to oral hygiene and precipitating
trauma to a greater extent than to dose or fractionation
scheme. A dose of 65 Gy given in 6-8 weeks does notnormally lead to osteonecrosis, but may give a greater
predisposition to fracture. This is site-dependent and ismore common in the weight-bearing head of the femur
than, for example, in the ribs [P14]. Another effect ofradiation on bone is to delay the healing process ofcallus formation after fracture. and this is worse in
adults [R13].
D.

HEART

213. For many years the heart has been considered to
be a radiation-resistant organ and only isolated
examples of radiation-induced carditis had appeared in
the literature. This was in part due to the limitation on
thoracic irradiation resulting from the much greater
sensitivity of the lungs. However, by the mid-1960s alarge number of patients had survived more than 1 year
after mantle irradiation for Hodgkin's disease and 25
cases of radiation-induced heart diseases were noted[S17]. This finding was subsequently confirmed by amore comprehensive study [S 18, Pt 9]. The changes
observed in the heart all involve fibrosis, and may
occur to varying degrees. Pericardia! effusions may leadto clinical symptoms. After higher doses constrictive
disease is seen, which may necessitate surgery, or may
result in death. In general the pericardium is a moresensitive tissue than the myocardium, althoughtransient early effects on the heart muscle have been
noted. The dose-response curve is very steep, with a595

threshold of 1350 ret. The dose to produce 5% mildcomplications is 1500 rct, and for 50% is 1650 ret.
Stewart and Fajardo [Sl8] stress the high incidence ofcomplications and severe damage after rctrcatment ofpatients suffering from Hodgkin's disease to a total
dose in excess of 60 Gy.

producing alveolar epithelial cell, depletion of which
would result in increased surface tension. nuid loss
across the alveolar wall, haemorrhage and eventually
fibrosis [V4].
F.

214. If a smaller volume of heart is irradiated thesame type of changes are observed, with diffuse fibrosisin the treated volume, but the tolerance dose for 5%
mild complications is increased to 1850 ret [S18]. Otherchanges have been observed, e.g., in the electrophysiological patterns [T9] as reviewed by Berdjis [822], but
most of these have not been as carefully quantified inrelation to dose as in the studies by Stewart andcolleagues [S18].
E.

LUNG

215. The lung is the most sens1t1ve organ in thethorax. Although there is a large functional reserve inthe pulmonary system, there is little capacity for regeneration and reformation of the elaborate structure afterwidespread cell depletion. A large literature exists onradiation responses in human lungs [V4]. In general,
radiotherapists try to avoid including large lungvolumes in a radiation field because the threshold dose
for tolerance is low. Phillips and Margolis [P2] haveestimated tolerance to be 900 ret for 5% complications
and 1040 ret for 50% complication. A dose of 700 ret to
the whole lung caused no measurable changes [C30].
The dose-response curve is however very steep [P2].
With total-body irradiation for treatment of leukaemia
or aplastic anaemia, where reconstitution of bonemarrow is performed, lung becomes the critical organ[T26]. Normally, single whole-body irradiation is given,
lasting several hours, for which the accepted tolerance
is in the region of 8 Gy. With non-uniform irradiationsuch as with 131 I for treatment of thyroid metastases in
the lung, fibrosis has not been observed, in contrast
with the effects of large fields of external irradiation.
216. Radiation pneumonitis may occur soon after
irradiation, followed weeks to months later by radiation
fibrosis. The reaction is complex, involving cell death,desquamation of epithelial cells, exudation into thealveolar space, thickening of the alveolar walls andfinally collagenous changes, possibly with calcification
or ossification [V4]. After irradiation of the chest wall inpatients with cancer of the breast, pleural effusion
leading to fibrosis has been reported [Rl].
217. The main change discernible in irradiatedpatients is radiological evidence of fibrosis [TIO, W20,
D23]. This is evident after irradiation of large or small
fields and is apparent even in the absence of any
measurable functional impairment. Fibrosis is thought
to be the end-result of a failed attempt to regenerate thecomplex units of normal alveoli. High doses to small
fields may also lead to lung fibrosis [D39]. Functionalchanges that have been observed include reduced vital
capacity and a reduced maximum exhalation volume.
The volume irradiated is extremely important.
Localized severe fibrosis can be well tolerated provided
there is a considerable volume of unirradiated tissue.
218. There is much debate about the primary cause ofradiation pneumonitis. Some authors postulate that the
primary target is the endothelial cell and that this leads
on to the occlusion of vessels, oedema and fibrosis [P2,
P6]. Others favour the damage to the surfactant596

LIVER

219. The liver, which was once considered to be aradioresistant organ is now known to tolerate doses of
40-50 Gy in 30 days to only part of the organ [K 14].
The threshold for measurable effects lo the whole liver
seems to be 30 Gy conventionally fractionated [K14, I2.
J6, K 15]. The changes observed are both dose and time
related (12].
220. In the early literature, very few irradiatedspecimens had been studied. Lacassagne [L12] quotes
only 30 livers at autopsy and about 12 studied bybiopsy in which changes after external irradiation had
been looked for. Most of the specimens were obtained
within weeks to months after irradiation and showedlesions characteristic of non-specific venous occlusivechanges. Endothelial cell sloughing, fibrosis andsclerosis are usually seen later. The most criticalelement in the liver appears to be the small central veinin each lobule. After irradiation of the whole abdomen
for cancer of the ovary when the "strip technique" wasused, liver necrosis was reported, increasing withincreasing dose per fraction [D51].

G.

URINARY SYSTEM

221. The urinary system, comprising kidney, ureter,
bladder and urethra, shows a wide range of radiosensitivities. The kidney is the most sensitive element, thebladder has an intermediate sensitivity and the ureters
are more resistant, although they seldom have their fulllength irradiated. For irradiation of abdominal
tumours, kidney change is frequently a limiting factor
and the kidneys are often shielded or the irradiation
field shaped to avoid their exposure if possible. The
kidney is a complex organ and a variety of functional
disturbances are observed, including acute or chronic
nephritis, hypertension and proteinuria [M21]. Stenosisof the ureters is a frequent complication of irradiationof the pelvis [F54].
222. Acute nephritis occurs within 6-12 months andcan be lethal, or may lead to chronic nephritis. Somepatients develop chronic nephritis without an early
acute phase. The pathology of early nephritis iscomplex with glomerular, tubular and capsularchanges. Chronic nephritis is characterized by sclerosis
and fibrosis. Hypertension usually accompanies thesechanges. It appears earlier after higher doses, anddepends upon the proportion of kidney that has been
irradiated.
223. Less severe damage can be detected as changes inrenal function. A fractionated dose of 20-24 Gy in 3-4
weeks usually produces between 10% and 60%
reduction in renal plasma now, with a reduction inglomerular filtration rate. The tolerance dose for thekidney is therefore normally set ,at about 23 Gy/5
weeks. Higher doses may be given if radioprotection isachieved by vasoconstriction with epinephrine. As withanimals, renal injury is more severe in the young
human. Urinary examination of children who werein utero during the atomic explosions at Hiroshima andNagasaki revealed proteinurea which was not found in
adults [F43].
224. The bladder will tolerate 55-60 Gy given in 20
fractions over 4 weeks [M22]. It is usually exposed to ahigh dose when cervical cancer is treated withcombined external beam and radium implants. The
damage observed ranges from erythema to fibrosis,
ulceration and contraction. A minor symptom is thefrequency of urination but severe oedema of theureteral orifices can lead to back-pressure on thekidneys resulting in hydronephrosis which may be fatal.
Little information is available on the effects ofradiation on the normal prostate. Late effects may
includeobstruction,
incontinence,
and,
most
frequently, impotence.

H. CENTRALNERVOUSSYSTEM
225. The central nervous system was in early times
regarded as a radio-resistant tissue. It has, however,negligible capacity for repopulation and there is now
much evidence from physiological experiments andradiotherapy experience for it no longer to be regarded
as resistant [L14, G24, G25, G26, B42, G44]. The lesions
generally observed are consistent with the primarydamage being to the vascular system and death orparalysis may result at times varying between 3 months
and 9 years, although mostly between 1 and 3 years.
Occasionally, an acute demyelinating process has been
observed [R14, L19] after moderately high doses (inexcess of approximately 60 Gy given in fractionatedtreatments), which may be transient or lethal. For a
recent review see [G44].
226. It is believed that relatively few large fractions,or just excessively large total doses are the cause of
most of the 57 cases of radiation-induced brain
necroses that have been found in a review of the world
literature [Kl6]. In this review only 1 case of dementia
was reported [W21] although this symptom has been
seen with higher frequency after fast neutron irradiations [C21]. This effect of size and number of fractions
is observed also in the spinal cord and has been
confirmed by animal studies (see paragraph 134) [G6,G7. V8, W6].
227. The tolerance dose for the whole brain is thought
to be about 55 Gy fractionated over 5-6 weeks. An
extra 10 Gy is sometimes given to a small area
containing a tumour. For small parts of the brain 65 Gy
fractionated over 6.5 weeks is considered safe. If thesedoses are exceeded, brain necrosis may result [Kl6,G27]. The threshold for morphological changes isapproximately 40 Gy when fractionated [040). A recent
review of the subject has been made by Franke andLierse [F45].
228. For the spinal cord the tolerance doses are lower
than for brain. The estimates of a safe dose for cervical,
thoracic and lumbar cord vary from 35 Gy in 4 weeks[PI 6] to 50 Gy in 5 weeks [K 16, PI 7). The dorsal cord
appears to tolerate a dose of 45 Gy in 4.5 weeks [K16].
Transient radiation myelopathy occurring 3-4 months
after therapeutic irradiation (in the range of 26 Gy over
29 days to 56 Gy over 70 days) has been reported. Thisis described as similar to the perception of an electric
shock when the spine is flexed [J23]. It is important thatinjury to the cord is inversely related to the length ofcord irradiated [Pl 8].

229. · Months or years after irradiation (local or wholebody), diffuse demyelination and encephalitis may
result [G26, B42, G25, G28). After irradiation of thehead with single doses mostly between 3 and 12 Gy (butup to a maximum of 30 Gy) acute radiation was
followed between 3 and 10 years later with small
degrees of demyelination and changes in brain circulation [G25, G27, G30]. In one individual who accidentally received 30 Gy to the head. brain necrosis had
developed by 3 years [G30]. Thirty to 50 Gy given in
fractionated radiotherapy at 2 Gy per fraction or single
treatments between 3 and 10 Gy caused profound
functional disturbances of the CNS, resulting in, forexample, impairment of memory and weakness [G30,G28]. Functional changes after radiotherapy to thecranial axis region in children with medulloblastoma
have been reported. Survivors for more than live years
developed changes in character, impairment of memory
and learning ability and even dementia and idiocy
resulted if the age at exposure was less than 1.5 years.
Severity of impairment was related to age at irradiation.
Children with acute lymphatic leukaemia irradiatedwith 24 Gy over two weeks to the CNS developed lossof memory (883].
I.

GONADS

230. The ovary is a highly radiosensitive organ. It
contains a limited number of germ cells which cannot
be replaced if they are depleted. A loss of all the ova(approximately 400 OOO in an adult human) results intotal sterility. Table 9 shows some of the publishedobservations on doses causing sterilization in women.
Single doses of 1.7-6.4 Gy have been shown to cause
temporary sterility, with higher doses required to
produce the same effect when fractionated. Permanentsterility results from 3.2-10 Gy in a single dose, or
higher fractionated doses. Doses in the range of 5.6 Gy
almost invariably produce permanent sterility. Doll andSmith [020] reviewed over 2000 women treated formenorrhagia by irradiation. A value of about 6 Gy
given in 2-4 fractions was referred as the dose to ablate
the human primordial oocyte population.
231. The radiosensitivity of the ovary depends on the
degree of maturity [M24] being more resistant in young
women, although the differences with age are hard to
estimate [A24]. This is unlike other species of animal.
Also, in women, unlike in rodents, the ova seem moreresistant than the bone marrow.
232. Very small doses of radiation were used in the
1920s to 1940s to treat infertility. A treatment of threetimes 0.5-0.75 Gy in 3 weeks to the ovary was reported
to increase the fertility of many women treated foramenorrhoea, resulting in normal pregnancies, normalchildren and normal grandchildren [K 17]. There seems
to be little or no evidence of an increase in malformed
offspring resulting from conception after irradiation of
the ovary or testis [L16].
233. The testis is also a sensitive organ, as indicated inTable 10. Doses as low as 0.1 to 0.15 Gy have beenrecorded as causing temporary sterility, although > 2
Gy and possibly about 6 Gy are needed to produce
permanent aspermi:L Type B spermatogonia seem to be
exceptionally sensitive, with Do being about 0.2 Gy. The
seminiferous epithelium in man requires many years
before recovery of the spermatogonial series may becompleted [L16]. Japanese fishermen exposed to fallout
received doses of gamma rays estimated at about 1.4 to591

6 Gy over 14 days, corresponding to approximately
0.7-3 Gy given as single doses. Their sperm counts wereseverely depressed, but began to increase by 2 years
after exposure and most of these men produced healthy
children [K51].
234. The testis is unusual in that fractionatedtreatment may be more effective than single doses, e.g.,
20 doses of 0.25 Gy each cause a more rapid depletion
and a slower recovery than after a single dose of 5 Gy
[L16, 1-121 ). This is attributed to the stimulation ofrelatively resistant type A spcrmatogonia into the much
more sensitive type B compartment.
J.

THE EYE

235. The eye was recognized as being vulnerable
almost as soon as x rays were produced. It was also
soon realized that the different components of the eye
had different sensitivities, and that the lens was
especially sens1t1ve when uniformly irradiated.
However, the threshold is greatly increased by nonuniform irradiation (881]. Although epithelial tissues
around the eye seem to have a sensitivity similar to thatof skin, the human lens responds to doses of - 2 Gy ina single treatment, or - 4 Gy when fractionated,
resulting in the formation of cataract [M25]. Table 11
indicates the sensitivity of different parts of the humaneye.
236. The extent of cataract formation, as well as theincidence, is dose dependent. Higher doses yield moreprogressive cataracts with greater loss of vision. The
latent period varies from 0.5 to 35 years, with anaverage of 2-3 years, although this latency is also dose
dependent [Fl8). Minimum stationary opacities havebeen observed after single doses of 1-2 Gy, but with 5
Gy more serious progressive cataracts occur. A single
dose of 7.5 Gy causes some degree of cataract
formation, with a probability of occurrence of 100%.
The lens is spared by fractionation with the slope ofStrandqvist curve perhaps slightly less than that forskin. Ten Gy over 3-12 weeks was shown to give 75%
incidence of cataract and 14 Gy over the same period
leads to 100% incidence (H25].
237. Occupational exposure during 10 or 20 years has
also been shown to affect the eye. At between 0.5 and 2
Gy the optical density and staining properties of thelens were increased. For doses between 1.5 and 4 Gy
the frequency of senile cataract was significantly
increased together with changes in the vascular system[L28, L29]. With mixed gamma and neutron irradiation,
doses of 0.7-1 Gy produced changes [L29]. Recent
reviews [C23, 853, 835) suggest that the threshold forcataract for occupational exposure or lengthy fractionation is in the range of 6-14 Gy.

K.

HAEMATOPOIETIC SYSTEM

238. The haematopoietic system is one of the moresensitive tissues in the body. Responses can be seen
after 0.5-1 Gy of radiation, whether it is given as asingle exposure [87) or as a series of small fractions[Tl 1). The bone marrow is the source for most circulating cells, the lymphocytes, granulocytes, erythrocytes
and platelets. The response of the peripheral elements
depends upon their normal turnover time, except thatthe lymphocytes respond very rapidly. These cells are
598

unusual in that they are generally believed to be differentiated end-cells yet are extremely radiosensitive, witha D0 of 0.2-0.3 Gy [TI I I and undergo interphase rather
than mitotic death. There are also thought to be
subpopulations of lymphocytes with different sensitivities [E20, S75]. A depiction of the lymphocytes is seen
within hours after irradiation, whereas the fall inplatelets and granu locytcs is delayed for several days
and the fall in erythrocytes occurs slowly, over weeks[87]. The differential and total blood counts bear somerelationship to dose received but the response of thelymphocytes is sufficiently dose dependent for it to be auseful dosimeter in some circumstances. The time atwhich the peripheral elements return to normal
depends upon the level of dose and hence on depletionof the bone marrow. After higher doses, the rate ofrepopulation appears to be greater than after low doses
which cause little depiction [B7].
239. Mitotic abnormalities are observed in the bonemarrow cells from about a few hours to two weeks after
irradiation [F21, P28) but no prolonged systematic
study has been performed at much later times. In thebone marrow of Japanese fishermen exposed toradioactive fallout in 1954, chromosome aberrations of
the stable type were found 15-25 years after exposure[K51].
240. If the depression in peripheral blood cells is too
severe the patient may die from infection (due to loss of
granulocytes) or haemorrhage (due to loss of platelets).
The timing of death from the haemopoietic syndrome
in man (at 3-6 weeks after exposure) coincides with theperiod of maximum depletion in these peripheral
elements. In other species the maximum depletion andthe ''haemopoietic death" also coincide but usuallyoccur at 10-30 days. The reason for this species
difference in timing is not understood [B7]. The
influence of radiation on the reticulo-endothelial
phagocytes of the spleen and liver in maintaining thebloodstream free of bacteria is important, and theability to resist infection may be reduced by doses
smaller than those required to cause death [M26].
241. Long-term changes resulting from irradiation ofbone marrow also occur. Evidence comes from threesources: local radiotherapy, systemic irradiation andatomic bomb survivors. Reduction in numbers of whitecells was found up to 7 years after radiotherapy ofmammary glands and adjacent tissues with doses of50-150 Gy over 1-3 months [D39). After localized
irradiation at rather higher doses than can be tolerated
by the whole body, long-term changes in the irradiatedbone marrow have been observed, although the reserve
capacity of the untreated bone marrow will maintainthe peripheral blood count at a normal level. Localchanges have been observed up to 3 years after
fractionated treatments of 20-65 Gy delivered locally,
and up to 18 months after 40--45 Gy to the sternum[S19). Baisogolov and Pavlov [850) investigated 45
cancer patients between I and 36 months after local
radiotherapy. Persistence of bone marrow aplasia wasdose-dependent with a threshold of 30 ± 5 Gy.
Hirashima et al. (1-168) showed that after local radiotherapy for uterine cancer to a total dose of 60 Gy in 1
month, the functional activity of T-lymphocytes was
significantly impaired immediately and at one year
after therapy, but had returned to normal by two years.
In an analysis of nine patients who received nonuniform irradiation of bone marrow between 2 and 5
Gy, Sudovora et al. have shown that recovery is
governed by the repopulation of individual areas.

indicating an absence of migration of human haematopoietic stem cells [S78]. In A-bomb survivors decreased
white blood cell counts have been observed for up to 15
years, accompanied by changes in the bone marrow[W23]. Extra-corporeal irradiation of human blood fortreatment of leukaemia has shown that red blood cells
and platelets are very radiation resistant but lymphocytes are sensitive [Cl 5}.
242. Thus the effect of small doses of radiation to thehaemopoietic tissues may produce a profoundresponse, but unless the total bone marrow stem cells
are depressed below a critical level, the numbers ofperipheral blood cells will recover and the patient willsurvive. After acute, accidental exposure the LDso for
man is between 3 and 5 Gy [LI 7] but maintenance insterile chambers, antibiotics and careful medical
support. including transfusions and bone marrow transplants, have enabled accident victims to survive higher
doses.

have been discussed in detail by llewley [B25) and Rossi{R17), LET. although a useful parameter for describing
radiation quality. is by no means fully adequate [15).
247. An alternative method of specifying radiation
quality is based on the lineal energy, y, (the energy
deposited in an event, divided by the mean chord
length of the volume in which it occurs) and z (theenergy deposited by one or more events, divided by themass of the volume in which it occurs) as recommended
by the ICRU [I3]. Spectra of y and z may be measured
using small proportional counters filled with approximately tissue equivalent gas [R17] but as yet neither theexperimental techniques nor biological knowledge are
adequate to predict biological effects.
B. BASIC DIFFERENCES IN RESPONSE TO
PHOTONS AND HIGH-LET IRRADIATIONS
1.

IV.

EFFECTS OF RADIATION QUALITYA.

BIOPHYSICAL ASPECTS

243. Energy is deposited by radiation as discrete"events", with about 50-100 eV of energy absorbed per
event [110]. According to target theory only one or few
such events are required to elicit a biological response,such as cell death. The quality of a radiation determines
the biological response. the quality of two radiations
being deemed the same if the biological effect per unit
dose is the same. The quality of a radiation is thought tobe primarily determined by the microscopic distribution of energy along the tracks of the particles. In thecase of photons and neutrons these are secondary
tracks. photons producing secondary electrons andneutrons secondary protons and other nuclei.
244. Specification of radiation quality is difficult. The
most used parameter is Linear Energy Transfer (LET)
where Loo = total stopping power of a particle in tissue.
The width of the track core is often specified, e.g., L200
specifies energy transferred per unit length of track toelectrons having initial energies of 200 eV or less.
Electrons with greater range will be considered as
producing separate tracks (o rays) [15].
245. The Relative Biological Effectiveness (RBE) isdefined as the dose of a reference radiation (usually of
low-LET x rays) divided by the dose of the radiation inquestion to produce a given level of damage. If the
RBE is referred to 60Co gamma rays or high-energy xrays, it is approximately 10-20% greater than if thereference radiation is 250-kVp x rays. However, thisdifference could be greater at very low doses [882).
RBE is a relevant parameter only if the damage is qualitatively identical in the two cases. This is normally thecase, but two examples of differences in response tophotons and neutrons are the gut architecture [H29] andthe disappearance of cells of the subependymal plate in
the brain [C11].
246. It is known from experiments on cells, using the
track segment technique, in which particles of a specificenergy traverse a cell, that RBE increases withincreasing LET to a maximum value and thendecreases. For a neutron beam there is a spectrum of
secondary charged particles and a mean LET may be
calculated. This may be a "dose mean·• or a "track
length mean". However, for a number of reasons which

Oxygen effect248. With few exceptions throughout radiobiology.
cells and tissues are more sensitive when irradiated in
the presence of oxygen than in its absence. With
increasing LET there is a constant decrease in theoxygen enhancement ratio (OER = ratio of doses withand without oxygen to produce a given .level ofdamage) such that with mammalian cells the OER
becomes 1 at a LET of about 180 keV /µm [826]. Over a
very wide range of neutron energies up to 50 MeV orprobably greater, the OER is significantly reduced
relative to photons, but to an approximately constantvalue, independent of energy, of about 1.5-1.8 [H22].
With lower energy neutrons (e.g., fission neutrons) the
OER is rather less. between 1 and 1.5 [B27]. These
values compare with 2.5-3.0 for photon irradiations. As
a neutron beam penetrates into tissue. the OER is
hardly altered [M27. 828, N5. 829].
2.

Repair as a function of radiation quality

249. Differences in biological effectiveness of beams
of varying quality are markedly affected by differencesin the ability of the tissue to undergo the various repair
processes. It is also important to establish whether or
not the gross biological response of a tissue is similar
after different qualities of radiation. If not, the concept
of RBE is inapplicable.
250. Repopularion (see Section LB.). It is necessary toestablish whether or not repopulation is the same after
comparable doses of x rays or fast neutrons for two
reasons. One is that an analysis of RBE depends on
there not being a difference and the second is to obtainknowledge of the effect of repopulation as a mode of
repair during a protracted course of high-LET
radiation. In general, it appears that there are noimportant differences in repopulation after x rays or
fast neutrons [830, B31, C16, 024, 025, F2, F14. F22,
F23, F24. F25. H23. W24].
251. Sublethal damage (see Section LB). With
increasing LET the shoulder of a cell survival curve
becomes reduced and repair between fractions is less.
This difference is illustrated schematically for x rays
and neutrons in Figure X. A major effect of thisdifference between neutrons and x rays is that the RBE
is dose dependent, increasing with decreasing dose ordose per fraction. With fractionated irradiations, theRBE will primarily depend on the dose per fraction,
599

Dos,

pearance of chromosome aberrations in liver irradiatedwith x rays, but not with neutrons, which may also be amanifestation of slow repair.
256. The indications are therefore that with x-irradiation slow repair may occur in slowly dividing tissues,
but is absent after neutrons. This has two consequences:(a)Figure X. Hypothetical survival curves
for x rays and neutrons Illustrating thesmaller shoulder on the high-LET curve
and the consequent Increase In ABEwith decreasing dose per fraction [F26]providing any repopulation between fractions is indeed
the same after the two types of radiation. Since the dose
per fraction depends on the number of fractions, theRBE will also, but secondarily, depend on the fraction
number. Tissues exhibit a considerable degree ofsparing due to recovery from sublethal damage, usually
far more than for cells in vitro. Therefore, at low doses
per fraction, the RBE for tissues may have high values.
252. These RBE considerations were first tested invivo using pig skin. It was shown that the RBE
increased with increasing number of fractions (due tothe decreasing dose per fraction [Figure Xl). It wassuggested that this increase in RBE might explain thesevere reactions observed by Stone [S20] in an earlytrial of neutron therapy, since the original dose calculations were based on information from single treatments
and various fractionated regimes were used in theclinical trial [F27, S2l].
253. Recovery from sublethal damage may occur later
for neutrons than for photons. There are some results
consistent with this observation [F26, B32] but others
which are not [H24, G16] and the question is not yet
fully resolved.
254. Potentially lethal damage (PLD) (see Section
I.B.). Whereas sub lethal damage occurs during aninterval between two dose fractions and manifests itself
by repeating the shoulder region of the cell survival
curve normally without a change in D 0 , PLO does not
require a second dose but only time before allowing
further cell division to occur and is normally manifest
by an increase in D0 • It appears that PLO is much
reduced or absent after neutrons [H25, G16, S2].
255. Slow repair (see Section J.B.) It was shown [F8]that when two doses of x rays were given to mouse lung,there was an increase in LDso due to pulmonary
damage with increasing separation of the two treatments. During the first few hours after the initial dose
this increase in LD50 is attributed to repair of sublethal
damage between the two fractions, but the further
increase was slow repair. In similar experiments withneutrons the initial repair of sublethal damage wasobserved (although, as expected, much reduced) but nofurther slow repair was observed. This phenomenon isthought not to be due to cell repopulation [C31]. It has
also been shown by Curtis [Cl] that there is a disap600

The RBE for slowly dividing tissues would
increase with increasing overall treatment time.
Such an increase has been observed for skindamage with fractionation over 6 months
compared with the same number of fractions inshorter time intervals [F9];(b) There would be a greater degree of residual injury
after neutrons than after x rays because of longterm repair occurring after x-ray damage but not
after neutron damage. Some evidence along theselines has been reported [D5, HS, F7].
257. As slow repair occurs after x rays then long
fractionated regimes should spare slowly proliferating
tissues which are presumed to be those involved in lateradiation reactions. Such sparing of tissue damage
would not occur with neutrons, so that the RBE would
be higher for late than for early damage. This is acontroversial issue and is not fully resolved at present.

C.

RBE AS A FUNCTION OF NEUTRON
ENERGY258. In recent years a variety of neutron sources havebeen used for radiobiological experiments relevant toradiotherapy. These neutrons are generally in the range
6-50 MeV. In contrast, most work on lower energy
neutrons was done earlier when the dosimetry was even
Jess certain than it is today.
259. Hall et al. [H35] presented RBE as a function of
the mean neutron energy for various in vitro and plantsystems and showed that RBE was maximal at about
400 kV (Figure XI). In general, the RBE at 400 kV was
4 times that at 10 MeV. This result is in broad
agreement with predictions based on the theory of dual
radiation action [K20]. Fission neutrons would
therefore have about twice the RBE of fast neutrons[026, D28, S24].
260. With normal tissues, most comparisons of RBE
with different energy neutrons have been obtained for
jejuna! crypt survival. Hendry and Greene [H36] haveshown that the RBE of uncollimated monoenergetic
neutrons (14 MeV d-T) is much smaller than for collimated beams [B36, H37] indicating that the dose fromscattering material contributes an important element toneutron dose, at least with intestinal damage. RBE
comparisons on both gut (clonal assay) and skin(average skin reactions) have been made for a variety ofbeams. The preliminary results are summarized in
Figure XII [F29]. In this case neutrons were produced
by deuterons of a given energy onto a beryllium target.
The neutrons produced have a spectrum of energies, themean being about 40% of the deuter.on energy. It isclear that the RBE decreases with increasing energy
and for neutrons of Ed = 16 MeV(Be) 1 it is 30-40%
greater than for Ed = 50 MeV(Be).

1
Ed - deuteron energy; e.g., 16 MeV(Be) deuterons onto a beryllium target.

16 MeVNEUTRON ENERGY (MeV)
,_

~~

100

0.1

:~~y•

8~ 20
::::w

100

10

~ ~ " " " I

TD= NSDNN°·04 T°· 11~/
IKtlltrt1 8 R.:iui, 19731a10.-------------------,
P3B8 LEUKAl}l!A C[LLS
6

w

a:,

a:

:

~_):~~:~;.

d-T·•~
I .___ _ _ _ _ _ _ _ _ _ _ _ _ _ _...!b:'...ll~i:--T-,-CE_L_L_S,-B-0_%_5-UR_V_IV_A_L--------~,
w
a:

Cl

I '------------------C=:..J
IOO.--r-~rrn....--.-~~~~~~~-~~~TRADESCANTIA

60w

In the case of skin, the T factor is probably due torepopulation and was therefore specifically chosen to
be the same for x rays and neutrons. The exponent of N
is less because sublethal damage is less for neutrons.
The formula was used successfully in the Neutron
Therapy Clinic at Hammersmith Hospital when theroutine neutron fractionation regime had to be altered.

4

2

co
a:

262. For clinical usage the Ellis formula has beenadjusted, based on isoeffect curves for early skindamage, i.e. [r-30]

40

20

.. ,
100

10

01

0.01

NEUTRON ENERGY (MeVl
Figure XI. RBE as a function of neutron energy for plantand mammalian cells In culture. The top panel Is a theoretical curve. The peak RBE at 0.3-0.4 MeV Is clearly Illustrated and It Is a factor of 3 or 4 greater than the RBE for
neutrons of energies In excess of about 10 MeV. The photon dose ranges were 2-12 Gy for the mammalian cells,
0.5-6 Gy for Vlcla faba and 0,1-4 Gy for Tradescantia[H35]
Neutron RBE
relolive to

W • GUT (W1THCRS. PC)
A ~ GUT (WITHCRS, '9-:'.Q
1--t • GVT1t-CPO>l1'&.G:;££J£,197G)
G 'GUT{&w•.n,1c1131'5.)

Ed=SOMeV(Se)o\ TAMVEC
1·5\·4R • SKIH(RASEY, PC)

S '- SJ1JNIBEWlcYt1c.lffr£)* t,£RMAllZED tolal T:..MVEC
~

w
fN/

1·3

~~

s

G

1-2

263. Exponents of N and T for tissue damage, whenmeasured for both x rays and neutrons, are given in
Table 12. They are seen to vary from tissue to tissue but
the factor for both N and T is small after high-LET
radiation, indicating little or no sparing by fractionation. Small T factors indicate the Jack of time-related
repair after neutrons in slowly proliferating tissues.
Small N factors may be a reflection of the highest LET
component of the neutron dose playing the dominantrole at low doses per fraction. Support for this interpretation is given by the reduction in OER observed withincrease in fractionation of neutron dose [H33].
Domination of the low dose region of the neutron
survival curve by the highest LET component of thebeam implies that the initial region of a neutron
survival curve would be exponential and with higher
doses would bend downwards [H34, G20]. This would
lead to the requirement for increasing the dose ofneutrons to produce a given level of damage only onchanging from a single dose to two or three fractions(i.e., on the bending part of the curve) without further
increase with increasing number of fraction, as is seen
to be the case with most tissues.
E.

NEUTRON RBE FOR NORMAL TISSUES

264. There are two ways of examining the nonstochastic effects of neutrons. One is the direct examination of tissue response to the high-LET radiation;
this is clearly the most desirable, but the information on
it is rather limited. The second method is to study the
RBE for various tissues, as a function of dose level.
This is a less direct approach, but if RBE considerations can be generalized, as seems to be the case, thenby using RBE as the conversion factor much of theavailable low-LET information can be extrapolated toneutrons or other high-LET radiation.

M

1·0

15

20

25

40

45

50

Deuleron energy on Beryllium

Figure XII. RBE for skin and Intestine, as a function ofneutron energies In the therapeutic range, I. e., meanenergies from about 7 MeV upwards [F29)D.

265. The relationship between RBE and dose/fraction
for damage to a variety of normal tissues was analysed
by Field [F28] who showed, as predicted from survival
curves, that the RBE was high at low doses per fraction
and decreased as the dose per fraction increased. The
curve drawn through this data was used by Sheline etal. [S21] to calculate the appropriate RBE values andthus equivalent doses of x rays in a reassessment ofStone's first neutron therapy trial.

NEUTRON FRACTIONATION

261. The two major factors governing the effects offractionation of dose in radiotherapy are the number offractions N and the overall treatment time T In the Ellis
formula (section l.F.). Values for the exponents of N
and T for damage to subcutaneous connective tissues
are 0.24 and 0.11, respectively, for x rays. It is now clear
from animal work that the exponents for N and T varyfrom tissue to tissue [AlO, H28, H66, H67, W6, Vl].

266. With the accumulation of more data it became
apparent that the RBE was different for different
tissues [H26]. This has been particularly clearly demonstrated with the Ed = 16 MeV(Be) beam from theHammersmith cyclotron giving neutrons with a meanenergy of about 7.5 MeV. More data exist from thisbeam than from any other. There are variations in RBE
between different tissues of almost a factor of 2 (Figure
XIII). Variation in RBE for normal tissue has also been601

Ed=l6"4cV(Bc)

0

0

u

•

"'2
,_
<t:

....I

w
c,-

w

UI

"'
2

5

10

15

DOSE PER ffl/\CTJOti or fl£UTROUS (Gy)Figure XIII. RBE versus dose per fraction for neutrons produced by bombarding beryllium with 16 MeV deuterons. In allcases there Is an Increase In RBE with decreasing doses per
fraction but there Is an overall factor of about 2 In the range oftissues Investigatedshown for other neutron beams [F29]. Differences in
RBE have been mainly associated with differences inthe degree of repair of sublethal damage [833, H27] but
slow repair may also play a role with some tissues.

1.

Skin

267. More data are available for skin than for othertissues. The RBE for damage to skin of mouse, pig, rat,
and man is shown in Figure XIV. The curve applies todamage leading to erythema, desquamation and regenerating clones of cells in the four species. The fact thatthe results from experimental animals and man fall on
the same curve indicates that it is reasonable, at least
for skin, to extrapolate results from animals to man. As
predicted by theory [K20] over most of the dose range
the RBE increases with decreasing dose, and the sameis true for irradiation at low dose rates, for example, by
252Cf [K29]. At the highest dose levels the RBE tends toincrease with increasing dose, and this is due tohypoxia in the skin which will only be important withthe largest doses. The above reactions observed in skinare primarily the result of damage to the basal epithelial
layer. However, some observations on late damage(deformity in mice feet) also fall on the main curve in
Figure XIV. This type of late damage has been shownto have a well-defined threshold which is higher thanthat for the production of an early reaction (as in thecase with photons), after which there is a rapid increasein effect with increasing dose.

268. The relationship between early and late reactions
was found to be similar for various treatments, both
single and fractionated, photons or neutrons. It is,however, doubtful whether the late deformities seen inrodents are relevant to the human problem. In rodents
these early and late reactions may stem from a common
cause [F5, D6]. Rodent skin is very thin compared with!hat in larger animals and man and does not respond by
producing extensive late subcutaneous fibrosis as isoccasionally seen in patients following radiotherapy.
Rodents may not therefore be suitable animals in whichto study late skin damage relevant to that which occurs
in man. despite the close correspondence with the early
reactions.
269. In studies on pig skin, Withers et al. [W25] found,in a 6-week course of treatment, that gamma rays given
twice weekly produced a worse late response than 5times weekly, for the same early response. With
neutrons (Ed = 50 McY(BE)) they found no increase insparing of late damage with an increase in neutron
fractionation from twice weekly to four fractions
weekly and both neutron regimes gave a more severelate response for a given early response than either ofthe gamma ray regimes. However, the authors suggestthat this was probably associated with the increased
absorption of neutrons in the subcutaneous fat. Humanskin was irradiated with x rays and fast neutrons toestablish RBE values for a neutron cancer trial [Fl4].
The results are quoted in Table 13.
270. Hendry et al. [H28] investigated necrosis inmouse tails. Necrosis seems to arise from an unhealed
ulceration and closely follows the acute skin response.
The RBE values both for skin damage and necrosis in
tails are higher than those observed for other acute endpoints in skin [Al OJ. However, the tail acts as a temperature-regulating organ, and there is evidence of hypoxia
in its skin which affects the sensitivity even at 16
fractions of 2-3 Gy x rays [H24]. This might increase
the dose required to produce an effect and also be
responsible for the high RBE values observed.
271. Retreatment of rodent skin a long time after a
primary treatment with x rays or neutrons has shown
more residual damage remaining after neutrons
compared with x rays [H8, F7]. This implies that theskin tolerance dose for either x rays or neutrons (andpossibly for other trauma) will be less after previous
neutron treatment than after x rays.
272. In summary, the RBE for single doses ofneutrons for production of skin damage is 1.5-2 andwill depend on the neutron energy. The effect offractionation with neutrons is much less than with xrays, and beyond two fractions the main contributing
factor will be repopulation. A summary of thresholddoses is given in Table 13.
2.

6

8

10

12

14

DOSE PER FRACTIOII OF IIEUTRDrlS (Gy)Figure XIV. RBE versus dose per fraction for the skinof four species. H, human; P, pig; R, rat; M and C,
mouse. The subscripts Indicate the number of fractions used. It Is clear that the Important factor Is thedose per fraction, not the number of fractions

602

Gastrointestinal system

273. RBE values for oesophageal damage in mice arerather higher than for most other tissues [H27, P20,
G18J. The damage is primarily to the basal epithelial
cells [P2, K5] which are of ectodermal origin, and one
might therefore expect RBE values similar to those ofskin rather than intestine. The histology of the mouse
oesophagus is also similar to skin. However, hypoxia
has been shown to influence the oesophageal sensitivity
in anaesthetized mice, at least at high doses per fraction[H2]. Minimum single doses of neutrons required tocause oesophageal death of mice are at least 8 Gy in asingle treatment and 20 Gy in 10 fractions in 11 days
[H2. P1).
274. RBE values for acute intestinal damage have
only been derived for mice. In general the values
obtained are slightly higher than those for skin (Figure
XI) and this may be due to the greater reduction insublethal damage compared with other tissues. For
example, the fraction of recovery from sublethal
damage after neutrons of 7.5 MeV mean energy
compared with that after x rays was 0.2 for gut damage
compared with 0.4-0.6 for skin damage [F23]. The
minimum single dose of this energy neutrons to
produce either a reduction in crypt count or animal
death was close to 4 Gy in a single treatment.
275. When two fractions of neutron are given, there isa small degree of repair of sub lethal damage. However,when the fraction number is increased above two. there
is no further sparing of neutron dose [W2]. There will.
however, be sparing due to cellular repopulation, just as
with x rays.
276. The homeostatic control in the small intestine issuch that although there may be rapid regeneration ofstem cells in the crypt, the numbers of cells differentiating may be considerably depleted by cell death infractionated regimes in therapy. This can be seen in a"stunting•· of villus height [MS] which is first noted after
doses greater than 1 Gy neutrons or in a change of thesurface architecture seen with the scanning electron
microscope [H29]. Differences in response for a given
level of crypt loss were seen using these techniques for xrays and neutrons with single doses and these differences may be exacerbated with fractionation. The architectural changes may be more relevant in the case oflong fractionation regimes but results are not yet availabile.
277. Late damage leading to fibrosis and narrowing of
the lumen or adhesions and ulceration may occur.
Geraci et al. [Gl 7], following irradiation of a 4-cm
segment of the ileum, have taken death within 6-90
days as a measure of such late intestinal complications
which occur at higher doses than that for the early
syndrome. These workers have suggested that the RBE
is also greater than for acute intestinal damage but datafrom which conclusions may be drawn with any
certainty are inadequate.
278. There is, in conclusion, no further effect ofincreasing the number of neutron fractions above 2, i.e.,
the exponent for N is zero, in contrast to the effects of xrays. There will, however, be considerable sparing
during protracted irradiation by cellular repopulation.
Single doses of neutrons greater than 4 Gy can cause areduction in the number of crypts leading to animal
death. Doses greater than 1 Gy cause architecturalchanges in the intestine.
3.

Cartilage

279. The RBE for fast neutrons has been measured for
growing cartilage. using two different methods. Kember[K 19] counted surviving clones in the cartilage of
6-week old rats and obtained RBE values slightly
higher than by the method of Dixon [D4, D27] whoquantified stunting of growth in 7-day old rats. The
average value for these measurements was similar to the
RBE obtained for skin at the same level of dose per

fraction. The results of Dixon [D27] indicate nothreshold for neutron-induced stunting in the young
rat. It was found that 1% stunting was caused by 0.13
Gy of fast neutrons. Kember [K19] measured a Do forneutrons of approximately 0.8 Gy which is similar tothat obtained in other tissues.
280. It has been suggested that cartilage in adults
might contain a large fraction of hypoxic cells because
the tissue is relatively avascular. Experiments by Dixon[D4] who varied the oxygen concentration in the air
breathed by young rats showed that all the cells wereslightly protected from x irradiation by hypoxia. butthat the effect was insufficient to cause a large increasein RBE. Kember [K 1] was unable to improve theoxygenation of the cartilage in young rats by the
animals breathing hyperbaric oxygen. Whether theseresults may be extrapolated to man is not clear.
4.

Lung

281. The RBE for lung damage to mice is lower thanfor skin and most other tissues, with the exception of
the bone marrow (see subsection IV.E.5) although thedifferences are not great. Unlike skin but similar tointestine, there is no further sparing of damage by
fractionation of neutrons beyond splitting the dose
[Fl 7]. This is in contrast to x irradiation, from which the
sparing of damage to lung continues to increase withfractionation [H30]. This difference may be due to slow
repair. which is important in lung (and possibly in othertissues which have a slow cell turnover) and which does
not occur after neutrons [F8].
S.

Nervous system

282. Spinal cord. The spinal cord shows considerable
capacity to repair sublethal damage after x irradiation.
The D2-D1 values for x rays are large ( - 9 Gy) and theslope of the isoeffect curve from 1-30 fractions is - 0.4[W6. V8]. Using 15 M_eV D-T neutrons, van der Kogel
and Barendsen [V6] have shown little recovery fromsublethal damage after neutrons and the isoeffect curveis flat between 5 and 23 fractions. The RBE values
obtained were similar to those for other normal tissues
with this beam. Geraci et al. [GS], using neutrons with amean energy of - 8 MeV (Ed = 22 MeV(BE)) also
obtained RBE values in mice similar to those for skin.
The RBE pertaining to lumbar cord irradiated withsingle doses of neutrons from 16 MeV deuterons onberyllium is higher than that for skin: with fractionatedirradiation preliminary results using doses to produce
10% myelopathy at one year post-irradiation also
indicates a higher RBE than for skin [W37].
283. The RBE for spinal cord is similar to that forskin and several other tissues. Experiments have been
performed with neutrons on the spinal cord of rats [W6,V6] and mice [GS, G7]. In mice. single doses of at least
6.8 Gy were required to cause paralysis and this wasincreased to approximately 10 Gy in 1O fractions.
However, in fractionated experiments, renal failure also
occurred at a similar threshold of 10 Gy [G7]. With rats,
single doses of more than 10 Gy are required to cause asmall probability of paralysis and they were increased
to approximately 18.5 Gy in 23 fractions [Vl, V8].
284. Brain. By counting cell numbers in the
subependymal plate of the rat brain, Chauser et al.
[C11J observed that with x-ray doses of Jess than about603

I 5 Gy there was a Joss in cells followed by a slow
recovery in numbers. With neutrons, a dose as small as
1.2 Gy caused a steady fall in cells at least up to 6
months, with no sign of recovery. As the response after
x rays or neutrons is so different, RBE varies with thetime of observation. At late times the RBE is higher
than for skin.
285. In the clinic Catterall reported that after neutron
treatments of 15.6 Gy in 12 fractions over 4 weeks,
gliomas in the brain were controlled but some patients
suffered a slowly increasing dementia [C33]. Similar
results were also reported by Parker from Seattle. The
dementia is associated with the development of microscopic areas of demyelination throughout the treatedvolume. In Edinburgh, Duncan and Arnott, treating
gliomas with 13 Gy of neutrons in 20 fractions over 4
weeks, observed cerebral oedema at about 6 weeks after
completion of treatment, which is not normally seen
after x irradiation, but dementia was not observed.

6.

Thyroid286. An assessment of the RBE for radiation damage
to rat thyroid has been made by using the end-point of
impairment of its proliferative potential. Usingrnonoenergetic 14 MeV neutrons, Malone et al. [M29}derived the "survival curve", for which the Do was 3.1
Gy. However, this value is very high, as is the value of
Do of about 4 Gy for x rays, owing to the unorthodox
interpretation of the term "survival". The RBE at about
1 Gy of neutrons was 3.2 and at about 5 Gy of neutrons
was 1.8. These values are in the range of those found forother tissues, indicating that the thyroid is not particularly sensitive to neutrons.

8.

289. The lens of the eye is avascular and, therefore, it
may be concluded that it is also rather hypoxic. The
RBE would, therefore, be expected to be about 1.5
times higher than for well-oxygenated cells and tissues,
because of the reduced oxygen effect with high-LET
radiations. Experimental RBE values have been determined by a variety of workers [BI 6, M25} and do seemto be higher than for other tissues at similar values ofdose per fraction. For example, Merriam et al. [M28)obtained values of 4.5 at 1.8-MeV neutrons up to 9 at
0.43-MeV neutrons. The x-ray doses in their experiments were about 5 Gy.
290. Bateman et al. (834] obtained much higher RBE
values with 0.43-MeV neutrons. but these were for thecomparat.iyely low doses required to increase the probability of causing opacities in a highly susceptible mousestrain. Di Paola and others [D42] also measured highRBE values, increasing with decreasing dose per
fraction from about 8 with 0.12-0.5 Gy of neutrons toabout 20 with 0.01 Gy of neutrons. These values werealso for increasing the probability of causing opacities,
as in Bateman's experiments, but the RBE values were
low. The RBE for 0.43-MeV neutrons would be
expected to be higher than for other energies (seesection IV.C).
291. The higher RBE for Jens opacities generally
found is borne out by the report of Abelson et al. [Al I]
that cyclotron workers exposed to neutrons overperiods ranging from 10-250 weeks were observed tohave lens changes with a mean dose of about 1 Gy ofneutrons. In a trial of fast neutrons in radiotherapy,
Roth et al. [R18} observed no changes with less than 0.8
Gy given as 12 fractions but slight permanent Joss ofvision with 2.2 Gy or more.

9.
7.

Testis287. The RBE for damage to the testis has beenobtained by two end-points: weight loss or sperrnatogonial stem cell survival. Weight loss of testis after
irradiation is due to the killing of spermatogonia. The
dose response curves obtained using this technique are
biphasic with both x rays and neutrons, indicating a
population of about half the total cells being moreresistant [K18, H32}. With x rays there is no repair ofsublethal damage in testis and the same is true forneutrons. When two doses of either radiation were
given either 4 or 7 days apart, the dose-effect curves
were not different from those obtained with single treatments [S22].
288. Homsey et al. [H32], using neutrons of Ed = 16
MeV(Be) observed an RBE of 2.5 for neutron doses ofless than 0.5 Gy and of 3.2 for larger doses. Geraci et al.
[G19], using neutrons of Ed = 21 MeV(Be), obtained
an RBE of 3.0 at low dose levels, but did not investigate
at high doses. De Ruiter et al. [D26), using 1-MeV
neutrons, obtained values at 5.5 and 4. I at lower andhigher levels, respectively. These results are consistent
with the differences in neutron energies used (seesection IV.C). Hornsey's results are therefore unusualin that over the dose range studied the RBE decreased
with decreasing dose, which is the opposite of results
found with other organized tissues (see Figure XIII).
The reason for this difference is not clear.
604

The eye

Haematopoietic tissues

292. The RBE for non-stochastic damage to stern cellsof the haematopoietic system is low and varies little
with dose per fraction [F28, B33, G19]. This is because
there is little accumulation and repair of sublethal
damage in these cells with x rays and virtually none
with neutrons. RBE, therefore, mainly reflects differences in Do, which are small.
293. There is also a dosirnetric factor which will cause
the neutron RDE to be low in bone marrow. Bone has a
low hydrogen content so that the absorption ofneutrons will be less than in other tissues because of thelower probability of collisions with protons. This is incontrast with an excess production of secondary
electrons by photoelectric absorption of x rays becauseof the high mineral content in bone. However, Broerseand Barendsen [833) conclude that although thesedosirnetric factors do play a significant role, there areindeed intrinsic differences between the biologicalresponse of cells of the bone marrow compared withmany other tissues.
294. The lack of repair capacity is also seen in
lymphocytes. The majority of untransformed lymphocytes are very radiosensitive, but the RBE values forkilling unstimulated human lymphocytes, rat lymphocytes or white cells in mice are about 1 and for lowering
the transformation index about 2 [G19, H31]. With
photons, the haematopoietic tissues are more sensitive
than the intestine, so animals which survi_ve _the earlyintestinal syndrome may die later from the haematopoietic syndrome. This is not normally the case withneutrons, the intestine usually being the limiting factor
in whole-body irradiation.
to.

Blood vessels

295. The effects of radiation quality on the responseof blood vessels has not been extensively studied. There
are only a few studies with fast neutrons. In theintestine the RBE for leakage of albumin and PVP was
estimated to be 3.4 ± 0.4 [T12] and 3.0 ± 0.5 [LlOJ_ The
RBE for capillary endothelium in subcutaneous tissues
in the rat has been estimated by Broerse et al. [B35],
using 14 MeV neutrons. For neutron doses between 2.5
and 5 Gy the RBE was 1.8-l.9. These values are similar
to those found for skin and intestinal epithelium. The
results of Aamoudse and Lamberts [A 12] suggest that
the RBE for radiation-induced atheromatosis in hypercholesterolaemic rabbits depends on dose. A neutron
dose of 5 Gy was more effective than the same dose of xrays, whereas for a dose of 10 Gy neutrons were lesseffective.
296. Steamer et al. [S23] conducted an electron
microscopic study of changes in the microvasculatureof the mouse ear between 12 and 20 months aftersublethal whole-body fission neutron irradiation. There
were degenerative changes in the smooth muscle ofarterioles which are seldom seen after x irradiation.
Although vascular damage was not sufficiently severe
to be quantified, evaluations indicated more severe
arteriolar degeneration after a total dose of 2.4 Gy offission neutrons fractionated over 24 weeks than after
the same single dose. This is the reverse of the normal
fractionation effect.

F_

MIXTURES OF NEUTRONS AND X RAYS

297. It is difficult from current knowledge to predict
how a combination of low- and high-LET radiation willaffect normal tissue tolerance and how the components
of a mixed beam might add to produce a given degreeof biological response. In principle, the treatments
could either be simply additive or there might be someinteraction between the different radiations to giveenhanced damage. Information from cell studies invitro is equivocal. Durand and Olive [D29] found thatneutrons apparently caused a reduction in recovery
from sublethal damage inflicted by x rays, whether
given before or after x irradiation. They also found thatthe shoulder on the neutron cell survival curve did not
represent recoverable sublethal damage. Others [R19,
N6] found some interaction between the sublethal
damage inflicted by x rays and neutrons when the tworadiations immediately follow each other. It has been
demonstrated in the stem cells of the intestinal
epithelium that the rate of recovery from sublethal
damage appears to be independent of its source [H24]and it has been suggested by Gragg et al. [016] and by
Homsey et al. [H33] that recovery from sublethal
damage with a neutron beam is simply due to its
low-LET component. However, the presence of thehigh-LET part of the beam, which only inflicts lethal
damage, will cause the total accumulation and repair ofsublethal damage to appear less than with a photon
beam. If the two radiations are separated by 24 hours,
when recovery from sublethal damage is complete, thenthe effects are simply additive [l-138).

298. There is little information on the effect of mixed
treatments of neutrons and photons on either slow
repair or potentially lethal damage, but there isevidence that tissues which have been treated withneutrons carry unrepaired damage for long periods.
The tolerance to a subsequent course of x rays is less ina tissue previously treated with neutrons than in one
previously treated to the same level of damage with xrays [H8, F9]. This observation may be particularly
important for exposure to mixed beams for an extended
period.

G.

OTHER TYPES OF HIGH-LET RADIATION

299. Biological experiments have been performed
with a particles, protons, negative n-mesons and withheavy ions. All of these particles have the property ofincreasing the LET with increasing penetration into
tissue, before the particles are brought to rest. Fast
protons in the range of 50-660 MeV have been shownin a wide range of biological materials to possess an
RBE value close to unity. The same value would be
expected to apply to man [R33]. For n-mesons theentrance particles have properties similar to those ofsparsely ionizing radiations. This is also true for highenergy protons and alpha particles. n-mesons have a"star region" of maximum dose deposition andmaximum LET in which the oxygen effect is reduced
and the RBE raised, but both to a rather lesser extent
than with fast neutrons. In the peak region the increasein RBE is primarily the result of less sublethal relative
to lethal damage after n-mesons relative to x rays [Y 4).
The Bragg peak for alpha particles and protons isextremely sharp, and in this region of a millimetre or
two the dose and LET are increased by a large factor
relative to the entrance characteristics. Heavy ions also
have a large peak dose and may reach LET values ofabout 1000 ke V/µm for very short distances, just before
the particles stop. These particles would then be
expected to have high LET values: for example, a figureof approximately 10 was found for liver injury [R33).

H.

SUMMARY

300. Throughout this section the emphasis has been
on effects of fast neutrons. For single treatments sufficiently large to cause non-stochastic injury, neutron
RBE values range between 1 and 5 compared withphotons, depending on the neutron energy. Included
within this range is a factor of about 2 in the variationof RBE for different tissues. Repair from sublethal
damage is less with high-LET radiation, so that in somecases there is no further "dose sparing" by increasing
fractionation beyond two fractions. Also the dose rate
effect with high-LET radiation is small. This will cause
an increase in RBE with decreasing dose per fraction(and thus with increasing number of fractions). Where
cellular repopulation is important (skin or intestine)
there is no reason to think that it will be dependent on
the quality of the radiation and the sparing which
occurs with x-irradiation will also apply to neutrons.
For slowly dividing tissues, for which radiation damage
occurs a long time after irradiation, repair by repopulation will be small for both x rays and neutrons. Sinceother repair processes after high-LET radiation arelimited, the neutron dose which may be tolerated if
given over a long period may not be significantly
greater than that in a single acute exposure.
605

V.

INTERNAL IRRADIATION BY
RADIONUCLIDES

301. When a radionuclide is introduced into a living
mammal, tissues absorb a proportion of the energy oftransition to the stable nuclide. The energy per unit
mass of tissue is largely delivered by radiations emitted
by the radionuclide or its daughters during their decay.
and constitutes a radiation dose. The biological effectsof the deposition of energy in a tissue are usuallyreported in the literature in relation to the mostaccurate expression for the dose obtainable, which isoften simply the activity introduced per unit weight ofanimal (Bq kg-I). However, other derived or measured
quantities are also given such as the tissue specificactivity (Bq g-1). the mean dose rate (Gy s-1), and themean cumulative dose (Gy). The latter might be thought
to provide a useful quantity for comparison with thetotal dose delivered for the same effect by external
irradiation. and forms the basis for the present recommended protection limits for internal exposure toradionuclides (11).
302. To interpret the results of studies in different
species and to relate them to those involving external
irradiation, it is necessary first to consider briefly the
relationships between the various expressions of the.
dose from radionuclides. Then the factors which may
influence the biological effects of a given dose will be
discussed. Data obtained from studies in experimental
animals together with the results of therapeutic. accidental and occupational exposures in man will be
reviewed together in this chapter.
A.

DOSE RELATIONSHIPS

303 .. Although the activity of a radionuclide introduced into an animal is of major importance in determining the dose to the tissues, it does not uniquely
characterize it. Direct measurements of the dose are notoften carried out owing to the technical difficulties
involved in the use of dosimeters in vivo. Radiation
doses and dose rates are therefore usually calculated
and a recent ICRU report (19] has provided a review ofthe methods available, particularly with reference to theclinical use of radionuclides.

specific absorbed fraction and is defined as the fractionof the energy of particles of type i emitted in the source
tissue which is absorbed per unit mass of the target
tissue. It depends on the nature and energy of theparticles, the attenuating characteristics of the tissues
and the geometry of the source and target regions.
306. The mean dose rate to a target tissue v from
activity A 0 contained in the whole animal is obtainedby summation of the contributions given in the above
equation for all the tissues in the body. This can be
expressed as

D = LA, .6 L\; <l>; (v ... r)jwhere :E A, = A0 • The target tissue may be an organ ora region of microscopic dimensions. The mean dose
rate is usually a function of time.
307. Calculation of the mean dose rate necessitatesobtaining values of <l>; and A,, and these are usuallycalculated using physical or biological models to extend
the applicability of the theoretical and experimental
data which is available. Typical models are discussed in[I9] and tabulations of useful data are appended toassist in such calculations.
308. It is clear from the above equation that the meandose rate to a given tissue arising from a given total
activity will be affected by the size of the organs contributing to the irradiation and in general will bedependent on the species as well as on normal
individual variations. Alterations over a period of time
may also be expected due to changes in the geometry of
structures caused by radiation effects, disease, naturalageing or growth.
2.

Mean curnulath·e dose

309. The cumulative dose D (Gy) averaged over atarget tissue v for a time t (0 is given by the time
integral of the mean dose rate D. When the geometry of
the source and target regions remains constant, theabove equation can be integrated to become

D = L Arr

304. In this chapter some of the expressions occurringin dose calculations are discussed in order to illustrate
the physical and biological factors which may be
expected to influence the dose delivered to a tissue
following the administration of a given activity of aradionuclide.
1.

Mean dose rate

305. The mean dose rate I) (Gy s-1) to a target tissue v
in animal from activity A, (Bq) of a radionuclide
contained in a single source tissue r is given in generalform by (19)I) (v - r) = A,

L L\; <l>j{v - r)j

The summation is taken over all the i types of particle
emission from the radionuclide, where particle is usedin the sense defined by ICRU (19] for directly andindirectly ionizing particles. L\; (J) is the mean energy ofthe particles of type i emitted per nuclear transformation and is a constant determined entirely by thecharacteristics of the radionuclide. <l>; (kg-I) is called the606

Z: L\; <l>; (v .- r)
I

where the quantity(Bq s)
0is called the cumulative activity (19).
310. The cumulative activity is usually derived frommeasurements of the concentration of activity in an
organ as a function of time after administration of theradionuclide and biological models are again used toextend the applicability of the data [19) to other tissues.
311. The many factors which influence the mean
cumulative dose received by an organ following theadministration of a given activity to an animal are thosewhich affect the cumulated activities in the various
tissues in addition to those already discussed affecting
the specific absorbed fractions.
312. The cumulated activities in the body depend on
the intake of activity, its transport, metabolism andre-utilization, as well as its excretion. These factors, intum depend on: the characteristics of the material
introduced, the nature of the radionuclide, its chemical

and physical form. the chemical and physical form of
the carrier; the method of introduction of the activity,
its distribution in time. route of entry. means of introduction: the animal species, weight, sex, age, condition,
response to diet, etc.
313. Every element has its own characteristic metabolism in the body, although the presence of the carrier
may affect it. The solubility of the carrier in body
fluids, in particular, may determine the initial transportand excretion of the activity. The metabolism of ananimal may be significantly altered if the activity incorporated is sufficiently high to produce radiation
damage. After a period of continuous introduction ofactivity, the concentrations in the body may reach anequilibrium state, and the dose then delivered to tissues
largely depends on the total time of irradiation, andmay be relatively easy to determine. In general the
distribution of the mean cumulative dose in the bodytissues is not the same as the distribution of activity, but
is related to it in a complex manner.
B.

318. The relationship of the sensitive site to the pointof emission of the radiation is important. Radionuclides which emit a significant amount of energy in theform of Auger electrons may simulate the dense
ionization produced by high-LET radiation. Figure XVshows results of calculations of the average energy
deposition per disintegration in spheres of various
diameters for 1251 and 3H, in comparison with the meanenergy transferred to the same volume by a 5 MeV
alpha particle with a LET of 100 keV /µm [I-156). Whenthe volume considered is sufficiently small, the energy
deposited by the decay of 12s1 is greater than that transferred by the alpha particle, whereas that deposited by
the decay of 3H is more than an order of magnitude
smaller. The energy deposited in individual events isgoverned by stochastic processes and considerable
variation about the mean values can be expected.

FACTORS INFLUENCING BIOLOGICALEFFECTS1.

Temporal distribution of dose

314. The dose rate to a tissue is generally a function oftime due to decay of the activity and metabolism ortransport of the radionuclide in the body. For insoluble
radionuclides in the gut, for example, the temporal
distribution of dose to the gut wall is usually determined by the speed of passage of the gut contents. In
most cases repair of sublethal damage will usuallyoccur during exposure and the effectiveness of themean cumulative dose will be much reduced over thatfrom a single short exposure Lo external x-irradiation,although some damage will still occur.
315. A basis for relating the effects of radionuclides tofractionated radiotherapy has been suggested by Bigler[B59] using the time, dose and fractionation factor,
TDF. concept of Orton and Ellis [01]. However, thevalidity of these concepts has yet to be established. The
dose rates involved are variable and considerably lower
than those used in brachytherapy (> 0.3 Gy/h) for
which the procedure was developed. In addition, thecritical dose rates may not be represented by the meandose rate to the organ but rather by the dose ratedelivered to critical structures within it [860].
2.

Spatial distribution of dose

316. The biological effects of radionuclide decay arecaused by one or several of the following processes[K40]: emitted radiation; chemical transmutation;
nuclear recoil; change of atomic charge. The emitted
radiation produces effects at distances depending on its
penetration whereas the last three essentially produce
effects within molecular dimensions close to the site ofthe disintegration.
317. Since the radiosensitive structures of cells arelocated at specific sites (for example, in the nuclear
DNA) the biological effects of radiation depend on the
microscopic distribution of energy along its path.
Radionuclides emitting alpha particles causing dense
ionization along their tracks, may be expected to be
many times more effective than similar distributions ofbeta- or gamma-emitting radionuclides in producing
tissue damage for the same absorbed dose.

DIA~ETER [nm)Figure XV. Average radiation energy deposited In spheres of various diameters
by decaying 12S1 and 3H (solid lines), orby a 5 MeV alpha particle traversing thesphere (dashed line) [HS6]319. Experimental studies using labelled DNA
precursors have shown [K40, F49] that the decay of 12s1
located in the DNA of mammalian cells is 10-100 times
more lethal per disintegration than JH in a similarmolecular position. In comparing the doses to the cell
nucleus in synchronized Chinese hamster cells [H56]125}-iododeoxyuridine was much more effective incausing cell death (LDso : 0.45 Gy; D0 : 0.74 Gy) thaneither 3H-thymidine (LDso : 3.8 Gy; D 0 : 0.74 Gy) or
external x-irradiation (LDso: 3.3 Gy; Do : 2.3 Gy).
320. Radionuclides uniformly distributed in tissues or
emitting particles with ranges which are large comparedto cellular dimensions produce relatively uniform
spatial distributions of dose. The biological effects arethen determined by the temporal distribution of
average tissue dose and the quality of the radiations
emitted.
321. When radionuclides, particularly the alphaemitters, have heterogeneous concentrations within thetissues on a microscopic scale (i.e., a microdistribution)607

and also emit particles with ranges comparable tocellular dimensions, their eflicacy for producing agiven effect is determined by the spatial relationship of
the radionuclides as well as by the distribution of doseto the radiosensitive structures within the cells [F48]. If
the localization of the radionuclide and the radiosensitive areas are congruent, the effectiveness of a given
average tissue dose may be much enhanced both due tolocalized processes such as transmutation, which areassociated with the disintegration, and to the particular
microdistribution of dose.
322. The microdistribution of dose in tissues may also
be important in comparing the relative efficiency of
uniform and locally non-uniform distributions ofactivity [F48]. The dose microdistribution and otherlocalized effects of radionuclide decay such as transmutation may be particularly important in considering theeffects of radionuclides incorporated into specific vital
molecules such as hormones or enzymes which control
the metabolic functions of tissues and systemic
processes.

C.

EFFECTS ON TISSUES

323. The object of this section is to review information on non-stochastic effects of radionuclides which
are likely to be of some significance for the health ofcontaminated individuals. The data are obtained fromstudies in experimental animals and reports of therapeutic, accidental and occupational exposures in man.
Although one of the most important physical variables
influencing the effects of radionuclides is the nature of
the radionuclide itself, the emphasis of this Annex is on
the radiobiology of individual tissues. Accordingly, theeffects are here classified in relation to the tissue rather
than the radionuclide.
324. The data on man are of most importance since
species effects may be expected to be significant, notonly because of inherent differences in the radiosensitivity of corresponding tissues, but also because of thedifferences in scale, morphology and metabolism,
which determine the distributions of the dose deliveredby a particular radionuclide. Often information
concerning the radiation dose delivered for a given
effect is not available, but even where it is, it should be
remembered that the dose may be estimated to the time
when the effects became evident, and the events
producing the effect may have occurred at a muchearlier time and for smaller dose. This concept of"wasted" dose has been reviewed by Mole [M52].

1.

Gastrointestinal tract

325. Radiocolloids have been used in radiotherapy forthe reduction of fluids accumulating in serosal cavities
as a result of malignant disease. The colloid labelledwith a suitable beta-emitting radionuclide (32P, 198Au,
90Y) is introduced into the cavity and irradiates thetissue surfaces and disseminated neoplastic cells in thefluid while sparing deeper tissues. From autopsy data it
has been estimated [H57] that 5550 MBq colloidal 198Au
in 400 ml saline injected into the peritoneal cavity
resulted in total doses to the retroperitoneal lymph
nodes, the omentum and the peritoneal serosa of about
77.5, 61.5 and 47.5 Gy, respectively. Mild radiation
608

sickness and haematological complications have beenrecorded and sometimes persistent leukopaenia. Ileus
and gastrointestinal complications have been seen up toten years after treatment, at which time the serosa wasfound to be thickened and fibrosed. Adhesions andfragility of the bowel wall have been noted affecting thewhole of the small intestine [H57].
326. When given in sufficient intraperitoneal amounts
to mice both 32p and 198Au colloids can cause morbidityand death. Such effects were observed in a study using
both radionuclides [H58]. After 15 days with 2-4 MBq
of 32p and 5.5-11 MBq of 198Au there was marked
blunting of the mucosa! folds in both large and small
intestines. Chronic inflammation was observed in the
submucosa with slight fibrosis. Architectural changes in
the myofibrils of the smooth muscle were also seen
leading to early interstitial fibrosis and diffuse myofibrillar degeneration. However, since the distance fromserosa to mucosa in mice is Jess than 1 mm (comparedto more than 2 mm in humans) it is difficult to extrapolate these results to man.
327. Acute irradiation of the G.I. tract from injected
insoluble beta emitters has been studied in rodents anddogs [S51]. The radiosensitive cells are in the crypts
located beneath the mucosa! surface at depths of some
0.2 mm in the large bowel of the rat and some 0.8 mm
in that of the dog. The dose delivered to these cells
depends on the energy of the beta radiations, the massof the intestinal contents and the residence time of theradionuclide in any particular segment of the bowel.
328. In the rat, the LD5os for suckling, weanling andadult animals for 106Ru-106Rh given by gavage were 55,
670 and 330 MBq/kg, respectively, and about 0.2
TBq/kg for I47Pm in adults [S51]. In the neonatal
animals the lower ileum showed the principal signs ofdamage and there was evidence that the 106Ru-106Rh
pair, like 141Ce (16], 95Nb [M53] and the actinides [S51]is absorbed into the epithelial cells of the mucosa in theimmature small bowel. In the adults receiving a normal
diet the main pathology was seen in the caecum andlower large bowel while the insensitivity of theweanlings was thought to be due to the relatively rapidtransit of the gut contents in these segments of theyoung animal. Deaths occurred in the adults when 280
MBq/kg 106Ru-106Rh and 0.16 TBq/kg 147Pm were
exceeded, usually in the first or second week after
treatment. Radiation doses to the target cells in the
caecum were estimated to be similar for both radionuclides and suggested a LDso110 for ingested insoluble
beta emitters in the rat of about 33 Gy [C26].
329. In dogs fed with t06Ru- 106Rh, the earliest death
was at nine days after a dose of 130 MBq/kg but thesurvival time could not be closely related to the doseand one animal survived nearly 21 weeks after
receiving 110 MBq/kg [S51]. Following ingestion of
92-150 MBq/kg the mucosa of the mid and lower colon
were usually denuded at focal sites within eight days,
and frequently the damage was irreparable. Animals
surviving acute death had persistent diarrhoea until
they were killed or died. The LDso for acute death fromingested J06Ru-106Rh was estimated to be 130 MBq/kg
and the LDsomo for delayed death, 100-110 MBq/kg[C26]. Direct measurements of the radiation dose
carried out by means of thermoluminescent dosimeters
sutured into the G.I. walls showed that the LDso dose in
the dog is about 40 Gy distributed over approximately
18 hours to critical tissue in the large bowel, regardlessof the mode of death.

2.

Bone and cartilage

330. Internal irradiation of bone has been investigatedin various species following the administration of osteotropic radionuclides [VIS]. It is convenient to divide
these bone seeking radionuclides into two broad
categories, volume and surface seekers. according totheir basic metabolic behaviour [M55). The alkaline
earths, radium, calcium and strontium are volume
seekers, distributing over a long period of timethroughout the bone mineral by chemical exchange.
From the blood stream they are rapidly transferred toaccessible bone surfaces before concentrating in osteocytes involved in active mineralization and often
ultimately being buried beneath new bone. Radium.
unlike calcium or strontium. may remain for several
days on the bone surfaces, particularly around theHaversian canals. Short-lived isotopes like 224Ra maylargely decay and irradiate these surfaces before they
are incorporated into bone matrix. Plutonium andthorium are examples of the surface seekers whichaccumulate on the periosteal and endosteal surfaces,
and may be resorbed or buried during growth or
remodelling of bone. Plutonium is also concentrated inbone marrow, both as aggregates in macrophages anddiffusely by a mechanism which is not understood.
331. Significant internal irradiation of bone in man
has resulted from the deposition of isotopes of radiumin the skeleton. 226Ra and 228Ra have been studied
extensively since 1947 in groups of watch-dial painters,
radium chemists and patients given radium therapeutically [A28, L36, S53]. Records in the United States havenow been centralized at the Centre for Human Radiobiology at the Argonne National Laboratory, Chicago[R39]. 224Ra was also given to about 2000 patients in theFederal Republic of Germany between 1944-1951 forthe treatment of tuberculosis and ankylosing spondylitis [S54, SSS]. 224Ra at lower dosage is still used fortreating ankylosing spondylitis in adults.
332. Severe bone dysplasia resulting in fractures
especially of the long bones, vertebral collapse andsevere bone pain has been associated with burdens of226Ra and 228Ra [E24]. The effects of these isotopes
cannot easily be distinguished in man [M56]. Hasterlik
and colleagues [H59] have listed the following lesions
seen on routine radiological examinations, often in
subjects without symptoms: coarsening of thetrabecular pattern; localized areas of bone resorption;
patchy sclerosis: small and large bone infarcts; aseptic
necrosis.

addition to complete plugging, a greater number ofcanals are found with highly calcified minor Iamellae[H62) although large and bizarre resorption cavities arealso present [J18].
335. Spiers has suggested [S56) that the skull lesions
associated with radium burdens are related to therelatively high marrow dose to be expected in theseareas. Measurements of mean path lengths in trabecularbone and in marrow cavities [S67] have enabled calculations to be made of the mean dose to the marrow spaces
and to the endosteum, considered as a tissue layer ofthickness 10 µm adjacent to trabecular surfaces (11). In
the human skull the ratio of the mean path length intrabeculae relative to marrow spaces in the parietal
bone was found to be 1.31 as compared to 0.16-0.30 forother bones, and the fraction of marrow irradiated was
calculated to be some three times greater (S56].
However, on the assumption that a terminal radium
burden of 0.37 MBq 226Ra was evenly distributed
through a 7 kg skeletal mass, the accumulated mean
marrow dose would only be 5-10 Gy in 50 years
whereas the dose to endosteal tissue would be 30-40
times greater. In parietal bone the marrow within rangeof the alpha particles would receive a dose 3-4 times
greater. A quality factor of 20 would apply to all thesedoses [P60].
336. Radium-224 largely irradiates bone surfaces andsites of active mineralization at the time when the bloodlevel is high. It has been estimated [S55] that the dosefrom 224Ra to the endosteal surface in man is some ninetimes higher than the average skeletal dose whereas for
226Ra it is less than two-thirds. Growth retardation, as
measured by height, has been reported [S54] in 70% ofchildren who had been injected with 224Ra at 1-5 years,
44% injected at 6-14 and 12% injected at 15-20 years.
Abnormal bone growths classified as osteochondromas
were seen [M57] in 15% of the 204 juveniles receiving amean skeletal dose of about 11 Gy from injections
0.85-1.7 MBq 224Ra/kg over an average period of 11months [S58]. These exostoses mostly developed in thelong bones at sites where the metaphyses incorporated
the activity: 73% were in males who have a natural
preponderance of the hereditary tumours. Tooth
breakage was also seen [M57] with maximum frequencyof 15% in the 59 children injected between 16-20 years,
although teeth are fully formed at this time. The tooth
loss is characterized by resorption of the tooth near the
gum line and breaking off of the crown. Similarchanges have been induced in rats following the administration of 224Ra and 226Ra [R41] and in dogs with
239Pu [TI9].

333. Some 20 years after the deposition of radium inthe skeleton, characteristic punched-out areas alternating with areas of increased density are seen in theskull [L37]. The long and flat bones have a moth-eaten
appearance. Increase in the number and severity of thelesions demonstrated over a period of years, occurs
together with a progressive decrease in the body burdenof radium. However, it has been concluded [H59] thatbody burdens in excess of 0.004 MBq 226Ra arenecessary before the radiographic lesions can be distinguished from those normally associated with ageing.

337. Bone dysplasia in animals resulting from theadministration of most bone seeking radionuclides has
been widely reported. The early uptake of sufficient
activity in epiphyseal growth cartilage, in the endosteal
surface of the metaphysis and in the periosteal surfaceof the diaphysis, may rapidly destroy osteogenic tissueand damage the blood supply, causing a reduction in
the rate and amount of growth. Irradiation to a highdose over a long period may result in bone fibrosis,
necrosis and fractures at characteristic sites.

334. The microradiographic appearance of bone in
subjects carrying radium burdens is similar to thatfound in dogs long after treatment with 226Ra [J18] or
90Sr [R40] and characteristic of vascular damage. Large
numbers of Haversian canals are seen to be plugged
with densely calcified material and the osteocyte
lacunae may also be affected [H62, R40, L38]. In

338. MacPherson and colleagues studied in great
detail the inhibition of growth in weanling rabbits
injected with 3.7 or 2.2 MBq/kg 90Sr [M58]. Cellular
damage was shown by an increase of disintegrating cell
nuclei and decrease in mitosis in an area of high uptake
in the metaphysis. A total dose of about 0.74 Gy
received at a rate of about 0.08 Gy/h was sufficient to609

cause a noticeable effect. The damage resulted in a
thickening of the cartilage plate with failure ofresorption. Damage to the blood supply, shown byleakage of red cells into the tissues, was noted aftersome 8 Gy at 3 days after injection. and in the animals
receiving several tens of Gy the damage was so severethat the thickened cartilage plate became separated as abar of dead bone. Fibrosis occupying marrow spaces
between the trabeculae was seen after some 30 days andcumulative doses of 190 Gy. These animals had amarked reduction in tibia! growth rate and ultimate
shortening of the limb, whereas no difference in growthfrom control animals was seen for the animals receiving
lower doses.
339. The incidence of radiation-induced bone
fractures has been reported in the beagles at Utah lTl 9].
Radiation-induced fractures are unique in that they
involve a minimum amount of pain and inflammatory
response. Following single I. V. injections the fracture
rate increased rapidly above 0.12 M Bq/kg 226 Ra and228Ra, 0.033 MBq/kg 239Pu and 0.0037 MBq/kg 228Th[T20, T21]. Fractures due to 90Sr were only seen in one
animal who received 3.7 MBq/kg. The anatomical
distribution depended on the radionuclide. Fracture
healing was low in animals treated with 228Th and 228Ra
but was high for 226Ra and 239Pu, 80% of the rib
fractures induced by 0.11 M Bq/kg 239Pu being repaired
in a satisfactory manner. The incidence and time of
appearance of fractures is related to the average skeletal
dose. Of the significant number produced in dogs by anactivity level of 0.11 MBq/kg 239Pu the earliest
occurred approximately 390 days post-injection with anaverage skeletal dose of about 32 Gy [Tl9].
340. In beagles at Davis, California, kept on a regimeof continuous intake of 90Sr and 90y in the diet frommid-gestation to 1.5 years of age [M69], few fractures
occurred at the highest levels of intake with maximum
body burdens of 13.1 MBq 90Sr delivering an averageskeletal dose of 133 Gy over 2 years [M68]. The smallest
dose from 90Sr for which any radiographic bonedamage was observed was about 70 Gy by 10 years ofage, and occurred at an intake level of 0.44 MBq/d
resulting in a maximum body burden of 1.7 MBq.
341. In the beagles given a total activity of 3.1 MBq
226Ra in 8 semi-monthly intravenous injections startingat 14 months of age, 25% of the animals sufferedfractures within six months of the last injection [M69].
In these cases the bone marrow had received an average
dose of less than 50 Gy [M68]. Trabecular coarsening
occurred in 100% and fractures in 50% of animals given
a total activity of 1 M Bq 226Ra. The earliest fracturesappeared soon after the last injection at 18 months,
when, by extrapolation of the reported dosimetry,
about 8 Gy would have been given on average to theskeleton.
342. Cartilage is inevitably irradiated during intraarticular injections of radioactive colloids for theradiotherapy of chronic synovitis. 198Au-colloid wasused initially [A27, M54] but its gamma-ray emission ismore penetrating than is necessary to sterilize the cellsof the synovium. In addition, the small size of thecolloid particles results in substantial leakage of activity
from the joint cavity and accumulation in the regional
lymph nodes [T18]. The pure beta emitters 90Y-silicate
citrate and 32P-chromic phosphate as colloids are
currently used for the therapy of knee joints [R38]. For
other joints such as in the hip, or the fingers, the lesspenetrating radiations from J86Re-sulphide or J69Er610

citrate, respectively, may be used [17]. The activities
administered have been determined empirically toprevent cartilage necrosis or flexion deformities. while
minimizing the failure rate of the radiation
synovectomy. For the knee some 110-180 MBq 9oy iscommonly used and the dose delivered to themembrane is estimated as about 60-80 Gy (S52]. The
dose falls rapidly beyond about 2 mm from the synovial
surface (861]. The colloid is phagocytosed into cells on
the surface of the synovial membrane, although some isdeposited on fibrin in the synovial fluid [W41}. Twocases of knee joint rupture have been reported, presumably arising from cartilage necrosis [D44).
3.

Lung

343. The lungs of miners of uranium, fluorspar andother minerals are subject to internal irradiation fromradon and its daughter products present in the air ofmines in concentrations varying widely between < 103
and 106 Bq per cubic metre of air. Radon diffuses
rapidly through the body and the greater part is exhaledwithin its half-life of 3.5 days. Its immediate daughter
products with a collective physical half-life of some 20
min become rapidly attached to the dust in the air of
the mine and a high proportion of the activity breathed
may be deposited in the respiratory tract. For a full
discussion of these problems see Annex D. The
induction of lung tumours in these workers and thepossible influence of other ambient factors such as
tobacco smoke on the induction of neoplastic and nonneoplastic diseases of the respiratory tract in man are
also treated in Annex L.
344. In animals internal irradiation of the lung byradionuclides has been studied following the inhalation
or intra-tracheal instillation of radioactive particles.
The radiation dose delivered to tissues by a given
radionuclide depends on its initial distribution ofdeposition and its rate of clearance from the lung.
345. Soluble materials may be cleared from the lungwithin a few days by rapid absorption into the bloodand by transport to the oesophagus by mucociliary
action followed by swallowing. They are then translocated throughout the body and may remain for long
periods in the skeleton or in other tissues depending on
their biochemical properties. Insoluble materials may
remain in the lung for years, being cleared by local
dissolution or transport (probably as intact particles) tothe bronchial and tracheobronchial lymph nodes. The
concentrations in regional lymph nodes may become
many times those in the lung and in both tissues
radioactive particles may form locations for thedelivery of high radiation dose rates.
346. A comprehensive review of the radiation effectsof radioactive particles deposited in the lungs of experimental animals has been published by the ICRP (18].
Non-neoplastic pulmonary lesions resulting in early
death occur when the activity is deposited in sufficiently high concentrations. Lower concentrations
result in progressive fibrosis and may lead to deathfrom pulmonary insufficiency. Data available fromseveral animal species suggests that such non-stochastic
processes might be expected to occur after an alveolar
deposition of more than 0.37 kBq/g lung of alphaemitting radionuclides [18].
347. Rats receiving lung burdens of 0.22-0.74 MBq/glung of relatively insoluble 238Pu02 and 239Pu0 2 diedwithin a few days from severe pulmonary oedema [S59).
Radiation pneumonitis caused early death in rats
exposed to a cumulative dose of 98 Gy from a burdenof about 0.15 lvfBq/g lung from relatively soluble
253Es(h (862]. In baboons, initial lung burdens of 3-10
kBq/g lung 239Pu02 resulted in death al 1-6 months[M59]. The earliest deaths were due to alveolar oedema
and vascular ·injuries, but after 2 months the alveolar
septa were thickened and collagen deposits andprogressive fibrosis led to respiratory insufficiency anddeath.
348. Deaths within 500 days due to radiation
pneumonitis and pulmonary fibrosis were seen in dogs
exposed to high concentrations of relatively insoluble
forms of beta/gamma emitting radionuclides such as
90Y. 91Y, 144Ce, and 90Sr in fused aluminosilicate
particles [M60, R42, 860. H60. S60, H61]. The alveolar
septa were seen to be thickened with hypertrophic andhyperplastic alveolar lining cells. Frequently the alveoli
were filled with protein material. Various degrees offibrosis occurred, including fibrotic thickening of thepleura. The extent of fibrosis was increased in thelonger surviving animals [119].
349. The rate of dose delivery to lung is an importantfactor in determining the cumulative radiation dose andthe time for death. 90y having a half-life of 64 h,requires a relatively low cumulative dose to produce agiven effect and such effects will occur earlier; on thecontrary, 90Sr with a half-life of 28.8 a requires a higher
cumulative dose and the effects are delayed. The
smallest initial Jung burdens to cause death in dogs
within 500 days from radiation pneumonitis andpulmonary fibrosis ranged from 22 MBq/kg for 9oy to
1.1 MBq/kg for 90Sr [H60, S60]. However, thecumulative dose delivered ranged from 93 Gy to 400
Gy and the minimum time to death from 7.5 days to
184 days, respectively.
350. A similar effect of dose rate may be seen foralpha emitters where the half-lives are long and thevariable is chiefly the rate of clearance from lung.
Death caused by respiratory insufficiency in beagle
dogs resulting from pulmonary fibrosis occurred about
1600 days post-exposure to a lung burden of insoluble
239Pu02 at levels >0.74 kBq/g lung [W42]. However,similar deaths were observed in less than 1000 days
following exposure to the more soluble 238Pu02 at levels>0.37 kl3q/g lung [P30]. The greater solubility of
238Pu02 than of 239Pu02, attributed to the high specificactivity of 238Pu [F50, F51]. was indicated by the fasterclearance from lung and the ten times greater retentionof 238Pu in the skeleton at 70 months post-exposure[B64. P31]. Similarly, following exposure to the evenmore soluble 238Pu nitrate at initial levels of about 0.37
kBq/g lung. death occurred in less than 300 days [P32].
351. In rats with initial lung burdens smaller thanthose necessary to produce acute effects. lungs are seen
to have a smaller infiltration of serum proteins but anincreasing deposition of fibrin and proliferation of
bronchiolar epithelium and alveolar lining cells up to ayear after exposure [S59]. Early hypoxaemia results in acompensatory increase in the blood mass and circulation time, although haemoglobin and erythrocyte
concentrations are normal [K41]. A second phase ofhypoxaemia appears at 8 months and at this time thetotal haemoglobin and erythrocyte mass remains
unchanged. Early ultrastructural changes consist of anincrease in the length of the air-blood pathway due tooedema [A32]. Later, proliferation of connective tissue

cells increases the thickness of the basement membrane.
The hypoxaemia is thus consistent with alveolarcapillary blockade.
352. In dogs quite small lung burdens (about 0.26
kBq/g lung 24 1Am02) produce local areas of dense
pulmonary
fibrosisandmineralization
withbronchiolar and alveolar cell hypoplasia [T22, B65].
There may be marked fibrous pleural thickening andobliterative fibrosis of small arteries. together withsome dense peribronchial fibrosis. Larger burdens
produce functional changes such as increased respiration rate, decreased vital capacity and decreased
partial pressure of oxygen and oxygen saturation [T22,
B66]. In baboons lung burdens of 37-74 Bq/g lung
239Pu02 lead to progressive fibrosis and respiratory
insufficiency culminating in death 1-3 years later[M59].
353. A different sequence of events has been observedin the Syrian golden hamster following 15 weekly instillations of 21opo with a half-life of 138 d (L40, A33].
Transient radiation pneumonitis and hyperplasia of thebronchiolar epithelium were observed together with aprogressive epithelization of alveoli with a large varietyof cell types. The latter became the dominant lesion at
30-180 days after the last instillation. This difference inpathology is presumably due to a species effect.

4.

Liver

354. Internal irradiation of the liver for therapeutic
purposes has been carried out in patients with coloniccancer using 32P-phosphate colloid immediately
following colonic resection [G34]. 550 MBq were
injected in equal amounts into catheters located in the
superior mesenteric and coeliac arteries. Previous trials
in rats [N14] had shown that when the colloid was
injected into the arterial supply of the gut, it became
well mixed in the portal circulation and 70% of theactivity was fairly uniformly distributed in the liver. A
total cumulative dose of some 50 Gy given to the liverby this means has caused no significant tissue damage
or functional changes, within the first year of follow-up,
although a temporary radiation hepatitis was seen in
one of the three patients one month after injection[G34].
355. In another much larger trial [A34], 90Y-resin
microspheres together with a chemotherapeutic agent,5-nuorouracil, were injected into the hepatic artery totreat liver metastases in patients with primary cancer ofthe colon and rectum. 3700 MBq 90Y was used, calculated to give a beta-radiation dose of some 100 Gy to
the liver. No significant effects were associated with theinternal irradiation in 25 patients surviving on average
26 months.
356. Following the injection of a pharmaceuticalpreparation containing soluble 224Ra. irradiation of theliver arises both from the decay of the radionuclide
during its initial deposition in soft tissues and from thatof its daughter products with their own characteristic
distributions in the body. 220Rn is readily soluble inlipids and 212Pb is bound to red cells as well as concentrating in the kidney and liver. In man chronic liverdisease, usually cirrhosis, has been reported in 8% of
106 adult males injected with 224Ra for the intended
therapy of tuberculosis and in 3% of 329 patientstreated for ankylosing spondylitis (S58]. The average
activity of 0.84 M Bq/kg given to male patients with611

tuberculosis was more than double that administered
for ankylosing spondylitis. The incidence was not
significant in women and it was suggested that thismight be related to the greater exposure of men to
known liver toxins such as alcohol [S58]. Fifteen of the
18 cases were identified between 12 and 24 years afteradministration of the activity. The radiation dose to theliver has not been reported.
357. Many studies of patients receiving thorotrast as
an intravascular contrast agent for angiography haveshown an unusually high incidence of non-malignant
liver disease [V17, D45, K42]. In 1237 patients traced in
Portugal [D45]. 2.7% of 931 deaths were attributed toliver cirrhosis or fibrosis. Some 25 ml of thorotrast wasusually injected corresponding to an activity of about
0.022 MBq 232Th02 [K43]. The radiation dose delivered
to tissues is difficult to estimate. However, the meanalpha dose to the liver of a 70 kg weighing man at 30
years after injection of 25 ml of thorotrast has been
calculated to be 7.5 Gy [K43]. For nine Japanesepatients who died of liver cirrhosis after a latent periodof 21-41 years, the dose rates to liver were estimated tobe between 0.17-0.53 Gy/a [K42] providing cumulative
doses between 4.7-16.8 Gy [K42, K50].
358. Massive internal irradiation of the liver can
produce liver cirrhosis in rats, rabbits and dogs [M61].
In rats injected with 38 MBq/kg 144Ce and 0.25
MBq/kg 239Pu nitrate liver cirrhosis was found in all
the animals surviving beyond 200 days. The liver doses
received were 160 and 57 Gy, respectively.
359. Hepatic changes induced by 239Pu have been
observed in the dogs at Utah [T23]. Following a single
intravenous injection of 0.11 MBq/kg tetravalent 239Pu
the activity deposits in the hepatic cells and remains for
2-3 months before being transferred to the reticuloendothelial cells lining the sinusoids. The evidence
suggests that the transfer occurs on the death of theparenchymal cell and is related to dose. The lesions
produced are principally hepatic cell necrosis followedby regenerative changes. Significant regeneration wasseen at doses as low as 0.62 kBq/kg 239Pu with mean
cumulative liver doses of less than 0.8 Gy. Regeneration
was sufficient to maintain normal liver weight, except
for some dogs given the highest doses of 0.11 MBq/kg
239Pu. In these cases liver atrophy was observed as earlyas 474 days from a dose of about 23 Gy. Based on theappearance of ascites, atrophy was probably significant
as early as 350 days from doses of 15-17.5 Gy.
360. Decreased pbagocytosis in liver was shown inmice after intravenous injection of polymeric 239Pu(0.67 and 1.33 mBq/kg). At the time, when this effectbecame manifest, the accumulated liver dose wasestimated to have been greater than 20 Gy. The
depressed function coincided with the translocation ofPu from the liver to the lung and kidney [K49].

5.

Kidney361. Severe renal disease has been frequently found inpatients who had received injections of 224Ra [S58].
Kidney insufficiency and a wide range of renal disease
were the recorded causes of death in nearly 13% of 222
patients. In both the living and dead subjects theincidence of recorded disease was 3.7% of 373 and 6.7%of 239 patients injected with a total activity grouped in
the ranges of 0.015-0.52 and 0.53-2.4 MBq/kg, respectively. However, such evidence for a dose-related effect612

must be considered with some caution because thehigher dose group contained larger numbers of patients
originally affected by tuberculosis and the use ofdifferent drugs in the two groups may have affected theincidence of kidney disease.
362. A characteristic radiation nephritis together witha significantly increased serum phosphorus have been
observed in beagles injected with 0.037-0.11 MBq
22BTh/kg [879, C27]. 228Th continually generates its
daughter 224Ra and some of this reaches the bloodstream and is redeposited in the tissues with its own
characteristic distribution. The average total dose to thekidneys contributed from 228Th, 224Ra and its daughters
has been estimated as some 10-30% of the averageskeletal dose [M62), less than approximately 3.6 Gy[S77].

6.

Thyroid363. The thyroid is regarded as a radioresistant organfrom the point of view of cell death and failure offunction. Results are available from irradiation in its
unstimulated normal state in order to reduce metabolic
rate and to control symptoms of angina in patients withcardiac insufficiency. At least 300 Gy is required tocause total ablation within a short time, e.g., 2 weeks.
This can be achieved with single oral doses of1850-3700 MBq of m1, resulting in an uptake of about
37 MBq/g in the thyroid [G12].
364. Unavoidable external irradiation of the thyroid
sometimes occurs in the treatment of head and neckcancers. Several authors have observed hypothyroidism
after normal fractionated therapy, e.g., [M23]. Theseauthors reported five cases of myxoedema within 4-12
months after doses of about 25-49 Gy received by the
thyroid. Rogoway et al. [R15] reported on patientstreated for Hodgkin's disease developing myxoedema
after irradiation of the thyroid to about 40 Gy in a
fractionated treatment. Of these, 4% developed
myxoedema after receiving both external radiation andlymphangiography, whereas no patients receiving either
lymphangiography or the external radiotherapy alone
were observed to develop hypothyroidism. This result
was attributed to an increased radiosensitivity of the
thyroid after stimulation into increased activity causedby the iodine present in the contrast medium used for
lymphangiography.
365. There are numerous reports of reduced thyroid
function caused by irradiation with 131 I or 1251. About
90% of the radioactivity is concentrated in the colloid
but the dose delivered by the relatively energetic beta/
gamma emissions from 1311 is distributed fairly
uniformly throughout the gland. Iodine-125, on theother hand, decays by electron capture and each disintegration is associated with a cascade of x rays andAuger electrons [D43]. A number of the latter haveenergies below 3 keV and about one-quarter of theradiation dose is delivered to the thyroid by electrons
with a range of less than 0.4 µm in tissue. The sites ofhormone synthesis, situated in the apices of the follicular cells close to the colloid-cell interface must
therefore receive a significantly higher dose than the
more distant cell nuclei. The mean dose to the glandfrom 1251 (in contrast to 131J) is therefore somewhat
higher than the dose to the nuclei of the parenchymal
cells. Difficulties may be expected in extrapolating
animal data to man owing to the difference in the scale
and morphology of the cells in different species.

366. Several clinical trials of 1251 for the treatment ofhyperthyroidism have been initiated on the basis thatthe reproductive capacity of the thyroid tissue is moreradiosensitive than hormone secretion. Some estimates[037, L42] have suggested that the microscopic dosedelivered at the colloid-cell interface is about four times
that at the nucleus, and about twice the dose averaged
over the gland, although these factors depend on thegland mass and the colloid fraction.
367. As with other cell types and tissues, it appears
that irradiation of the thyroid at low dose rate allows
time for the repair of sublethal damage. In cell survival
studies in rats [035] a study on the effects of x rays, 131 I
and 1251 gave D 0 of 4.5, 55 and 94 Oy, respectively,
when the mean dose to the gland was used forcomparison. The extrapolation number for x rays was
1.7 whereas for radioiodine the survival curves wereexponential from the origin. The difference between
131 I and 125) was attributed to the relative sparing ofparenchymal cell nuclei due to the inhomogeneous dose
distribution from 125I. particularly when it was notedthat about 30% of the proliferating cells would be
stromal and located at greater distances from the active
colloid than the follicular cells.

s368. Electron microscopic examination of thyroid
tissue following irradiation has indicated that Ill I
produces diffuse damage whereas 125J produces
localized effects at the colloid-cell interface [L41]. Fromexperiments using rats, several workers have concluded
that 131 I is less effective than 1251 in disturbing hormone
synthesis than in affecting the response to TSH [036,
Vl8, L41]. However, Jongejan and van Putten found nosuch evidence and concluded that the ratio of 1251/131 I
activities necessary to produce similar effects on iodine
uptake, serum T4 and damage to thyroid structure layin the range of 11-17 [J20]. Gross et al. had calculated aratio of 16 for both the mean radiation dose to thegland and the radiobiological effect as determined byradioiodine uptake suppression [036].
369. A large body of data exists for treatment ofhyperactive thyroid glands, usually by orally administered radioactive 1311. In its hyperactive state thethyroid is more radioresponsive. Werner et al. [W22]observed a return to normal, or even hypothyroidism
after fractionated doses of 1.5-3.7 M8q 131J, giving
estimated total doses of 2-8 Gy. A greater proportion ofchildren than of adults responded, as has also beenreported by Einhorn and Wikholm [E12]. Somewhat
higher doses are normally used to reduce elevatedfunction and if hypothyroidism results it is permanentrather than transient [F12]. The hypothyroidism
develops slowly. In 7.5% of the cases it is apparent
within the first year [W22, 823], and subsequently 3%
per year of the patients develop symptoms up to 26% at
7 years [823].
370. The total dose delivered to the gland depends on
the uptake and rate of biological clearance. For
diagnostic doses with a relatively long retention in the
thyroid, the ratio of total doses delivered per unit
activity of 1311 and m1. is as low as 1.6 for an uptake of
25% [M63]. However, IJIJ delivers some seven times theinitial mean dose rate to a 20 g thyroid compared withthat from an equal activity of 1251 [S50].
371. Mean activity levels of 1251 were used for therapy
in single and, where necessary, multiple doses ranging
between 37 and 1480 MBq, corresponding to concentrations between 0.44 and 37 M8q/g thyroid [A35). It isdifficult to compare the frequ-ency of induction of
hypothyroidism between groups, because of variationsin the populations treated and their diets. However, atleast two centres [867, S61) have abandoned trials
because the results showed no improvement on thoseobtained with 131). A reduction in the dose necessary to
reduce the incidence of hypothyroidism was accompanied by an unacceptable increase in the rate ofpersistent hyperthyroidism. Follow-up periods havebeen too short to indicate whether the rate of delayed
hyperthyroidism from 1251 is lower than that following
treatment with 131 J [B67]. Clinically, the loss of function
in hypothyroid patients is not considered very serious
and can be easily managed by administration ofsynthetic thyroid hormone, providing the late
appearance and insidious nature of the symptoms arerecognized.
372. In 1954 following a thermonuclear explosion at
Bikini radioactive fallout was deposited on the
Marshall Islands. Inhalation or ingestion of iodine
radioisotopes (principally lllJ, 132I, 1331, 135J) by the
population resulted in exposure of the thyroid glands tosignificant internal, in addition to external, irradiation.
Within nine years thyroid nodules were noted inchildren who had received the highest dose on
Rongelap Atoll [L43]. In a subsequent follow up overthe next 15 years [L43], 67% of individuals exposed atages below 10 years and 15% of the remainder,
developed nodules which have since been surgicallyremoved. Doses to the thyroid were estimated to lie in
the ranges 10.2-42.6 and 5-30 Gy, respectively.
373. Five children exposed at ages below 5 years
showed some degree of growth retardation and twoboys developed myxoedema [S62]. A recent study [L43]has shown that the population as sampled on Rongelap
Atoll have a significantly impaired thyroid reserve as
indicated by a smaller increase in T4 following TSH
stimulation. Additional biochemical evidence such as
basal and TRH induced serum TSH, and serum T4
concentrations suggests that at least four of 43 subjects
have impaired thyroid function some 25 years after athyroid dose from mixed radioiodine isotopes,
estimated in three of these to be less than 3.5 Gy.
374. There is little data on the incidence of hypothyroidism in subjects receiving small radiation doses fromradioiodine [H69, H70]. Preliminary results of a studyof patients receiving 1311 for diagnostic uptake tests [U3]have indicated an incidence of 1.8% within an averagefollow-up period of 16 years. Hypothyroidism became
evident in 2.0% of 146 patients and 3.3% of 151 patients
who had received doses in the range of 0.31-0.80 and
0.81-19 Oy, respectively. However, in a study of 1378
children exposed to 1311 fallout, the incidence of overt
hypothyroidism over a similar period of follow-up was
not found to be significantly different from that in 3801
non-irradiated controls [R51].
375. Radiation-induced damage may not result
primarily from effects on the thyroid parenchymal cells.
In culture, these are rather radioresistant [D21] and theyalso appear unresponsive in the whole animal. Rather,
the effects could be mediated via an autoimmune
reaction. initiated by a large sensitizing dose of thyreoglobulin into the circulation [M23, 823, 813] or byradiation effects on the microvasculature, particularly
after acute doses [R 1]. Another possible explanation
could be the impairment of long-term proliferative
potential of epithelial cells.
613

7.

Gonads376. The effects of intramuscular injections of 0.048
M Bq/g body weight 32p on the ovary and testes of
30-day old mice have been studied at autopsy 30 days
later [S63]. The ovaries showed severe damage withcomplete absence of normal oocytes or follicles. The
seminiferous tubules of the testis were affected nonuniformly. Sperm cells were seen in considerably
reduced numbers. Sertoli cells and interstitial cells were
not affected.
377. Samuels studied the localization and oocyte
survival in the ovaries of mice following intraperitoneal injections of 2!0Po which became localized in
the follicular cells [S64]. Significant loss of oocytes
occurred at four days after injections of 37 mBq/g bodyweight with an apparently non-threshold dose-effectrelationship. There was no dependence on the age ofthe animal between 21-150 days. An activity of 3.7
Bq/g body weight destroyed oocytes at all stages ofmaturation within 30 days, at which time no pathological changes were seen in the uterus. In comparison
with external 60Co irradiation (see section IV.A.), theRBE appeared to depend on dose rather than dose rate
and was thought to become as high as 50 from a meandose of 110 µGy to the ovary resulting in a primaryoocyte survival of 79%. For a cell survival of 2.7% at 30
days an RBE of 4.8 was calculated from a mean dose to
the ovary of 54 µGy.
378. Activities of 0.18-0.74 MBq 90Sr injected intravenously in female mice on the 11th day of pregnancy
seriously affected the oocytes in the developing ovaries[R44]. After the maximum dose, the total number ofoocytes relative to those in unirradiated controls was
21 % at 56 days and 15% at 170 days post-partum. The
reduction in cells at ail stages of development wasstrongly dose-dependent but the naked oocytes and the
young follicles appeared to be the most sensitive. Overa relatively short period of 100 days the irradiated mice
produced litters of normal size and frequency.
indicating that the pool of mature follicles was sufficiently large to compensate for the losses in young
oocytes.
379. Further work by the same authors showed astrong relationship between the loss in oocytes and thetime of administration of the activity [R45]. 90Sr is more
effective in the mouse the later it is injected between 8
and 19 days of the intra-uterine life. However. it has
been shown using external irradiation [868] that thesensitivity of the oocytes decreases markedly between
the 15th and the 19th day, increasing only again atbirth. It has therefore been suggested [R45] that some of
the 90Sr activity injected after the 15th day when the
foetal skeleton has started to ossify, will be incorporated into it and together with 9oy provide an
additional source of irradiation to the ovary. In the
foetal mouse the gonads are within the range of manyof the beta rays originating in the skeleton. This mightalso account for the very marked effect of 90Sr administered just before birth when the oocytes are in theradiation-sensitive dictyate stage. An activity of 0.011
MBq 90Sr given to the mother at this time produced asignificant reduction in naked oocytes at 56 days postpartum, [R46] even though the mean activity measured
in the ovaries at 10 days post-partum was only 17 mBq
kg-1 90Sr with 9.2 mBq kg-1 90 Y (wet weight).
614

380. Tritium can be incorporated into all parts of theliving animal, particularly as 3HQH. The effects on theovary have been studied [D46] in 14-day old micefollowing continuous administration of 3HQH to themothers in the drinking water during pregnancy andlactation. Oocyte survival decreased exponentiallywithout threshold in the range of 3-410 kBq/ml body
water, as measured in the urine. The LDso was 74
kBq/ml, which would deliver a radiation dose of 0.0044
Gy/day. Continuous external y-irradiation of the micewith 60Co from conception to 14 days post-partum
showed that the higher gamma dose rates were more
effective in cell killing, but that the response wasdefinitely smaller than that using 3H, with an LDso of
about 0.01 Gy/day. The RBE therefore varied inverselywith dose, ranging from 1.6 for 0.5 Gy of gamma rays
to 1.9 for 0.25 Gy and up to 2.8 for the lowest
exposures.
381. The effect on mice of 99mTc given as
pertechnctate in daily intravenous doses to pregnant
and lactating females has been investigated [L44]. The
tissue distribution, and response to injected NaCl04, of
99mTc in the foetus, was different from that in maternal
tissue, and suggested the involvement of Tc in foetal
metabolism. Significant effects on the body weight ofmature mice were found extending into the third
generation from doses as low as 185 kBq/d, giving
about 10 mGy to the primary foetus during gestation.
Hairlessness and sterility were observed in mice
exposed to 99mTc in the milk secreted by lactating
mothers given 1.8-18 MBq/d. However, it is difficult todistinguish radiation effects from the chemical toxicity
of technetium since no stable isotope exists.
8.

The eye382. An increased incidence of cataract has been
noted in patients who had received injections ofPeteosthor containing 224Ra, principally for thetreatment of ankylosing spondylitis or tuberculosis[S58]. Periods of 7-26 years have intervened between
therapy and cataract diagnosis. Since cataract isnormally rare in young people, an incidence of 4% atages between 14-46 years in 204 patients receiving
224Ra as juveniles was particularly striking. In adults
the incidence was 1% in 300 men receiving less than
0.53 MBq 224Ra/kg and 4.5% in 155 of those receiving
greater doses.
383. If radium isotopes arc concentrated in thepigmented cells of the iris, as has been observed in dogs
and rodents [T24], the emitted alpha radiation may wellaffect cell division in the lens and account for the
induction of cataract. However it has not yet been
determined if these lesions have a special character orare similar to those produced by uniform external
irradiation. In addition, a possible association with any
prolonged drug therapy or with the diseases originallyaffecting the patients cannot be excluded at this time.
384. Introduction of polymeric plutonium nitrate into
dogs by inhalation has been found to result in an
accumulation of about 0.01 % of the total activity in theeye [S39]. The radiation dose received by the cornea
was greater than that received by either the lens or theaqueous humour. No changes in the retina wereobserved for doses of less than JO mGy, but local
retinal dystrophy occurred in 75% of animals receiving
doses of 1.7 Gy and 30% of those receiving 10-100
mGy.

9.

llnemalopoietic tissues

385. The late effects of chronic irradiation of the bonemarrow by radium has been studied in female dial
painters first employed before 1930. An analysis of theserum protein levels [P33] suggested a slight increase in
a-2 globulin with age in those groups with the higher
intakes of activity > 37 kBq/kg. There was little
evidence for late effects of radium on white cell counts[P35). A symptom-free but statistically significant
reduction in haematocrit was found in the groups
receiving the highest skeletal doses [P34], especiallythose with greater than 10 Oy. although these did notcontain a higher frequency of low haematocrit values
suggestive of anaemia. The dose rate to marrow withintrabecular bone of a man with a 37 kBq burden of 226Ra
has been estimated to be about 16 mOy/year [M64].
386. The use of radioiodine to treat patients withmetastatic thyroid cancer is generally limited by thedose to the bone marrow (869]. In a large series inwhich the majority of patients had previously received
a total surgical thyroidectomy, the activity of DIJ.
sodium iodide administered was chosen to deliver 3 Oy
to the blood. After nausea. depression of the bonemarrow proved the most frequent serious complication.
387. Radiophosphorus. 32P, has been widely usedsince 1939 in the treatment of patients with primarypolycythaemia. Single or multiple doses are given until
the patients red cells are reduced to acceptable levels.
Spiers et al. [S65] have reviewed a series of patients
given single doses of 144-222 mBq 32p and showed thatthe dose rates to bone marrow follow a single exponential decay with a half-life of 6.7 d. The cumulative
dose to the bone marrow was calculated to be 1.42 Oy
per treatment or about 0.24 Oy/37 mBq injected. Latenon-stochastic effects of such treatments have not beenreported.
388. Following the demonstration of selective uptakeof sulphur in chondrosarcoma [038] and to a lesser
extent in chordoma (W43], attempts have been made totreat these malignant tumours with 35S injected as
Na2S04 [A36, B70, M65]. In a recent series [M65] dosesof 185-222 mBq/kg were administered intravenously
and the treatment repeated at intervals determined by
the clinical and haematological response. A maximumof eight treatments were given over 88 weeks but in 13
patients the cumulative activity administered was in therange of 370-1780 mBq/kg. For an administered doseof 11 to mBq/kg it was calculated that the averageradiation dose to normal cartilage and bone marrow
was 40.5 and 9.9 Oy. respectively. From 70 to 90% of
the activity was excreted in the urine over the first threedays and most of the activity in the blood cleared with abiological half-life of 12 hours. In most patients the firstdose had a minimal effect, but with each successive
dose the prompt marrow depression increased andrecovery became less complete. Thrombocytopaenia,
leukopaenia and finally anaemia developed progressively and were dose-related. Only one patient withchondrosarcoma showed unequivocal improvement
and all patients developed severe marrow hypoplasia,
especially with respect to megakaryocytes and myelocytes.
389. Haematopoietic death has been described in thedogs at Utah given a series of single intravenous injections of various bone seeking radionuclides. Of thosegiven 3.6 mBq/kg 90Sr three died due to severe
progressive thrombocytopaenia. leukopaenia andanaemia. Perivascular cuffing of central veins in theliver (which is characteristic of myeloid leukaemia) was
also described together with myelofibrosis in somecases [D47]. The lowest average dose received one year
before death was 38.4 Oy [M66) to the skeleton.
390. Following a single intravenous injection of 555
kBq/kg body weight of 239Pu in mice. a moderate
reduction in the apparent half-survival time of erythrocytes was measured [J24]. Polymeric plutonium entering
the circulation is engulfed by the reticuloendothelial
cells of the bone marrow, which are consequently
subjected to continuous localized alpha-particle irradiation.
391. A single intravenous injection of 104 MBq 5SFein high specific activity (37 mBq/µg) causes early deathin mice with severe depletion of haematopoietic cells inbone marrow and spleen. and atrophy of lymphoidtissues [L45]. Iron exists almost exclusively in intracellular form in the body and SSFe with a long half-life(2.7 a) is continually re-utilized. The radionuclide decays
by electron capture depositing 75% of its decay energy
within a range of 1 µm. The median survival time foranimals given 52 MBq and 26 MBq 55Fe was 117 and439 days, respectively, in comparison with 847 days forcontrols. In these irradiated animals there was only
slight atrophy of lymphoid tissues and nodular haematopoiesis of the regenerative type was sometimes seen in
the spleen. However, they developed a dose-dependent
pancytopaenia which was attributed to the inhability of
the inactivated stem cells to replenish the loss from thevarious haematopoietic cell lines due to radiation
damage. The effect was primarily seen in the erythroid
series.
392. The chronic effects of 652n have been studied in
the rabbit [L46]. Zinc is a trace element influencing theactivity of many enzymes and hormones and essential
to the function of certain enzymes such as carbonic
anhydrase. Following daily oral administration of 6Szn
as zinc chloride, the activity becomes very widely distributed in body tissues, reaching equilibrium within 3months with a maximum concentration in the liver[A37}. 65Zn decays mainly by K-capture associated withthe emission of several short-range Auger electrons.
The function of vital molecules into which the 65Zn isincorporated would almost certainly be altered bytransmutation of the radionuclide as it decays. inaddition to any localized effects caused by the particles
emitted and the radiation dose delivered.
393. The morphological changes observed in the
blood-forming tissues are directly related to the leveland duration of the continuous 652n administration. In
a group of animals given activity levels of 0.37 m Bq/kg
providing mean whole-body doses of 4.5 Oy/day, histological examinations after 3-5 months showed hyperplasia of the reticulo-endothelial elements in the spleen
and lymph nodes. the appearance of foci of extramedullary haemopoiesis, and an increase in the number ofcells of the white series in the bone marrow [039].
Seven of the 20 rabbits in the group died during thisperiod, 3 from bronchopneumonia with pleurisy andpericarditis and the remainder from a necrotic suppurative process spreading over the lymph nodes. Suchinflammatory lesions of the lymph nodes may beconsidered characteristic of the chronic action of 6SZn
and have been attributed to the progressive formationof antibodies to proteins of the animals own tissues[F32]. Suppuration of cervical lymph nodes has been
noted after 11-12 months in animals given activity
615

levels as low as 3.7 k8q/kg/d with corresponding mean
whole-body doses 40 µGy/d [039].
394. For sufficiently high levels of administered 65Zn
activity, erythopoiesis and lymphopoiesis are progressively depressed leading to the appearance of abnormal
erythrocytes, reticulocytopaenia and lymphocytopaenia[871). At intermediate levels few such changes are seen,
but at low activity levels [R47], providing mean
whole-body doses of 40 µGy/d, there is an initialdepression of erythropoiesis followed after 6-12
months by hyperplasia of the red and white series andmarked reticulocytosis in the bone marrow. In the
peripheral blood there is persistent reticulocytosis andtransient increases in the number of lymphocytes,
neutrophils and basophils. A similar apparently stimulating effect on haematopoiesis is observed for low
dosage of other radionuclides such as 35S [K44].
However, the granulocytic series seem to be particularly
sensitive to exposure to 65Zn [872]. There is a gradualincrease in the relative and absolute number of theyoung neutrophils in the bone marrow and an intensified release of rod nuclear neutrophils into the blood.
395. The haematological effects of inhaled radionuclides arise both from irradiation of haematopoietic
tissue by activity translocated from the lung, and also
by direct irradiation of the blood circulating in thelungs and the other tissues containing active deposits.
The effects are therefore highly dependent on thesolubility of the inhaled particles in the body fluids,
and on the half-life and metabolism of the radionuclide.
396. The chlorides of the beta/gamma emitting
radionuclides 90Sr, t44Ce, 9ty are relatively soluble in
the lung and are rapidly deposited in the skeleton. After
their inhalation at high activity levels in dogs, deaths
occurred in the following 12-44 days as a result ofmarrow hypoplasia, panleukocytopaenia, terminal
haemorrhage and bacterial infection [M67]. The
cumulative average beta dose to the skeleton to death
ranged from 6-13 Gy arising from long-term retained
burdens of 2.7-3.7 mBq 90Sr/kg body weight, 5.2-11.8
mBq 144Ce/kg body weight and 7.4-20 mBq 9IY/kg
body weight. For lower retained burdens, animals
survived this acute phase and exhibited smaller depressions in the blood elements.
397. After inhalation of sufficient activities of thetransuranic radionuclides in rodents and dogs, leukocytopaenia [B65, S59, B73] and depression of myelopoiesis have been observed [B66]. However, in dogs adose-related lymphocytopaenia was the earliest andmost consistent effect seen following inhalation of bothtransuranic radionuclides and insoluble particles
containing beta/gamma radionuclides. Lymphocytopaenia has not been associated with either illness orpremature death of the animals.

lymphocytopaenia depend on the dose of alphaemitting radionuclides but can probably be detected
after pulmonary depositions of ;.. 18.5 Bq/g lung [I4].
399. For beta/gamma emitters in fused aluminosilicate particles the lymphocyte response in dogs
depended on the radionuclide [121]. For short-lived 90y
where the irradiation must have been largely confinedto the lung, the maximum lymphocyte depression
occurred 7-14 days after exposure with recovery tonormal levels by 50 days. For 91Y, depression occurred
more slowly and by two years there were indications ofrecovery. For 144Ce, the depression occurred during thefirst 200 days and was maintained over the remaining
two years of observation. For 90Sr the dose-related
depression of lymphocytes was progressive over two
years and was seen to persist for at least 2000 days
[S66]. A reduced function in the surviving lymphocytes
has also been demonstrated but it is not known whether
T or 8 lymphocytes are primarily affected [875].
400. Irradiation of the tracheobronchial, mediastinalor hepatic lymph nodes may also result from radionuclides translocated from the lungs. The mode of transferof the activity from lungs to lymph nodes is unknown
but for insoluble particles such as 239Pu02 is probably
mediated by macrophages. Concentrations of suchparticles can accumulate over a period of years to reachmany times the levels in the lung, and retention of theactivity in the nodes may be very prolonged.
401. Lesions of lymph nodes following the inhalationof alpha-emitting radionuclides and 144Ce in fusedalumino-silicate particles have been described inrodents and dogs [S59, D48, H61]. The primary lesions
in nodes containing active deposits are characterized bylymphadenitis and fibrosis with some degree ofdepletion of the germinal centres. Lymphoid atrophy
has also been observed following the administration ofhigh levels of plutonium even in nodes without active
deposits.
402. Following exposure to 239Pu02 in dogs the histological changes observed in lymph nodes up to some
400 days proved to bear little relationship to theestimated cumulative radiation doses [YS). This was
possibly due to variations in the rate of activity concentration and temporal distribution of the dose delivered
to tissues. However, the changes correlated well withthe mean dose rate, appearing to have a threshold at
which no pathology was observed of some 50 mGy/
day to the lymph nodes from an initial deposition of
about 1.1 kBq/g lung. At 400 days after depositions ofmore than about 3.7 kBq/g lung, lesions were apparent
in nodes receiving mean dose rates of more than 70
mGy/day. Lymph node lesions have also been seen atmuch longer times after lung depositions of 239Pu02 as
low as 26 8q/g lung (876].
10.

398. Lymphocytopaenia was observed in dogs within
2 weeks after exposure to high lung burdens ofplutonium [W42, 874, P32, 873} and within 400 days
following depositions of about 3.7 Bq/g lung 239Pu02
with dose rates of more than 2.4 mGy/ day delivered tolungs and lymph nodes [Y5]. It was not seen in the 3-6
years following depositions of < 7.4 Bq/g lung [P36].
For lung burdens of 111-1480 Bq/g lung it became
apparent after 1 year and persisted throughout life[P37). From a review of the animal data it has beenconcluded that the magnitude and delay in onset of
616

Vascular system

403. Vascular damage can lead to the development ofsclerotic changes in internal organs following chronic
irradiation. A form of nodular periarteritis affecting
small and medium sized arteries was noted in 22%, 18%
and 7.5% of rats surviving beyond 200 days from asingle oral administration of 83 mBq/kg t06Ru,
0.018-18 mBq/kg 144Ce and 63 mBq/kg 137Cs [M61).
404. Vascular changes were studied in the bones of thedogs from Utah contaminated with bone-seeking

radionuclides (122]. The most sens1t1ve measure of avascular action was the length of vessels per unit area
obtained from microphotographs. Table 14 shows thelowest values of injected activities, burden time andskeletal dose, where significant vascular reduction
occurred in the compacta.
D.

SUMMARY

405. Taking into account the difficulties of calculating
the doses delivered to tissues from internal irradiation.
this limited review of the data indicates that the effectsof beta- or gamma-emitting radionuclides are notinconsistent with those expected from comparable
mean tissue doses delivered at low dose rate by external
x irradiation. The distribution of tissues affected isdetermined by the particular spatial and temporal
distribution of the radionuclide in the body.
406. Alpha-, low-energy beta- and Auger-electronemitting radionuclides produce microdistributions ofenergy around a disintegrating atom which sometimes
coincides with a radiosensitive structure in the tissue,
resulting in an enhanced effect. The enhancement withrespect to external x irradiation may be expressed by an
RBE factor which also takes account of effects due tothe quality of the emitted radiation, the density ofionization and other results of decay, in particular thetransmutation of the atom. RBE's as high as 50 for
210po and nearly 3 for 3H have been reported fordamage to oocytes in the mouse.
407. Another possible delayed effect of irradiation byradionuclides may be the indirect damage to tissues
caused by alterations in metabolism or by autoimmunity. The low dose from iodine radioisotopes
necessary to produce long-term impairment in thyroid
function, as indicated by the data from the Marshallislanders, and also that from 65Zn found to produce
lymph node necrosis in rabbits call for further study.

VI.

THE ROLE OF VASCULAR AND
LYMPHATIC DAMAGE

408. Many factors other than direct effects on parenchymal cells may affect tissue response to irradiation,
including hormonal changes, reactions mediatedthrough the nervous system and modifications to thevascular system. Such changes have been considered in
sections II. H and I, III. H and V. C. while the damage
to vascular and lymphatic tissues is discussed in moredetail in the present chapter in relation to the irradiation of organs and tissues. The role of vascular andconnective tissue damage as a possible cause ofgeneralized non-specific effects leading to life span
shortening in whole-body irradiated animals is treatedseparately in Annex K.
409. Irradiated tissues frequently show vascularchanges, particularly at late times after irradiation. For
this reason, and because the turnover time of theendothelial cells is generally thought to be long, i.e ..
between 2 and 24 months (reviewed by Hirst et al. [H4]),
it is often postulated that vascular damage is thecommon pathway for late radiation injury [Rl). This is
the reason why radiation damage to blood vessels is
discussed in a separate chapter. It should however bepointed out immediately that, owing to the intimate
association of vascular and parenchymal elements, it isextremely difficult to decide whether long-term effects
on parenchymal cells are the direct consequence of
irradiation. or the indirect result of failure of thevascular or connective tissue elements.
410. After doses of radiation in the radiotherapy
range, tissues which show no early reactions in parenchymal cells often show progressive vascular changes
over a period of many months. Histological changes inblood vessels and interstitial fibrosis precede atrophy ofparenchymal cells in liver [12, R20]. kidney [M 10, Cl 7).
heart [F31) and lung [13, M7, A13]. In general, changes
in vascular function have been observed before severelate atrophy of tissues. Several authors have specifically
noted that functional vascular changes precede damage
to cells which are dependent on the vascular supply[G2. H39, K21, 021]. Increased vascular permeability isobserved in the lung and in the mesentery before signsof fibrosis are apparent [T13].
411. These observations suggest that impaired
vascular function may cause tissue atrophy at late times
after irradiation. However, in the CNS, the situation ismore complicated. At moderate doses (10-20 Gy)
vascular lesions predominate after a long latent period,
but higher doses ( > 40 Gy) cause white matter necrosis
at earlier times, in the absence of severe vascular lesions[H14, H41, V9). This may be interpreted as an early
response, which only occurs above a certain thresholdfor the glial elements [H42]. Sequential studies havealso been performed in order to examine in which cells
the damage is first expressed [P22]. Changes inlymphatics have been noted in the radiotherapy dose
range. Alteration in lymphatic morphology occurs
rather earlier than in blood vessels [A23, Z6, 847).
A.

MORPHOLOGICAL CHANGES

412. Many descriptive studies of gross changes inblood vessels have been made, particularly for the skin.
The time course of changes differs in different tissues,
probably in relation to the death of surrounding parenchymal cells. The pattern of response also differs in
different vascular elements, perhaps in relation todifferences in the blood vessel walls. In capillaries andsinuses the endothelial cells are the main componentsof the vessel wall, whereas in venules, veins, arterioles
and arteries, the thicker walls contain structuralelements consisting of elastin, collagen, fibroblasts andsmooth muscle cells. In the largest vessels the walls are
sufficiently thick to require their own capillary
network. Vascular damage can be roughly divided into
early. intermediate and late changes.
413. Early changes occur roughly within minutes todays after irradiation. The earliest visible change iserythema, resulting from dilation of the capillaries.
After very high doses of the order of 10 Gy this may
occur within hours; after lower doses (1 Gy) erythemaoccurs after a few days. It has be"en postulated that
histamine-like substances. released from dying
epithelial cells, may cause this effect in skin [D30, El 4];
however, capillary dilation has also been observed in
the heart [F31) in which no early cell death occurs.
Electron microscope studies have shown abnormalities
in lung endothelial cells within 3 hours of exposure to
20 Gy [M30). Vacuolation and lifting of endothelial
cells has been observed within the first month after
irradiation, preceding changes in the lung epithelial
cells [P6). In skin. vacuolation of endothelial cells has
been observed within 10 days [ZJJ but at this time many617

epithelial cells have also died and the vascular changes
may be a response to these dying cells.

cells (e.g., by 51Cr). which do not cross even a leaky
vessel wall [S26, J8].

414. Intermediate changes occur within approximately six months. Within each organ they show apatchy distribution with some areas being normal,
whilst in others degenerative changes are apparent. In
both lung [P6, M30) and heart [F31], electron micrographs show cytoplasmic swelling and endothelial cellsloughing. Thrombi sometimes obliterate capillaries. In
some tissues, e.g., heart and kidney, endothelial changes
precede changes in the parenchymal cells [P22].
Changes in the other components of larger vessel walls
are seen at this time, e.g., effusion of plasma proteinsleading to oedema, which is not drained by thelymphatics. It has been suggested that this protein
leaking progresses to the hyalinization that characterizes large arteriolar lesions [23).

419. These techniques have been used in studying awide variety of irradiated tissues, after a range ofdifferent x-ray doses, and over different observation
periods. Some of the studies are reviewed below.

415. Late changes which are seen after about six
months consist in degeneration of the walls of arteries.
arterioles and capillaries. Endothelial proliferation at
this time may lead to "sausage segments" by partially orcompletely obliterating the lumen [W26, M43]. Thickening of the basement membrane [P6, M31] andreplacement of the lumen by collagen [P6, A13) also
occur. Gross external changes, described as telangiectasis, are seen in many irradiated tissues [R21). In thearteries and arterioles, tortuosities are also seen, with
regions of dilation and constriction [H43, 837, L21].
Loss of endothelial and smooth muscle cells occurs andincreased amounts of acellular material, including
collagen. are deposited in vessel walls [Rl, H40, 23,
W26, W27]. Changes in blood vessels and a reductionin their number can also be shown by computer
analysis of microangiography results [E21).
B.

Skin

420. This has been the most widely studied tissue invarious species including rodents, dogs and pigs. In
early studies using dyes in rabbit skin, waves ofincreased permeability were observed after 1-30 Gy.
The exact timing varied in the different studies partly
due to the different skin areas investigated [R24]. An
early phase was seen almost immediately [P23, J9J witha second phase beginning at 20 minutes and lasting a
few hours [E14, R24, J9]. Further waves of reaction
were seen extending over the first month (Jl 0, Jll]. The
threshold dose at which a measurable change wasobserved was about l Gy [J12].
421. Other studies were carried out on rabbits [M32],
guinea pigs [S27], and rats [L23] using a variety oflabelled proteins. Changes in permeability are observable for several weeks. but return to normal by 6
weeks after 10 Gy in rats. In general, rats and miceappear to be less sensitive to permeability changes than
rabbits and guinea pigs [R25].
422. In dogs, the leakage of dextran molecules ofvarying size has been tested after 10-40 Gy. Some effectwas observed at all doses with a peak at 2 weeks. With
increasing dose the size of the dextran molecules that
could leak out was increased [A14].

FUNCTIONAL CHANGES

416. The function of the vasculature is to carry anadequate supply of nutrients to all parts of the bodyand to remove the waste products. Blood flow, vascularvolume and vessel permeability have all been studied
by means of radioactive tracer techniques.
417. In order to study blood flow, a radioactive tracer
may be introduced into the blood (e.g.. 42K or 86Rb)
and the extraction in different tissues assessed from theincorporated radioactivity. Alternatively, the tracer
may be introduced directly into the tissue (e.g., 22Na,
99mTe, 122Xe) and its rate of clearance via the bloodstream assessed. For the extraction studies the isotopes
used must be taken up and retained by cells, whereas
for the clearance assays the isotope must be freely
diffusable [S25, K22, L22].
418. Early experiments to measure vascular permeability involved the intra vascular injection of dyes whichbind the plasma proteins and assessment of the degreeof blueing of the tissue [R22, R23]. More recently large
molecules have been used, labelled with radioactive
isotopes, which would not normally diffuse across thevessel walls (e.g., albumin). Increased permeability
leads to leakage of these molecules and to a greater
accumulation of radioactivity in the tissues. The studies
often require sequential sampling, or sampling at afairly Jong time after intravenous administration of thelabelled molecules. It is easier to interpret thesepermeability studies if an independent estimate of theblood volume can be made and this is often achieved
concurrently by using radioactively labelled red blood
618

I.

423. Blood flow changes are more variable thanpermeability changes, with both increases anddecreases being reported at various times after irradiation. In general, changes are not observed until many
months after irradiation. For example, no changes wereobserved in rat skin until 10 months after doses up to 40
Gy ([K21), Van de Mereck quoted by [D31)) after whichtime flow was reduced with a threshold dose of 15 Gy.
In mouse foot skin flow was increased during the first
20 weeks after 10 x 4 Gy to 10 x 7 Gy [H44]. In tail skin,no change in resting blood flow was seen, but thehyperaemic response observed after releasing
temporaryocclusionwas
reduced, suggesting
impairment of vascular function several months after
irradiation [D32]. Glatstein (02] could detect nochanges up to 12 months after 15 Gy in mice but
Hopewell [H45] observed increased blood flow anddecreased vascular volume in hamster cheek pouches
between 2 and 12 months after 20-30 Gy.
424. Pig skin has been investigated both by tracer
techniques and by assessing the ability to vascularize askin flap attached by a single pedicle. Above athreshold dose of 8 Gy more rapid flow was observed at
3 weeks, followed by a reduction at 12 weeks and a
return to normal at I year. There may be a second
decrease at 18 months [M33, H46]. Similar changes
have been observed after 38 Gy/6 fractions/18 days,
but after 80 Gy/30 fractions/39 days only slightchanges were seen during the period 3-12 months[H46). The skin flap assay of vascular function showeda progressive failure from 0-6 weeks after 20 Gy withno further change to 28 weeks [P24, W28]. Similarchanges were observed after 6 fractions/ I 8 days orafter 30 fractions/39 days [W28].
425. Human skin has been studied by thermographylW29) and by clearance of 22Na [R26). In the isotope
studies, blood now was measured up to 10 years after
cumulative doses of 36-200 Gy. Of 37 patients studied.
only one showed reduced clearance in the irradiatedskin and 12 showed increased clearance despite theappearance of dense fibrosis, scarring and atrophy[R26). A more recent analysis of this data suggests a
trend towards reduced now at later times after exposure[D31]. The thermography studies showed increased now
during early acute erythema (2-3 months) [W29).
Studies of blood vessels in patients developing
radiation ulcers have been made using isotope
techniques. After fractionated radiotherapy with doses
between 40 and 120 Gy a reduction in circulation wasnoted together with sclerosis and fibrosis and anincrease in the probability of blood clot formation.
Blood and lymph vessel occlusion was observed which
affected other tissues, e.g., nerves, bones and lungs.
Disturbances in circulation sometimes led to swelling of
the extremities [B46. 847, 848, 849]. There is little information about the response of blood vessels to vasoactive substances. The response to pharmacologicalmediators such as Compound 48/80 or carrageenan (allof which cause increased permeability) is not significantly affected by doses of 5-200 Gy of x rays to the rat
foot [M34, V10).

induced an initial peak at 3-4 hours and a second
increase at 24 hours. Graham [G22) observed a biphasic
increase in permeability after 8 Gy whole-body irradiation. with an early increase during the first hour and asecond prolonged phase between 8 hours and 7 days.
Vatistas and Homsey [V3] also showed increased
permeability, the extent of which was dose-dependent
with a threshold of about 2.5 Gy. After whole abdomen
irradiation of rats, Davies and Gamble [D33] observed
increased permeability within 24 hours after 5-10 Gy.
429. Recently. changes have been studied in mesenteric vessels, in isolation from the ileum they supply.
enabling the separate effects on vessels and parenchyma to be distinguished [H40). In these experiments
the vascular response was studied from 3 weeks to 24
months after 20, 30 or 45 Gy. Increased permeability
was observed within 6 weeks after the two higher doses,with a maximum at 3 months and a return to normal by
12 months. A second phase was observed at 18 months.
Very little change was observed after 20 Gy. Changes inblood volume and in vessel diameter were observed
over the same period for single doses greater than 20
Gy. Thus, the dose required to cause changes in bloodvessels could be greater when they are not in close
contact with dying parenchymal cells, although theexperiments referred to only involved larger bloodvessels.
3.

426. Irradiation does affect the response to physiological agents involved in the regulation of blood flow
to a tissue. The vessels of the rat foot show a reduced
response to acetylcholine (vasodilation) at 24 hours andat 4-6 weeks after 30 Gy, but no change in the response
to noradrenaline (vasoconstriction) [M34]. However,
Lindop et al. [L21] found an increased response toadrenaline in the mouse ear between 1 and 55 weeks
after exposure. with a threshold of 15 Gy. Indirect
evidence suggests that blood vessels lose the capacity torespond to stress by vasodilation at late times after
irradiation. The hyperaemic response of both the mousefoot [H44] and mouse tail (032]. which is normallyobserved on release of a temporary vascular occlusion,is reduced 4-6 months after exposure.
427. In conclusion, the lowest dose at which observable effects have been seen is 1 Gy for permeabilitychanges in rabbit skin [J12) and 15 Gy or 8 Gy forblood now measured in rats [K21] and in pigs [M33J,
respectively.

2.

Intestine

428. Several authors have reported early changes invascular permeability in the gastrointestinal tract after
irradiation but it is difficult to say whether these could
also be related to the early death of epithelial cells
within the fust 3 days. Willoughby [W30] found anincreased capillary permeability in the vascular bed of
the rat small intestine which began at about 18-24
hours and reached a maximum at 72 hours after 15 Gyof x rays to the abdomen. Turner and Fowler [T12] andBromfield and Dykes (838) measured 131 J-serum
albumin leakage in the small intestine of rats after
whole-body irradiation. Significant leakage occurredfrom the intestine at 3-5 days after doses of 5 Gy or
more. Harris and Noonan [H47] observed two waves ofincreased permeability from intestinal blood vessels
after whole-body irradiation. Doses of 7 .5 or 15 Gy

Cartilage and bone430. Kember and Coggins [K25] investigated theeffects of x rays on the epiphyseal blood supply to
growing cartilage in young rats to test the hypothesisthat the primary cause of damage would be to the bloodvessels [M37). After 9 Gy (soft tissue dose) there was a
reduction in the number of blood vessels but thoseremaining seemed normal. Before the number of vessels
was restored, damage to the cartilage plate was fully
repaired. There was stunting in growth from this dose.
but this was fully explicable on the basis of the parenchymal cell survival [K 1]. It was concluded that damage
to the vascular supply was not the primary cause ofstunting.
431. Blood vessels in the vicinity of the cartilage plate
pass through small channels (20 to 35 µm diameter) inthe bony plate before reaching the cartilage space
adjacent to it. Depending on the energy of the x rays
used, the dose to the blood vessels may be increased by
the presence of the bone. When this was accounted for.
Kember and Coggins [K25] noted that even after dosesof about 30 Gy in a single treatment to vessels passing
through the bony plate. some vessels remained active.
However. with doses of this magnitude, some clones ofcells in the growth cartilage aborted at 5-6 weeks after
irradiation. The possibility that this resulted fromvascular injury at these higher dose levels could not be
ruled out.
4.

Lung

432. In spite of the numerous histological reports ofoedema in irradiated lungs there are few studies ofvascular permeability. Travis et al. [T13] observed
increased vascular permeability in rat lung at 4 and 8
weeks, but not at 2 and 12 weeks, after 20 and 40 Gy to
the hemithorax, while 5 Gy had no effect. In similar
experiments on the mouse lung, Homsey [H52]observed significant leakage at 4 weeks, which persisted619

at 8-18 weeks. The effect was dose-dependent with athreshold at about 10 Oy. Maisin [M7) found anincreased permeability at 30 minutes and at 3-7 days
after 20 Gy to the mouse lung. Between 7 and 18
months there was a gradual decrease in permeability.

but only a slight depression of hepatocyte function,
during the first month. Between 2-28 months there wasa gradual reduction in both blood flow index and \i.ver
function. A dose of 7 Oy caused no significant latechanges but 15 and 30 Oy had comparable effects.

433. Long-term sequential studies of pulmonary
blood flow in rats demonstrate reduced now at 1-3
months after doses in excess of 10 Oy to one lung
(Rana, quoted by Keyeux et al. [K21]). Blood now
returned to normal by 4-5 months after 10 Oy, but aprolonged depression of flow was observed after dosesof 12.5 and 15 Oy. A dose of 20 Oy caused a completearrest of the circulation within 6-12 months. Further
experiments using 133Xe injected intravenously,
confirmed that there were two different phases of
response [K21]. Clearance was allowed at 7-14 days,
preceding the acute phase of radiation pneumonitis andthe subsequent slowing of blood now after 70 days
coincided with the development of permanent histological lesions.

438. There is also one study of hepatic blood now
which does not depend on active uptake by liver cells.
Using the 86Rb extraction method, Glatstcin [02]showed no significant change in liver blood flow inmice after local single doses of 10 or 15 Oy up to 12
months after radiation exposure.

434. Glatstein [02] used 86Rb to measure vascularfunction after irradiation of one lung in the mouse. The
uptake of 86Rb decreased 3-4 months after single dosesof 11 or 15 Oy, but subsequently returned to normal
levels. Experiments in rats by Jovanovic et al. [113]
indicate that the volume of lung tissue irradiated isimportant. Following irradiation of one lung with
10-20 Oy, blood flow was reduced during the acutephase (up to 90 days) and also during the late phase(4-18 months). By contrast, irradiation of both lungs
with doses of 5-15 Oy was followed by an increased
blood flow during the acute phase. A reduced flowfrom poorly ventilated lung alveoli was observed
during the later phases, but there was no significant
change in the ventilated region.
5.

Liver

435. In studies of liver circulation, the clearance fromthe blood of colloids which are taken up by Kupffer
cells has been used as an index of hepatic blood flow.
This is a reasonable method providing there is noaccompanying change in the ability of Kupffer cells tofunction. Therefore, only the studies in which liver cellfunction has been assessed separately are discussed.
436. Fridrich and Schafner [F32] observed decreased
clearance of radiogold colloid, which was attributed toreduced blood flow, immediately after doses of 5 to 20
Oy to the livers of mice. The fact that uptake in spleenremained stable suggests that delayed clearance is notdue to radiation damage to the reticulo-endothelial
system. since if this were the case phagocytosis in.thespleen would increase compensatorily. Impairment of
the indocyanine green (ICO) clearance was reported byPaumgartner et al. [P25] at 2-11 days after local proton
irradiation of the liver. Experiments with bromosulphtalein and labelled rose bengal ([K24, W32], Royer
quoted by [D34]) indicate that the hepatic cell function
is not affected during the first few weeks after irradiation so that clearance studies give a measure of bloodflow at these times.
437. In an attempt to evaluate the function of both thehepatic cells and the vascular network, Keyeux et al.
[K21] used colloidal gold to measure circulatorychanges and labelled rose bengal to measure liverfunction in rats. A single dose of 15 Oy caused atransient marked reduction of liver blood flow index,
620

6.

Kidney439. The effective renal plasma flow (ERPF) may be
estimated by measuring the disappearance of a tracer
such as hippuran from the blood following a single
intravenous injection, providing the tracer used iscleared by the kidneys. The disadvantage of thistechnique is that any impairment of the secretaryfunction of the kidney tubules will also result inapparent reduction of the effective renal plasma flow.
Although isotope clearance and extraction methods are
not subject to this disadvantage, the 85Rb extraction
method has only been used in one study on mice.
440. The majority of experimental investigations into
renal function have been in dogs. Mendelsohn andCaceres [M10] measured renal function after 20, 27.5
and 37 Oy, given in 13 days to the remaining kidney inunilaterally nephrectomized dogs. After 20 Oy there
were no significant changes in renal blood flow. Afterthe higher doses there was a temporary increase in bothblood now and tubular secretion during the first week,
followed by a depression in function which reached aminimum at 9-11 weeks. This subsequently returned tonormal by 36 weeks after 27.5 Gy but remained at 70%of the controls after the highest dose. Concannon et al.
[C19] irradiated both kidneys of dogs with 19, 25 and 31
Oy in 12 fractions over 13 days. All doses caused
persistent depression of renal blood flow from 10 to 60
weeks. Oup et al. [021], using subcutaneous exteriorized kidneys, observed decreased renal plasma now
at 5-7 months after 5 and 10 Oy as single doses, andafter 10 and 20 Oy in 10 fractions over 19 days. There
were no histological signs of radiation-induced damage.
Maier and Casarett [M36] used radiohippuran
renograms to evaluate renal function in dogs. At 4-6
weeks excretion was reduced after 10 and 20 Oy but not
after 5 Oy.
441. In pigs, the renal plasma flow is progressively
reduced between 1-6 months after exposure [H12]. The
single dose required to reduce function to 30-40% of
normal at 6 months was 12.6 Gy. This was defined by
the authors as the "tolerance dose". There was a further
reduction in flow during 9-24 months, the tolerance
dose falling to between 10.7-12.6 Oy [H48]. After
fractionated treatments the maximum depression ofplasma flow was observed at 6 months. There is good
agreement between the data for pigs and dogs.
442. Estimation of renal function in rodents has been
limited because of the small physical size of theanimals. Smith and Boss [S28] measured renal function
in exteriorized rat kidneys after single doses of x rays.
No changes in renal blood now were observed during
the first 4 weeks after 25 and 30 Oy but 40 Oy caused a
depression in now at 28 days. Chauser et al. [C8]measured renal plasma flow in the rat at late times afterlocalized irradiation of a single kidney in situ. Doses of
I O Gy caused no effect by 20 weeks. Doses of 20 and 30
Gy caused total kidney failure by 12 and 20 weeks,
respectively, with accompanying histological damage.
443. Thus, by the classical methods for measuring
ERPF, there is a reduction in blood now which is dose
and time dependent. Similar results have been obtainedusing the 86Rb extraction method in mice [G2]. Twomonths after irradiation of both kidneys with single
doses of 11 to 19 Gy, blood now had decreased and it
continued to decline for at least one year. The effectwas dose dependent and preceded fibrosis by several
months.
444. An extensive study of renal function in man has
been performed by Avioli et al. [A15]. They observed anearly decrease in renal plasma now during fractionatedtherapy as soon as a dose of 4.5 Gy had been accumulated. After completion of therapy there was aprogressive fall in plasma flow which persisted for 12months after cumulative doses of 20 and 24 Gy.
7.

Central nervous system

445. Although the central nervous system is highly
sensitive to slight decreases in oxygen and glucose
supply and histological examination of irradiated brain
and spinal cord indicate that there are radiationinduced lesions in blood vessels, there are few studies
of vascular function in the CNS after local irradiation.
446. There is evidence that the blood-brain barrier isimpaired by ionizing radiation. Permeability to protein,
phosphorous, iodine, sodium and chloride can beincreased [K.23]. However, labelled proteins areprobably the best agents with which to demonstrategross permeability changes in the capillary endothelium[N7]. In rats, a dose of 100 Gy to the head caused nosignificant leakage of intravascular albumin between
1-96 hours [K.23]. But, in the rabbit, permeability of theblood-brain barrier to albumin was increased at 24hours after x-ray doses of only 8 Gy [W31].
Mogil'nitskiy and Brumshteyn (quoted by Keyeux[K23]) observed leakage of protein into the pericapillary spaces of brain vessels in dogs at 48 hours after
10-30 Gy and Clemente and Holst [C18] found that
vascular permeability was increased in monkeys. The
most severe changes in the blood-brain barrier wereseen less than a day after doses of 45 and 60 Gy but 15
Gy also caused a detectable effect. Later effects havebeen studied in monkeys. No changes in the bloodbrain barrier were seen before 28 weeks after 35 Gy but
then increased permeability was observed until 40
weeks (T14].
447. Leith and Gaugl [L24] measured cerebral bloodflow in the rabbit using an electromagnetic flow probe
placed round the internal carotid artery. Doses of 100
Gy caused a transient decrease in flow at 1 hour and afurther decline between 3-6 hours. However, Keyeux[K23] found that 200 Gy to the rat brain caused nochange in blood now at 48 hours, although blood
volume was increased.
448. Delayed effects have been observed after lower
doses. Keyeux et al. [K21] used local irradiation of the
rat brain, and showed no change in blood volume at 8.5
months after 15 Gy, but blood flow was increased, witha threshold dose between 10 and 15 Gy. Moustafa andHopewell [M35] observed modifications in vascularfunction after 20 and 30 Gy, but no changes after 5 or
IO Gy. The first change occurred 3 months after irradiation when there was a reduced blood flow. At 6 and 9months blood flow was increased but by 12 months it
had returned to normal.
449. Conflicting results have been obtained in themonkey, following localized irradiation of the rightoccipital lobe [Tl4]. Blood now in both white and grey
matter was reduced 28 weeks after a single dose of 35
Gy. At 40 weeks there was some recovery in the grey
matter but not in the white. Changes in human brain
haemodynamics have also been noted during acuteradiation sickness [G27, T16, G29].

C.

ENDOTHELIAL CELL SENSITIVITY

450. Since endothelial cells are present in all bloodvessels, and since damage to these cells has been
observed as one of the first pathological changes inmany tissues [P22], several attempts have been made tomeasure their radiosensitivity. Because the turnovertimes for endothelial cells are very long, from 2 months
to 3 years [H4, T3, S4, E15, S29], it is generally assumed
that radiation-induced cell death would not occur for
many months or years. However experiments on rats,
rabbits and guinea pigs, in which the number ofendothelial cells was counted in defined areas of theaorta, demonstrated a decrease in endothelial cellnumbers at 5-11 days after irradiation. It was postulated that this was the result of interphase death. The
dose required for 25% loss of cells was 4.9 Gy for
guinea pig and 9 Gy for rabbit and rat. In these experiments the estimated values of Dq were 2.5 Gy for guinea
pig, 8.3 Gy for rat and 8.8 Gy for rabbit [S43, S44].
More recent data [K4, H4] indicate that a small subpopulation of cells may exist with a cell cycle time of about
1 day. Therefore the kinetics of endothelial cells andtheir mode of death after irradiation are not knownwith sufficient certainty.
451. Other attempts to measure endothelial survival
curve parameters have mostly involved stimuli to
induce proliferation and to speed up expression ofradiation damage. If the stimulus is applied before
irradiation, the resulting survival curve refers to proliferating endothelial cells and may not be relevant to thenormal slow turnover state. If the stimulus is applied
after irradiation, the time of stimulation is found to bevery important, owing presumably to repair of a slow
type of potentially lethal injury [V2, R3].
452. Several studies have also been undertaken of
endothelial cell survival in culture [N8, D35] but thesurvival characteristics of cells in vitro are mostly
similar and not always the same as for cells in vivo.
Essentially three methods have been employed inmeasuring in vivo endothelial survival parameters: (a)skin grafting, which stimulates growth of capillaryloops linking host to graft; (b) stimulation of bloodvessels in a subcutaneous air pouch by local applicationof agents such as croton oil or uric acid; (c) a techniqueof continuous labelling in utero which has been applied
to the bone marrow [H64].
453. One of the earliest estimates of cell survival curveparameters was reported by Hopewell and Patterson[H49] in pigs. Three weeks after irradiation of a local
area of skin, grafts of irradiated and unirradiated skinwere transposed. Irradiated grafts on normal vascular621

beds survived whereas normal grafts on irradiated beds
sloughed off, indicating that the vascular bed was theimportant component. Capillary loops were visualized
in the graft by injecting a dye at 48 hours after graftingand counting the number of loops linking host to graft.
A dose-response curve with a 0 0 of - 10 Gy and a Dqof - 3 Gy was derived from these data.
454. Reinhold [R27] obtained a D0 of -9 Gy after
irradiating an area of a subcutaneous air pouch in therat. Endothelial cell proliferation was stimulated by the
local application of uric acid and the number ofcapillary sprouts was counted 5 days after stimulating
division.
455. In later experiments, however, Reinhold andBuisman [R2] obtained a much lower value of Do by amodified version of the same system. These studies gavea survival curve with a Do of about 1.7 Gy. an extrapolation number of 7 and a Dq of about 3.4 Gy. Split doseexperiments at 24 hours, using an initial dose of 5 Gygave a Di-Dt value of about 3 Gy. The majordifference between the two series [R27] and [R2] is thatin the second experiment a longer period was allowed
between proliferative stimulus and assay.
456. Van den Brenk [V11) has also used a longer
follow-up period. Granuloma pouches were raised in
the rat subcutis less than 5 minutes before irradiation
by injecting air and croton oil beneath the panniculus
carnosus. Both air pouch and adjacent tissue were
irradiated. Thirteen days later, the air pouch was
excised and opened. In unirradiated pouches a small
confluent layer of granulation tissue formed. In
irradiated pouches. discrete colonies of vasculaturedeveloped which could be counted, enablingendothelial cell survival curves to be plotted. These had
a Do of 2.4 Gy, an extrapolation number of about 2 anda Dq of about 1.8 Gy. In later experiments, Van den
Brenk et al. [V2) found no significant change in survival
parameters if the radiation was given immediately
before raising the air pouch. In these experiments,
Di-Dt for the 24-hour interval was found to be 1.8 Gyafter a first dose of 1.45 Gy.
457. It is not clear why the above investigations gavesuch widely different values for D 0 • Cell survival
parameters in vitro for a rapidly growing cell line ofendothelial cell origin have been estimated to have D 0= 2 Gy, N = 2.3 [NB]. It seems that high values for Do(9-10 Gy) are obtained if the time interval between
endothelial cell stimulation and assay is short [H49,
R27]. It may be speculated that lethally-irradiated cells
may perform one or two divisions before they die,maintaining functional integrity of the capillaries for a
few days, whereas a later assay might detect the deathof these cells and loss of the capillaries.
458. When the time between irradiation and subsequent stimulation is extended, repair of potentiallylethal damage may occur before the damage isexpressed. The three weeks between irradiation andgrafting in the experiments of Hopewell and Patterson[H49] may have allowed repair of potentially lethal
damage and this may account for the high D 0 observed.
Van den Brenk et al. [V2] observed a dose sparing of
5-6 Gy when a 2-3-week gap was allowed between
irradiation and the raising of the air pouch. Similarly.
Reinhold and Huisman [R3] observed a repair phenomenon if the interval between irradiation and the uricacid stimulus was delayed for up to 60 days. The timecourse of the repair appeared to be exponential and622

had the effect of increasing the Do from 1.7 to 2.4 Gy
for an interval of 16 days. This type of repair might berelated to "slow repair" discussed earlier. In addition,
repair of Elkind-type sublethal injury was observed in
split-dose experiments, with a survival ratio of 5.
459. Gillette et al. [G23] studied the neovascularization after surgery on irradiated dogs' eyes. Theysuggested that cells stimulated before irradiation weremore sensitive than cells stimulated after irradiation but
their data are unconvincing. A split-dose increment
D2-D1 of 3.5 Gy was obtained whether surgery was
performed before or after irradiation.
460. Hirst et al. [H4, H40] measured depopulation andsubsequent repopulation of endothelial cells in themesenteric arterioles. A surprisingly early wave ofdepletion was observed, being more consistent with ashort cycle time for 1-2% of the cells, than with auniformly slow turnover of all cells. The subsequent
repopulation was consistent with a Di-D 1 of 7 Gy (asmeasured in split-dose experiments) and a Do in excess
of 5 Gy. The rate of depopulation of the smooth muscle
cells is. however, consistent with a generally slow
turnover of all cells.
461. The above results suggest that the radiosensitivityof endothelial cells in vivo may be impossible to define
because cells which attempt division soon after irradiation will be more sensitive than those that attempt
division at later times when a significant amount of
repair of potentially lethal damage may have occurred.
D.

MECHANISMS UNDERLYING VASCULARDAMAGE

462. A number of different mechanisms leading to theobserved changes in vascular function have been postulated; they may be relevant at different times or after
different doses in each of the tissues studied. The
suggestions include widening of intra-endothelial cellgaps, changes in the amount of pinocytosis, changes inmembrane permeability, depletion of cells, hyperplasia,
leaking of proteins and development of fibrosis. The
time course and extent of some of these individualchanges are likely to be innuenced by death ofsurrounding parenchymal cells. Hence the pattern of
response must be considered separately for fastrecovering tissues such as intestine and skin, and forslow-turnover tissues such as lung and heart. In general,an early phase of dilation and increased permeability
accompanies the early wave of desquamation which
occurs in both intestine and skin. This has not been
extensively investigated in slowly proliferating tissue. It
is generally found that tissues show a gradual decreasein blood flow and an increase in permeability is seen atlater times.
463. Gaps between endothelial cells have been
observed in electron microscopic studies of skin within
10 days of irradiation [H50]. Maisin [M30]. however,suggests that increased pinocytosis causes the increased
permeability, although the correlation between these
two is poor [M38].
464. Parenchymal cell death will produce chemical
mediators (e.g., histamine or 5-hydroxytryptamine)increasing small vessel permeability [W33]. This has
actually been postulated as the cause of the earlychanges observed [D30, V10]. The mediators in the latephase do not appear to be the same as those in the earlyphase. and may involve release of lysosomal enzymes
which cause the release of vasoactive polypeptides fromplasma proteins [El4. M32, 114, 115, S30, El6].
465. At longer time intervals, e.g., 1-6 months after
moderate doses, changes in endothelial morphology
and in cell number arc observed in rapidly and slowly
proliferating tissues [P6, Cl7, A13. H40, Z3, W27, M39].
Vacuolation, sloughing and cell depletion have been
observed in several tissues and this is probably thephase when direct damage to the endothelial cells is
being expressed. At six weeks a good correlation has
been shown between endothelial depletion in mesenteric arteries, and increased permeability, but not atlater times [H40), probably because of other intluencessuch as deposition of collagen.
466. At late times after irradiation, a reduction inblood llow with constriction and occlusion of bloodvessels are seen. These changes have been attributed to
localized proliferation of endothelial cells, which
protrude into the lumen [Ml 7, Cl 7, H43] and have been
related to the increased thymidine uptake seen in rabbit
heart endothelium at 30-70 days [F33]. An alternative
postulate relates to the insudation of the vessel walls byplasma proteins and their replacement by collagen
leading to thickened walls, which limit the vessel
diameters [Z3). The processes are clearly complex andany or all of the changes which have been describedmay occur with time after irradiation.
E.

COLLAGEN DEPOSITION

467. A characteristic of late radiation damage intissues is an increase in the amount of acellularmaterial. In particular, collagen is increased, althoughsmall foci of oedema and fibrin may also persist for
many months or even years after treatment [Rl. W34].
Moreover, the microscopic and biochemical appearances of collagen may be abnormal because the fibres
tend to lose their orientation and take on a dense
hyaline appearance [W34, G43].
468. Several authors have suggested that the increasein collagen is the final stage in the resolution of oedema
fluid and fibrin which are observed at early and intermediate times after irradiation [Rl, J3, L23, J16]. andthat fibrosis in vessel walls and intercellular spaces
finally leads to parenchymal cell death. The sequenceof changes observed in many irradiated tissues actually
supports this view. Vascular changes and interstitial
fibrosis precede atrophy of parenchymal cells in liver[12, R20], kidney [MlO. C17), heart [F31], lung [J3. M7.
A13, 116] and brain [H14. P21). On the contrary, otherauthors suggest that radiation has a direct lethal effecton parenchymal cells [H41, E 17. C20, R28, Z4, M40],
and that parenchymal cell death is followed byreplacement fibrosis as a secondary effect when thecells cannot be regenerated [F34]. Therefore, collagensynthesis after irradiation is of interest.
469. In general. the concentration of collagen in adulttissue is maintained by a balance between synthesis anddegradation. Radiation could upset this balance, either
by altering the number of cells involved in synthesis ordegradation, or by affecting the synthesis and degradation of collagen by surviving cells. Synthesis ismeasured by incorporation of labelled precursors(pro line or glycine) after irradiation: degradation ismeasured by labelling before irradiation and following
the subsequent loss of activity. In skin and in

granuloma tissue, synthesis is depressed and degradation is increased for 3 weeks after 7.5-15 Gy locally.
or 7.5-10 Gy whole-body irradiation [N9, A16, T15.
K26, K27, 011]. Similar changes have been seen inmuscle but not in tail tendon collagen [K26, K27]. With
whole-body irradiation some effects may be secondary
to starvation [K27). and after localized irradiation
decreased degradation of collagen in granulation tissue
has even been seen [R29. W35].
470. The depression of collagen synthesis taking place
within 6 hours of irradiation is attributed to a direct
effect on collagen biosynthesis, but the decrease at 2-3
weeks is attributed to reduced cell numbers available
for synthesis [R29]. Collagen production per cell isincreased, possibly because of less degradation.
resulting in an accumulation of insoluble collagen.
471. The relevance of these early changes to the development of late radiation fibrosis is questionable.
Degradation is inhibited only during the first three days
after exposure [R29] whereas late radiation fibrosis
develops over several months and gradual increases inthe total collagen of adult rat skin have been measured
between 4 and 12 months after irradiation [K28].
472. Radiation fibrosis may be the result ofprogressive organization of exudate from damaged
blood vessels [Rl, 13, L23, 116, R30]. An increase in thenumber of mononuclear cells, including fibroblasts, hasbeen observed in irradiated tissues in which collagenalso increases (13, M7, R20, F31, D30. M39, R30]. This
increase may persist, suggesting active collagensynthesis at months or even years after exposure (J3.
R20, F3 l, M39, W34]. Increased collagen deposition
has been observed after 36 weeks in mouse lung [Ll 1]
and at 20 weeks in mouse kidneys [C8) with a threshold
between 10 and 20 Gy.
473. The collagen that is produced is less soluble thannormal [011, R29] but the detailed differences inchemical structure and cross linking are not known.
External changes in pH may influence polymerizationand thickness of collagen fibres and fibrin may be
involved in collagen hyalinization [839. W36].

F.

CHANGES IN LYMPHATICS

474. Since the network of lymph vessels and lymph
nodes forms an integral part of the vascular system.
radiation effects on the dynamics and permeability ofthe blood vessels may result in reactive changes in thelymphatic system. In particular, the latter usually reacts
to reduce circulatory disturbances caused by damage tothe blood vessels, either through increasing drainage bylymph vessels or by opening of lymphatic-venous
communications.
475. In general. the lymphatic vessels can withstandhigh doses of radiation before their function is
impaired. Hodes and Griffith [HSl} found no change inlymph flow in irradiated rats at 3-6 weeks after 22 Gy.
In an extended study. Engeset [E18] also found no
disturbances in lymph flow up to 1 year after 30 Gy to
the rat limb. At later times lymph flow was not interrupted but was directed into newly formed vessels as
fibrosis obstructed the original channels. Similarfindings are reported in dogs by Sherman and O'Brien[S31]. Hind limb irradiation with 10-36 Gy did notaffect lymph flow for 18 months after exposure.
623

476. The Sandison-Clark rabbit ear chamber was usedby Van den Brenk [V12] as an experimental system forstudying the effects of external radiation on lymphatics.
A dose of 40 Gy did not induce endothelial swelling
sufficient to cause blockage of lymphatic vessels up to
15 months after irradiation. Doses exceeding 50 Gy
were required to cause destruction of lymphatic vessels.
Lenzi and Bassani [L25] concluded that the threshold
was even higher, i.e., 60 Gy in rabbit uteri. They
described some dilations and varicosities which became
progressively more pronounced after 80 Gy. The
lymphatics were tortuous, varicose and rigid but patentin all cases.
477. Lymphangiography has often been used toestimate lymph now in patients who have received
therapeutic doses of radiation. In some early observations radiation to total fractionated doses of 20 Gy or
greater did not appear to cause a reduction in flow up
to 1 year after exposure [L25, P26, VB, Al7, M41]
although lymphatic vessels may appear rigid andflattened [L25] and lymph nodes may be reduced in size
and increased in density [K34, 26] or destroyed [A17,
M41]. More recent work suggests doses in the lower
limit of that range. In a study of 32 patients whodeveloped skin ulcers between 6 months and 15 years
after radiotherapy lymphatic changes were observed,
including narrowing of the main vessels, anastomoses
and the opening of vessels normally in reserve (848,B47, 26]. In some cases there may be leaking of contrast
medium and the development of collateral lymphatic
circulation [A18] but, in the majority of cases,
lymphatic vessels did not undergo any marked changes
in configuration [A17, M41].
478. Lymphangiography can only give a rather crude
estimate of lymph flow rate but it can demonstratecessation of flow either from intraluminal causes orfrom extravascular compression due to fibrosis. Resultsof lymphangiographic studies in man show that there isa progressive decrease in the size of irradiated lymph
nodes reaching a minimum at 9-12 months after
therapy. However, although lymph nodes become
fibrotic the nodal sinuses remain patent. Irradiation
per se does not cause obstruction of lymph vessels
although perivascular fibrosis may cause a deviation oflymphatics.
479. In conclusion, lymphatic vessels in experimental
animals and in man appear to be rather radioresistant.
In most cases, large doses (single doses of 40 Gy to rats,
fractionated dose of 75 Gy in 60 days to man) do notcause a change in lymph flow at 6-15 months after
exposure. Any changes of lymph flow have frequently
been found to be due to extravascular fibrosis, while
irradiated lymphatics remain fully patent.
G.

SUMMARY

480. After doses of radiation in the radiotherapy
range, progressive morphological changes occur in allelements of the vasculature such that at late times after
exposure vascular function is reduced. In general,changes in vascular function are observed before theoccurrence of late atrophy of tissues, which suggeststhat vascular damage plays an important role in all lateradiation injury after such relatively high doses.
481. Table 15 summarizes threshold doses for detectable changes in vascular function. Abnormal vascularpermeability tends to occur at lower doses than marked

624

reduction in blood now. For any given species there is awide variation between the threshold doses for different
tissues, e.g., for the rat these range between 5 Gy in themesentery to 15 Gy in the liver. These differences mayof course reflect the different assay techniques used.
However, it is also likely that they renect intrinsic
differences in various sections of the vascular system in
different tissues. It should be recalled, finally, that thegeneral response of a tissue depends on both the parenchymal and vascular components and that it may not
be possible to view either in isolation.

VII.

SUMMARY

482. Although the effects of irradiation on some bodytissues were considered by the Committee in more
recent specialized reviews, the whole field of morphological and functional changes in irradiated normal
tissues of animals and man had not been systematicallyevaluated since 1962. A re-examination of the wholesubject was therefore carried out with the main
objective of identifying for each tissue and for various
modalities of irradiation the effects and the doses that
may become critical for the function of that tissue. As asecondary objective the Committee wished to analyse
the main physical and biological factors which might
modify these doses and effects. These objectives
required a study of the dose-time relationships in eachtissue, based on both animal data and on the observation of clinical effects in man.
483. The study was confined to the so-called nonstochastic or deterministic effects. Whereas the effects
referred to as stochastic take place in one or a few cells
and appear in an irradiated population as hereditaryeffects or tumours, the non-stochastic ones affect manycells and appear as tissue damage. In general, nonstochastic effects require that a minimum dose, called
the threshold dose, be delivered before they can bedetected. The clinical severity of the injury increases
with increasing dose. The time of appearance of tissue
damage is very variable as it may span from a few
hours or days to many years after exposure, dependingon the type of effect and on the characteristics of theparticular tissue.
484. The concept of dose threshold is difficult todefine and must be discussed in relation to each tissue
and effect because it depends to a large extent on thesensitivity of the measuring technique. The loss offunctional capacity of a given tissue, for example, may
actually exhibit a much higher dose threshold than theappearance of subtle ultrastructural changes detectable
only by sophisticated technology. Similarly, there is aneed to distinguish between the threshold ofappearance of clinical changes which have clear pathological connotations. While recognizing that theseconcepts have important practical implications, theCommittee felt that a thorough discussion of tissue
pathology was beyond the scope of this study which
was primarily aimed at an assessment of the effects asreported, irrespective of their significance for practical
purposes.
485. The amount of information that has accumulatedon these subjects during the last twenty years is verylarge and an interpretative, rather than a comprehensive, treatment was therefore necessary. This was
facilitated by the significant advancement in knowledge

of the basic mechanisms of cell and tissue response toirradiation. The premise of the Committee's review isthat the non-stochastic response of a given tissue toradiation depends primarily on the level of killing of
the component cells and that the degree of damage andits time of occurrence are related to the special way inwhich each given tissue is structured. Therefore an
introductory treatment of the basic concepts ofradiation effects on cells and tissues was required. In
this part of the Annex the Committee discussed themechanisms and the phenomenological characteristics
of cell survival as a function of time and dose, repair
phenomena, the normal mechanisms of cell proliferation in tissues and the changes induced by radiation
thereupon. All this should be viewed as a unifying
frame of reference for the specialized and systematic
analysis of effects in various tissues.
486. Although the analysis of the Committee has
considered separately the animal and the human data,
the similarities between the observed effects warrant acommon summary of the subject matter. with thenecessary qualifications to point out major discrepancies.
487. In skin the early radiation reactions may increase
from a temporary reddening through various degrees ofseverity to . ulceration and necrosis. Late changes
involve thinning of the skin, Joss of hair, colour changes
and dilatation of the blood vessels. In order to produce
observable changes in animal skin by external irradiation, doses of the order of 7 to 10 Gy must normally beadministered in acute exposures. However, this tissue
has a very large capacity to repair radiation damage
and thus, if radiation is delivered over a long time
period, up to 5 times or more doses may be tolerated.
Observations on radiotherapy patients generally
confirm these findings. With single acute treatments
temporary loss of hair results in man after 3-5 Gy andreversible changes cause no serious consequences. The
area of skin irradiated is important, with more severechanges appearing for larger irradiated areas. A
number of biological variables are known to influence
the level of the threshold dose: among them theanatomical location of the skin, the age of theirradiated person, and the normal skin colour. Mucosae
exhibit changes analogous to those seen in the skin atsimilar doses.

tract, since they arc not uniformly sensitive. Considering the early forms of radiation injury, the stomach inman may tolerate up to 40 Gy of long-term fractionatedtreatment. The small intestine may also withstandfractionated doses of conventional radiotherapy of theorder of 30-40 Gy. The large intestine is even moreresistant and shows only transient symptoms at similardoses. while the oesophagus appears to tolerate up to 60
Gy. The late consequences of these large doses (particularly those given to large volumes) arc little known anddifficult to quantify. The liver is a very slowly proliferating organ, but its component cells may be stimulated
into division by different types of injury including
radiation: this could unmask latent damage that would
not otherwise become apparent. In animals, single
doses of over 10 Gy are necessary to induce permanentchanges in liver and these doses may be increased up to
six times upon extended fractionation. In man, liver is
now known to tolerate 40-50 Gy in 30 days given toparts of the organ, the threshold for measurable effects
being around 30 Gy of conventional fractionatedradiotherapy.
490. The lung is regarded as being the most sensitive
organ in the thorax and after moderate doses
pneumonitis may develop which leads eventually,
through a complex chain of pathological reactions. tofibrosis and loss of function. With whole-body irradiation and providing bone marrow function is
maintained, the maximum dose which may be tolerated
by lung is approximately 8 Gy, if given over several
hours. The sensitivity of the lung with respect to longcourses of irradiation is moderate. This is because it
possesses a large capacity to repair intra-cellular
damage, although it lacks the proliferative ability toreconstruct, by cellular repopulation, its elaborate
structure. Doses of the order of 40 Gy in conventional
radiotherapy (i.e., in 30 fractions) may lead to an appreciably increased incidence of complications. Amongother thoracic organs, the heart is regarded, on thecontrary, to be rather radioresistant in experimental
animals where it shows only microscopic changes in themuscle cells and blood vessels after moderate doses. Inman, a high incidence of cardiac complications
consisting mainly of pericarditis and eventually fibrosis
is seen after long fractionation courses to total doses inexcess of 60 Gy.

488. The blood and blood-forming cells appear to beparticularly sensitive. The lymphocytes and the stem
cells are inactivated by doses of a fraction of a Gy
causing the disappearance of these cells from the bonemarrow and the circulating blood. Blood forming
organs have however a remarkable capacity for regeneration and may show complete recovery. In man, thehaemopoietic system is also one of the most sensitive
tissues. Responses may be observed after 0.5-1 Gy,
whether given in a single exposure or as a series ofsmall fractions. If depression of the peripheral blood
cells is too severe death may occur, due to infection(loss of white cells) or to haemorrhage (loss of platelets)
which are the major symptoms of the so-called haemopoietic syndrome. The LDso for man lies in the range of
3-5 Gy.

491. The urinary system shows a wide range of sensitivities and among the various organs the kidney isbelieved to be the most vulnerable, followed by the
bladder and the ureters. Acute and chronic nephritis
followed by hypertension and proteinuria usually result
from high radiation doses to the kidney. In experimental animals, morphological and physiopathologicalchanges have been reported after single acute treatments with threshold doses between 5 and 12 Gy. With
long-term fractionation these doses might be increased
by a factor of at least 3. In man, 20-24 Gy in 3-4 weeks
produce evident alterations in kidney function, so thatthe tolerance dose is normally regarded to be around 23
Gy in five weeks. In both man and animals the kidney
appears to be more sensitive at around the time of birth.
Doses of 55-60 Gy in 4 weeks arc regarded as thetolerance doses for urinary bladder erythema, ulceration and eventually fibrosis.

489. External irradiation of the gastrointestinal
system may lead to a variety of acute and chronic
symptoms ranging from dyspepsia and diarrhoea withloss of fluid and blood, to localized ulcers and bowel
strictures and obstructions. The review has treatedseparately the various sections of the gastrointestinal

492. The reproductive organs are particularly
sensitive. Irradiation of the testis causes temporary
sterility, which may become permanent after larger
doses. The testis appears to be unique in that its
component cells cannot undergo repair. Continuous
625

irradiation causes more, rather than less, damage thansingle acute treatments. In man, acute doses as low as
0.1 Gy have been reported to cause temporary sterility,
alrhough doses in excess of 2 Gy and possibly up to 6
Gy arc needed to produce permanent aspermia. Many
years may be necessary for complete recovery of the
production of spermatogonial cells after severely
damaging doses. The adult ovary is more resistant than
the testis because, by the time of birth, the oogonial
cells have all progressed to the more resistant oocytcs.
However, if irradiation is delivered to the developing
ovary, fractionated treatments to a total of 2 Gy may
cause severe damage in dogs and monkeys. Permanentsterility is caused in women by single doses in excess ofabout 3 Gy, or higher fractionated doses.
493. The threshold doses applying to the central
nervous system differ for different structures. The
lesions consist in alterations of the fibre structure, lossof myelin, encephalitis and necrosis. The damage isbelieved to result, at least in part, from primary lesionsof the blood vessels and it is irreversible. The central
nervous system, like the lung, has limited capacity forregeneration but a large capacity for repair of intracellular damage. An increasing amount of information in
animals supports the view that structural damage to thenervous cells may occur after doses of 1-6 Gy. These
doses may produce cellular degeneration of the brainsome months after treatment with destruction ofsections of the cortex. In man the tolerance dose for thewhole brain is around 55 Gy delivered in 5-6 weeks,
but morphological changes are seen after 10 Gy of
fractionated treatment. Threshold doses for the spinal
chord are lower, in the region of 35 Gy in 4 weeks.
494. Irradiation of growing cartilage leads essentiallyto disturbances in the process of bone formation, withresulting deformities. Growing cartilage is known to be
one of the most sensitive tissues and the threshold doseto cause growth stunting is probably small and possibly
zero. In the young animal, about 3% stunting per Gy
has been reported. In children, total doses of 10 Gy or
more given in daily fractions over a few weeks are sufficient to cause some degree of reduced growth. The
younger the child, the more severe the degree ofstunting. Mature cartilage, on the other hand, may
tolerate up to 70 Gy in prolonged fractionation
schemes. In general, adult bone is considered to be
fairly resistant and doses of 65 Gy given in 6-8 weeks
do not normally cause necrosis: there may be howeverpredisposition to fracture, depending on the mechanical stress normally exerted on the bone.
495. Of the many tissues in the eye (lacrimal glands,
conjunctiva, cornea, sclera, retina) the lens appears tobe the most sensitive to radiation. with production oflens opacitications or clinical cataract. Initial effects
are seen in man after 2 Gy of acute exposure. In
animals which are particularly prone to the development of cataract, like the mouse, much lower doses
are usually required to cause earlier cataract thannormal. Fractionated irradiation may be rather lesseffective in increasing the threshold dose than in manyother tissues. As to the endocrine organs, in the adultthe pituitary is regarded as radioresistant. Adrenals
respond to the stress of irradiation in such a way that itis difficult to assess the amount of direct effects onthem. The thyroid is a slowly proliferating tissue inwhich radiation effects may become apparent after
many years. Doses of the order of 10 Gy in a single
treatment are necessary to cause morphological damage
to cells and signs of malfunction.
626

496. The time sequence between changes in the bloodvessels and parcchymal tissue lesions suggests that
vascular injury may play an important role in allradiation-induced disturbances appearing in tissues(cell loss, fibrosis). After high doses of radiation, suchas those used in clinical radiotherapy, morphologicaldamage is known to occur in blood vessels and longafter exposure these changes may lead to disturbancesof the vascular function. Threshold doses for relatively
subtle changes, such as abnormal vascular permeability,
tend to occur at lower doses (down to 5 Gy) than moremarked functional injuries like the reduction in bloodnow ( 1O Gy or more). A detailed study of available datasuggests that blood vessels located in different tissues
may have different thresholds of reaction and that theoverall response of a given tissue may depend on the
joint response of the parenchymal and vascular components, in such a way that it may not be possible to viewthe reaction of either component in isolation.
497. The Annex examined for each tissue the effects
produced by radiations of different qualities (particularly by fast neutrons) that are known to produce, dosefor dose, a higher degree of biological effects than x or
gamma rays. For single acute doses sufficiently large tocause detectable non-stochastic injury, the relative
biological effectiveness (RBE) of neutrons is in therange of 1-5 times that of x or gamma rays. The RBE
increases in the course of fractionated treatments withthe decrease of the dose per fraction or with theincrease in the number of fractions. For tissues where
post-irradiation repopulation is important (skin,intestine) there is every reason to expect that repopulation is independent of the quality of radiation; forslowly dividing tissues repopulation will be small withall radiations. However, since other modalities of repair
are relatively less effective for neutrons, the doses ofthis radiation that could be tolerated if given over along period of time will not be much greater than thedoses for the same radiation given as acute exposures.
498. Consideration of the non-stochastic effects
produced by beta- or gamma-emitting radionuclides
administered internally showed that tissue injuries areusually consistent in type and degree with those causedby comparable mean tissue doses of external irradiation
at low dose rate. The tissues affected by treatment witha given nuclide depend on the particular distribution ofthat nuclide in the body; the amount of injury depends
on the radiation characteristics and on the temporal
distribution of the energy delivered. Models to relate
the temporal distribution of absorbed doses from aradionuclide to that of fractionated external irradiationon the basis of equal effects have not yet been fully
explored. There are also uncertainties concerning the
microdistribution of the energy delivered to the
biological targets within the cells and they affect theassignment of precise RBE values to radionuclides
emitting non-penetrating radiation, such as alphaparticles and low-energy Auger electrons.

VIII.

NEEDS FOR FUTURE RESEARCH

499. In general, this Annex has shown that nonstochastic damage is observed only with doses that areconsiderably greater than those producing stochastic
injury. Nevertheless, further study of non-stochastic
effects is important. The preceding chapters have repeatedly emphasized that the expression of non-stochastic
injury is dependent on the proliferation kinetics of thetissue and on the relationship between the proliferating

cells and those responsible for the tissue-specificfunctions. There is generally a lack of information
about the relationships between the various normal cell
kinetic parameters and the timing and extent of injury.
In addition. little is known of radiation-inducedchanges in proliferation kinetics during or after irradiation. particularly under chronic exposure conditions.
Information is especially scarce for tissues with long
turnover times in which the response is normallymanifest a long time after irradiation.
500. Although a considerable body of data exists on
tissue effects after single doses of irradiation or after asmall number of dose fractions, there is a need for more
information about effects of long term fractionation orcontinuous irradiation lasting over a significant portionof an animal's lifetime. Similarly, mathematical models
which account for fractionation effects need to beextended to very long treatment times in order to confidently extrapolate existing data on man. Clearly theexperimental and theoretical aspects of this problem
need to be carefully related.
501. The translation of loss of clonogenic capacity of
individual cells to impairment of tissue function isextremely complex and variable from tissue to tissue. In
most cases the target cells of composite tissues andorgans are not known: new techniques and muchresearch on methodology are needed to gain information about them and the pathways of injury leading
to functional impairment. The role of blood vessel
damage and whether it is a primary or secondary effectof irradiation is unclear. Further studies are alsoneeded on the pathogenesis of radiation induced
fibrosis and sclerosis.
502. New and more sensitive and quantitative endpoints are needed to study effects of radiation in arange of tissues. including endocrine organs, reproductive organs, central nervous system, lung, liver.
kidney, eye, haematopoietic tissues, etc. Of special
interest are changes occurring late after irradiation. The
existence of possible relationships between early andlate responses would also be of importance for thequantification of long-term damage. Remote consequences of partial-body irradiation have as yet received
scant attention. In recent years there have been great
advances in knowledge of the immune system, but few
comparable radiation studies have been made, particularly at low doses and dose rates. Also, in animal inves-ligations lillle attention has been paid to alterations in
response as a function of animal age or stage of development.
503. A reasonable body of data exists on RBE as afunction of dose per fraction, but mainly for early
effects and at doses greater than a few Gy. Below thisdose level or at low dose rates little information exists.
Data is also lacking on tissues which show damage lateafter irradiation. In complex organs the RBE may varyfrom one cell type to another so that the measured
overall response of the organ may be qualitatively
different with radiations of different LET. Such effects
require careful examination.
504. Of fundamental importance in the response oftissues to long term irradiation is their capacity forrepair. Intracellular repair mechanisms leading torepair of sublethal damage. potentially lethal damage
and, in some tissues. slow repair are as yet not wellunderstood and further knowledge of the mechanismsof cell killing and repair are required. Repair by regeneration is also an important factor, but after irradiation
this may be incomplete and there may be replacementof functional parenchymal cells by fibrosis. Repair of
all types requires further investigation after both lowand high-LET radiations for precise quantitative evaluations in all tissues.
505. The response of tissues to deposited radionuclides is often very difficult to evaluate owing to uncertainties in the dose distribution, together with variationsin activity with time. This is particularly true where thedecay scheme is complex. Efforts should be made to
define the dosimetry more accurately. Studies areneeded of effects of radionuclides emitting short range
particles (e.g., Auger electrons). particularly where they
are deposited in critical structures or molecules.
506. Quantitative results in man are urgently needed.
but difficult to obtain. New methods to derive datafrom radiotherapy patients are required as is thecontinued careful monitoring of any situation ofhuman exposure to doses resulting in stochastic damage
to individual tissues or to the whole body. There arc
wide differences in the type and severity of the nonstochastic effects considered in this Annex. For
practical applications it is important that attempts
should be made to quantify this damage in terms of thedegree of detriment.

627

Ta b l e
Qz-Dl values for various tissues
2 1
(Gy)

Ref.

5.0-7.0
8,9
5.0
Epidermal clones
3.5
5.7
LD/50
5.6
8.5
LD/50
4.5
Macrocolony assay
4.0
Growth stunting
4.0
3.5
LD/50 (both lungs) 4.0-5.0
3.5
ED/50
9.5
6.0
3 .o~..I
Clonal assay
Spleen nodules
1.0

l!l l

Stimulated dermal
blood vessels
Colonies in
granuloma pouch
Ce 11 counts inmesentery

3.0

[R2)

1.8

(V2]

7.0

[H4]

TissuesSpecies

Endpoint

Skin

Pig
Rat
Mouse
Mouse

Radiodermatitis

Oesophagus

Mouse

Gastrointestinal
tract
Cartilage

House

Lung

Mouse

Spinal cord

Rat

TestisHaemopoi eti ctissues
Endothelial
cells

Mouse
House

!I

Rat

Rat

[H21
(Pl
[HJ)
(W5)
(D4]
(Kl]
[FJ]
[P2)
[W6l
[Vl
[W7]
[Tl)

Decreases with increasing time between fractions.

T a b l e

Chan es inSpecies

Fraction
nurrber

Overalltime

lncrer.ient
Gy/dayDoublingtime(days)

5

5-28
7-14
14-21
up to 35
17-35
1-7
4-g

0.25
0.30
0.29
0.28-0.34
0. 32
0. 70
0.90

3.2
3.2
3
3
3.2
1

1-5
1-7
7-14
14-21

1.00
0.48
0.42
0.29

1
2
2.3
3,3

2

Human
!louseHouse
ltousePlucked skin
House
Mouse

2

roliferation after irradiation of skinract, onati on ata
1

Pig
Mouse

up to 25
15
2
5

2
2

Table

4

3

Threshold skin erythema doses
for single doses of x rays
SpeciesPig
Ratrlouse

628

W4

(D3

Dose
(Gy)
10-15

10
10

Area irradiatedReference

Approximately 20 cm2
Whole footWhole foot1 Fl2)[f10,W38}
rr21

Ref.
(FlO)
[D31
'DJ
fC4)
.Dl4)
[CS)
[Fl6]
[\Ill]
1
fE7
•
J
f[7'
(E7J

T a b 1 e

4"Threshold doses" for damage to kidney of various species
Species Dose (Gy)
Dog

< 20

Pig
Rabbit
Rat

10
- 12
5
5

Type of injury

Tubular function[MIO)
Renal enzy11e changes(P7l
Funct i ona 1 and enzymic changes[Zl
Decrease in size and mass, histologicaland functional changes
tMll
Function
H12
Probability of lethality
C7)
Hypertension
ILl3)
Nephrosclerosis
BI 1)
Functiona 1 and enzymic changes{KS]
Plasma flow and collagen deposition(CB)
Uephrosclerosis(B12 J
Accelerated glomerulosclerosis(Gl,C9 J
Blood flow
[G2)
Lethality after unilateral nephrectomy [PB)
Inhibition of growth(Dl I
Decrease in weight
[G3)

6
6
5-10

j

< tO

Mouse

Ref.

10
5

< 10

8
10-15
10

Ta b l e

5

LD 50130 }haem~poietic synd;ome)or different species
LO !?_I50(Gy)

Species

Approximate
weight
(gm)

LO ~I
50
(Gy)

Mouse
Desert mouse
GerbilHamsterRat
Guinea pig
i•larmoset
RabbitMonkey
Dog
Sheep
Goat
Man
Swine
Burro

25
30
40
80
200
8DO
3000
3500
400C
12000
45000
5000C
7000C
20000040000(

6.4,7.1
9.0
15.2
10.5
9.0
6.1,8.6
9.0
7.1
4.5
2.6
2.0
8.4
7.5
4.0
6.0
2.7
2.5
1.6
2 .1
2.3
2.4
3.0 di3.0 £I
2.0
2.5
2.5

al
ol

,1
di

H6]
B7]
L17;
B18J

629

T a b l e

6

Su11111C1ry of threshold doses in experimental animals

TissueEndpoint

Single dose
(Gy)

Multifractions or continuous irradiation (Gy)

Skin a/Oesophagus~/
GI tract
Cartilage
and bone ~/lhreshold erythema
LD/50
LD/50

-7
- 20
8-15

;, 10
50 in 10 F
2 Gy/day

Stunting

1 Gy resulted inHeart a/Fibrosis, deathLungs a/LD/50
Liver a/Histological changes
Kidney-a/
VariousCentra I-nervous
system a/
Neurophysiologicalchanges
Paralysis
Thyroid a/
Malfunction
Pituitary
Weight loss of theanimalAdrenals
TestisOvary
Eye a/
Haemopoietic

Weight loss of glands
Permanent changes
Sterility
Reduction in cells
and fertility
Lens opacities
LO/SO
Cell depletion

3-5 % stunting

> 20
?:

50 in 30 F
30-60 in 10-20 F
Sparing by fractionation

10

> 10

5-15
3

- 15
- 100 in 60 F
10
40-100 continuous
1-6 in the very
young. Very large
doses in adults
4-6
- 20
3-10
0.0012-0.006 Gy/day
Very large species - 2 fractionated
3-5

11-14 fractionated2-15- 0.5 Gy/day

a/ These tissues have been specifically irradiated, as opposed to whole-bodytreatment.

Table

7

Atomic bomb survivors b clinical sym toms and si ns of radiation injuries
01

Degree ofseverityFirst week

Very severe(Group I)

Nausea and vomiting (4*-)
Fever (++)
Fever, apathy, delirium,
Emaciation
diarrhoea (4*-)
leukopaenia (4*-)
Oropharyngeal lesions (+) a/ Anaemia- Haemorrhagic
Leukopaen i a (4*-)
diathesis (+)
Epilation {:F

Severe{Group II)

Second week

Nausea and vomiting {++)
Anorexia
Fatigue

Fever (++)
Leukopaenia (+)
Anaemia (:JModerately
severe(Group III)

Gastrointestinal b/
syndrome (++)

Leukopaenia (+)

Mild(Group IV)

Gastrointestinal
syndrome (:4:J

Leukopaen i a (+ )Third week

Approximate
mortality andtime of deathin weeks

100 % firstand second

Anorexia, emaciation, fever,diarrhoea, epilation {-IH-l
Oropharyngeal lesions {-IHHaemorrhagic diathesis (-IH-)
Leukopaenia (++), anaemia (++)
Anorexia, emaciation, fever,diarrhoea, epilation (+ - ++)Oropharyngeal lesions (+ - ++)Haemorrhagic diathesis T+ - ++)Leukopaenia (++), anaemia ( +)Fever (+)
Epilati'iin (+)
Dropharyngeal lesions (+)
Haemorrhagic diathesis T+)
Leukopaenia (~)-

50 % third
to sixth
Less than
10 % sixthor laterNone

a/ These lesions (ulcerations) occurred on all mucous membrane surfaces but were more prevalent in lymphoidareas than elsewhere. The tonsil, pharynx, larynx, nasal passages, and tongue were frequently involved.
y Gastrointestinal syndrome includes nausea, vomiting, anorexia, and diarrhoea. (-1!+)(-t+)(+) and (+)
connote grade of symptoms and signs in order of decreasing severity and frequency, such that+ inaicatesthat the symptom was not always present. Approximate ranges of kerma are 4.5 to 6 Gy (or more) Group I;
2-4.S Gy Group II: 2-3 Gy Group III; 1-2 Gy Group IV. Estimates of these doses are subject to change
but it is anticipated that the modifications will not be large.

630

T a b l e

8Acee table doses from conventional radiation thera

a/

1

1-5%
Acceptable
dose (Gy)

StructureirradiatedInjury after 5 years

Skin
Ora 1 mucosa
Oesophagus
StomachIntestine
Colon
Rectum
Sa 1 i vary glands
Liver
KidneyBladder
Ureters
Testes
Ovary
UterusVaginaBreast, child
adult
Lung
Capillaries
Heart
Bone, child
adult
Cartilage,child
adult
CNS (brain)
Spinal cord
Eye
CorneaLens
Ear (inner)
Vestibular
Thyroidl\drena 1
Pituitary
Muscle, child
adult
Bone marrow

Ulcer, severe fibrosis
55
Ulcer, severe fibrosis
60
Ulcer, stricture60
Ulcer, perforation
45
Ulcer, stricture
45
Ulcer, stricture
45
Ulcer, stricture
55
Xerostomia
50
Liver failure, ascites
35
Nephrosclerosis
23
Ulcer, contracture
60
Stricture, obstructions
75
Permanent sterilization 5-15
Permanent sterilization
2-3
Necrosis, perforation<100
Ulcer, fistula90
No development
10
Atrophy and necrosis<SO
Pneumonitis, fibrosis
40
Telangiectasia, sclerosis 50-60
Pericarditis, pancarditis 40
Arrested growth20
Necrosis, fracture
60
Arrested growth
10
Necrosis60
Necrosis50
Necrosis, transection
50
Panophthalmitis,haemorrhage 55
Keratitis
50
Cataract5
Deafness<60
Meniere's syndrome
60
Hypothyroidism
45
Hypoadrenalism<60
Hypopituitarism
45
No development
20-30
Atrophy<100
Hypoplastic
2
20
35-45
Atrophy
Sclerosis
50
Death
2

Lymph nodes
Lymphatics
Foetus25-50%
Acceptable
dose (Gy)
70
75
75
50
65
65
80
70
45
28
80
100
20
6-12
<200
<100
15
<100
60
70-100
<100
30
150
30

Irradiation
field
100 cm~
50 cm 275 cm
100 cm~100 cm 2
100 cm 2
100 cm2
50 cm
whole
whole
whole
5-10 cm
whole
whole
whole
5 cm
3
5 cm
whole
lobe
whole210 cm
10 cm2
whole
whole
whol~
5 cm
whole
whole
whole
whole
whole
whole
whole
whole
whole
whole
whole
localized

100

<60
<60
100
<60
12
100

150

200-300
40-50
5.5

40-50
<70
<80
4.5

a/ Usually the 1-5 % acceptable dose is considered reasonable in radiotherapy;
25-50 % is not.

Table

9

Ooses causing temporary or permanent sterility of human ovary
EffectTolerance dose (Gy)Ref.

Temporary or reduced
sterility

1.5 fractionated a/

[T17]
(G13]

1. 7

4

Permanent sterility

12 fractionated (3/day)
174 (in 3 series/2.5 years)
3.2
2.5-5 fractionated[P18J[R34,Pl8]
[G14;

4

6.25
8-10

2 (in 3 series/2 years)
6.25-12 fractionated (30F/6 week)
6-20
fractionated (30F/6 week)
3.6-7.2 fractionated (2-4F)

[G13]

[R34}
[PlBJ
1Pl9J
[L20]
[J7]

[R16~

[L16 J[D20]

631

Ta b l e

10

Uoses causing temporary or pennanent sterility of human testis
EffectTolerance dose (Gy)Ref.

Temporary sterility

0.1-1.0 fractionated
1. 5-3
1-2
fractionated
2.5

1H2o!

545 1

(H55,S46]
[Gl3]
[010]

4

Permanent sterility

2-3
9.5

[H55,S45]
[Cl2]
[H21]
[Gl3J

fractionated

6

5-6
4.S-6

fractionated

Table

(l16]

11

Effects of radiation on the human eye[f125 J
Tissue

Dose (Gy)

EffectSingle dose

Early erythema
Lid skin
Lacrymal gland Atrophy· Conjunctiva
Late teleangiectasia
Cornea
Early oedema andkeratitis
ScleraLate a trophy
Retina
Early oedema
Late degeneration
Lens
Cataract

Fractionated dose

10

6 x days •50-60 30F /6 weeks
30-50 (3-5 weeks)
30-50

2-10

200-300
30-35
30-50
17
4 x days 0 ·4-6
20

Ta b 1 e

12

N and T factors for neutrons compared with x rays
x raysTissueSubcutaneous
Skin
Tail
Tai 1
Lung
Spinal cord
Spinal cord
Brain
Sma 11 intestine

632

DamageFibrosis
Erythemadesquamation
Necrosis
Erythemadesquamation
Pneumoniti s
Myelopathy
Myelopathy
Necrosis
Crypt damage

fleutrons

Neutrons

fl

T

ll

T

16 HeVd/Be

0.24
0.26

0.11
0.11

0.04

0.11

14 t1eVd-T
16 MeVd/Be

0.39
0.39

16 HeVd/Be
14 MeVd-T
16 fleVd/Be
16 MeVd/Be
16 f1eVd/Be
50 HeVd/Be

0.27
0.44
0.38
0.38
0.29

0.07
0.03
0.00
0.00

Ref.
[E4]
(F30]

o.oo
0.03

[H28]
[i'\10]

0.00
0.00
0.00
0.00
0.00
0.00

0.00 !F8,H30], VI ,VB)[W6,H66J
0.00 fH67)
W2)

Table13

Threshold skin erythema doses
for fast neutrons

Species

Dose
(Gy)

Pig
Rat
Mouse
Man

5

4
5

2

Area irradiatedRef.

Approximately 20 cm2
Whole footI/hole footApproximately 20 cm 2

fB30]
[F2)
[F26]
(F14]

Tab I e14

Lowest in·ection, burden time, and skeletal dosewere s1gn1 ,cant vascu ar re uct1on occurs a tervarious radionuclides(J22]
Radionuclide(kBq/kg)
41
3.5
6.3
1.2
3700

Skeletal dose
(Gy)

Days post
injection

226Ra
239Pu
22BRa
228rh
90sr

1900 days
2200 days
2500 days
1900 days
1000 days

Ta b I e

23
3.5
5
2.5
80

15

Threshold doses for chan9es in vascular function(single treatments)

TissueSpecies

Functiona 1
study

Thresholddose (Gy)

Skin

Pig
RabbitRat

Flow
Permeability
Permeability
Flow
Flow
Permeability
Permeability
Permeabi 1i ty
Permeability
Permeability
Flow
Permeabi 1i ty
Flow
Permeabi 1 ty
Permeabil ty
Permeabi l ty
Flow
Flow
Flow
Flow
Flow
Flow
Flow
Flow

8
1
20
15
20
5
2.5
5
20
20
10

Intestine
Mesentery
Lung

Hamster
Rat
Mouse
Rat
Mouse
Rat
Mouse

Brain

KidneyLiver

MonkeyDog
Rabbit
Rat
Man
Pig
Dog
Rat
Mouse
Rat
Mouse

10
11

15
10
18
10
4.5/3F
- 12
10
10-20

Reference
(M33j
(Jl2
[L23!
[K21
[H45i
[T12]
(VJ]

[033)
[H40)
[Tl3]
[ K21)
[H53]
(G2]
!C18]

K23)
[N7)
[ K21 J
[AlSJ
(Hl2, H48]
(1136]

[CS;

11

[G2;

15
5
> 15

[K21
[F32
[G2J

l
633

REFERENCES

AI

A2

A3

A4

AS

A6

A7

AS

A9

AlO

A 11
A12

Al3

A14

A15

A 16

A17
A18

A19
A20
A21

634

Alper, T. Hypothesis. Elkind recovery and "sublethal
damage": a misleading association. Brit. J. Radio!. 50:
459-467 ( 1977).
Arcangeli, G., M. Friedman and R. Paoluzzi. A quantitative study of late radiation effect on normal skin andsubcutaneous tissue in human beings. Brit. J. Radio!.
47: 4~50 (1974).
Asscher, A.W. and S.G. Anson. Arterial hypertension
and irradiation damage to the nervous system. Lancet
2: 1343-1346 (1962).
Andersen, A.C. and L.S. Rosenblatt. Effects offractionated whole-body x-ray exposures on reproductive ability and median survival of female dogs
(beagles) p. 11.1-11.14 in: Dose Rate in Mammalian
Radiation Biology (D.G. Brown, R.G. Cragle and T.R.
Noonan, eds.). CONF-680410 (1968).
Andersen, A.C. and M.E. Simpson. Effect offractionated x-irradiation during oogenesis in the
beagle. Radial. Res. 43: 232 (1970).
Andersen, A.C., V.G. Nelson and M.E. Simpson.
Fractionated x-radiation damage to developingmonkey ovaries. J. Med. Primatol. 1: 318-325 ( 1972).
Andersen, A.C., A.G. Hendrickx and M.H. Momeni.
Fractionated x-ray damage to developing ovaries in thebonnet monkey (Macaca radiata). Radiat. Res. 71:
398-405 (1977).
Amory, N.l. and !.B. Brick. Irradiation damage of theintestines following 1000 kv roentgen therapy. Evaluation of tolerance dose. Radiology 56: 49-57 (1951).
Alper, T. The modification of damage caused byprimary ionization of biological targets. Radial. Res. S:
573-586 (1956).
Andreozzi, U., S. Homsey and R. Myers. The
relationship of OER, RBE and number of fractions forx- or neutron-irradiation induced skin damage. lnt. J.
Radiat. Biol. 36: 33-41 (1979).
Abelson, Ph. and P.G. Kruger. Cyclotron-induced
radiation cataracts. Science 110: 655-657 (1949).
Aarnoudse, M.W. and M.B. Lamberts. Depolymerization of mucopolysaccharides by x-rays and fastneutrons. lnt. J. Radiat. Biol. 20: 437-445 (1971).
Adamson, l.Y.R., D.H. Bowden and J.P. Wyatt. A
pathway to pulmonary fibrosis: and ultrastructural
study of mouse and rat following radiation to thewhole-body and hemithorax. Am. J. Pathol. 58:
481-498 (1970).
Arturson, G. and L. Thoren. Capillary permeability
following ionizing radiation, p. 83-87 in: Intermedes
Proceedings 1968: Combined Injuries and Shocks (B.
Schildt and L. Thoren, eds.), 1968.
Avioli, L.V., M.Z. Lazor, E. Cotlove et al. Early effectsof radiation on renal function in man. Am. J. Med. 34:
329-337 (1963).
Archer, R.R., E.J. Greenwell, E.J. Ware et al. Irradiation effect on wound healing in rats. Radial. Res. 41:
10~112 (1970).
Ariel, J.M., M.I. Resnich and R. Oropeza. The effect ofirradiation (external and internal) on lymphatic
dynamics. Am. J. Roentgenol. 99: 404-414 (1967).
Averelle, H.E. and J.H. Gerguson. Lymphographic
alterations of pelvic lymphatics after radiotherapy. J.
Am. Med. Assoc. 186: 554-557 (1963).
Afrikanova, L.A. and G.M. lsailova. Communication( 1982).
Afrikanova, L.A. Personal communication.
Antonova, A.M. Reactive changes in neurons of cerebellum cortex after local irradiation, p. 3-11, in:Reactive and Regenerative Processes in Nervous
System. Tbilisi, 1971 (in Russian).

A22
A23

A24
A25
A26
A27

A28
A29
A30
A3 I
A32

A33
A34

A35

A36

A37

A38

A39

BI

Andrews, G.A. Radiation accidents and their
management. Radial. Res. Suppl. 7: 300-327 (1967).
Amosov, I.S., M.S. Bardychcv, V.A. Degtyarev et al.
The vessels of the skin in the process of formation andhealing of experimental radiation ulcers (microangiographic study). Medical Radiology. 24(2): 44-47 (1979)(in Russian).
Ash, P. The inlluence of radiation on fertility in man.
Brit. J. Radio I. 53: 271-278 ( 1980).
Anderson, R.E. and N.L. Warner. Ionizing radiationand the immune response. Adv. Immunol. 24: 216-335( 1976).
Alper, T. Cellular Radiobiology. Cambridge University
Press. Cambridge, 1979.
Ansell, B.M., A. Crook, J.R. Mallard et al. Evaluationof intra-articular colloidal gold 198Au in the treatmentof persistent knee effusions. Ann. Rheum. Dis. 22:
435-439 (1963).
Aub, J.C., R.D. Evans, L.H. Hempelmann et al. The
late effects of internally-deposited radioactive materials
in man. Medicine 31: 221-329 (1952).
Archer, V.E., J.K. Wagoner and F.E. Lundin. Lungcancer among uranium miners in the United States.
Health Phys. 25: 351-371 (1973).
Archer, V.E., H.P. Brinton and J.K. Wagoner.
Pulmonary function of uranium miners. Health Phys.
JO: 1183-1194 (1964).
Archer, V.E., J.D. Gillam and J.K. Wagoner. Respiratory disease mortality among uranium miners. Ann.
N.Y. Acad. Sci. 271; 281-292 (1976).
Aristov, V.P. Ultrastructure of the alveolar-capillarybarrier in rats following single inhalation of plutonium·
239 citrate, p. 381-390 in: Biological Effects ofRadiation from External and Intemal Sources. (Y. I.
Moskalev and V.S. Kalistratova, eds.). AEC-tr-7457(1972).
Anderson, E.C .. L.M. Holland, J.R. Prine et al. Current
summary of intravenous microsphere experiments. LA7254-PR (1978).
Ariel, J.M. Treatment of metastatic cancer to the liverfrom primary colon and rectal cancer by the intraarterial
administrationof chemotherapy
andradioactive isotopes. p. 357-366 in: Therapy in Nuclear
Medicine (R.P. Spencer, ed.). Grune and Stratton, New
York, 1978.
Atkins, H.L. Treatment of Hyperthyroidism: Use of
131 I and 125J. p. 85-89 in: Therapy in Nuclear Medicine(R.P. Spencer, ed.). Grune and Strallon, New York,
1978.
Andrews, J.R., R.L. Swarm, L. Schlachter et al. The
effects of one curie of sulphur 35 administered intravenously as sulphate to a man with advanced chondrosarcoma. Am. J. Roentgenol., Rad. Th. Nucl. Med. 83:
123-134 (1960).
Avrunina, G.A. Distribution of 65zn in the body ofrabbits and doses received by them on chronic administration of 65znCl2 orally, p. 20-30 in: The Toxicologyof Radioactive Substances Vol. 5. (A.A. Letavet and E.
P. Kurlyandskaya, ed.). Pergamon Press, Oxford, 1970.
Avetisov, G.M. and V.R. Dvornikov. Hystologicalstudy of skin reaction after irradiation by x-rays ofdifferent energy. Medical Radiology 20 (1): 77-78(1975) (in Russian).
Avetisov, G.M., V.S. Budylin, V.G. Gorlov et al.
Studies of the detrimental action of whole body irradi·
ation with x rays of 17, 50 and 180 kV. Radiobiol.
Radiother. 13: 491-498 (1972) (in German).
Blackett, N.M., P.J. Roylance and K. Adams. Studiesof the capacity of bone marrow cells to restore eryth·ropoiesis in heavily irradiated rats. Br. J. Haematol. 10:453-467 (1964).

82

Brown, S.O. Effects of continuous low intensity
radiation on successive generations of the albino rat.
Genetics 50: 1101-1113 (1964).

133

Brown, J.M. and J.C. Probert. Early and late radiation
changes following a second course of irradiation.
Radiology 1 I 5: 711-716 (1975).
Berry, R.J., G. Wiernik and T.J.S. Patterson. Skin
tolerance to fractionated x-irradiation in the pig - howgood a predictor is the NSD formula? Brit. J. Radio!.
47: 185-190 (1974).

B4

B5

86

87

B8

BIO

Bll

B12

B13

814

815

B16

B17

B 18

Bl9

820
B21

B22

B23

B25
B26

Brown, J.M., D.R. Goffinet. J.E. Cleaver et al. Preferential radiosensitization of mouse sarcoma relative tonormal skin by chronic intra-arterial infusion of
halogenated pyrimidine analogs. J. Natl. Cancer Inst.
47: 75-89 (1971 ).
Brown, J.M. The effects of acute x-irradiation on thecell proliferation kinetics of induced carcinomas andtheir normal counterpart. Radiat. Res. 43: 627-653(1970).
Bond, V.P., T.M. Fliedner and J.O. Archambeau.
Mammalian Radiation Lethality: A disturbance incellular kinetics. Academic Press, New York, 1965.
Bisgard, J.D. and H.B. Hunt. Influence of roentgenrays and radium on epiphyseal growth of long bones.
Radiology 26: 56-68 (1936).
Bennett, L.R., S.M. Chastain, J.S. Flint et al. Lateeffects of roentgen irradiation: studies on rats
irradiated under anoxia. Radiology 61: 411-419 (1953).
Berdjis, C.C. Cortisone and radiation. II I. Histopachology of the effect of cortisone on the irradiated rat
kidney. Arch. Pathol. 69: 431-439 (1960).
Berdjis, C.C. Irradiation and kidney tumours. Histopathogenesis of kidney tumours in irradiated mice.
Oncologia 12: 193-202 (1959).
Brown, S.O., G.M. Krise, H.B. Pace et al. Effect ofcontinuous radiation on reproductive capacity andfertility of the albino rat and mouse, p. 103-110 in:
Effects of Ionizing Radiation on the Reproductive
System (W.D. Carlson and F.X. Gassner, eds.).
Pergamon Press. New York, 1964.
Baker, T.G. The sensitivity of oocytes in post-natalrhesus monkeys to x-irradiation. J. Reprod. Fertil. 12:
183-192 (1966).
Baker, T.G. and H.M. Beaumont. Radiosensitivity ofoogonia and oocytes in the foetal and neonatalmonkey. Nature 214: 981-983 (1967).
Bateman, J.L. and C.C. Berdjis. Organs of special
senses. p. 669-686 in: Pathology of Irradiation (C.C.
Berdjis, ed.). Williams and Wilkins, Baltimore, 1971.
Brecher, G., K.M. Endicott, A.B. Gump et al. Effects of
x-ray on lymphoid and haemopoietic tissues of albino
mice. Blood 3: 1259-1274 (1948).
Bond, V.P. and J.S. Robertson. Vertebrate radiobiology(lethal actions, and associated effects). Ann. Rev. Nucl.
Sci. 7: 135-162 (1957).
Becker, AJ., E.A. McCulloch and J.E. Till. Cytologicaldemonstration of the clonal nature of spleen colonies
derived from transplanted bone marrow cells. Nature
197: 452-454 (1963).
Borek, J. The radiation biology of the cutaneous
glands. Radiology 27: 651-655 (1936).
Baclesse, F. Clinical experience with ultrafractionatedroentgen therapy, Chapter 6 in: Progress in Radiation
Therapy. Grune and Stratton, New York, 1958.
Berdjis, C.C. The cardiovascular system, p. 377-407 in:
Pathology of Irradiation (C.C. Berdjis, ed.). The
Williams and Wilkins, Baltimore, 1971.
Beling, N. and J. Einhorn. Incidence of hyperthyroidism and recurrences following 131I treatment ofhyperthyroidism. Acta Radio!. 56: 275-288 (1961).
Bewley, D.K. Radiation quality and its influence on
biological response. Brit. Med. Bull. 29: 7-11 (1973).
Barendsen. G.W. Responses of cultured cells, tumours
and normal tissues co radiations of different linear
energy transfer. Curr. Top. Radiat. Res. Quart. 4:
293-356 {1968).

1327

Berry, R.J. and J.R. Andrews. The effect of radiation
ionization density (LET) upon the reproductive
capacity of mammalian tumour cells irradiated andassayed in vivo. Brit. J. Radio!. 36: 49-55 (1963).
828
Berry, R.J. Hypoxic protection against fast neutrons ofdifferent energies: a review. Eur. J. Cancer 7: 145-152(1971).
B29
Bewley, D.K., B. Cullen, S.B. Field et al. A comparison
for the use in radiotherapy of neutron beams generated
with 16 and 42 MeV deuterons on beryllium. Brit. J.
Radio!. 49: 360-366 (1976).
B30 Bewley, D.K., J. Fowler, R.L. Morgan et al. Experiments on the skin of pigs with fast neutrons and 8 MeV
x-rays, including some effects of dose fractionation.
Brit. J. Radio!. 36: 107-115 (1963).
B3 I Berry, R.J. "Small clones" in irradiated tumour cells in
vivo. Kinetics of regrowth of immune leukaemia cells
surviving irradiation with x-rays, fast neutrons andaccelerated charged particles. Brit. J. Radiol. 40:
285-291 ( 1967).
832 Bewley, D.K., S.B. Field, R.L. Morgan et al. The
response of pig skin to fractionated treatments with fastneutrons and x-rays. Brit. J. Radio!. 40: 765-770 (1967).
B33
Broerse, J.J. and G.W. Barendsen. Relative biologicaleffectiveness of fast neutrons for effects on normal
tissues. Curr. Top. Radiat. Res. Quart. 8: 305-350(1973).
B34 Bateman, J.L., H.H. Rossi, A.M. Kellerer et al. Dosedependence of fast neutron RBE for lens opacificationin mice. Radial. Res. 51: 381-390 (1972).
B35
Broerse, J.J., H.S. Reinhold, G.H. Buisman et al.
Effects of 15 MeV neutrons on capillary endothelium inthe rat. Radial. Res 56: 180-185 (1973).
B36 Broerse, J.J., A.C. Engels, P. Lelieveld et al. The
survival of colony-forming units in mouse bonemarrow after in vivo irradiation with D-T neutrons, xand gamma-irradiation. Int. J. Radial. Biol. 19:
101-110 (1971).
B37 Brecher, G. and C.F. Tessmer. Late effects on vascular
tissue. p. 186-191 in: Time and Dose Relationships inRadiation Biology as Applied to Radiotherapy. BNL50203(C-57) (1969).
B38 Bromfield, A.R. and P.W. Dykes. Radiation-induced
protein leakage into the small intestine. Nature 201:633-634 (1964).
839 Bard, J.B.L. and J.A. Chapman. Polymorphism incollagen fibrils precipitated at low pH. Nature 219:
1279-1280 (1968).
840 Brooks, A.C. and F.W. Lengemann. Comparison ofradiation-induced chromatid aberrations in the testes
and bone marrow of the Chinese hamster. Radiat. Res.
32: 587-595 (1967).
841
Belousova, 0.1.. P.D. Gorizontov and M.I. Fedotova.
Radiation and the blood system. Atomizdat, Moscow,
1979 (in Russian).
B42 Barabanova, A.V. and A.K. Gouskova. Clinicalmedicine 137 (1964) (in Russian).
B43
Belousova, O.I., P.O. Gorisontov and M.I. Fedotova.
Radiation and the blood system. Atomizdat, Moscow,
1979 (in Russian).
B44 Barabanova, A.V., L.L. Sokolina and L.V. Novikova.
Clinical-dosimetric relationships at local irradiationfrom sources of different energy. Medical Radiology
19(10): 46-50 (1974) (in Russian).
B46
Bardychev, M.S., S.I. Chekalina and V.J. Byrichin. The
state of the clotting and fibrinolysis of the blood inpatients with radiation ulcers of skin. Medical
Radiology, 18(7): 81-84 (1973) (in Russian).
1347 Bardychev, M.S. and A.F. Zyb. Regional blood circulation in late radiation ulcers of the skin. Medical
Radiology, 19(2): 47-54 (1974) (in Russian).
B48
Bardychev, M.S .. T.V. Oliper and L.I. Guseva. Clinics
and treatment of radiation fibrosis with disorders ofregional haemo- and lympho-circulation of the extremities and secondary neuritis. Medical Radiology 23 (8):34-40 (1978) (in Russian).
849 Bardychev, M.S., 1.0. Tomashevsky and A.K.
Kurpeshova. Late radiation damage of the skin and

635

B50

B51
852

853

B54

B55
856
B57
B58
859

860

B61

862
863
864

865

B66
867
868
869

636

organs of breast. Medical Radiology, 23: 123-131(1978) (in Russian).
Baisogolov, G.D. and V.V. Pavlov. The state of haematopoiesis in local fractional irradiation. 111. The hacmatopoiesis at remote periods after irradiation. Medical
Radiology 16(11): 40-44 (1971) (in Russian).
Brooks, A.L. Chromosome damage in liver cells fromlow dose rate alpha, beta and gamma irradiation:
derivation of RBE. Science, 190: 1090-1092 (1975).
Barth, G. and W. Kern. Strahlenbiologie und Klinik
der Sicbbestrahlung. p. 495-530 in: Allgemeinc
Strahlen-Therapeutische Methodik. Tei! I, Handbuch
der Medizinischen Radiologie (L. Diethelm, eds.).
Band XVI, Tei! I, (0. Vieten and F. Wachsmann, eds.).
Springer, Berlin, Heidelberg, New York. (1970).
Bendel, I., W. Schuttmann and D. Arndt. Cataract oflens as late effect of ionizing radiation in occupationally exposed persons, p. 309-319 in: Late Biological
Effects of Ionizing Radiation, Vol. I. IAEA, Vienna,
1978.
Beebe, G. W. Non-carcinogenic late effects of ionizing
radiation: human data. p. 672-679 in: Radiation
Research (S. Okada, M. Imamura and T. Terashima,eds.). Toppan, Tokyo, 1979.
Bichsel, H. A fortran program for the calculation ofenergy loss of heavy charged particles. UCRL-17538(1979).
Berger, M.J. Energy deposition in water by photons
from point isotropic sources. J. Nucl. Med. Suppl. 1:
15-25 (1968).
Berger, M.J. Distribution of absorbed dose aroundpoint sources of electrons and beta particles in waterand other media. J. Nucl. Med. Suppl. 12: 5-23 (1971).
Brownell, G.L., W.H. Ellett and A.R. Reddy. Absorbed
fractions for photon dosimetry. J. Nucl. Med. Suppl. 1:
27-39 (1968).
Bigler, R.E. Relationship of external radiation doses tointernal dosimetry, p. 17-31 in: Therapy in Nuclear
Medicine (R.P. Spencer, ed.). Grune and Stratton, New
York, 1978.
Bigler, R.E. Dosimetry for evaluation of the biologic
effects of radiation treatment using internally depositedradionuclides and labelled compounds. p. 221-229 in:Radio-pharmaceutical
Dosimetry
Symposium(Cloutier, R.J .. J.L. Coffey, W.S. Snyder et al., eds.).
U.S. Health, Education and Welfare Office report(FDA) 76-8044 (1976).
Bowring, C.S. and D.H. Keeling. Absorbed radiationdose in radiation synovectomy. Brit. J. Radiol. 51:
836-837 (1978).
Ballou, J.E. and W.G. Morrow. The long-term
biological effects of intracheally instilled 253EsCl3 in
rats. BNWL-1750 (1973).
Boecker, B.B., F.F. Hahn, C. Hanika-Rebar et al.
Toxicity of 144Ce inhaled in a relatively insoluble form
by immature beagle dogs. LF-58, (1977).
Bair, W.J. Recent animal studies on the deposition,
retention and translocation of plutonium and othertransuranic compounds. p. 51-83 in: Diagnosis andTreatment of Incorporated Radionuclides. IAEA,
Vienna, 1976.
Buldakov, LA., E.R. Lyubchanskii and A.P. Nifatov.
Problemsof plutonium
toxicology.
Lovelace
Foundation for Medical Education and Research.
Albuquerque, 1970.
Buldakov, L.A. Metabolism and biological effects ofinhaled 241Am and 239Pu in dogs. Health Phys. 22:
873-874 (1972),
Bremner, W.F., J.R. McDougall and W.R. Greig.
Results of treating 297 thyrotoxic patients with 1251.
Lancet 2: 281-282 (1973).
Beaumont, H. The radiosensitivity of germ-cells at
various stages of ovarian development. Int. J. Radial.
Biol. 4: 581-590 (1962).
Benua, R.S., N.R. Cicale, M. Sorenberg et al. The
relation of radioiodine dosimetry to results and complications in the treatment of metastatic thyroid cancer.
Am. J. Roentgenol. 87: 171-182 (1962).

870

871

872

873

B74

Bostrom, H., B. Edgren, D. Friberg et al. Case ofchondrosarcoma with pulmonary and skeletal metastases after hernipelvectomy successfully treated with
S-35 sulphate. Acta Orthop. Scand. 39: 549-564 (1968).
Ueloborodova, N.L. and Ye.K. Red'kina. Haemopoiesis following prolonged intake of radioactive zinc, p.
60-?S in: The Toxicology of Radioactive Substances,Vol. 5. (A.A. Letavet and E.B. Kurlyandskaya, eds.).
Pergamon Press, Oxford, 1970.
Bcloborodova, N.L., Ye.S. Gaidova and Ye.K.
Red'kina. Haernopoiesis and morphological changes in
the organs of rabbits following prolonged administration of 65zn without carrier, p. 84-90 in: The
Toxicology of Radioactive Substances, Vol. 5. (A.A.
Letavet and E.13. Kurlyanskaya, eds.). Pergamon Press,
Oxford, 1970.
Bair, W.J. and J.F. Park. Comparative disposition offour types of plutonium diozides inhaled by dogs, p.
181-197 in: Proceedings of the First International
Congress of Radiation Protection, Part 1. Pergamon
Press, Oxford, 1966.
Bair, W.J. and D.H. Willard. Plutonium inhalation
studies. IV. Mortality in dogs after inhalation of
239Pu02 Radial. Res. 16: 811-821 (1962).

B75

Benjamin, S.A., R.K. Jones, M.B. Snipes et al. Comparative effects of inhaled relatively insoluble forms of
90y, 144Ce and 90Sr on canine peripheral lymphocyte
function, p. 192-196 in: LF-49 (1974).

876

13air, W.J., J.F. Park and W.J. Clarke. Long-term studyof inhaled plutonium in dogs. AFWL-TR-65-214. 1966.

B77

Becciolini, A., G.B. Gerber and J. Deroo. In vivo
absorption of carbohydrates in rats suffering from thegastrointestinal syndrome. Acta. Radio!. Tuer. 16:
87-96 (1977).

B78

lleer, J.Z. Heritable lesions affecting proliferation ofirradiated mammalian cells, p. 363-417, in: Advancesin Radiation Biology. Vol. 8 (1979).

B79

Berlmer, D.L., W. Stevens, C.J. Nabors et al.
Biochemical changes induced by internally depositedradionuclides in beagle dog blood: a statistical study.
p. 471-486 in: Delayed Effects of Bone Seeking Radionuclides. (C.W. Mays, W.S.S. Jee, R.D. Lloyd et al.,eds.). University of Utah Press, Salt Lake City, Utah,
1969.

880

Bazin, H. Pathogenesis of microbial infection afterradiation injury. EUR 6671 (1980).

881

Britten, M.J.A., K.E. Halnan and W.J. Meredith.
Radiation cataract: new evidence on radiation damage
to the lens. Brit. J. Radio!. 39: 612-617 (1966).

882

Bond, V.P., C.B. Meinhold and H.H. Rossi. Low-dose
RBE and Q for x-ray compared with gamma-ray radiations. Health Phys. 34: 433-438 (1978).

883

Bleger, W.A. and T.W. Griffin. White matter necrosis,
mineralizing microangiopathy and intellectual abilities
in survivors of childhood leukemia : irradiation andmethotrexate therapy, in: Radiation damage to thecentral nervous system. (H.A. Gilbert and A.R. Kagan,eds.). Raven Press, New York, 1980.

Cl

Curtis, H.J. Biological mechanisms of delayed
radiation damage in mammals. Curr. Top. Radiat. Res.
Quart. 3: 139-174 (1967).

C2

Cohen, L. Radiation response and recovery: radiobiological principles and their relation to clinical practice,in: The Biological Basis of Radiation Therapy (E.E.
Schwartz, ed.). Lippincott, New York, 1966.

CJ

Chen, K.Y. and H.R. Withers. Survival characteristics
of stem cells of gastric mucosa in C3H mice exposed to
local y-irradiaiton. lnt. J. Radial. Biol. 21: 521-534(1972).
Cohen, L. Theoretical "iso-survival" formulae forfractionated radiation therapy. Brit. J. Radio). 41:
522-528 (1968).

C4

CS

Comas, F.V. The time factor in fractionated irradiationof mouse skin, p. 18.1-18.10 in: Dose Rate in
Mammalian Radiation Biology (D.G. Brown, R.G.
Cragle and T.R. Noonan, eds.). CONF-680410, 1968.

C7
CS
C9

ClO
Cl I
C12
C13

C14
C15
C16
C17
C18

C19
C20
C21
C22

C23

C24

C25
C26
C27
C28
C29
C30

C31

Calwell, W.L., H. Hattori and R.K. Rhamy. Effect ofirradiation on renal enlargement following uninephrectomy in the rabbit. J. Ural. 103: 399-402 (1970).
Chauser, B.M., F.R. Hudson and M.P. Law. Renalfunction in the rat following irradiation. Radiat. Res.
67: 86-97 (1976).
Cosgrove, G.E., A.C. Upton and L.H. Smith. Radiation
glomerulosclerosis and other late effects: innuence ofradiological factors and AET. Radiat. Res. 25: 725-735(1965).
Carsten, A. and W. Zeman. The control of variables inradiopathological studies in mammalian nervous tissue.
Int. J. Radiat. Biol. 10: 65-74 (1966).
Chauser, B., C. Morris, S.B. Field et al. The effects offast neutrons and x-rays on the subependymal layer ofthe rat brain. Radiology, Suppl. 2, 122: 821-823 (1977).
Callaway. J.L., V. Moseley and S.W. Barefoot. Effectsof roentgen ray irradation on the tests of rabbits. Arch.
Dermatol. Syph. 56: 471-479 (1947).
Casarett, G.W. and H.A. Eddy. Fractionation of dosein radiation-induced male sterility, p. 14.1-14.10 in:
Dose Rate in Mammalian Radiation Biology (D.G.
Brown, R.G. Cragle and T.R. Noonan, eds.). CONF680410 ( 1968).
Curney, C.W. and N. Wackman. Impairment of erythropoiesis by irradiation. Nature 190: 1017-1018(1961).
Cronkite, E.P. Extracorporeal irradiation of the bloodand lymph in the treatment of leukaemia and for
immuno-suppression. Ann. Intern. Med. 67: 415 (1967).
Catterall, M.. C. Rogers, R.H. Thomlinson et al. An
investigation into the clinical effects of fast neutrons.
Brit. J. Radiol. 44: 603-611 (1971).
Casaretl, G.W. Pathology of single intravenous doses ofpolonium. Radial. Res., Suppl. 5: 246-321 (1964).
Clemente, C.C. and E.A. Holst. Pathological changes inneurons, neuroglia, and blood-brain barrier induced by
x-irradiation of head of monkeys. Arch. Neurol.
Psychiatr. 71: 66-79 (1954).
Concannon, J.P., R.E. Summers, R. Brewer et al. Highoxygen tension and radiation effect on the kidney.
Radiology 82: 508-519 (1964).
Crompton, M.R. and D.D. Layton. Delayed radionecrosis of the brain following therapeutic x-irradiationof the pituitary. Brain 84: 85-101 (1961).
Catterall, M. Communication (1982).
Clifton, K.H., R.T. Mulcahy and R.K. Dermott. The
radiobiology of thyroid epithelium: cell survival andneoplasia, p.753-760 in: Radiation Research (S. Okada,
M. Imamura, T. Terasima and H. Yamaguchi, eds.).
Toppan, Tokyo, 1979.
Charles, M.W. and PJ. Lindop. Skin and eye irradiation: examples of some limitations of international
recommendations in radiobiological protection. p.
547-561 in: Application of the Dose Limitation System
for Radiation Protection. IAEA, Vienna, 1979.
Carlson, T.A. and R.M. While. Formation of fragment
ions from CH3Tet2S and C2HsTe125 following thenuclear decay of CH3l125 and C2HsJ125, J. Chem. Phys.
38: 2930-2934 (1963).
Cloutier, R.J., E.E. Watson, R.H. Rohrer et al. Calculating radiation dose to an organ. J. Nucl. Med. 14:
53-55 (1973).
Cross, F.T., G.W.R. Endres and M.F. Sullivan. Dose to
the GI tract from ingested insoluble beta emitters.
Radial. Res. 73: 37-50 (1978).
Cochran, T.H. Histopathological findings, p. 73 in:
AECU-3522 (1957).
Chvapil, M. Pharmacology of fibrosis and tissue injury.
Environ. Health Perspectives 9: 283-294 (1974).
Crystal, R.G. The biochemical basis of pulmonary
function. Lung Biology in Health and Disease. Vol. 12.
Dekker, New York, 1976.
Carcelen, A., M. Zaharia, E. Caceres et al. Pulmonary
function tests during adjuvant lung irradiation for
osteogenic sarcoma. Cancer Treatment Reports 64: No.
4-5, 701-703.
Coultas, P.G., R.G. Ahier and S.B. Field. Effects ofneutron and x-irradiation on cell proliferation inmouse lung. Radial. Res. 85: 516-528 (1981).

C32

Chen, K.Y. and H.R. Withers. Survival characteristics
of stem cells of gastric mucosa in C3H mice subjected
to localized gamma irradiation. lnl. J. Radiat. Biol. 21:
521-534 (1972).
C33 Catterall, M. and S.K. Bewley. Fast neutrons in thetreatment of cancer. Academic Press, London, 1979.
DI
Denekamp, J. Changes in the rate of proliferation innormal tissues after irradiation, p. 810-825 in:Radiation Research: Biomedical, Chemical andPhysical Perspectives (0. Nygaard, H.l. Adler and
W.K. Sinclair, eds.). Academic Press, New York, 1975.
D2
Durand, R.E. and R.M. Sutherland. Effects of interccllular contact on repair of radiation damage. Exp. Cell
Res. 71: 75-80 (1972).
D3
Denekamp, J., M.M. Ball and J.F. Fowler. Recovery
and repopulation in mouse skin as a function of timeafter irradiation. Radiat. Res. 37: 361-370 (1979).
D4
Dixon, B. The effect of radiation on the growth ofvertebrae in the tails of rats. 11. Split doses of x-rays
and the effect of oxygen. lnt. J. Radial. Biol. 15:
215-226 (1969).
D5
Denekamp, J. Residual radiation damage in mouse skin
5-8 months after irradiation. Radiology 115: 191-195(1975).
D6
Denekamp, J. Early and late radiation reactions inmouse feet. Br. J. Cancer 36: 322-329 (1977).
D7
Denekamp, J., F.A. Stewart and B.G. Douglas. Changes
in the proliferation rate of mouse epidermis after irradiation: continuous labelling studies. Cell Tissue Kinet.
9: 19-29 (1976).
D8
Denekamp, J. Changes in the rate of repopulation
during multi-fraction irradiation of mouse skin. Brit. J.
Radio!. 46: 381-387 (1973).
D9
Dutreix, J., A. Wambersie and C. Bounik. Cellular
recovery in human skin reactions: application to dose,
fraction number, overall time relationship in radiotherapy. Eur. J. Cancer 9: 159-167 (1973).
DlO Douglas, B.G. and J.F. Fowler. The effect of multiple
small doses of x-rays on skin reactions in the mouseand a basic interpretation. Radiat. Res. 66: 401-426(1976).
Dll Denekamp, J. and S.R. Harris. The response of mouseskin to multiple small doses of radiation, p. 342-350 in:
Cell Survival After Low Doses of Radiation (T. Alper,ed.). John Wiley and Sons, New York, 1975.
D12 Douglas, B.G., J.F. Fowler, J. Denekamp et al. The
effect of multiple small fractions of x-rays on skinreactions in the mouse, p. 351-361 in: Cell Survival
After Low Doses of Radiation (T. Alper, ed.). John
Wiley and Sons, New York, 1975.
D13 Devik, F. Studies on the duration of DNA synthesis
and mitosis in irradiated and regenerating epidermis
cells in mice by means of tritium-labelled thymidine.
lnLJ. Radial. Biol. 5: 59-66 (1962).
D14 Dutreix. J., M. Tubiana, A. Wambersie et al. The
innuence of cell proliferation in tumours and normal
tissues during fractionated radiotherapy. Eur. J. Cancer
7: 205-213 (1971).
DlS Dixon, B. The effect of radiation on the growth ofvertebrae in the tails of rats. I. Single doses of x-rays
and the effect of oxygen. lnt. J. Radiat. Biol. 13:
355-368 (1967).
D16 Dettmer, C.M., S. Kramer, D.H. Driscoll et al. A
comparison of the chronic effects of irradiation upon
the norrnal, damaged and regenerating rat liver.
Radiology 91: 993-997 (1968).
D17 DeMignard, V.A., P.R. Patek and S. Bernick.
Responses of the liver to "target" irradiation. Am. J.
Pathol. 47: 339 (1965).
D18 Donaldson, S.S., P.S. Moskowitz, E.L. Cany et al.
Radiation-induced inhibition of compensatory renal
growth in weanling mouse kidney. Radiology 128:491-495 (1978).
D19 De Boer, J. The effects of chronic whole-body irradiation on the reproduction of C57 black mice, p. 59-72
in: Effects of Ionizing Radiation on the Reproductive
System (W.D. Carson and F.X. Gassner, eds.).
Pergamon Press, New York, 1964.

637

D20

Doll, R. and P.G. Smith. TI1e long-term effects of xirradiation in patients treated for metropathia haemorrhagia. Br. J. Radial. 41: 362-368 (1968).

D41

D21

Duncan, W. and A.H.W. Nias. p. 138-139 in: ClinicalRadiobiology. Churchill, Livingstone, 1977.

042

D22

Desjardins, A.U. Osteogcnic tumour: growth injury ofbone and muscular atrophy following therapeutic
irradiation. Radiology 14: 296 (1930).

D23

Deeley, T.J. A clinical trial to compare two different
tumour dose levels in the treatment of advanced
carcinoma of the bronchus. Clin. Radiol. 17: 299-301(1966).

D24

Denekamp, J., J.F. Fowler, K. Kragt et al. Recovery
and repopulation in mouse skin after irradiation withcyclotron neutrons as compared with 250 kV x-rays or
15 MeV electrons. Radial. Res. 29: 71-84 (1966).

D25

Denekamp, J. and S.B. Field. Repair and repopulationin mouse skin during fractionated neutron and x-irradiation. Eur. J. Cancer 10: 241-247 (1974).

D26

De Ruiter, J., A.L. flootsma, M.F. Kramer et al.
Response of stem cells in the mouse testis to fission
neutrons of I MeV mean energy and 300 kV x-rays.
Methodology, dose-response studies, relative biologicaleffectiveness. Radiat. Res. 67: 56-68 (1976).

D27

Dixon, B. The effect of radiation on the growth ofvertebrae in the tails of rats. III. The response tocyclotron neutrons. Int. J, Radial. Biol. 15: 541-548(1969).
Davids, J.A.G. Acute effects of 1 MeV neutrons on the
haemopoietic tissues, intestinal epithelium and gastricepithelium in mice, p. 565-576 in: Advances in
Radiation Research, Vol. II (D.F. Duplan and
A. Shapiro, eds.). Gordon and Breach, New York, 1973.

D28

D29

Durand, R.E. and P.L. Olive. Irradiation of multicell
spheroids with fast neutrons versus x-rays: a qualitative
difference in sublethal damage repair capacity or
kinetics. In!. J. Radiat. Biol. 30: 589-592 (1976).

043

D44
D45

046

047

048

D49
D50

D51

El

D30

Devik, F. Study of the local roentgen reaction on theskin of mice, with specific reference to the vasculareffects. Acta Radial., Suppl. 119 (1955).

E2

D31

Dunjic, A. The influence of radiation on blood vessels
and circulation. X. Blood flow and permeability inirradiated skin. Curr. Top. Radial. Res., Quart. 10:
151-169 (1974).

E3

D32

De Ruiter, J. and L.M. Putten. Measurement of bloodflow in the mouse tail after irradiation. Radial. Res. 61:
427-438 (1975).

E4

D33

Davies, R.W. and J. Gamble. Changes in the rate oftransudation of vascular fluid in the isolated rat
mesentery following irradiation. J. Physiol. 266: 71-77(1977).

E6

D34

Dunjic, A. The influence of radiation on blood vessels
and circulation. VIII. Blood flow and permeability inliver, kidney and lung. Curr. Top. Radiat. Res. Quart.
10: 109-134 (1974).

E7
ES

D35

De Gowin, R.L., L.F. Lewis, J.C. Hoak et al. Radiosensitivity of human endothelial cells in culture. J. Lab.
Clin. Med. 84: 42-48 (1974).

E9

D36

Denekamp, J. and J.F. Fowler. Cell proliferation
kinetics and radiation therapy, p. 101-137 in: Cancer: aComprehensive Treatise (F.F. Becker, ed.). Plenum
Press, New York, 1976.

D37

Darenskaja, N.G. Biological effects of inhomogenious
irradiation. Atomizdat, Moscow, 1974 (in Russian).
Darenskaja, N.G. and G.M. Avetisov. Modelling of theorganism injury at inhomogeneous irradiation, p.
104-113 in: Theoretical assumptions and models of theprocesses of radiation injury of the systems oforganism. Puschino, 1975 (in Russian).

E12

Domshlak, M.P., Yu. G. Grigoriev, N.G. Darenskaya et
al. Late effects in man after radiation therapy. Medical
Radiology 7: 10-14 (1962) (in Russian).
Dagayshina, V.N. About extrapolation to the man ofthe experimental data on the reaction of brain toradiation. Medical Radiology 23: 40-41 (1978) (inRussian).

E14

D38

D39

D40

638

ElO
El 1

E13

Doria, G. Immunological effects of irradiation: waiting
for a model. Int. J. Rad. On col. Biol. Phys. 5:1111-1116 (1979).
Di Paola, M., M. Bianchi and J. Haarli. Lens opacification in mice exposed 14 MeV neutrons. Radiat. Res.
73: 340-350 (1978).
Dillman, LT. and F.C. Von der Lage. Radionuclide
decay schemes and nuclear parameters for use inradiation-dose estimation. Medical Internal Radiation
Dose Committee, Pamphlet No. 10, Society of Nuclear
Medicine, New York, 1975.
Davis, P. and M.J.V. Jayson. Acute knee joint rupture
after 90y, Ann. Rheum. Dis. 34: 62-63 (1975).
Da Silva Horta, J., M.E. Da Silva Horta, L.C. Da Motta
et al. Malignancies in Portuguese thorotrast patients.
Health Phys. 35: 137-135 (1978).
Dobson, R.L. How toxic is tritium? Relevance ofhigh-dose results and gamma-ray data to evaluating
low-level, chronic exposure. Environ. Health Perspect.
22: 145-147 (1978).
Dougherty, J.1-I., G.N. Tayler and C.W. Mays. 90Sr
toxicity in adult beagles. in: Biomedical implications ofradiostrontium exposure (M. Goldman and L.M.
Bustad, eds.). CONF-710201 (1972).
Dagle, G.E., and J.F. Park. Plutonium-induced
lymphadenitis in beagles, p. 239-245 in: Radiation andthe Lymphatic System. CONF-740930 (1976).
Dillman, L.T. Communication (1980).
Dancewicz, A.M., A. Mazanowska and G.B. Gerber.
Late biochemical changes in the rat lung after
hemithoracic irradiation. Radial. Res. 67: 482-490(1976).
Deldos, L. and J.P. Smith. Ovarian cancer with special
regard to radiotherapy. Natl. Cancer Inst. Monograph42. 1975.
Elkind, M.M., A. Han and K.W. Volz. Radiation
response of mammalian cells grown in culture. IV.
Dose dependence of division delay and post-irradiation
growth of surviving and non-surviving Chinese hamster
cells. J. Natl. Cancer Inst. 30: 705-721 (1963).
Elkind, M.M. and H. Sutton. Radiation response of
mammalian cells grown in culture. I. Repair of x-ray
damage in surviving Chinese hamster cells. Radial. Res.
13: 556-593 ( 1960).
Ellis, F. Tolerance dosage in radiotherapy with 200 kV
x-rays. Brit. J. Radial. 15: 348-350 (1942).
Ellis, F. Dose, time and fractionation: a clinicalhypothesis. Clin. Radiol. 20: 1-7 (1969).
Etoh, H., Y.H. Taguchi and J. Tabachnick. Movementof beta-irradiated epidermal basal cells to the spinousgranulosa layers in the absence of cell division. J.
Invest. Dermatol. 64: 431 (1975).
Emery, E.W .. J. Denekamp, M.M. Ball et al. Survival ofmouse skin epithelial cells following single and divided
doses of x-rays. Radial. Res. 41: 450-466 (1970).
Erickson, B.H. Effect of 60Co y-irradiation on the stemand differentiating spermatogonia of the post-puberalrat. Radial. Res. 68: 433-448 (1976).
Erickson, B.H. Radioresponse of the prepuberal
porcine ovary. lnt. J. Radial. Biol. 13: 57-67 (1967).
Erickson, B.H. Effect of y-radiation on the prepuberalbovine ovary. Radial. Res. 31: 441-451 (1967).
Erickson, B.H., R.A. Reynolds and R.L. Murphree.
Late effects of 60Co y-radiation on the bovine oocytes
as reflected by oocyte survival, follicular development
and reproductive performance. Radial. Res. 68:
132-137 (1976).
Einhorn, J. and G. Wikholm. Hypothyroidism after
external irradiation to the thyroid region. Radiology
88: 326-328 (1967).
Einhorn, J. and N. Einhorn. Effects of irradiation on
the endocrine glands, p. 386-400 in: Frontiers ofRadiation Therapy and Oncology, Vol. 6 (J.M Vaeth,ed.). University Park Press, Baltimore, 1972.
Eassa, E.M. and G.W. Casarett. Effect of epsilonamino-n-caproic acid (EACA) on radiation-induced
increase in capillary permeability. Radiology 106:679-688 (1973).

El5
E16

E17

El 8
E 19

E20

Engerman, R.L., D. Pfaffenbach and M.D. Davis. Cellturnover of capillaries. Lab. Invest. 17: 738-743 (1967).
Eassa, E.M. and G.W. Casarett. Evaluation of the effectof epsilon-amino-n-caproic acid on the capillarypermeability of the rabbit's skin induced by x-irradiation. Radiat. Res. 35: 562 (1968).
Earlam, M.S.S. and A. llolliger. Experimental renal
diseases produced by x-ray. J. Pathol. Bacteriol. 34:
603-634 (1931).
Engeset, A. Irradiation of lymph nodes and vessels.
Acta Radio!., Suppl. 229 (1964).
Erickson, B.H. Effect of 60Co radiation on the stem anddifferentiating spermatogonia of the post puberal rat.
Rad. Res. 68: 433-448 (1976).
Ermolaeva, N.V. and M.V. Belyaeva. About the
population of lymphoidal cells reacting on irradiation,action of degranol and hydrocortisone by the decay ofDNA. Radiobiologiya 16: 609-615 (1976) (in Russian).

E2l

Eidus, L.Ch., Yu. V. Koshevoi, M.Ch. Levitman et al.
Quantitative estimation of the dynamics of the postirradiation changes of micro-circulation system in thebrain of the rat. Medical Radiology. 24(12): 11-14(1979) (in Russian).

E22

Evans, R.D. X-ray and y-ray interactions, p. 93-155 in:Radiation Dosimetry Vol. I. Fundamentals (F.H. Attix
and W.C. Roesch, eds.). Academic Press, New York,
1968.

E23

E24

E25

Fl

F2

Ellett, W.H. and R.M. Humes. Absorbed fractions forsmall volumes containing photon-emitting radioactivity. J. Nucl. Med. 12. Suppl. 5: 25-32 (1971).
Evans, R.D. The effects of skeletally depositedalpha-ray emitters in man (Silvanus Thompson
Memorial Lecture). Brit. J. Radio!. 39: 881-895 (1966).
Ellis, F. Fractio;iation in radiotherapy. p. 34-51 in:Modern Trends in Radiotherapy, Vol. 1 (T.J. Deeley
and C.A. Wood, eds.). Butterworths, London, 1967.
Fowler, J.F., D.K. Bewley, R.L. Morgan et al. Experiments with fractionated x-irradiation of the skin ofpigs. 11. Fractionation up to five days. Brit. J. Radio!.
38: 278-284 (1965).
Field, S.B., T. Jones and R.H. Thomlinson. The relative
effects of fast neutrons and x-rays on tumour andnormal tissue in the rat. 11. Fractionation: recovery andreoxygenation. Brit. J. Radio!. 41: 597-607 (1968).

F14

FI 5

Fl6
FI 7

FIS

F19

F20
F21

F22

F23

F24

F25
F26

F3

Field, S.B. and S. Homsey. Damage to mouse lung withneutrons and x-rays. Eur. J. Cancer 10: 621-627 (1974).

F27

F4

Fu, K., T.L. Phillips, L.J. Kane et al. Tumour andnormal tissue response to irradiation in vivo. Radiology
114: 709-716 (1975).

F28

FS

F6

Field, S.B. and M.P. Law. The relationship between
early and late radiation damage in rodent skin. Jnt. J.
Radiat. Biol. 30: 557-564 (1976).
Field, S.B. Early and late reactions in skin of rats
following irradiation with x-rays or fast neutrons.
Radiology 92: 381-384 (1969).

F7

Field, S.B .. S. Marston and R. Tompkins. Residual
injury after x-rays and fast neutrons (to be published).

F8

Field, S.B. and S. Homsey. Slow repair after x-rays andfast neutrons. Brit. J. Radiol. 50: 600-601 (1977).
Field, S.B. Early and late normal tissue damage after
fast neutrons. lnt. J. Radial. Oncol. Biol. Phys. 3:
203-210 (1977).

F9

FlO

Flt

F12

F13

Fowler, J.F.. R.L. Morgan, J.S. Silvester et al. Experiments with fractionated x-ray treatment of the skin ofpigs. Brit. J. Radiol. 36: 188-196 (1963).
Fowler, J.F. and J. Denekamp. Radiation effects on
normal tissues, p. 139-180 in: Cancer: a comprehensive
Treatise (F.F. Becker, ed.). Plenum Press, New York,
1976.
Fowler, J.F., K. Kragt, R.E. Ellis et al. The effect ofdivided doses of 15 MeV electrons on the skin of mice.
Jnt. J. Radiat. Biol. 9: 241-252 (1965).
Field, S.B., C. Morris, J. Denekamp et al. The responseof mouse skin to fractionated x-rays. Eur. J. Cancer 11:
291-299 (1975).

F29

F30
F31
F32
F33
F34
F35
F36

F37

Field, S.8., R.L. Morgan, R. Morrison et al. The
response of human skin to irradiation with x-rays or
fast neutrons. lnt. J. Radiat. Oncol. Biol. Phys. 1:
481-486 (1976).
Fic:ld, S.B. and S. Homsey. The response of mouse skinand lung to fractionated x-rays, p. 362-368 in: Cell
Survival After Low Doses of Radiation (T. Alper, ed.).
J. Wiley and Sons, New York, 1975.
Fowler, J.F., J. Denekamp, J. Delapeyre et al. Skinreactions in mice after multifraction x-irradiation. Int.
J. Radiat. Biol. 25: 213-223 (1974).
Field, S.B., S. Homsey and Y. Kutsutani. Effects offractionated irradiation on mouse lung and a phenomenon of "slow repair". Brit. J. Radiol. 49: 700-707(1976).
Focht, M.E., G.R. Merriam, M. Schwarz et al. A
method of radiation cataract analysis and its use inexperimental fractionation studies. Radiology 87:
465-474 (1966).
Fliedner, T.M., V.P. Bond and E.P. Cronkite. Structural
cytological and autoradiographic (H3-thymidine)changes in the bone marrow following total body
irradiation. Am. J. Pathol. 38: 599--623 (1961).
Fiechter, G.H. and R. Klein. Dose-time-volume
relationship in squamous cell carcinoma of the larynx.
Radiology 82: 1032-1041 (1964).
Fliedner, T.M., E.P. Cronkite, S.A. Killmann et al.
Granulopoiesis. II. Emergence and pattern of labellingof neutrophilic granulocytes in human beings. Blood
24: 683-700 (1964).
Field, S.B., T. Jones and R.H. Thomlinson. The relative
effects of fast neutrons and x-rays on tumour andnormal tissue in the rat. Brit. J. Radiol. 40: 834-842(1967).
Field, S.B. and S. Hornsey. RBE values for cyclotron
neutrons for effects on normal tissues and tumours as afunction of dose and dose fractionation. Eur. J. Cancer
7: 161-169 (1971).
Fowler, J.F., J. Denekamp and S.B. Field. RBE values
for regrowth of C3H mouse mammary carcinoma after
single doses of cyclotron neutrons or x-rays. Eur. J.
Cancer. 9: 853-857 (1973).
Fakhri, O. Master of Science Thesis, University of
London, 1967.
Field, S.B. An historical survey of radiobiology andradiotherapy with fast neutrons. Curr. Top. Radiat.
Res. Quart. 11: 1-36 (1976).
Fowler, J.F. and R.L. Morgan. Pretherapeutic experiments with the fast neutron beam from MRC cyclotron.
VIII. General Review. Brit. J. Radio!. 115-121 (1963).
Field, S.B. The relative biological effectiveness of fastneutrons for mammalian tissues. Radiology 93:915-920 (1969).
Field, S.B. and S. Homsey. Neutron RBE for normal
tissues. p. 181-186 in: High-LET radiations in clinicalradiotherapy (G.W. Barendsen, J. Broerse and K.
Brenz, eds.) Pergamon Press, New York, 1979.
Field, S.B. The Ellis formula for x-rays and fastneutrons. Brit. J. Radiol. 45: 315-317 (1972).
Fajardo, L.F. and J.R. Stewart. Capillary injury
preceding radiation-induced myocardial fibrosis.
Radiology 101: 429-433 (1971).
Fridrich, R. and M. Schafner. The liver blood flow after
local x-irradiation. Experientia 21: 40-41 (1965).
Fajardo, L.F. and J.R. Stewart. Pathogenesis ofradiation-induced myocardial fibrosis. Lab. Invest. 29:
244-257 (1973).
Florey, H.W. General Pathology. Lloyd-Luke, London,
1970.
Fajardo, L.F. and J.R. Stewart. Pathogenesis ofradiation-induced myocardial fibrosis. Laboratory
Investigation 29: 244-257 (1973).
Fedorenko, B.S., V.V. Shichodyrov, N.I. Ryzhov et al.
Anatomopathological changes of kidneys in dogs after
irradiation by protons of high energy. Cosm. Biol. andMed. 6: 14-18 (1970) (in Russian).
Fredorenko, B.S., V.G. Kondratenko, V.A. Stakanov etal. The influence of protons on testicles. Cosm. biol.
and med. 10: 16-19 (1974) (in Russian).

639

F38

F39

F40

F42

F43

F44

F45

F46

F47

F48

F49

F50
F51

F52

F53

F54
Gl

G2

G3

G4

05

G6

640

Fedorova, N.L. The assessment of functional activity of
dog's testicles after chronic gamma-irradiation in thecourse of six years. Radiobiologiya 16 (5): 727-731(1976) (in Russian).
Fedorova, N.L. and B.A. Markelov. Functional activityof dog's testicles at chronical and combined gammairradiation in the course of three years. Cosm. Biol. andMed. 12: 42-46 (1978) (in Russian).
Fedorova, N.L. and B.A. Markelov. Dog's spermatogenesis after interruption of three years chronic
gamma-irradiation. Radiobiologiya 19: 81-85 (1979) (inRussian).
Fedotova, M.I. and 0.1. Belousova. Dynamics of stern
hemopoetic cells and differentiated cells of bonemarrow of mice after chronic gamma-irradiation.
Radiobiology. In press. (in Russian).
Freedman, L.R. and R.K. Keehen. Urinary findings ofchildren who were in utero during the atomic bombingsof Hiroshima and Nagasaki. Yale J. Biol. Med. 39:
196-206 (1966).
Flaskamp, W. Ober Rontgenschaden und Schaden
durch radioaktive Substanzen. Sonderbande zur Strahlenther. XII. Urban und Schwarzenbert, Berlin, 1930.
Franke, H.C. and W. Lierse. Strahlenbedingte
Reaktionen des Gehirns und des Riickenmarks. Strahlentherapie 154: 587-598 (1978).
Fain, J., M. Mormin and M. Montret. Spatial energy
distribution around heavy-ion path. Radiat. Res. 57:
379-389 (1974).
Flammersfeld, A. Eine Beziehung zwischen Energie
und Reichweite fiir Beta-Strahlen kleiner und mittlerer
Energie. Naturw. 33: 280-281 (1946).
Feinendegen, L.E. and E.P. Cronkite. Effect of microdistribution of radionuclides on recommended limits inradiation protection, a mode. Curr. Top. Radiat. Res.
12: 83-99 (1977).
Feinendegen, L.E. Biological damage from the Auger
effect, possible benefits. Radial. Environ. Biophys. 12:
85-99 (1975).
Fleischer, R.L. On the "dissolution" of respirable Pu02
particles. Health Phys. 29: 69-73 (1975).
Fleischer, R.L. and O.G. Raabe. On the mechanism of"dissolution" in liquids of Pu02 by alpha decay. HealthPhys. 35: 545-548 (1978).
Filatov, P.P. The effect of prolonged administration ofradiozinc (65zn) on the antigenic structure of rabbit
tissues, p. 124-138 in: The Toxicology of Radioactive
Substances Vol. 5. (A.A. Letavet and E.B. Kurlyandskaya, eds.). Pergamon Press, Oxford, 1970.
Fine, R., B. McCullough, J.F. Collins et al. Lungelasticity in regional and diffuse pulmonary fibrosis. J.
Appl. Physiol. 47: 138-144 (1979).
Fletcher, G.H. Textbook of Radiotherapy. 3rd Edition.
Lea and Febiger, Philadelphia, 1980.
Guttman, P.H. and H.l. Kohn. Progressive intercapillary glornerulosclerosis in the mouse, rat andChinese hamster associated with aging and x-ray
exposure. Arn. J. Pathol. 37: 293-307 (1960).
Glatstein, E. Alterations in rubidium-86 extraction innormal mouse tissue after irradiation. An estimate oflong-term blood flow changes in kidney, lung, liver,skin and muscle. Radiat. Res. 53: 88-101 (1973).
Geraci, J.P., P.D. Thrower and M. Mariano. Cyclotron
fast neutron RBE for late kidney damage. Radiology
126: 519-520 (1978).
Glatstein, E., R.C. Brown, G.D. Zanelli et al. The
uptake of rubidium-86 in mouse kidneys irradiatedwith fractionated doses of x-rays. Radiat. Res. 61:
417-426 (1975).
Geraci, J.P., P.D. Thrower, K.L. Jackson et al. The
relative biological effectiveness of fast neutrons forspinal cord injury. Radial. Res. 59: 496-503 (1974).
Goffinet, D.R., G.W. Marsa and J.M. Brown. The
effects of single and rnultifraction radiation courses on
the mouse spinal cord. Radiology 119: 709-713 (1974).

G7

Geraci, J.P., K.L. Jackson, G.M. Christensen et al. RBE
for late spinal cord injury following multiple fractionsof neutrons. Radial. Res. 74: 382-386 (1978).
G8
Gowen, J.W. and J. Stadler. Acute irradiation effects on
reproductivity of different strains of mice, p. 45-58 in:
Effects of Ionizing Radiation on the Reproductive
System (W.D. Carlson and F.X. Gassner, eds.).
MacMillan, New York, 1964.
G9
Gowen, J.W. and J. Stadler. Life in environs of continuing higher levels of added radiant energy frompuberty to death as expressed by mice. Environ. Res. 1:
145-170 (1967).
G 1O Gilbert, C. W. and L.G. Lajtha. The importance of cell
population kinetics in determining response to irradiation of normal and malignant tissue, p. 474-497 in:Cellular Radiation Biology. The Williams and Wilkins,
Baltimore, 1964.
Gl 1 Gong, J.K., T.J. MacVittie and J.E. Vertalino. A
method for determining residual injury in the haemopoietic system of the x-irradiated rat. Radial. Res. 37:
467-477 (1969).
G12 Goolden, A.W. and J.B. Davey. The ablation of normal
thyroid tissue with iodine-131. Brit. J. Radial. 36:
340-345 (1963).
G13 Glucksmann, A. The effects of radiation on reproductive organs. Brit. J. Radio!., Suppl. 1: 101-109(1947).
G14 Gans, B., C. Behary and B. Levie. Ovarian regenerationand pregnancy following massive radiotherapy fordysgerrninoma. Obstet. Gynecol. 22: 596-600 (1963).
G16 Gragg, R.L., R.M. Humphrey and R.E. Meyn. The
response of Chinese hamster ovary cells to fast neutron
radiotherapy beams. II. Sublethal and potentially lethal
damage recovery capabilities. Radiat. Res. 71: 461-470(1977).
G17 Geraci, J.P., K.L. Jackson, G.M Christensen et al.
Acute and late damage in the mouse small intestine
following multiple fractionation of neutrons or x-rays.
lnt. J. Radial., Oncol., Biol., Phys. 2: 693-696 (1977).
Gl8 Geraci, J.P., K.L. Jackson, G.M. Christensen et al.
Single dose fast neutron RBE for pulmonary andoesophageal damage in mice. Radiology 120: 701-703(1976).
G19 Geraci, J.P., K.L. Jackson, G.M. Christensen et al.
Cyclotron fast neutron RBE for various normal tissues.
Radiology 115: 459-463 (1975).
G20 Gragg, R.L., R.M. Humphrey and R.E. Meyn. The
response of Chinese hamster ovary cells to fast neutron
radiotherapy beams. I. Relative biological effectivenessand oxygen enhancement ratio. Radial. Res. 65: 71-82(1976).
G21 Gup, A.K., J.U. Schlegel, T. Caldwell et al. Effect ofradiation on renal function. J. Ural. 97: 36-39 (1967).
G22 Graham, M.M. The measurement of capillary permeability changes in the irradiated rat using a double
isotope technique. Radial. Res. 51: 519 only (1972).
G23 Gillette, E.L., G.D. Maurer and G.A. Severin.
Endothelial repair of radiation damage following betairradiation. Radiology 116: 175-177 (1975).
G24 Glasunov, l.S., V.V. Blagoveshenskaya, V.A. Ivanov et
al. About radiation demielination encephalomielosis.
Journal of Neuropathology and Psychiatry 1601-1604(1979) (in Russian).
G25 Glasunov, I.S., V.V. Blagoveshenskaya, V.A. Ivanov et
al. Acute radiation sickness caused by gamma-neutron
irradiation. Clinical Medicine N4: 55 (1979) (inRussian).
G26 Gouskova, A.K. Dynamics of pathological processes in
the central nervous system of humans after prolonged
exposure to relatively low doses of ionizing radiation.
Clinical Medicine N5: 20 (1960) (in Russian).
G27 Glasunov, l.S. and V.V. Glagoveshenskaya. Late effectsof acute radiation sickness. Journal of Neuropathology
and Psychiatry. Clinical Medicine N8: 1129 (1968) (inRussian).
G28 Gouskova, A.K. and G.D. Baisogolov. Action ofradiation on organism. Clinical medicine (1955) (inRussian).

029

Glasunov, l.S., V.A. Ivanov, A.A. Grafov et al. Bloodcirculation in patients with radiation sickness, in:Proceedings of the Journal of Nervous Diseases 11
MOLMI, Moscow (1971) (in Russian).
030 Gouskova, A.K. and G.D. Baisogolov. Radiation
sickness of man. Medizina, Moscow, 1971 (in Russian).
031 Grigoriev, Yu.G. Radiation protection during cosmic
nights. Atomizdat. Moscow, 1975 (in Russian).
032 Grundner, H.G. and L. Rausch. Strahlenschaden an derHaut nach Arbeit mit Radionukliden - ein kasuistischer
Beitrag. Der Hautarzt 16: 522-523 (1965).
033 Gauwerky, F. Ober die Strahlensch11digung deswachsenden Knochens. Strahlcntherapie 113: 325-350(1960).
034 Grady, E.D. Adjuvant therapy for colon cancer byinternal irradiation to the liver, p. 351-357 in: Therapy
in Nuclear Medicine (R.P. Spencer, ed.). Grune andStratton, New York, 1978.
035 Greig, W.R., J.F.B. Smith, J.S. Orr et al. Comparative
survivals of rat thyroid cells in vivo after 131 I, 125( andx-irradiations. Brit. J. Radio!. 43: 542-548 (1970).
036 Gross, J., M. Ben-Porath, A. Rosin et al. A comparisonof radiobiologic effects of 13 t I and 1251 respectively on
the rat thyroid, p. 291-306 in: Thyroid Neoplasia(S. Young and D.R. Inman, eds.), Academic Press,
London, 1968.
G37 Gillespie, G.C., J.S. Orr and W.R. Greig. Microscopic
dose distribution from 12SI in the toxic thyroid glandand its relation to therapy. Brit. J. Radiol. 43: 40-47(1970).
G38 Gottschalk, R.G. and C.H. Allen. Uptake of radioactive
sulphur by chondrosarcoma in man. Proc. Soc. Exp.
Biol. Med. 80: 334-339 (1952).
039 Gaidova, Ye.S. Morphological changes in experimental
animals following chronic exposure to radioactive zinc
(65zn), p. 160-179 in: The Toxicology of Radioactive
Substances Vol. S (A.A. Letavet and E.B. Kurlyandskaya, eds.). Pergamon Press, Oxford, 1970.
G40 Gerber, G.B., G. Gerber, K.l. Altman et al. Studies on
the metabolism of tissue proteins. III. The turnover ofsoluble proteins and elastin labelled with 14C-proline
and its relation to exposure to total body X-irradiation.
Int. J, Rad. Biol. 4: 615-621 (1962).
G41 Gross, N.J. Experimental radiation pneumonitis:changes in physiology of the alveolar surface. J. Lab.
Clin. Med. 92: 991-1001 (1978).
G42 Gits, J, and G.B. Gerber. Electrolyte loss, the maincause of death from the gastrointestinal syndrome?
Radiat. Res. SS: 18-28 (1973).
043 Gerber, G.B. The role of connective tissue in late effectsof radiation, p. 698-705 in: Radiation Research (S.
Okada, M. Imamura, T. Terashima et al. eds.). Toppan,
Tokyo 1979.
044 Gilbert, H.A. and A.R. Kagan. Radiation Damage to
the Nervous System. Raven Press, 1980.
Hl
Homsey, S. The radiosensitivity of the intestine, p.
78-88 in: Strahlenschutz in Forschung und Praxis,
Band XIII. G. Thieme-Verlag, Stuttgart, 1973.
Homsey, S. and S.B. Field. The effects of single andH2
fractionated doses of x-rays and neutrons on theoesophagus. Eur. J, Cancer (in press).
1-13
Homsey, S. and S. Vatistas. Some characteristics of thesurvival curve of crypt cells of the small intestine of themouse. Brit. J. Radio!. 36: 795-800 (1963).
H4
Hirst, D.G., J. Denekamp and B. Hobson. Proliferation
studies of the endothelial and smooth muscle cells of
the mouse mesentery after irradiation. Cell Tissue
Kinet 13: 91-104 (1980).
1-15
Hahn. G.M. and J.B. Little. Plateau phase cultures ofmammalian cells. Curr. Top. Radial. Res. Quart. 8:
39-83 (1972).
H6
Hall, E.J. Radiobiology for the Radiologist. Second
Edition. Harper and Row, New York. 1973.
H7
Hunter, R.D. and J.G. Stewart. The tolerance to reirradiation of heavily irradiated human skin. Brit. J.
Radio!. 50: 573-575 (1977).
H8
Hendry, J.H., I. Rosenberg, D. Greene et al. Re-irradiation of rat tails to necrosis at six months after

treatment with a "tolerance" dose of x-rays or neutrons.
Ilrit. J. Radio!. 50: 567-572 (1977).
H9
Hendry, J.H. The tolerance of mouse tails to necrosis
after repeated irradiation with x-rays. Ilrit. J. Radio!.
51: 808-813 (1978).
H 10 Howard, A. and S.R. Pelc. Synthesis of desoxyribonucleic acid in normal and irradiated cells and its
relation to chromosome breakage. Heredity, Suppl. 6:261-273 (1953).
Hl 1 Hegazy, M.A.1-1. and J.F. Fowler. Cell population
kinetics and desquamation skin reactions in plucked
and unplucked mouse skin: II. Irradiated skin. Cell
Tissue Kinet. 6: 587-602 (1973).
H12 Hopewell, J.W. and R.J. Berry. The predicitive value of
the NSD system for renal tolerance to fractionated xirradiation in the pig. Brit. J. Radio!. 47: 679-686(1974).
1-113 Hopewell, J.W. and G. Wiernik. Tolerance of the pig
kidney to fractionated x-irradiation, p. 75-84 in: Radiobiological Research and Radiotherapy, Vol. 1. IAEA,
Vienna, 1977.
H14 Hopewell, J.W. and E.A. Wright. The nature of latentcerebral irradiation damage and its modification byhypertension. Brit. J. Radio!. 43: 161-167 (1970).
H15 Huckins, C. The spermatogonial stem cell populationin adult rats. III. Evidence for a long cycling
population. Cell Tissue Kinet. 4: 335-349 (1971).
H16 Hodgson, G.S. Erythrocyte 59Fe uptake as a function ofbone marrow dose injected in lethally irradiated mice.
Blood 19: 460-467 (1962).
H17 Hellman, S., H.E. Grate and J.T. Chaffey. Effects ofradiation on the capacity of the stem cell compartment
to differentiate into granulocytic and erythrocyticprogeny. Blood 34: 141-156 (1969).
H18 Holthusen, H., H. Meyer and W. Molineus. in:Ehrenbuch der ROntgenologen und Radiologen aller
Nationen. Urban and Schwarzenberg, Munich 1959.
H19 Hamilton, F.E. Gastric ulcer following irradiation.
Arch. Surg. 55: 394-399 (1947).
H20 Heller, C.G. Radiobiological factors in manned spacenight, p. 127-128 in: Langham Report of the Space,
Radiation Study Panel of the Life Sciences Committee.
National Academy, Washington, D.C., 1967.
H21 Heller, C.G. and M.J.O. Rowley. Communication(1982).
H22 Hall, E.J. The dependence of RBE and OER on
neutron energy for damage to mammalian cells andplant systems, p. 1066 in: Radiation Research,
Biomedical, Chemical and Physical Perspectives (O.F.
Nygaard, H.I. Adler and W.K. Sinclair, eds.).
Academic Press, New York, 1975.
H23 Howlett, J.F., R.H. Thomlinson and T. Alper. A
marked dependence of the comparative effectiveness ofneutrons on tumour line, and its implication for clinical
trial. Brit. J. Radio!. 48: 40-47 (1975).
H24 Homsey, S., U. Andreozzi and P.R. Warren. Sublethal
damage in cells of the mouse gut after mixed treatment
with x-rays and fast neutrons. Brit. J. Radio!. 50:
513-517 (1977).
H25 Hall, E.J. and U. Kraljevic. Repair of potentially lethal
radiation damage: comparison of neutron and x-ray
RBE and implication for radiation therapy. Radiology
121: 731-735 (1976).
H26 Homsey, S. The relative biological effectiveness of fastneutrons for intestinal damage. Radiology 97: 649-652(1970).
H27 Homsey, S. and S.B. Field. The RBE of cyclotron
neutrons for effects on normal tissues. Eur. J. Cancer
10: 231-234 (1974).
H28 Hendry, J.H., I. Rosenberg, D. Greene et al. Toleranceof rodent tails to necrosis after ''daily" fractionatedx-rays or 0-T neutrons. Brit. J. Radiol. 49: 690-699(1976).
H29 Hamlet, R., K.E. Carr, P.G. Toner et al. Scanningelectron microscopy of mouse intestine mucosa after
cobalt-60 and D-T neutron irradiation. Brit. J. Radio!.
49: 624-629 (1976).
641

H30

Homsey, S., Y. Kutsutani and S.B. Field. Damage tomouse lung with fractionated neutrons and x-rays.
Radiology 116: 171-174 ( 1975).
HJ I Hedges, M.J. and S. Homsey. The effect of x-rays andneutrons on lymphocyte death and transformation. lnt.
J. R:idiat. Biol.33: 291-300 ( 1978).
H32 Hornsey, S., R. Myers and P. Warren. RBE for the twocomponents of weight loss in the mouse testis for fastneutrons relative to x-rays. lnt. J. Radiat. Biol. 32:
297-301 (1977).
H33 Homsey, S., U. Andreozzi and R. l\lyers. Factors to beconsidered in deciding on fraction size for neutron
therapy, p. 49-57 in: Radiobiologieal Research andRadiotherapy. IAEA, Vienna, 1977.
H34 Homsey, S. and S.B. Field. Some factors affecting therelationship of total dose and fractionation with x-rays
and fast neutrons, p. 252-259 in: Atti dei Colloqui
dell'lstituto <lei Radio 0. Alberti. Spedali Ci\'ili di
Brescia, Italy, 1975.
H35 Hall, EJ., J.K. Novak, A.1\-1. Kcllerer et al. RBE as afunction of neutron energy. I. Experimental observations. Radial. Res. 64: 245-255 (1975).
H36 Hendry, J.H. and D. Greene. Re-evaluation of
published RBE values for mouse intestine. Brit. J.
Radial. 49: 195-196 (1976).
H37 Hendry, J.H., D. Major and D. Greene. The response ofmouse intestine, irradiated at 10 cm depth in a water
phantom with single and fractionated doses of 14 MeV
neutrons. Eur. J. Cancer JO: 325 (1974).
H38 Hendry, J.H., I. Rosenberg and D. Greene. Addition ofneutron and gamma-ray fractions for intestinal
damage. Radiology 121: 483-486 (1976).
H39 Hopewell. J.W., J.L. Foster, Y. Gunn et al. Role ofvascular damage in the development of late radiation
effects in the skin, p. 483-492 in: Late Biological
Effects of Ionizing Radiation. Vol. I. IAEA, Vienna,1978.
H40 Hirst, D.G., J. Denekamp and E.L. Travis. The
response of mesentric blood vessels to irradiation.
Radial. Res. 77: 259-275 (1979).
H41 Hopewell, J.W. and E.A. Wright. The effects of dose
field size on late radiation damage to the rat spinal
cord. lnt. J. Radial. Biol. 28: 325-333 (1975).
H42 Hopewell, J. W. Late radiation damage to the central
nervous system: a radiobiological interpretation.
Neuropathol. App. Neurobiol. (to be published).
H43 Hopewell. J.W. The late vascular effects of radiation.
Brit. J. Radiol. 47: 157-158 (1974).
H44 Horne, N.L., M. Thompson, A.E. Howes et al. Acuteand chronic effects of x-irradiation on blood now inthe mouse limb. Radiology 113: 713-722 ( 1974).
H45 Hopewell,J.W. Early and late changes in the functional
vascularity of the hamster cheek pouch after local xirradiation. Radial. Res. 63: 157-164 (1975).
H46 Hopewell, J.W. and C.M.A. Young. Changes in the
microcirculation of normal tissues after irradiation. lnt.
J. Radiat. Oncol. Biol. Phys. 4: 53-58 (1978).
H47 Harris, J.W. and T.R. Noonan. Early vascular permeability changes in whole-body x-irradiated rats. Radiat.
Res. 34: 357-365 (1968).
H48 Hopewell, J.W. and R.J. Berry. Radiation tolerance ofthe pig kidney: a model for determining overall timeand fractionation factors for preserving renal function.
lnt. J. Radial. Oncol. Biol. Phys. 1: 61-68 (1975).
H49 Hopewell, J.W. and T.J.S. Patterson. Effects ofprevious x-irradiation on revascularisation of free skingrafts in the pig. Proc. Br. Microcirc. Soc.,
Northhampton, September 1971.
H50 Hurley, J.V., K.N. Ham and G.B. Ryan. The
mechanism of the delayed response to x-irradiation of
the skin of hairless mice and of rats. Pathology I: 3-18
(1969).
H51 Hodes, P.J. and J.Q. Griffith. Effect of roentgen irradiation upon lymphatic now in rats. Radiology 37:
203-204 (1941).
H54 Hirashima, K. Comparative study on the functional
assay methods of the haematopoietic stem cells. Acta
Haem. Jap. 37: 651-652 ( 1974).

642

H55

H56

H57

H58

H59

H60

H61

H62
H63

H64

H65
H66
H67

H68

H69
H70

11

12
13

14
15

16
17

Hahn, E.W., S.M. Feingold and L. Nisce. Aspcm1ia
and recovery of spermatogenesis in cancer patients
following incidental gonadal irradiation during
treatment: a progress report. Radiology 119: 223-225( 1976).
Hofer, K.G., G. Keough and J. Marshull Smith.
Biological toxicity of Auger Emitters: Molecularfragmentation versus electron irradiation. Curr. Top.
Radial. Res. 12: 335-354 ( 1977).
Hazra, T.A. and R. Howells. Uses of beta emitters for
intracavitory therapy, p. 307-312 in: Therapy in
Nuclear Medicine, (R.P. Spencer, ed.). Grune andStratton, New York 1978.
Huvos, A.G., E.E. Rogott, B.S. Hilaris et al. Pathological changes in mice following the intraperitoneal
administration of radionuclides. Radiology 113:
203-207 (1974).
Hasterlik, R.J., A.J. Finkel and C.E. Miller. The cancer
hazards of industrial and accidental exposure toradioactive isotopes. Ann. N.Y. Acad. Sci. 114:
832-837 (1964).
Hobbs, C.H., F.F. Hahn, R.O. McClellan et al. Toxicity
of 9ly inhaled in a relatively insoluble form by beagle
dogs. LF-58 (1977).
Hahn, F.F., C. Hanika-Rebar, B.B. Boecker et al.
Toxicity of 144Ce inhaled in a relatively insoluble formby aged beagle dogs. LF-58 (1977).
Hindmarsh, M and J. Vaughan. The distribution ofradium in certain bones from a man exposed to radium
for 34 years. Brit. J. Radial. Suppl. 7: 71-80 (1957).
Haas, R.J., F. Bohne and T.M. Fliedner. Cytokinetic
analysis of slowly proliferating bone marrow cells
during recovery from radiation injury. Cell and Tissue
Kinetics 4: 31-45 (1971).
Haas, R.J., K. Meyer-Hamme and T.M. Flicdner. The
role of transplanted slowly proliferating bone-marrowcells for regeneration of lethally X-irradiated rat bonemarrow. Scand. J. Haematol. 9: 121-129 (1972).
Hubmann. F.H. Effect of X-irradiation on the rectumof the rat. Brit. J. Radial. 54: 250-254 (1981).
Homsey, S. and A. White. lsoeffect curve for radiation
myelopathy. Brit. J. Radio!. 53: 168-169 (1980).
Homsey, S., C.C. Morris and R. Myers. The
relationship between fractionating and total dose for
X-ray induced brain damage. lnt. J, Radial. Oncol.
Biol. Phys. 7: 393-396 (1981).
Hirashima, K .. Y. Kawase, M. Ohtani et al. Quantitative changes of the T-lymphocytes and hemopoietic
stem cells of patients with cancer of the cervix of theuterus following radiotherapy. J. Radiat. Res. 19: 15
only (1978).
Holm. L.E., G. Lundell, A. lsraelsson et al. Incidenceof hypothyroidism occurring long after 131 J therapy for
hyperthyroidism. J. Nucl. Med. 23: 97-102 (1982).
Holm, L.E. Changing annual incidence of hypothyroidism after 131 I therapy for hyperthyroidism,
1951-1975. J. Nucl. Med. 23: 103-107 (1982).
International Commission on Radiological Protection.
Recommendations of the International Commission on
Radiological Protection. Annals of the ICRP. ICRP
Publication 26. Pergamon Press, Oxford, 1977.
Ingold, J.A., G.B. Reed, H.S. Kaplan et al. Radiation
hepatitis. Am. J. Roentgenol. 93: 200-208 (1965).
International Commission on Radiation Units andMeasurements. Radiation Quantities and Units. ICRU
Report No. 19 (1971).
International Commission on Radiation Units andMeasurements. Quantitative Concepts and Dosimetryin Radiobiology. ICRU Report No. 30 (1979).
International Commission on Radiation Units andMeasurements. Linear Energy Transfer. ICRU Report
No. 16 (1970),
Inaba, J. and F.W. Lengemann. Intestinal uptake andwhole-body retention of suckling rats. Health Phys. 22:
169-175 (1972).
lngrand, J. Characteristics of radioisotopes for intraarticular therapy. Ann. Rheum. Dis. (Suppl.) 32: 3-9(1973).

18

19

I JO

JI
J2

J3
J4

JS

J6

J7

J8

J9

JlO

J 11

J12

J13

JI 4

J15

J16

J17
118

119

J20

J21

International Commission on Radiological Protection.
Biological effect of inhaled radionuclides. ICRP Publication 3 I. Pergamon Press, Oxford, 1980.
International Commission on Radiation Units andMeasurements. Methods of assessments of absorbed
dose in clinical use of radionuclides. !CR U Report No.
32 (1979).
International Commission on Radiation Units andMeasurements. Radiation Quantities and Units. ICRU
Report No. 33 (1981).
Jolles, B. and R.G. Mitchell. Optimal skin tolerance
dose levels. Brit. .1. Radio!. 20: 405-409 ( 1947).
Jennings, F.L. and A. Arden. Acute radiation effects inthe oesophagus. Arch. Pathol. 69: 407-412 ( 1960).
Jennings, F.L and A. Arden. Development of experimental radiation pneumonitis. Arch. Pathol. 71:
437-446 (1961).
Jacobson, LO., E. Goldwasser and C. W. Gurney, p.
423 in: Haemopoiesis (Wolstenholme and O'Connor,eds.). Churchill, London, 1960.
Juraskova, V. The effects of continuous irradiation ofbone marrow on the colony-forming activity and differentiation of the stem cells. Folia Biol. 13: 79-83 (1967).
Johnson. P.M., F.M. Grossman and H.L. Atkins.
Radiation-induced hepatic injury. Its detection by
scintillation scanning. Am. J. Roentgenol. 99: 453-462(1967).
Jacox, H.W. Recovery following human ovarian irradiation. Radiology 32: 538-545 (1939).
Jones, T., J. Morley and T.J. Williams. Use ofradioactive isotopes for continuous recording ofincreased vascular permeability in the rabbit ear. J.
Physiol. 207: 10-11 (1970).
Jolles, B. and R.G. Harrison. Enzymic processes andvascular changes in the skin radiation reaction. Brit. J.
Radio!. 39: 12-18 (1966).
Jolles, B. and M. Remington. The role of diffusible
substances in skin radiation response. Brit. J. Radio!.
33: 67-72 (1960).
Jolles, B., M. Remington and I. Simon-Reuss. Indirect
radiation effects and diffusible factors in irradiatedtissues. Acta Radio!. Ther. Phys. Biol. 56: 57-64 (1961).
Jolles, B. and R.G. Harrison. Loss and re-establishmentof tissue radiosensitivity. J. Radio!. Electro!. 47:
547-554 (1966).
Janovanovic, D. and D. Bemelmans-Ochrymowicz.
Evaluation of late lung functional changes in rat
following local irradiation by selective right radiocardiography, p. 61--62 in: Abstracts of the Eighth Annual
Meeting of the European Society for Radiation
Biology, Basko Polje, September 1971, Yugoslavia.
Jolles, B. and R.G. Harrison. Proteases and thedepletion and restoration of skin responsiveness toradiation. Nature 205: 920-921 (1966).
Jolles, B. and R.G. Harrison. Enzymic processes invascular permeability and fragility changes in the skinradiation reaction. Bibliogr. Anat. 9: 482-487 (1967).
Jennings, F.L. and A. Arden. Development of radiation
pneumonitis: time and dose factors. Arch. Pathol. 74:
351-360 (1962).
Johns, H.E. The Physics of Radiology. Second Edition.
Thomas, Springfield, Illinois, 1961.
Jee, W.S.S. and J.S. Arnold. Effect of internallydeposited radioisotopes upon blood vessels of corticalbones. Proc. Soc. Exp. Biol. Med. 105: 351-356 (1960).
Jones, R.K., F.F. Hahn, C.H. Hobbs et al. Pulmonary
carcinogenesis and chronic beta irradiation of lung, p.
454-467 in: Experimental Lung Cancer: Carcinogenesis and Bioassays (E. Karbe and J.F. Park, eds.).
Springer-Verlag, Berlin, 1974.
Jongejan, W.J. and L.M. Van Putten. The effects of 1311
and 125] in mouse and rat thyroid. lnt. J. Radial. Biol.
22: 489-499 (1972).
Jones, R.K., B.B. Boecker, J.A. Hobbs et al. Influenceof radiation-dose pattern from inhaled beta-gamma-

emitting radionuclides on canine peripheral lymphocytes. p. 83-89 in: Radiation and the Lymphatic
System. CONF-740930, 1976.
.122
Jee, W.S.S., M.H. Bartley, N.L. Dockum et al. Vascularchanges in bones following bone-seeking radionuclides,
p. 437-456 in: Delayed Effects of Bone Seeking
Radionuclidcs (C.W. Mays, W.S.S. Jee, R.D. Lloyd etal., eds.). Univ. Utah Press, Salt Lake City, 1969.
.123
Jones, A. Transient radiation myelopathy. Brit. .I.
Radio!. 37: 727-744 (1964).
J24
Joshima, H., M. Kashima and 0. Matsuoka. The effects
of polymeric plutonium on erythrocyte survival inmice. J. Radial. Res., 17: 192-203 (1976).
Jernc, N.K. Towards a network theory of the immune
J25
system. Ann. lmunn. 125: 373-389 (1974).
K1
Kember, N.F. Cell survival and radiation damage in
growth cartilage. Brit. J. Radial. 40: 495-505 (1967).
K2
Kronig, S. and W. Friedrich. Physikalische und biologische Grundlagen der Strahlentherapie. Sonderband
der Strahlentherapien, 1918.
K3
Kirck, J., W.M. Gray and E.R. Watson. Cumulative
radiation effect. Part I. Fractionated treatment regimes.
Clin. Radio!. 22: 145-155 (1971).
Karr, H., B. Schultze and W. Maurer. AutoradioK4graphic investigations of glial proliferation in the brainof adult mice. II. Cycle time and mode of proliferationof neuroglia and endothelial cells. J. Comp. Neurol.
160: 477-490 (1975).
KS
Kurohara, S.S. and G.W. Casarett. Effects of single
thoracic x-ray exposure in rats. Radiat. Res. 52:
263-290 (1972).
K6
Kember, N.F. An in viva cell survival system based on
the recovery of rat growth cartilage from radiation
injury. Nature 207: 501-503 (1965).
K7
Kinzie, J., R.K. Studer, B. Perez et al. Noncytokinetic
radiation injury: anticoagulants as radioprotective
agents in experimental radiation hepatitis. Science 175:
1481-1483 (1972).
KS
Karcher, K.H. and G. Schulz. Functional and morphological changes in the rat kidney following local irradiation. Strahlentherapie 131: 395-407 (1966) (inGerman).
K9
Krehbiel, R.H. and J.C. Plagge. Number of rat ova
implanting after substerilizing x-irradiation of one orboth ovaries. Anat. Ree. 146: 257 (1963).
KIO Kandori, F. Studies on radiation cataract: determination of threshold dose level of radiation cataract.
Am. J. Ophthalmol. 41: 627--632 (1956).
K 11 Kallman, R.F. and H.I. Kohn. T11e reaction of themouse thymus to x-rays measured by changes in organ
weight. Radiat. Res. 2: 280-293 (1955).
K12 Knospe, W.H., J. Blom and W.H. Crosby. Regeneration of locally irradiated bone marrow. I. Dosedependent long-term changes in the rat with particularemphasis upon vascular and stromal reaction. Blood
28: 398-415 (1966).
K13 Knospe, W.H., J. Blom and W.H. Crosby. Regeneration of locally irradiated bone marrow. II. Inductionof regeneration in permanently aplastic medullary
cavities. Blood 31: 400-405 (1968).
Kl4 Kurohara, S.S., N.L. Swensson, J.A. Usselman et al.
Response and recovery of liver to radiation as demonstrated by photoscans. Radiology 89: 129-135 (1967).
K15 Kraut, J.W., M.A. Bagshaw and E. Glatstein. Hepaticeffects of irradiation, p. 182-195 in: Frontiers ofRadiation Therapy and Oncology. Vol. 6 (J.M. Vaeth,ed.). University Park Press, Baltimore, 1972.
Kl6 Kramer, S., M.E. Southard and C.M. Mansfield.
Radiation effects and tolerance of the central nervous
system. Front. Radial. Ther. Oncol. 6: 332-345 (1972).
K17 Kaplan, I.I. Genetic effects in children and grandchildren of women treated for infertility and slerility byroentgen therapy: report of a study of 33 years.
Radiology 72: 518-521 (]959).
K 18 Kohn, H.J. and R.F. Kallman. Testes weigh! loss as aquantitative measure of x-ray injury in the mouse,
hamster and rat. Brit. J. Radio!. 27: 586-591 (1954).

643

K 19
K20
K2 l
K22
K23

K24
K25
K26

K27

K28

K29

K30

K31
K32
K33

K34

K36
K37

K38

K39

K40

644

Kember, N.F. Radiobiological investigations with fastneutrons using the cartilage clone system. Brit. J.
Radiol. 42: 595-597 (1969).
Kcllerer, A.M. and H.H. Rossi. The theory of dual
radiation action. Curr. Top. Radial. Res. Quart. 8:
85-158 (1973).
Keyeux, A., A. Dunjic, E. Royer et al. Late functionaland circulatory changes in rats after local irradiation.
lnt. J. Radial. Biol. 20: 7-25 (1971).
Kcty, S.S. Measurement of regional circulation by the
local clearance of radioactive sodium. Am. Heart J. 38:
321-328 (1949).
Keyeux, A. The influence of radiation on blood vessels
and circulation. IX. Blood now and permeability in thecentral nervous system. Curr. Top. Radiat. Res. Quart.
10: 135-150 (1974).
Koletsky, S. and G. Gustafson. Liver damage in rats
from radioactive colloidal gold. Lab. Invest. 1: 312-323(1952).
Kember, N.F. and J. Coggins. Changes in the vascularsupply to rat growth cartilage during radiation injury
and repair. lnt. J. Radial. Biol. 12: 143-151 (1967).
Konno, K., K.I. Altman and L.H. Hempelmann.
Factors affecting metabolism of muscle collagen. II.
Effect of radiation exposure. Proc. Soc. Exp. Biol. Med.
101: 320-321 (1959).
Konno, K., K.R. Traelnes and K.I. Altman. The effectof whole and partial body x-irradiation on the metabolism of collagen in polyethylene sponges and theurinary excretion of pyrrole-2-carboxylic acid. Int. J.
Radiat. Biol. 8: 367-372 (1964).
Kitagawa, T., A.S. Glicksman, E.B. Tyree et al.
Radiation effects on skin and subcutaneous tissue. A
quantitative study of collagen content: modification
with L-triiodothyranine. Radial. Res. 15: 761-766(1961).
Kurpeshev, O.K., B.M. Vtyurin, N.P. Savina et al.
Radiation reactions and injuries of normal tissues incontact neutron 252Cf therapy. Medical Radiology 23(3): 9-15 (1978) (in Russian).
Kabachenko, A.N. The specificity of the formation of
the radiation lens opacification in mice after irradiation
with 645 MeV protons and gamma-rays 60Co. Cosm.
biol. and med. 31-35 (1974) (in Russian).
Kabachenko, A.M. and B.S. Fedorenko. Cataractogenic action of protons with energies 25 and 50 MeV.
Cosm. Biol. and Med. 59-62 (1977) (in Russian).
Kondratenko, V.G. The action of ionizing radiation on
the testicles of animals. Uspechi sovremennoj biologii
83: 305-319 (1977) (in Russian).
Karpovsky, A.L., E.A. Kresavin, T.E. Mashinskaya et
al. The assessment of damage by protons of different
energy on neurons of central nervous system, p. 54-55
in: VIII Symposium on Cosmic Biol. and Med. Varna,
1975.
Kuhn, E.F., Z. Molnar and K. Bohm. Late effects ofradiotherapy on the lymph system examined bylymphography, p. 181-186 in: Late Biological Effectsof Ionizing Radiation. Vol. 1. IAEA, Vienna 1978.
Kolar, J., R. Vrabec and V. Bek. Entwicklungstorungen
der weiblichen Brust nach Rontgenbestrahlung im
Kindesalter. Strahlentherapie 104: 596-599 (1957).
Klump, G., G. Kovacs, G. Linhart et al. Abscopal
changes in local radio-resistance following whole body
irradiation. IV Congres International de Radiobiologie
et de Physico-Chimie des Rayonnements, Evian 1970.
Book of Abstract, No. 451.
Knop, G. and W. Paul. Interactions of electrons andalpha particles with matter. p. 1-36 in: Alpha- Betaand Gamma-ray Spectroscopy Vol. I, (K. Siegbahn,ed.). North-Holland, Amsterdam, 1965.
Kaul, A., H.D. Roedler and G.J. Hine. Internal
absorbed dose from administered radiopharmaceuticals, p. 423-453 in: Medical Radionuclide Imaging,
Vol. II. IAEA, Vienna, 1977.
Krisch, R.E. and M.R. Zelle. Biological effects ofradioactive decay: the role of the transmutation effect.
Adv. Radiat. Biol. 3: 177-213 (1969).

K41

K42
K43
K44

K45

K46
K47

K48
K49

K50
K51

K52

Ll
L2

L3

L4

LS
L6

L7
LB

L9

Kalmykova, Z.I. Respiratory insufficiency andcompensation thereor in the presence of injury to rats
rrom plutonium 239 inhalation, p. 398-406 in:
Biological Effects of Radiation from External andInternal Sources. AEC-tr-7457 (1972).
Kato, U., T. Mori and T. Kumatori. Thorotrast
dosimetric study in Japan. Env. Res. 18: 32-36 (1979).
Kaul, A. and W. Noffz. Tissue dose in Thorotrast
patients. Health Phys. 35: 113-123 (1978).
Kurlyandskaya, E.13. Toxicology of radioactive zinc-65,
p. 1-11 in: The Toxicology of Radioactive Substances.
Vol. 5, Zinc-65 (A.A. Letavet and E.B. Kurlyandskaya,eds.). Pergamon Press, Oxford, 1970.
Kobayashi, K. Effects of whole-body and partial-body
irradiation upon epidermal mitotic activity duringwound healing in mouse skin. Radiat. Res. 69: 513-529(1964).
Kunz, J., M. Braselmann and 0. Keim. Zur Wirkung
von Roentgenstrahlen aud den 35S Sulfat Einbau in die
Rattenaorta. Acta Biol. Med. Germ. 13: 228-232 (1964).
Kojima, E., F. Sato, S. Tsuchibhashi et al. Hematological changes after partial-body or whole-body irradiation in mice. Nippon Acta Radiologica 33: 344-350(1973).
Kirk, J., W.M. Gray and E.R. Watson. Cumulative
radiation effect. II. Continuous radiation therapy: long
lived sources. Clin. Radiol. 23: 93-105 (1972).
Kashima, M., H. Joshima and 0. Matsuoka.
Relationship between physicochemical form of
plutonium and its behaviour in tissues and effect on
reticuloendothelial system in mice. Nippon Acta
Radiologica 41: 250-262 (1981).
Kato, Y., T. Mori and T. Kumatori. International
Meeting on Radiology or Radium and Actinides inMan. Lake Geneva, Wisconsin, October 1981.
Kumatori, T., T. Ishihara, K. Hirashima et al.
Follow-up studies over a 25-year period on theJapanese fishermen exposed to radioactive fallout in
1954. p. 33-54 in: The Medical Bases for Radiation
Accident Preparedness (K.F. Hilbner and S.A. Fry,eds.). Elsevier North Holland, Amsterdam, 1980.
Kaplan, S.L. and M.M. Grumbach. Pathophysiology of
G.H. deficiency and other disorders of G.H. metabolism. p. 45-55 in: Problems in Pediatric Oncology(L. Canza and A.W. Root, eds.). Academic Press,
London, 1980.
Lajtha, L.G. and R. Oliver. Some radiobiologicalconsiderations in radiotherapy. Brit. J. Radio!. 34:
252-257 (1961).
Lamerton, L.F., A.M. Pontifex, A.M. Blackett et al.
Effects of protracted irradiation in the blood forming
organs of the rat. I. Continuous exposure. Brit. J.
Radiol. 33: 287-301 (1960).
Lesher, S. and J. Bauman. Cell kinetic studies of theintestinal epithelium: maintenance of the intestinal
epithelium in normal and irradiated animals. Natl.
Cancer Inst. Monogr. 30: 185-195 (1969).
Lord, B.I. The control of cell proliferation in haemopoietic tissues, p. 826-833 in: Radiation Research:
Biomedical, Chemical and Physical Perspectives (0.
Nygaard, H.I. Adler and W.K. Sinclair, eds.).
Academic Press, New York, 1975.
Lamerton, L.F. Cell proliferation under continuous
irradiation. Radial. Res. 27: 119-138 (1966).
Lesher, S., J. Cooper, R. Hageman et al. Proliferative
patterns in the mouse jejuna! epithelium after
fractionated abdominal x-irradiation. Curr. Top.
Radial. Res. Quart. 10: 229-261 (1975).
Law, M.P., R.G. Ahier and S.B. Field. The response ofmouse skin to combined hyperthermia and x-rays. Int.
J. Radial. Biol. 32: 153-163 (1977).
Leith, J.T., W.A. Schilling, J.T. Lyman et al.
Comparison of skin responses of mice after single or
fractionated exposure to cyclotron-accelerated helium
ions and 230 kV x-irradiation. Radial. Res. 62: 195-215(1975).
Leblond, C.P., R.C. Greulich and J.P.M. Pereira.
Relationship of cell formation and cell migration in therenewal of stratified squamous epithelia, p. 39-67 in:Advances in Biology of Skin. Pergamon Press. Oxford,
1964.
LIO Lamerton, L.F., G.G. Steel and D.R. Wimher. Sensitivity of mammalian tissues to continuous exposure.
Brookhaven Symposium in Biology 14: 158-175 (1961).
LI I Law, M.P., S. Homsey and S.B. Field. Collagen content
of lungs of mice after x-ray irradiation. Radial. Res. 65:
60-70 (1976).
L12 Lacassagne, A.B.M. The liver, in: Pathology of Irradiation (C.C. Bcrdjis. ed.). Williams and Wilkins,
Baltimore, 1971.
L13 Lamson, B.G., M.S. Billings, L.H. Ewell et al. Lateeffects of total body roentgen irradiation. IV. Hypertension and nephrosclerosis in female Wistar rats
surviving IOOO rad hypoxic total body irradiation.
Arch. Pathol. 66: 322-329 (1958).
Ll4
Livshits, W.N. Physiological effects of nuclear radiations on the central nervous system. Biol. Med. Phys. 7:
173-248 ( 1960).
LI 5 Lewis, P.D. and M. Lai. Cell generation in the
subependymal layer of the rat brain during the earlypost-natal period. Brain Res. 77: 520-525 ( 1974).
L16 Lushbaugh, C.C. and R.C. Ricks. Some cytokinetic andhistopathologic considerations of irradiated male andfemale gonadal tissues. Front. Radial. Ther. Oncol. 6:228-248 (1972).
Lt7
Lushbaugh. C.C. Reflections on some recent progressin human radiobiology, p. 277-314 in: Advances in
Radiation Biology. Academic Press, New York, 1969.
LIS
Lajtha, LG. Response of bone marrow stem cells toionizing radiations, Curr. Top. Radial. Res. 1: 139-163(1965).
L19 Lampert, P.W. and R.L. Davis. Delayed effects ofradiation on the human central nervous system: "early"and "late" delayed reactions. Neurology 14: 912-917(1964).
L20 Lacassagne, A., B.M. Duplan, J.F. Marcovitch et al.
The action of ionizing radiations on the mammalianovary, p. 498-501 in: The Ovary, Vol. 2. Academic
Press, New York. 1962.
L21
Lindop, P.J., A. Jones and A. Bakowska. The effect of
14 MeV electrons on the blood vessels of the mouseearlobe, p. 174-180 in: Time and Dose Relationships inRadiation Biology as Applied to Radiotherapy. BNL50203 (1969).
L22 Lassen. N.A .. J. Lindberg and 0. Munck. Measurementof blood-flow through skeletal muscle by intramuscular
injection of xenon-133. Lancet 1: 686-689 (1964).
L23
Law, M.P. and R.H. Thomlinson. Vascular permeability in the cars of rats after x-irradiation. Br. J.
Radio!. 51: 895-904 (1978).
L24 Leith, J.T. and J.F. Gaugl. Changes in the specificgravity of rabbit brain after high doses of x-irradiation.
lnt. J. Radiat. Biol. 21: 573-582 (1972).
L25 Lenzi, M. and G. Bassani. The effect of radiation on thelymph and on the lymph vessels. Radiology 80:
814-817 (1963).
L26 Lubimova, R.M. Change of intracranial pressure inanimals after whole-body x-ray irradiation. Referats on
medical radiology, p. 58 (1959) (in Russian).
L27
Lubimova, R.M. Changes in brain blood circulation
after irradiation. Refcrats on medical radiology, p. 37(1959)(in Russian).
L28 Lvovskaya, E.N. The state of the eye in persons
inindustrial
gamma-defectoscopy.
working
Proceedings of MO NIKI 12: 44-48 (1976) (in Russian).
L29 Lvovskaya, E.N. The state of the eye in persons
working at roentgen-radiological facilities in Moscow.
Proceedings of NIIGT i PZ. p. 209-214 (1974) (inRussian).
LJO Larsen, P.R., R.A. Conard, K. Knudsen et al. Thyroid
hypofunction appearing as a delayed radioactive
fallout in a Marshallese population, p. 101-115 in: Late
Biological Effects of Ionizing Radiation, Vol. 1. IAEA,
Vienna, 1978.
LJ 1 Lesch, R. Radiation-induced injury of the liver. Hdb.
Exp. Pharmakol. XVI. Part 5: 227-304 (1976).

L32

L33

L34

L36

L37

L38
L39

L40

L41

L42

L43

L44

Lee Wilke, W., R.D. Phemister and R.S. Jaenke.
Neonatal irradiation nephropathy in the growing dog.
I. Renal morphological and functional adaptations
following neonatal, sublethal. whole-body irradiation.
Radial. Res. 78: 61-71 (1979).
Leny, U., W. Schilttman, D. Arndt et al. Late effects ofionizing radiation on the human skin after occupational exposure, p. 321-329 in: Late Biological Effectsof Ionizing Radiation. Vol. I. IAEA, Vienna, 1978.
Locvinger, R. and M. Berman. A scheme for absorbed-dose calculations for biologically-distributed
radionuclides. J. Nucl. Med. Suppl. 1: 7-14 (1968).
Looney, W.B., R.J. Hasterlik, A.M. Brues cl al. A
clinical investigation of the chronic effects of radium
salt administered therapeutically. Am. J. Roentgenol.
Radium Ther. Nucl. Mcd. 73: 1006-1037 (1955).
Looney, W.B., R.J. Hasterlich, A.M. Brues et al. A
clinical investigation of the chronic effects of radiumsalts administered therapeutically (1915-1931). Am. J.
Roentgcnol. Radium Thcr. Nucl. Med. 73: 1006-1037( 1955).
Lloyd, E. The distribution of radium in human bone.
Brit. J. Radio!. 34: 521-528 (1961).
Lundin, F.E .. J.K. Wagoner and V.E. Archer. Radondaughter exposure and respiratory cancer: Quantitative
and temporal aspects. NIOSH and NIEHS Joint
Monograph No. 1. U.S. National Technical Information Service, Springfield, 1971.
Lisco, H., A.R. Kennedy and J.B. Little. Hislologic
observations on the pathogenesis of lung cancer inhamsters following administration of polonium-210,
p. 468-474 in: Experimental Lung Cancer: Carcinogenesis and Bioassays (E. Karbe and J.F. Park, eds.).
Springer-Verlag, Berlin, 1974.
Lewitus, Z. and J. Rechnic. Electron-microscopic andisotopic evidence for a difference between the radiobiological effects of iodine-131 and iodine-125, p. 44-51
in: Radioaktive Isotope in Klinik und Forschung, BandII, (R. Hofer, ed.). Urban and Schwarzenberg, Vienna,
1975.
Lewitus. Z., M. Ben-Porath, Y. Genge et al. Differencesin the radiobiological action of 1rs1 and 131 I in the
thyroid cell, p. 405-417 in: Biophysics Aspects ofRadiation Quality, IAEA, Vienna, 1971.
Larsen, P.R. and R.A. Conard. Thyroid hypofunction
appearing as a delayed manifestation of accidental
exposure to radioactive fallout in a Marshallese
population. BNL-24104 (1978).
Lathrop, K.A., I.V. Gloria and P.V. Harper. Responseof mouse foetus to radiation from Na99m Tc04,
p. 211-221 in: Biological and Environmental Effects
of Low-Level Radiation. Vol. II. IAEA, Vienna, 1975.

L45

Laissue, J.A., H. Burlington, E.P. Cronkite et al. Effects
of a single high dose of SSFe in mice. Virchows Arch.
Cell Path. 29: 321-335 (1979).

L46

Letavet, A.A. and E.B. Kurlyandskaya, (eds.). The
Toxicology of Radioactive Substances, Vol. 5.
Pergamon Press, Oxford, 1970.
Masuda, K. Survival of synchronized L cells irradiatedwith 14 MeV neutrons. lnt. J. Radial. Biol. 20: 85-86(1971).

Ml

M2

M3

M4

MS

M6

McComb, W.S. and E.G. Quimby. The rate of recoveryof human skin from the effects of hard or soft-roentgenrays or gamma rays. Radiology 27: 196-207 (1936).
Marcuse, W. Nachtrag zu dem Fall von Dermatitis und
Alopecienach
Durchleuchtungsversuchcn
mit
ROntgenstrahlen. Dtsch. Med. Z. 21: 691 (1896).
Morgan, R.L. Fast neutron therapy, p. 171-186 in:Modern Trends in Radiotherapy (T.J. Deeley and
C.A.P. Wood, eds.). Buuerworths, London, 1967.
Meder, J. and A. Michalowski. Changes in theabsorptive surface of mouse jejunum as a measure ofacute radiation effect (to be published) (1982).
Maisin. J., A. Wambersie, M. Lambiet-Collier et al.
Intestinal proliferation after multiple fractions of
gamma-irradiation. Radial. Res. 71: 338-354 (1977).

645

M7
1\18

M9

MIO
Ml 1

M 12
M 13
M 14

M15

M16

Ml?

M18

Ml 9

M20

M21

M22
M23

M24

M25
M26

M27

M28

646

Maisin, J.R. The ultrastructure of the lung of mice
exposed to a surpralethal dose of ionizing radiation on
the thorax. Radiat, Res. 44: 545-564 ( 1970).
Moss, W.T. and F.J. Haddy. The relationship between
oxygen tension of inhaled gas and the severity of acuteradiation pneumonitis. Radiology 75: 55-58 (1960).
Mostofi, F.K. and C.C. Berdjis. Radiopathology ofkidney, in: Pathology of Irradiation (C.C. Berdjis, ed.).
Williams and Wilkins, Baltimore, 1971.
Mendelsohn, M.L. and E. Caceres. Effect of x-ray tokidney on renal function of dog. Am. J. Physiol. 173:
351-354(1953).
Maier, J.G. and G.W. Casarett. Cellular growth andtissue radioscnsitivity. Tissues in vivo and the conceptof radiation nephritis. Ann. N.Y. Acad. Sci., Series II
26: 599-627 (1964).
Michaelson, S.M., W. Quinlan, G.W. Casarett et al.
Radiation-induced thyroid dysfunction in the dog.
Radial. Res. 30: 38-47 (1967).
Malone, J.F. The radiation biology of the thyroid. Curr.
Top. Radiat. Res. Quart. I O: 253-268 ( 1975).
Meistrich, M.L., N.R. Hunter, N. Suzuki et al. Gradualregeneration of mouse testicular stem cells after
exposure to ionizing radiation. Radial. Res. 74:
349-362 (1978).
Mole, R.H. and D.G. Papworth. The sensitivity of rat
oocytes to x-rays. Int. J, Radiat. Biol. 10: 609-615(1966).
Merriam, G.R. and E.F. Focht. A clinical and experimental study of the effect of single and divided doses ofradiation on cataract production. Trans. Am. Ophthal.
Soc. 60: 35-52 (1962).
Meder, J. and A. Michalowski. Changes in cellularity
and/or weight loss of mouse haemopoietic tissues as ameasure of acute radiation effect (1982) (to be
published).
McCulloch, E.A. and J.E. Till. The radiation sensitivityof normal mouse bone marrow cells by quantitative
marrow transplantation into irradiated mice. Radiat.
Res. 13: 115-125 (1960).
McCulloch, E.A. and J.E. Till. The sensitivity of cells
from normal mouse bone marrow to gamma-radiationin vitro and in vivo. Radial. Res. 16: 822-832 (1962).
Mole,
R.H.
Deductions
about
survival-curveparameters from iso-effect radiation regimes: observations on lethality after whole-body irradition of mice, p.
299-307 in: Cell Survival After Low Doses ofRadiation (T. Alper, ed.). John Wiley and Sons, New
York, 1975.
Maier, J.G. Effects of radiations on kidney, bladderand prostate. Front. Radiat. Ther. Oncol. 6: 196-227(1972).
Morrison, R. and T.J. Deeley. The treatment ofcarcinoma of the bladder by supervoltage x-rays. Brit.
J. Radio!. 38: 499-458 (1965).
Markson, J.L. and G.E. Flatman. Myxoedema after
deep x-ray therapy to the neck. Brit. Med. J. 1:
1228-1230 (1965).
Mandi, A. A quantitative study of the sensitivity ofoocytes to x-irradiation. Proc. R. Soc., Ser. B 150:
53-71 (1959).
Merriam, G.R., A. Szechter and E.F. Focht. The effectsof ionizing radiations on the eye. Front. Radiat. Ther.
Oncol. 6: 346-385 (1972).
McRipley, R.J., R.J. Selvaray, M.M. Glovsky et al. The
role of the phagocyte in host-parasite interactions. VJ.
The phagocytic and bacterial capabilities of leukocytes
from patients undergoing x-irradiation. Radial. Res.
31: 706-720 (1967).
McNally, N.J. and D.K. Bewley. A biologicaldosimeter using mammalian cells in tissue culture andits use in obtaining neutron depth dose curves. Brit. J.
Radiol. 42: 289-294 (1969).
Merriam, G.R. Jr., B.J. Biavati, J.L. Bateman et al. The
dependence of RBE on the energy of fast neutrons. IV.
Induction of Jens opacities in mice. Radial. Res. 25:
123-138 (1965).

M29

M30
M31
M32
M33
M34
M35
M36
M37
M38

M39
M40

M41
M42
M43
M44

M45

M46

M47

M48
M49

M50

M51

Malone, J.F., J.H. Hendry, D. Porter et al. The responseof rat thyroid, a highly differentiated tissue, to .sing!~
and multiple doses of gamma or fast neutron 1rrad1ation. Brit. J. Radio!. 47: 608-615 (1974).
Maisin, J.R. The innuence of radiation on blood vessels
and circulation. I II. Ultrastructure of the vessel wall.
Curr. Top. Radiat. Res. Quart. 10: 29-57 (1974).
McDonald, L.W. and T.L. Hayes. TIie role of capillaries in the pathogenesis of delayed radionccrosis ofbrain. Am. J, Pathol. 50: 745-764 (1967).
Mount, D. and W.R. Bruce. Local plasma volume andvascular permeability of rabbit skin after irradiation.
Radial. Res. 23: 430-445 (1964).
Moustafa, H.F. and J.W. Hopewell. Blood !lowclearance changes in pig skin after single doses of xrays. Brit. J, Radio!. 52: 138-144 (1979).
Moss. W.T. and S. Gold. The acute effects of radiations
on the physiology of small blood vessels. Am. J.
Roentgenol. 90: 294-299 (1963).
Moustafa, H.F. and J.W. Hopewell. Late functionalchanges in the rat brain after local x-irradiation. Brit. J.
Radio!. 53: 21-25 (1980).
Maier, J.G. and G.W. Casarett. Patho-physiologic
aspects of radiation nephritis in dogs. UR-626 (1963).
McLean, F.C. and A.M. Budy, p. 161 in: Radiation,
Isotopes and Bone. Academic Press, New York 1964.
Majno, G. and G.E. Palade. Studies on inflammation.
I. The effect of histamine and serotonin on vascularpermeability. An electron microscopic study. J.
Biophys. Biochem. Cytol. 11: 571-605 (1961).
Mostoli, F.K., K.C. Pani and J. Ericsson. Effects ofirradiation on canine kidney. Am. J. Pathol. 44:
707-719 (1964).
Mohr, H.J .. K. Morgenroth, Jr. and K. Schnepper. The
morphological and submicroscopic reaction of guinea
pig kidneys during aimed single dose and fractionatedroentgen irradiation. Strahlentherapie 129: 571-585(1966).
Markovits, P., R. Blache, C. Gasquet et al. Les images
radiologiques des lymphographies faites apres irradiation. Ann. Radiol. 12: 835-847 (1969).
Meistrich, M. Communication (1982).
Maisin, J., J.R. Maisin and A. Dunjic. The gastrointestinal tract, in: Pathology of Irradiation (C.C. Berdjis,ed.). Williams and Wilkins, Baltimore, 1971.
Minamisawa, T., T. Tsuchiya and H. Eto. Changes in
the averaged evoked potentials of the rabbit during andafter fractionated x-irradiation. Electroencephalography and Clinical Neurophysiology 33: 591-601(1972).
Minamisawa, T. and T. Tsyicha. Long-term changes in
the averaged evoked potentials of the rabbit after
irradiation with moderate x-ray doses. Electroencephalography and Clinical Neurophysiology 43: 416-424(1977).
Mosier, H.D. and R.A. Jansons. Pituitary content ofsomatotropin, gonadotropin and thyrotropin in rats
with stunted linear growth following head x-irradiation.
Proc. Soc. Expt. Biol. Med. 128: 23-26 (1968).
Muksinova, K.N., V.V. Suchodeev and L.D. Murzina.
Kinetics of cell populations in the compartment ofdividing neutrophiles of bone-marrow during
prolonged
external
irradiation.
Problemsofhematology and blood transfusion, p. 16-21 (1979) (inRussian).
Muksinova, K.N. Changes in the quantity and proliferative ability of stem cells after prolonged gamma-irradiation. Radiobiologiya 16: 693-698 (1976) (in Russian).
Muksinova, K.N., V.S. Voronin, V.M. Lyzanov et al.
Change in the functional state of erythropoiesis during
prolonged fractionated irradiation. Radiobiologiya 10:
541-547 (1970) (in Russian).
McKay, L.R., S.M. Shaw and A.L. Brooks. Metaphase
chromosome aberrations in the Chinese hamster liverin vivo after either acute or fractionated 60Co irradiation. Radiat. Res. 57: 187-194 (1974).
Maisin, J., A. Dunjic and J.R. Maisin. Lymphatic
system and thymus in: Pathology of irradiation (C.C.
Berdjis, ed.). Williams and Wilkins, Baltimore, 1971.

M52

Mole, R.H. On wasted radiation and the interpretationof experiments with chronic irradiation. J. Natl. Cancer
Inst. 15: 907-914 {1955).
M5J Mraz, F.R. and G.R. Eisele. Gastrointestinal
absorption of 95Nb by rats of different ages. Radial.
Res. 69: 591-593 (1977).
M54 Makin, M., R.C. Robin and J.A. Stein. Radioactive
gold in the treatment of persistent synovial effusion.
Isr. Med. J. 22: 107-111 (1963).
M55 Marshall, J.H. The retention of radionuclides in bone,p. 7-27 in: Delayed Effects of Bone Seeking Radionuclides (C.W. Mays, et al., eds.). University of Utah Pres~.
Salt Lake City, 1969.
M56 Malctskos, C.J., A.T. Keave, N.C. Telles et al.
Retention and absorption of 224Ra and 234Th and somedosimetric consequences of 224Ra in human beings, p.
29~8 in: Delayed effects of bone-seeking radionuclides (C.W. Mays et al. eds.). University of Utah Press,
Salt Lake City, 1969.
M57 Mays, C.W., H. Spiess and A. Gerspach. Skeletal
effects following 224Ra injections into humans. HealthPhys. 35: 83-90 (1978).
MS8 MacPherson, S., M. Owen and J. Vaughan. The relationof radiation dose to radiation damage in the tibia of
weanling rabbits injected with 90Sr. Brit. J. Radio!. 35:
221-234 (1962).
M59 Metivier, H., D. Nolibe, R. Masse et al. Excretion andacute toxicity of 239Pu02 in baboons. Health Phys. 27:
512-514 (1974).
M60 Muggenburg, B.A., A.H. Rebar, S.A. Benjamin et al.
Toxicity of Inhaled 90SrCli in beagle dogs. p. 62-65 in:
LF-58 (1977).
M61 Moskalev, Y.I.. V.N. Streltsova and L.A. Buldakov.
Late effects of radionuclide damage, p. 489-510 in:
Delayed Effects of Bone-seeking Radionuclides (C.W.
Mays, et al., eds.). Univ. of Utah Press, Salt Lake City,
1969.
M62 Mays, C.W., T.F. Dougherty, G.N. Taylor et al. p. 387
in: Delayed Effects of Bone-seeking Radionuclides(C.W. Mays, et al., eds.). Univ. of Utah Press, Salt Lake
City, 1969.
M63 Medical International Radiation Dose Committee.
Dose Estimate report No. 5. Summary of current
radiation dose estimates to humans from 1231, 124 1, l25J,
126J, 130J, 131J and 132J as sodium iodide. J. Nucl. Med.
16: 857-860 (1975).
M64 Marshall, J.H. and S.F. Hoegerman. Estimation ofalpha-particle dose from 226Ra to blood, p. 56-62 in:
ANL-75-3 (1974).
M65 Mayer, K.M., K.S. Pentlow, R.C. Marcove et al.
Sulphur-35 Therapy for Chondrosarcoma andchordoma, p. 185-192 in: Therapy in Nuclear Medicine(R.P. Spencer, ed.). Grune and Stratton, New York,1978.
M66 Mays, C.W., T.F. Dougherty, G.N. Tayler et al. Bonecancer induction by radionuclides: incidence vs. dose,p. 2192-2210 in: Hearing on Environmental Effects of
Producing Electric Power, Joint Committee on Atomic
Energy, U.S. Congress, Vol. II, Part 2, January 27-30
and February 24-26, 1970.
M67 McClellan, R.O., LS. Rosenblatt, S.W. Bielfelt et al.
Early mortality from inhaled 90SrC12, 91YC13 and
144CeCl3 and intravenously injected 137CsCl in beagledogs, p. 59-60 in: LF-41 (1969).
M68 Momeni, M.H., R.J.R. Williams, G.L. Fisher et al.
Local dosimetry and qualitative changes in226Ru- and90Sr- 90y. labelled beagle humeri. Health Phys. 30:
21-34 (1976).
M69 Momeni, M.H., J.R. Williams, N. Jow et al. Dose rates,
dose and time effects of 90Sr + 90y and 226Ra on
beagle skeleton. Health Phys. 30: 381-390 (1976).
M70 Michailowski, A. Effects of radiation on normal
tissues: hypothetical mechanisms and limitations of insitu assay of clonogenicity. Radiat. Environ. Biophys.
19: 157-172 (1981).
M71 Maisin, J. Effets somatiques des radiations ionisantes.
Consensus 4: 141-157 (1978).

M72

M74

M75

M76

NI

N2

N3

N5

N6

N7

N8
N9

NJO

Nl l
N12

N13

N14

01

02

03

04
05
06

Minamisawa, T., K. Yamamoto and T. Tsuchiya.
Long-term effects of moderate x-ray doses on the
averaged evoked potentials in the rabbit. Electroenceph. Clin. Neurophysiol. (1982) (in press).
Matsuoka, 0., T. Tsuchiya and H. Eto. Radiation effecton intestinal function. 11. Comparative study of species
difference in radiation effect on intestine. Nippon Acta
Radiologica 24: 910-914 (1964).
McKenzie, A. L. Cell survival description of the
cumulative radiation effect. Acta Radio!. Ther. Phys.
Biol. 18: 45-56 (1979).
Meyer, O.T. and A.N. Dannenberg. Radiation,
infection and macrophage function. II. Effect of wholebody irradiation on the number of pulmonary alveolar
macrophages and their levels of hydrolytic enzymes. J.
Reticuloendotb. Soc. 7: 79-80 (1970).
Noyes, W.D., C.A. Finch, H. Wasserman et al. Partial
marrow shielding and total-body irradiation. J. Appl.
Physiol. 18: 629-632 (1963).
Nowell, P.C. and L.J. Cole. Clonal repopulation in
reticular tissues of x-irradiated mice. Effects of doseand limb shielding. J. Cell Physiol. 70: 37~ (1967).
Neuhauser, E.B.D., M.H. Wittenborg, C.Z. Berman etal. Irradiation effects of roentgen therapy on thegrowing spine. Radiology 9: 637-650 (1952).
Nias, A.H.W., D. Greene and D. Major. Constancy of
biological parameters in a 14-MeV neutron field. Int. J.
Radial. Biol. 20: 145-151 (1971).
Ngo, F.Q.H., A. Han, H. Utsumi et al. Comparative
radiobiology of fast neutrons: relevance to radiotherapy and basic studies. Int. J. Radiat. Oncol. Biol.
Phys. 3: 187-193 (1977).
Nair, V. and L.J. Roth. Effect of x-irradiation andcertain other treatments on blood brain barrier permeability. Radiat. Res. 23: 249-264 (1964).
Nias, A.H.W. (1972) (Cited by H.S. Reinhold and G.H.
Buisman. Brit. J. Radio!. 46: 54-57, 1973).
Nimni. M.E., C. Lyons and L.A. Bavetta. Collagen andhexosamine changes in subcutaneous granuloma
irradiated locally with a Co60 source. Proc. Soc. Exptl.
Biol. Med. 122: 134-137 (1966).
Nevskaja, G.F., V.V. Sedov, N.I. Ovdienko et al.
Functional late change in dog's kidneys after inhomogeneous acute irradiation with protons, p. 22-23 in:
Late effects and risk of radiation. Union Conference,
Moscow, 1978 (in Russian).
Nadareishwili, K.Sh. Influence of ionizin~ radiation on
cardiovascular system. Tbilisi, 1966 (in Russian).
Nakazawa, T., O. Yukawa, S. Ushijima et al. Effects of
x-irradiation on drug-metabolizing enzyme systems inliver microsomes of male and female rats. Radiat. Res.
66: 373-383 (1976).
Nordman, E.M. and R.A. Valavaara. Gastrointestinal
complications after external megavoltage treatment.
Strahlentherapie 154: 16-19 (1978).
Nolan, T.R., E.D. Grady, A.J. Crumbley et al. Internal
hepatic radiotherapy. Am. J. Roentgenol. Radium
Ther. Nucl. Med. 124: 590-595 (1975).
Orton, C.G. and F. Ellis. A simplification in the use of
the NSD concept in practical radiotherapy. Brit. J.
Radio!. 46: 529-537 (1973).
Oakberg, E.F. Duration of spermatogenesis in themouse and timing of stages of the cycle of the seminiferous epithelium. Am. J. Anat. 99: 507-516 (1956).
Oakberg, E.F. A description of spermiogenesis in themouse and its use in analysis of the cycle of the seminifcrous epithelium and germ cell renewal. Am. J. Anat.
99: 391--414 (1956).
Oakberg, E.F. Spermatogonial stem-cell renewal in themouse. Anat. Ree. 169: 515-532 (1971).
Oakberg, E.F. Gamma-ray sensitivity of the spermatogonia of the mouse. J. Exp. Zoo!. 134: 343-356 (1957).
Oakberg, E.F. and E. Clark. Effect of dose anddose-rate on radiation damage to the mouse spermatogonia and oocytes as measured by cell survival. J. Cell
Comp. Physiol., Suppl. 1, 58: 173-182 {1961).

647

07

08

09

010

011

013

014
015

016

PI
P2

P3

P4

PS
P6

P7

P8

PIO

Pl 1

P12
P13

Pl4

P15

648

Oakberg, E.F. and E. Clark. Species comparisons ofradiation response of the gonads, p. 11-24 in: Effects of
Ionizing Radiation on the Reproductive System (W.D.
Carlson and F.X. Gassner, eds.). Pergamon Press, New
York, 1964.
Oakberg, E.F. Mammalian gametogenesis and species
comparisons in radiation response of the gonads, p.
3-10 in: Effects of Radiation on Meiotic Systems.
JAE/\, Vienna, 1968.
Oakbcrg, E.F. Gamma-ray sensitivity of oocytes ofimmature mice. Proc. Soc. Exptl. Biol. Med. 109:763-767 (1962).
Oakes, W.R. and C.C. Lushbaugh. Cause of testicular
injury following accidental exposure to nuclear radiations. Radiology 59: 737-743 (1952).
Ohuchi, K. and S. Tsurufuji. Degradation and turnoverof collagen in mouse skin and the effect of whole-body
irradiation. Biochim. Biophys. Acta 208: 475-581(1970).
Osanov, D.P., V.A. Rakova, O.V. Klykov et al.
Influence of depth distribution of the basal cells on
their survival at the irradiation of skin by ~-particles ofdifferent energy. Radiobiologiya 16: 59-62 (1976).
Orton, C.G. Time-dose factors (TDF's) m brachytherapy. Brit. J. Radio!. 47: 603-607 (1974).
Okuda, K. and M. Fujii. Effects of radiation anddiarrhoea on intestinal absorption of vitamin B12, p.
228 in: Gastrointestinal Radiation Injury {M.F.
Sullivan,ed.)
Excerpta
MedicaFoundation,
Amsterdam, 1968.
Ohkita, T. Review of thirty years study of Hiroshima
and Nagasaki atomic bomb survivors: Acute effects. J.
Radial. Res. Suppl. 16: 49-66 (1975).
Phillips, T.L. and G. Ross. Time-dose relationships in
the mouse oesophagus. Radiology 113: 435-440 (1974).
Phillips, T.L. and L. Margolis. Radiation pathology andthe clinical response of lung and oesophagus, p.
254-273 in: Frontiers of Radiation Therapy andOncology, Vol. 6 (J.M. Vaeth, ed.). S. Karger, Basel,
1972.
Phillips, R.A. and L.J. Tolmach. Repair of potentiallylethal damage in x-irradiated HeLa cells. Radial. Res.
29: 413-432 (1966).
Probert, J.C. and J.M. Brown. A comparison of threeand five times weekly fractionation on the response of
normal and malignant tissues of the C3H mouse. Brit. J.
Radio!. 47: 775-780 (1974).
Paterson, R. Treatment of malignant disease by radiumand x-rays. Williams and Wilkins, Baltimore, 1949.
Phillips, T.L. An ultrastructural study of the development of radiation injury in the lung. Radiology 87:
49-54 (1966).
Pospisil, M. and K.A. Zaruba. A contribution to histochemistry of kidney in irradiation disease. Sb. Ved.
Prac. Lek. Fak. Karlov Univ. 6: 179-183 (1963).
Phillips, T.L. and G. Ross. A quantitative technique formeasuring renal damage after irradiation. Radiology
109: 457-462 (1973).
Proukakis, C. and P.J. Lindop. Haematopoietic
changes following irradiation, p. 447-495 in: Pathologyof Irradiation (C.C. Berdjis, ed.). Williams and Wilkins,
Baltimore, 1971.
Porteous, D.D., R. Alexanian and L.G. Lajtha. The
fasted mouse in the study of bone marrow stem-cellkinetics. lnt. J. Radial. Biol. 7: 95-100 (1963).
Porteous. D.D. and L.G. Lajtha. On stem cell recovery
after irradiation. Brit. J. Haematol. 12: 177-188 (1966).
Probert, J.C. and B.R. Parker. The effects of radiation
therapy on bone growth. Radiology 114: 155-162(1975).
Parker, R.G. Tolerance of mature bone and cartilage inclinical radiation therapy, p. 312-331 in: Frontiers ofRadiation Therapy and Oncology, Vol. 6 (J.M. Vaeth,ed.). Karger, Basel. 1972.
Pierce, R.H., M.D. Hafermann and A.R. Kagan.
Changes in the transverse cardiac diameter following
mediastinal irradiation for
Hodgkins' disease.
Radiology 93: 619-624 (1969).

Pl6
PI 7
PI 8

P19

P20

P21

P22

P23

P24

P25

P26

P27

P28

P29

P30

P31
P32

P33

P34

P35

P36

P37

P38

P39

P40

Pallis, C.A .. S. Lowis and R.L. l\forgan. Radiation
myelopathy. Brain 84: 460-478 (1961).
Phillips, T.L. and F. Bushke. Radiation tolerance or the
spinal cord. Am. J. Roentgenol. 10S: 659-664 (1969).
Paterson, R. The treatment of malignant disease byradiotherapy. Second Edition. Williams and Wilkins,
Baltimore, 1963.
Peck, W.S., J.T. McGreer, N.R. Kretschmar et al.
Castration of the female by irradiation. Radiology 34:
176-186 (1940).
Phillips, T.L., H.H. Barshall, E. Goldberg et al.
Comparison of RBE values of 15 MeV neutrons fordamage to an experimental tumour and some normal
tissues. Eur. J. Cancer 10: 287-292 (1974).
Pennybacker, J. and D.S. Russell. Necrosis of the brain
due to radiation therapy: clinical and pathologicalobservations. J. Neural. Neurosurg. Psychiatr. 11:
183-198 (1948).
Phillips, T.L., S. Benak and G. Ross. Ultrastructuraland cellular effects of ionizing radiation. Front. Radiat.
Ther. Oncol. 6: 21-43 (1972).
Painter, E. In discussion on problems and effects ofradiation on capillary permeability (M. McCutcheon,ed.). J. Cell Comp. Physiol., Suppl. 2: 121-122 (1952).
Patterson, T.J.S., R.J. Berry and G. Wiernik. The effectof x-radiation on the survival of skin flaps in the pig.
Brit. J. Plast. Surg. 25: 17-19 (1972).
Paumgartner, G., J. Longueville and C. Levy. Phagocytic activity and hepatic function following localized
proton radiation to the liver. Aerosp. Med. 38: 248-251(1967).
Perez-Tamayao, R., J.R. Thornbury and R.J. Atkinson.
"Second-look" lymphography. Am. J. Roentgenol. 90:
1078-1086 (1963).
Petrov, R.B. and R.M. Chaitov. Migration of stem cells
from shielded bone marrow under inhomogeneous
irradiation. Radiobiologiya 12: 67-75 (1972) (inRussian).
Pyatkin, E.K., N.N. Alexandrov, A.I. Vorobyev et al.
Chromosome aberrations induced in human bonemarrow cells by therapeutical local y-irradiation.
Mutat. Res. 16: 103-109 (1972).
Phemester, R.D., R.W. Thomassen, R.W. Nordin et al.
Renal failure in perinatally irradiated beagles. Radiat.
Res. 55: 399-410 (1973).
Park, J.F., J.E. Lund, H.A. Ragan et al. Bone tumors
induced by inhalation or 238Pu02 in dogs. Recent
Results in Cancer Res. 54: 17-35 {1976).
Park, J.F. Dose-effect studies with inhaled plutoniumoxide in beagles. PNL-2500 (1978).
Park, J.F., W.J. Bair and E.B. Howard. Acute toxicity
of inhaled plutonium-239 nitrate in beagle dogs. HealthPhys. 15: 172 only (1968) also in BNWL-714 (1968).
Polednak, A.P. Long-term effects of radium exposurein female dial workers: serum proteins. Environ. Res.
13: 396-406 (1977).
Polednak, A.P. Long-term effects of radium exposurein female dial workers: Haematocrit and Blood
Pressure. Environ. Res. 13: 237-249 (1977).
Polednak, A.P. Long-term effects of radium exposurein female dial workers: Differential white blood cellcount. Environ. Res. 15: 252-261 (1978).
Park, 1.F.1 D.L. Catt, P.L. Hackett et al. Late effects ofinhaled 2J8Pu02 in beagles, p. 10-16 in: BNWL-1950(1975).
Park, J.F., W.J. Bair and R.H. Busch. Progress in beagle
dog studies with lransuranium elements at BattelleNorthwest. Health Phys. 22: 803-810(1972).
Prockop, D.J., K.l. Kivirikko, L. Tuderman et al. The
biosynthesis of collagen and its disorders. New Eng. J.
Med. 301: 77-85 {1979).
Penney, D.P. and P. Rubin. Specific early fine structural changes in the lung following irradiation. lnt. J.
Radiat. Oncol. Biol. Phys. 2: 1123-1132 (1976).
Penney, D.P., D.L. Shapiro, P. Rubin et al. Effects ofradiation on mouse lung and potential induction ofradiation pneumonitis. Virchow·s Arch. Cell Path. 138:
1-10 (1981).

P59

Proceedings of Conference on Radiosensilization andRadioprotection, Florida, 1981 (in press).
P60
Proceedings of the MRC Committee on Protection
against Ionizing Radiations. Brit. J. Radial. 54: 81-84(1981 ).
QI
Quastler, H. The nature of intestinal radiation death.
Radiat. Res. 4: 303-320 (1956).
Q2
Quastler, H., J.P.M. !Jensted, L.F. Lamerton et al.
Adaptation to continous irradiation: observations on
the rat intestine. Brit.J. Radial. 32: 510-512 (1959).
R1
Rubin, P. and G.W. Casarelt. Clinical Radiation·
Pathology. Saunders, Philadelphia, 1968.
R2
Reinhold, H.S. and G.H. !Juisman. Radiosensitivity ofcapillary endothelium. Brit. J. Radial. 46: 53-57 (1973).
R3
Reinhold, H.S. and G.H. !Juisman. Repair of radiation
damage to capillary endothclium. !Jrit. J. Radial. 48:
727-731 (1975).
R4
Regaud, C. and R. Ferraux. Discordance des effets derayons x, d'une part dans le tcsticule, par lefractionnement de la dose. C.R. Soc. Biol. 97: 431(1927).
R5
Reisner, A. Hauterythem und Riintgenstrahlung.
Ergebn. Med. Strahlenforschg. 6: l (1933).
R6
Russell, D.S., C.W. Wilson and K. Tansley. Experimental radionecrosis of the brain in rabbits. J. Neural.
Neurosurg. Psychiatr. 12: 187 (1949).
R7
Russell, W.L. X-ray-induced mutations in mice. Cold
Spring Harbor Symp. Quant. !Jiol. 16: 327-336 (1951).
R8
Russell, L.B. and W.L. Russell. An analysis of thechanging radiation response of the developing mouseembryo. J. Cell Comp. Physiol. 43: 103-149 (1954).
R9
Rugh, R. and J. Wolff. Threshold x-irradiation sterilization of the ovary. Fertil. Steril. 8: 428:437 (1957).
RIO Riley, E.F., T.C. Evans, R.B. Rhody et al. The relative
biological effectiveness of fast neutrons and xradiation. Radiology 67: 673-684 (1956) ...
Rll Robinson, C.V., S.L. Commerford and J.L. Bateman.
Migration of haemopoietic stem cells from the tail ofthe mouse. Radial. Res. 25: 234 only (1965).
R12 Roswit, B., S.J. Malsky and C.B. Reid. Radiation
tolerance of the gastrointestinal tract. Front. Radial.
Tuer. Oneal. 6: 160-181 (1972).
R13
Regen, E.M. and W.E. Wilkins. On rate of healing of
fractures and phosphatase activity of callus of adultbone. J. Bone Joint Surg. 18: 69-79 (1936).
R14 Rider, W.D. Radiation damage to the brain. A new
syndrome. J. Can. Assoc. Radio!. 14: 67-69 (1963).
RI5 Rogoway, W.M., S. Finkelstein, S.A. Rosenberg et al.
Myxoedema developing after lymphangiography andneck irradiation. Clin. Res. 14: 133 (1966).
R16 Rubin, P. and G.W. Casarett. A direction for clinicalradiation pathology, 1-16 in: Frontiers of Radiation
Therapy and Oncology (J.M. Vaeth, ed.). Karger, Basel,
1972.
R17 Rossi, H.H. Microscopic energy distribution in
irradiated matter. p. 43-92 in: Radiation Dosimetry.
Vol. I, Second Edition (F.H. Attix and W.C. Roesch,eds.). Academic Press, New York, 1968.
R18 Roth, J., M. Brown, M. Catterall et al. Effects of fastneutrons on the eye. Brit. J. Ophthalmol. 60: 236-244(1976).
R19 Railton, R., R.C. Lawson and D. Porter. Interaction or
y-rays and neutron effects on the proliferative capacityof Chinese hamster cells. Int. J. Radiat. Biol. 27: 75-82(1975).
R20 Reed, G.B. and A.J. Cox, Jr. The human liver afterradiation injury. A form of ven-occlusive disease.
Amer. J. Pathol. 48: 597-611 (1966).
R21 Reinhold, H.S. The influence or radiation on bloodvessels. Curr. Top. Radial. Res. Quart. 10: 58-74 (1974).
R22 Ramsdell, S.G. The use of trypan blue to demonstrate
the immediate skin reaction in rabbits and guinea pigs.
J. lmmunol. 15: 305-311 (1928).
R23 Rawson, R. Binding of T-1824 and structurally related
diazo dyes by plasma proteins. Am. J. Physiol. 138:708-717 (1942).

Ridgon, R.H. and H. Curl. Effect of roentgen irradiation on capillary permeability and inflammation in
the skin of the rabbit. Am. J. Roentgenol. 49: 250-257( 1943).
R25 Reinhold, H.S. Some aspects or the effects of radiationon the vascular system. p. 1315-1324 in: Advances inRadi~tion Research, Vol. Ill (J.F. Duplan and A.
Chap1ro, eds.). Gordon and Breach, New York, 1973.
R26 Roswit, IJ., L.H. Wisham and J. Sorrentino. The circulation of radiation-damaged skin: radiosodium
clearance studies. Am. J. Roentgenol. 69: 980-990(1953).
R27 Reinhold, H.S. Radiation and the microcirculation.
Front. Radiat. Tuer. Oncol. 6: 44-56 (1972).
R28 Rich, J.G., S. Glagov, K. Larsen et al. Histochemical
studies or rat kidney arter abdominal x-irradiation.
Arch. Pathol. 72: 388-409 (1961).
R29 Rantanen, J. Radiation injury of connective tissue: abiochemical
investigation
withexperimental
granuloma. Acta Radial., Suppl. 330 (1973).
R30 Redd, B.L., Jr. Radiation nephritis: review case reportand animal study. Am. J. Roentgenol. '83: 88-106(1963).
R31 Rosenr~ld. G. The function and capacity of the adrenal
cortex immediately before radiation sickness death. J.
Lab. Chem. Med. 51: 198 (1958).
R32 Risley, P.L. Effects or ionizing radiation and isotope
studies on male accessory sex organs, p. 229-241 in:
Effects of Ionizing Radiation on the Reproductive
System (W.D. Carlson and F.X. Gassner, eds.).
Macmillan, New York, 1964.
R33 Ryzhov, N.I. Radiobiological effects or heavy ions. (Inpress) (in Russian}.
R34 Ray, G.H., H.W. Trueblood, L.P. Enright et al. Oophoropexy: A means of preserving ovarian function
following pelvic megavoltage radiotherapy for
Hodgkin's disease. Radiology 96: 175-180 (1970).
R35 Rausch, L. and E. Ander. Untersuchungen zur
Beziehung zwischen iirtlicher und allgemeiner Strahlenempfindlichkeit. Sonderbande zur Strahlenther. 62:
198-205 (1966).
R36 Rausch, L., W. Koch and G. Hagemann. Klinische unddosimetrische Untersuchungen zur Frage der kritischen
Dosis und typischer Strahlenschaden am Skelett
bestrahlter Angiom-Patienten. Sonderbande zur Strahlentherapie 55: 198-514 (1964).
R37 Rajewsky, B. (ed). Strahlendosis und Strahlenwirkung.
Tareln und Erlauterungen fiir den Strahlenschutz. G.
Thieme, Stuttgart, 1956.
R38 Rosenthall, L. Use of Radiocolloids for Intra-Articular
Therapy for Synovitis in: Therapy in Nuclear Medicine(R.P. Spencer, ed.). Grune and Stratton New York
1978.
'
'

R24

R39

R40
R41

R42

R43
R44
R45
R46

Rowland, R.E., and P.M. Failla, A.T. Keane et al.
Some dose-response relationships for tumour incidence
in radium patients. ANL-7760 (1970).
Rowland, R.E. Plugged haversian canals in a radiumcase. ANL-6199 (1960).
Reichart, P.A., J. Althoff, W. Eckhardt et al. 224Ra and226Ra experimentally induced dental changes in rats.
J. Oral Path. 8: 157-169 (1979).
Rebar, A.H., B.A. Merickel, S.A. Benjamin et al.
Toxicity of inhaled 144CeC]J in beagle dogs. LF-58(1977).
Regaud, C. The influence of the duration of irradiationon the changes produced in the testicle by radium.
Compt. Rend. Soc. Biol. 86: 787-789 (1922).
Ronnback, C., B. Henricson and A. Nilsson. Effect ofdifferent doses of 90Sr on the ovaries of the foetal
mouse. Acta Radio!. Suppl. 310: 200-209 (1971).
Ronnback, C. Effect of 90Sr on ovaries of foetal mice
depending on time for administration during
pregnancy. Acta Radio!. Oncol. 18: 225-234 (1979).
Ronnback, C. Effect of different 90Sr doses on the
microscopic structure of foetal mouse ovaries. Acta
Radial. Oneal. 19: 145-152 (1980).

649

R47

R48

R49

R50

RSI

R52

Sl
S2

S3

S5
S6

S7

SS

S9

SlO

SI I

Sl 2

S13

S14

SIS

S16
S17

SJ8

650

Red'kina, Ye K. Aspects of haemopoiesis following
chronic intake of rndiozinc in a dose of 0.1 µCi/kg, p.
75-84 in: The Toxicology of Radioactive Substances
Vol. 5 (A.A. Lctavet et al., eds.). Pergamon Press,
Oxford, 1970.
Rausch, L. Ober den Vorgang der Erholung im
bestrahlten Gewebe, zugleich cin Beitrag wr Frage derKombinationsnoxe. Strahlenlherapie 118: 286-287( 1962).
Reinhold, H.S. Late changes in the architecture ofblood vessels of the rat brain after irradiation. llrit. J.
Radial. 53: 693--696 (1980).
Radioprotection: chemical compounds, biologicalmeans (A. Locker and K. Flemming, eds.). Experientia.
Suppl. 27, 1977.
Rallison, M.L., B.M. Dobyns, F.R. Keating et al.
Thyroid disease in children. A survey of subjects potentially exposed to fallout radiation. Am. J. Med., 56:
457:463 (1974).
Reyners, H., E. Gianfelici de Reyners and J.R. Maisin.
Effets tardifs de !'irradiation sur l'ultrastructure duconex cerebral chez le rat. C.R. Soc. Biol. 173: 669--679(1979).
Sinclair, W.K. Cyclic x-ray responses in mammaliancells in vitro. Radiat. Res. 33: 620:643 (1968).
Shipley, W.U., J.A. Stanley, V.D. Counenay et al.
Repair of radiation damage in Lewis lung carcinoma
cells following in situ treatment with fast neutrons andx-rays. Cancer Res. 35: 932-938 (1975).
Strandqvist, M. Studien iiber die kumulative Wirkung
der Rontgenstrahlen bei Fraktionierung. Acta Radiol.,Suppl. 55 (1944).
Stevens, L.G. Injurious effects on the skin. Brit. Med. J.
1: 998 (1896).
Sweany, S.K., W.T. Moss and F.J. Haddy. The effects
of chest irradiation on pulmonary function. J. Clin.
Invest. 38: 587-593 (1959).
Shaver. S.L. X-irradiation injury and repair in thegerminal epithelium of male rats. I. Injury and repair in
adult rats. Am. J. Anat. 92: 391-432 (1953).
Shaver, S.L. X-irradiation injury and repair in thegerminal epithelium of male rats. II. Injury and repair
in immature rats. Am. J. Anat. 92:433-449 (1953).
Stadler, J. and J.W. Gowen. Patterns of reproductivityof different strains of mice under continuous irradiation. Ree. Genet. Soc. Am. 31: 118 (1962).
Stadler, J. and J. W. Gowen. Observations on the effectsof continuous irradiation over ten generations on
reproductivities of different strains of mice, p. 111-122
in: Effects of Ionizing Radiation on the Reproductive
System (W.D. Carlson and E.X. Gassner, eds.).
Pergamon Press, New York, 1964.
Schenken, L.L. and R.F. Hagemann. Time-dose
relationships in experimental radiation cataractogenesis. Radiology 117: 193-198 (197 5).
Smith, L.H. and 0. Vos. Sensitivity and protection ofmouse bone marrow cells x-irradiated in vitro. Int. J.
Radiat. Biol. 5: 461-470 (1962).
Stevens, R.H. Retardation of bone growth following
roentgen irradiation of an extensive nevocarcinoma of
the skin of an infant four months of age. Radiology 25:
538-546 (1935).
Spangler, D. TI1e effect of x-ray therapy for closure of
the epiphysis: preliminary report. Radiology 37:
310-315 (1941).
Spiers, F.W. A review of the theroretical and experimental methods of determining radiation dose in bone.
Brit. J. Radiol. 39: 216-221 (1966).
Seldin, H.M. Radio-oesteomyelitis of the jaw. J. Oral
Surg. Anesth. 13: 112-119 (1955).
Stewart, J.R., K.E. Cohn, L.F. Fajardo et al. Radiationinduced heart disease. A study of twenty-five patients.
Radiology 89: 302-310 (1967).
Stewart, J.R. and L.F. Fajardo. Radiation-induced
heart disease. Front. Radial. Ther. Oncol. 6: 274-288( 1972).

S19
S20
S2J

S22
S23

S24

S25

S26

S27

S28

S29
S30

S31
S32

S33
S34

S35

S36
S37

S38

S39

S40
S41

Sykes. M.P., F.C.H. Chu and W.G. Wilkerson. Localbone marrow changes secondary to therapeutic irradiation. Radiology. 75: 919-924 (1960).
Stone, R.S. Neutron therapy and specific ionization.
Am. J. Roentgenol. 59: 771-785 (1948).
Sheline, G.E., T.L. Phillips, S.B. Brennan et al. Effectsof rast neutrons on human skin. Am. J. Roentgenol.
111:31-41 (1971).
Silini, G., S. 1-lornsey and D.K. Bewley. Effects of x-ray
and neutron dose fractionation on the mouse testis.
Radial. Res. 19: 50-63 (1963).
Steamer, S.P., R.L. Devine and E.J.B. Christian. Latechanges in the irradiated microvasculature: an electron
microscope study of the effects of fission neutrons.
Radial. Res. 65: 351-370 (1976).
Sigdestad, C.P.. R.M. Scott, R.F. Hagemann et al. Intestinal crypt survival: the effect of cobalt-60, 250 kVp
x-rays and fission neutrons. Radial. Res. 52: 168-178(1972).
Sapirstein, L.A. Regional blood now by fractional
distribution of indicators. Am. J. Physiol. 193: 161-168(1958).
Studer, R. and E.J. Potchen. Transcapillary transpon oflabelled proteins. I. Regional albumin transfer. J. Nucl.
Med. 10: 442-443 (1969).
Song, C.W., R.S. Anderson and J. Tabachnick. Early
effects of beta irradiation on dermal vascular permeability to plasma proteins. Radiat. Res. 27: 604--615(1966).
Smith, L.H. and W.R. Boss. Effects of x-irradiation on
renal function of rats. Am. J. Physiol. 188: 367-374(1957).
Spaet, T.H. and I. Lejnieks. Mitotic activity of rabbit
blood vessels. Proc. Soc. Exptl. Biol. Med. 125:
1197-1201 (1967).
Song, C.W., J.J. Drescher and J. Tabachnick. Effect ofanti-innammatory compounds on beta-irradiationinduced increase in vascular permeability. Radial. Res.
34: 616--625 (1968).
Sherman, J.0. and P.H. O'Brien. Effect of ionizing
irradiation on normal lymphatic vessels and lymph
nodes. Cancer 20: 1851-1858 (1967).
Sato, F., D. Muranatsu, S. Tsuchihachi et al. Radiation
effects on cell populations in the intestinal epitheliumof mice and its theory. Cell Tissue Kinet. 5: 227-235(1972).
Sinclair, W.K. The shape of radiation survival curves ofmammalian cells cultured in vitro. p. 21-42 in: Biophysical aspects of radiation quality, lAEA, Vienna, 1966.
Sommers, S.C. Effects of ionizing radiation uponendocrine glands, p. 408-446 in: Pathology of Irradiation (C.C. Berdjis, ed.). Williams and Wilkins,
Baltimore, 1971.
Senn, J.S. and E.A. McCulloch. Radiation sensitivity ofhuman bone marrow cells measured by a cell culture
method. Blood 35: 56--60 (1970).
Sebrant, Yu.V. Biological action of external 13-irradiation. Atomizdat, Moscow, 1970 (in Russian).
Shcherbova, Ye.N .. G.P. Gruzdev and Yu.V. lvanov.
Some new principles characterizing the species radiosensitivity of mammals. Radiobiologiya 14: 423-425(1974) (in Russian).
Stakanov, Y.A., V.G. Kondratenko and A.M. Kuzin.
Changes in the state of the DNP of the nuclei of
spermatogenic cells caused by radiation. Radiobiologiya 14: 643--646 (1974) (in Russian).
Sinyakov, E.G., L.A. Buldakov, L.A. Plotnikova et al.
The dynamics of radiation dose accumulation andclinical changes in the structure of the eye after inhalation of transuranic elements. Medical Referative
Journal 5: 831 (1979) (in Russian).
Schwez, V.W. Radiosensitivity of haemopoietic stem
cells, p. 127-128 i.n: Current Topics of medicine andradiobiology. Moscow, 1975 (in Russian).
Shcherbova, Ye.N. and G.P. Gruzdev. About theheterogeneity of the lymphocytes populations (theregularities in radiosensitivity), p. 21-25 in: Problemsof haematology and blood transfusion. Atomizdat,
Moscow. (1974) (in Russian).

S42

Strei in, G.A. (ed.). Effect of shielding part of the bonemarrow after fractionated whole-body irradiation.
Medizina, Leningrad, 1978 (in Russian).
S43
Shcherbova, Ye.N., G.P. Gruzdev and Yu. V. Ivanov.
Vulnerability of the endothelium of the large vessels inradiosensitive and radioresistant animals. Radiobiologiya 10: 548-551 (1970) (in Russian).
S44 Shcherbova, Ye.N. and Yu.V. Ivanov. Interphase deathand repair of radiation damage in the endothclium of
the aorta. Radiobiologiya 18: 684-688 (1978) (inRussian).
S45
Sandernan, T.F. The effects of x-irradiation on malehuman fertility. Brit. J. Radio!. 39: 901-907 (1966).
S46 Speiser, B., P. Rubin and G. Casarett. Aspermia
following lower truncal irradiation in Hodgkins
disease. Cancer 32: 692-698 (1973).
S47
Sado, T., S. Kobayashi, H. Kamisaku et al. Immunological competence of aging mice exposed to x- or
gamma-rays during young adulthood. p. 115-125 in:
Late Biological Effects of Ionizing Radiation, Vol. 11,
IAEA, Vienna, 1978.
S48
Sado, T. Late effects of radiation on immune system, p.
688-697 in: Radiation Research (S. Okada, et al. eds.).
Toppan, Tokyo, 1979.
S49
Snyder, W.S., M.R. Ford, G.G. Warner et al. Estimatesof absorbed fractions from monoenergetic photon
sources uniformly distributed in various organs of aheterogeneous phantom. J. Nucl. Med. 10. Suppl. 3(1969).
S50 Snyder, W.S., M.R. Ford, G.G. Warner et al. Absorbed
dose per unit cumulated activity for selected radionuclides and organs. Medical Internal Radiation Dose
Committee, Pamphlet No. 11, Society of Nuclear
Medicine, New York, 1975.
S51
Sullivan, M.F., P.S. Ruemmler, J.L. Beamer et al. Acutetoxicity of beta-emitting radionuclides that may bereleased in a reactor accident and ingested. Radial. Res.
73: 21-36 (1978).
S52 Stevenson, A.C., J. Bedford, G.W. Dolphin et al. Cytogenetic and scanning study of patients receiving intraarticular injections of gold-198 and yttrium-90. Ann.
Rheum. Dis. 32: 112-123 (1973).
S53
Sharpe, W.D. Chronic radium intoxication: clinicaland autopsy findings in long-term New Jersey
survivors. Environ Res. 8: 243-383 (1974).
S54 Spiess, H. 224Ra induced tumours in children andadults, p. 227-246 in: Delayed effects of bone seeking
radionuclides (C.W. Mays, W.S. Jee, R.D. Lloyd et al,eds.). University of Utah Press, Salt Lake City, 1969.
SSS
s.eiess, H. and C.W. Mays. Bone cancers induced by
2~4Ra (ThX) in children and adults. Health Phys. 19:
713-729 (1970).
S56
Spiers. F.W., J.R. Whitwell and P.J. Dorley. Dose inbone marrow cavities from Radium-226. Personalcommunication to J.M. Vaughan (1971) in: The effectsof Radiation on the skeleton. Clarendon Press, Oxford,
1973.
S57
Spiers, F.W. Radioisotopes in the human body.
Academic Press, New York, 1968.
S58
Spiess, H., A. Gerspach and C.W. Mays. Soft-tissue
effects following 224Ra injections into humans. HealthPhys. 35: 61-81 (1978).
S59
Stuart, B.O., W.J. Bair, W.J. Clarke et al. Acute toxicity
of inhaled plutonium oxide 238 and 239 in rats. AFWLTr-68-49 (1968).
S60
Snipes, M.B., F.F. Hahn, B.A. Muggenburg et al.
Toxicity of inhaled 90Sr in fused aluminosilicate
particles in beagle dogs. LF-58 (1977).
S61
Siemsen, J., M.S. Wallack, R.B. Martin el al. Early
results of 125J therapy of thyreotoxic Graves's disease.
J. Nucl. Med. 15: 257-260 (1974).
S62 Sutow, W.W. and R.A. Conard. The effects of fallout
radiation on Marshallese children, p. 661~73 in:Radiation Biology of che Feta! and Juvenile Mammal(R. Sikov and D.D. Mahlum, eds.). CONF-690501,
1969.

S63
S64
S65

S66
S67

S69

S70

S71
S72
S73

S74
S75

S76
S77

S78

TI

T2
T3
T4
TS
T6

n
T8
T9

Srivastava. P. and S.R. Chadha. The effect ofradiophosphorus on the development of the gonads inmice. Strahlenlherapie 139: 738-743 (1970).
Samuels, L.D. Effects of polonium-210 on mouseovaries. lnt. J. Radial. Biol. 11: 117-129 (1966).
Spiers, f-'.W., A.H. Beddoe, S.D. King et al. The
absorbed dose to bone marrow in the treatment ofpolycythaemia by 32p, Brit. J. Radio!. 49: 133-140(1976).
Snipes, M.B., B.B. Boecker, F.F. Hahn et al. Toxicity of
inhaled 90Sr in fused aluminosilicate particles in beagle
dogs. LF-56 ( 1976).
Spiers, F.W., G.D. Zanelli, P.J. Darley et al. Beta
particle dose rates in human and animal bone in:
Biomedical implications of radiostrontium exposure(M. Golmand and L.K. Bustad, eds.). CONF-710201(1972).
Shrivastava, P.H.. L. Hans and J.P. Concannon.
Changes in the pulmonary compliance and productionof fibrosis in x-irradiated lungs of rats. Radiology 112:439-440 (1974).
Stodtmeister, R. and T.M. Fliedner. Morphologicalaspects of myelofibrosis, observed in rats following
sublethal whole body irradiation and subsequent
allogenic bone marrow cell transfusion. Folia Haematologica 100: 23-50 (1973).
Sato, F., S. Tsuchihashi, W. Nakamura et al. LD50(30)and daily death distributions of whole- or partial-body
irradiated mice. J. Radiat. Res. 13: 100-108 (1972).
Sullivan. M.F. (ed.). Gastrointestinal Radiation Injury.
Excerpta Medica Foundation, Amsterdam, 1968.
Stewart, F.A., B.D. Michael and J. Denekamp. Lateradiation damage in the mouse bladder as measured byincreased urination frequency. Radiat. Res. 75: 649~59(1978).
Stewart, F.A., J. Denekamp and D.G. Hirst. Proliferation kinetics of the mouse bladder after irradiation.
Cell Tissue Kinet. 13: 75-89 (1980).
Steffen, J.A., K. Swierkowska, A. Michalowski et al. Jn
vitro kinetics of human lymphocytes activated by
mitogens, in: Mutagen-induced Chromosome Damage
in Man, (Evans, H.J. and D.C. Lloyd, eds.). University
Press, Edinburgh, 1978.
Sato F. and H. Eto. A model for radiation injury. V. On
the target theory. Nippon Acta Radio!. 26: 1130-1137(1966).
Stover, B.J., D.R. Atherton. D.S. Buster et al. The Th228
decay series in adult beagles: Ra224, Pb212 and Bi212 inselected bones and soft tissues. Radiat. Res., 26:
132-145 (1965).
Sudorova, LA., N.A. Vyalova, A.V. Barabanova et al.
Post-irradiation recovery of the bone marrow of man
and morphodynamics of the pool of undifferentiatedcells. Arch. ofTher. 19: 127-131 (1981) (in Russian).
Till, J.E. and E.A. McCulloch. Early repair processes inmarrow cells irradiated and proliferating in vivo.
Radiat. Res. 18: 96-105 (1963).
Thomlinson, R.H. Changes of oxygenation in tumours.
Front. Radial. Ther. Oneal. 3: 109-121 (1968).
Tannock, !.F. and S. Hayashi. The proliferation ofcapillary endothelial cells. Cancer Res. 32: 77-82(1972).
Teates, C.D. Effects of unilateral thoracic irradiation
on lung function. J. Appl. Physiol. 20: 628-636 (1965).
Tyree, E.G., A.S. Glicksman and J.J. Nickson. Effect of
1-triiodothyronine on radiation-induced pulmonary
fibrosis in dogs. Radial. Res. 28: 30-36 (1966).
Travis, E.L., B. Vojnovic, E.E. Davies et al. A plethismographic method for measuring function in locally
irradiated mouse lung. Brit. J. Radio!. 52: 67-74 (1979).
Till. J.E. and E.A. McCulloch. A direct measurement of
the radiation sensitivity of normal mouse bone marrow.
Radiat. Res. 14: 213-222 (1961).
Tefft, M. Radiation effect on growing bone andcartilage. Front. Radiat. Ther. Oneal. 6: 289-311 (1972).
Takoaka, A., H. Kaneda, M. Urano et al. An electrocardiographic study of cardiac damage secondary to

651

TIO
TI l

Tl2
TD
T14

TI 5
Tl 6

Tl 7

T18
Tl9

T20

T21
T22
T23

T24
T25

T26

T27
T28

T29

DO

652

radiotherapy of malignant intrathoracic tumours.
Radio!. Clin. Biol. 37: 1-12 (1968).
Teates, D. and G. Cooper. Some consequences of
pulmonary irradiation. A second long-term report. Am.
J. Roentgenol. 96: 612-619 (1966).
Tubiana, M. Clinical treatments of leukaemia bysplenic irradiation, p. 306-377 in: Cell Survival After
Low Doses of Radiation: Theoretical and ClinicalImplication (T. Alper, ed.). John Wiley and Sons,
London, 1975.
Turner, B.A. and J.F. Fowler. The RBE of fast neutronsin producing intestinal and skin injury in rats. Brit. J.
Radio!. 36: 101-106 (1963).
Travis, E.L., H. Hargrove, C.J. Klobukowski et al.
Alterations in vascular permeability following irradiation. Radial. Res. 67: 539 only (1976).
Tanaka, A., H. Ueno, Y. Yamashita et al. Regional
cerebral blood flow in delayed brain swelling following
x-irradiation of the right occipital lobe in the monkey.
Brain Res. 96: 233-246 (1975).
Traelnes, K.R., H. Ernst, K.I. Altman et al. The effectof x-irradiation on collagen metabolism in polyvinylsponge granulomas. Radiat. Res. 47: 224-232 (1971).
Torubarov, F.S. Reaction of human brain vessels to theaction of ionizing radiation in: Mechanisms ofradiation action on biological membranes and excitablesystems. Tbilisi, 1976 (in Russian).
Thomas, P.R.M., D. Winstanley, M.J. Peckham et al.
Reproductive and endocrine function in patients with
Hodgkin's disease: effects of oophoropexy and irradiation. Brit. J. Cancer 33: 225-231 (1976).
Topp, J.R. and E.G. Cross. The treatment of persistentknee effusions with intra-articular radioactive gold.
Can. Med. Assoc. J. 102: 709-714 (1970).
Taylor, G.N., W.R. Christensen~ L. Shabestari et al. The
general syndrome induced by-39Pu in the beagle, p.
59-74 in: Radiobiology of Plutonium (B.J. Stover and
W.S.S. Jee, eds.). The J.W. Press, Salt Lake City, 1972.
Taylor, G.N., W.R. Christensen, W.S.S. Jee et al. Intercomparison of pathological fractures in beagles
injected with226Ra, 228Ra, 239pu or 90Sr. Health Phys.
12: 361-367 (1966).
Taylor, G.N., W.S.S. Jee, W.R. Christensen et al.
Thorium-induced fractures in beagles. Health Phys. 12:
889-893 (1966).
Thomas, R.G. Metabolism, dosimetry and biologicaleffects of inhaled 241Arn in beagle dogs. Health Phys.
22: 863-871 (1972).
Taylor, G.N., W.S.S. Jee, J.L. Williams et al. Hepaticchanges induced by 239Pu, p. 105-128 in: Radiobiologyof Plutonium (B.J. Stover and W.S.S. Jee, eds.). The
J.W. Press, Salt Lake City, 1972.
Taylor, G.N., T.F. Dougherty, C.W. Mays et al.
Radium-induced eye melanomas in dogs. Radial. Res.
51: 361-373 (1972).
Timmermans, R., G.B. Gerber and J •. Gits. Absorptionof different amino acids by an intestinal preparationfrom normal rats and from rats exposed to supralethal
x-irradiation. Rad. Environ. Biophys. 14: 53-60 (1977).
Thomas, E.S., C.D. Buckner, M. Banaji et al. One
hundred patients with acute leukaemia treated bychemotherapy, total-body irradiation and allogeneic
marrow transplantation. Blood 49: 511-533 (1977).
Turner, B.A. and J.F. Fowler. The RBE of fast neutronsin producing intestinal skin injury in rats. Brit. J.
Radiol. 36: 101-106 (1963).
Turesson, I. and G. Notter. The response of pig skin tosingle and fractionated high dose-rate and continuous
low dose-rate irradiation. I II. Re-evaluation of the
CRE-system and the TDF-system according to thepresent findings. Ing. J. Radiat. Oncol. Bio. Phys. 5:
l 773-1779 (197 5).
Turesson, I. and G. Notter. Skin reactions after
different fractionation schedules giving the same
cumulative radiation effect. Acta Radiol. Tuer. Phys.
Biol. 14: 475-484 (1975).
Turesson, I. Fractionation and dose-rate in radiotherapy. An experimental and clinical study of the

Ul

U2

U3

U4

US

U6
Vl

V2

V3

V4

V5

V6
V7

VB
V9

VlO

Vl I

Vl 2
V13

cumulative radiation effect. Thesis, University of
Goteborg, ( 1979).
United Nations. Sources and Effects of Ionizing
Radiation. United Nations Scientific Committee on the
Effects of Atomic Radiation 1977 report of the General
Assembly, with annexes. United Nations sales publication No. E.77. IX.I. New York, 1977.
Upton, A.C., K.W. Christenberry, G.S. Melville et al.
The relative biological effectiveness of neutrons, x-rays
and gamma rays for the production of lens opacities.
Observations on mice, rats, guinea pigs and rabbits.
Radiology 67: 686-696 (1956).
U.S. Nuclear Regulartory Commission. Reactor Safety
Study. An Assessment of Accident Risks in U.S.
Commercial Nuclear Power Plants. WASH-1400(1975).
United Nations. Report of the United Nations Scientific Committee on the Effects of Atomic Radiation.
Official Re~ords of the General Assembly, Twenty·
fourth Session, Supplement No. 13 (A/7613). New
York, 1969.
United Nations. Report of the United Nations Scientific Committee on the Effects of Atomic Radiation to
the General Assembly, with annexes. Volume I: Levels,
Volume II: Effects. United Nations publication No.
E.72. IX.17 and 18. New York, 1972.
Urbain, J. Idiothypic induction and immune networks.
p. 81-93 in: Proceed. IV. Int. Congr. Immunol.
Academic Press, London, 1980.
Van der Kogel, A.J. Radiation tolerance of the spinal
cord: dependence on fractionation and extended
overall times, p. 83-90 in: Radiobiological Researchand Radiotheraphy, Vol. I. IAEA, Vienna, 1977.
Van den Brenk, H.A.S., C. Sharpington, C. Orton et al.
Effects of x-irradiation on growth and function of therepair blastema (granulation tissue). II. Measurementsof angiogenesis in the Selye pouch in the rat. Int. J.
Radiat. Biol. 25: 277-289 (1974).
Vatistas, S. and S. Homsey. Radiation-induced protein
loss into the gastrointestinal tract. Brit. J. Radiol. 39:
547-550 (1966).
Van den Brenk, H.A.S. Radiation effects on thepulmonary system, p. 569-591 in: Pathology of Irradiatioi;i (C.C. Berdjis, ed.). Williams and Wilkins,
Baltimore, 1971.
Verga, V. and A. Cali. Veranderungen des Lebergewebes der Ratte und insbesondere des argentophilen
Gertistes nach direkter fraktionierter Rontgenbestrahlung der Leber. Strahlentherapie 112: 608-612(1960).
Van der Kogel, A.J. and G.W. Barendsen. Late effectsof spinal cord irradiation with 300 kV x-rays and 15
MeV neutrons. Brit. J. Radio!. 47: 393-398 (1974).
Van der Kogel, A.J. Radiation-induced nerve root
degeneration and hypertrophic neuropathy in the
lumbosacral spinal cord of rats: the relation withchanges in aging rats. Acta Neuropathol. 39: 139-145(1977).
Van der Kogel, A.J. Radiation tolerance of the rat
spinal cord: time-dose relationships. Radiology 122:505-509 ( 1977).
Van der Kogel, A.J. and H.A. Sissingh. Repair characteristics of different target cells in the rat spinal cord.
lnt. J. Radial. Biol. 34: 566 only (1978).
Van den Brenk, H.A.S., M.C. Crowe and M.G. Stone.
Functional integrity and inflammatory reactions of
exchanges vessels and lymphatics in x-irradiatedtissues. Brit. J. Exptl. Pat ho I. 58: 499 (1977).
Van den Brenk, H.A.S. Macro-colony assay formeasurement of reparative angiogenesis after x-irradiation. Int. J. Radiat. Biol. 21: 607-611 (1972).
Van den Brenk, H.A.S. The effect of ionizing radiations
on the regeneration and behaviour of mammalianlymphatics. Am. J. Roentgenol. 78: 837-849 (1957).
Vuksanovic, M., M. Viamonte and J.E. Martin. The
place of lymphagioadenography in the diagnosis andduring the treatment of malignant diseases. Am J.
Roentgenol. 96: 205-221 (1956).

V 14

Vasculescu. T .. Ch. Pasculescu, V. Papivian et al.
Influence of small doses of x-rays on central nervous
system. Radiobiol. Radiother. 366-375 (1973).
Vl 5 Vaughan, J.M. The effects of irradiation on theskeleton. Clarendon Press, Oxford, 1973.
V16 Vesely, K. and J. Sada. Incidence of specific occupational disease in· the Czechoslovak uranium industry.
NP 18271 (1968).
V17 Van Kaick, G., D. Lorenz, H. Muth et al. Malignancies
in German thorotrast patients and estimated tissue
dose. Health Phys. 35: 127-137 ( 1978).
VIS Vickery, A.L. and E.D. Williams. Comparative
biological effects of 125J and 131 J on the rat thyroid.
Acta Endocrinol. 66: 201-212 (1971).
V19 Vaughan, B.E. and E.L. Alpen. Moderate level x-ray
effect on active transport mechanism in dog intestine.
lnt. J. Radial. Biol. 3: 265-277 (1961).
V20 Vaughan, B.E., J.T. Cummins and H.A. Ridley. Differential effects of irradiation on gastric acid andbioelectric potential in the rat, in: Gastrointestinal
Radiation Injury. (M.F. Sullivan, ed.) Excerpta Medica
Foundation, Amsterdam (1968).
W1
Withers, H.R. and M.M. Elkind. Microcolony survival
assay for cells of mouse intestinal mucosa exposed toradiation. Int. J. Radiat. Biol. 17: 261-267 (1970).
W2
Withers, H.R., K. Mason, B.O. Reid et al. Response ofmouse intestine to neutrons and gamma rays in relation
to dose fractionation and division cycle. Cancer 34:
39-47 (1974).
W3
Withers, H.R. The capacity for repair in cells of normal
and malignant tissues, p. 54-64 in: Time and Dose
Relationships in Radiation Biology as Applied toRadiotherapy. BNL-50203 (1970).
W4
Withers, H.R. The dose survival relationship for irradiation of epithelial cells of mouse skin. Brit. J. Radiol.
40: 187-194 (1967).
W5
Withers, H.R. and M.M. Elkind. Radiosensitivity andfractionation response of crypt cells of mouse jejunum.
Radiat. Res. 38: 598-613 (1969).
W6White, A. and S. Homsey. Radiation damage to the rat
spinal cord: the effect of single and fractionated dosesof x-rays. Brit. J. Radiol. 51: 515-523 (1978).
W7
Withers, H.R., N. Hunter, H.T. Barkely, Jr. et al.
Radiation survival and regeneration characteristics ofspermatogenic stern cells of mouse testis. Radiat. Res.
57: 88-103 (1974).
W8
Winston, B.M., F. Ellis and E.J. Hall. The Oxford NSD
calculator for clinical use. Clin. Radio!. 20: 8-11 (1969).
W9
Winter, G.D. The poor healing of burns, p. 614-619 in:
Research on Burns (P. Mathers, T.L. Barclay and Z.
Conickova, eds.). Huber, Bern, 1971.
WlO Withers, H.R., H.D. Thames, B.L. Flow et al. The
relationship of acute to late skin injury in 2 and 5
fraction/week y-ray therapy. Int. J. Radial. Oncol. Biol.
Phys. 4: 595-601 (1978).
Wl 1 Withers, H.R. Recovery and repopulation in vivo bymouse skin epithelial cells during fractionated irradiation. Radiat. Res. 32: 227-239 (1967).
W12 Withers, H.R. Response of tissues to multiple small
dose fractions. Radial. Res. 71: 24-33 (1977).
W13 Wimber, D.R. and L.F. Larnerton. Cell population
studies on the intestine of continuously irradiated rats.
Radial. Res. 18: 137-146 (1963).
W14 Wells, A.B. The effect of acute and fractionated dosesof x-rays on the growth of the mouse tibia. Brit. J.
Radio!. 42: 364-371 (1969).
W!5 Wara, W.M., T.L. Phillips, L.W. Margolis et al.
Radiation pneumonitis: a new approach to thederivation of time-dose factors. Cancer 32: 547-552(1973).
W16 Weinbren. K.. W. Fitschen and M. Cohen. The
unmasking by regeneration of latent irradiation effects
in the rat liver. Brit. J. Radio!. 33: 419-425 (1960).
Wl7 Wilson, C., J.M. Ledingham and M. Cohen. Hypertension following x-irradiation of the kidneys. Lancet
1: 9-16 (1958).

W20

Wellington, J.L. and R.D. Lynn. Effects of irradiation
on lung function. Can. J\fed. Ass. J. 90: 1341-1344(1964).
W21 Wachowski, T.J. and H. Chenault. Degenerative effectsof large doses of roentgen rays on the human brain.
Radiology 45: 227-246 ( 1945).
W22 Werner, S.C., H. Hamilton and M.R. Nemeth. Therapeutic effects from repeated diagnostic doses of 131) in
adult and juvenile hyperthyroidism. J. Clin. Endocrirn:Jl. 12: 1349-1355 (1952).
W23 Wakisaka, G. Long-term observation on the haemopoietic function of the atomic bomb survivors and the
disturbances due to the irradiation of the haernqpoietic
organs. Abstract in: Nucl. Sci. Abstr. 22: 4635 (1968).
W24 Westra, A. and G.W. Barendsen. Proliferation characteristics of cultured mammalian cells after irradiation
with sparsely and densely ionizing radiations. lnt. J.
Radiat. Biol. 11: 477-485 (1966).
W25 Withers, H.R., H.D. Thames, D.H. Hussey et al.
Relative biological effectiveness (RBE) of 50 MeV (Be)neutrons for acute and late skin injury. Int. J. Radiat.
Oncol. Biol. Phys. 4: 603-608 (1978).
W26 Wolbach, S.B. The pathological histology of chronic
x-ray dermatitis and early x-ray carcinoma. J. Med.
Res. 21: 415-449 (1909).
W27 Warren, S. Effects of radiation on normal tissues. VI.
Effects of radiation on the cardiovascular system. Arch.
Pathol. 34: 1070-1079 (1942).
W28 Wiernik, G., T.J.S. Patterson and R.J. Berry. The effectof fractionated dose-patterns of x-radiation on thesurvival of experimental skin flaps in the pig. Brit. J.
Radiol. 47: 343-345 (1974).
W29 White, R.L., A.M. El-Mahdi, H.L. Ramirez et al.
Therrnographic
changes following
preoperative
radiotherapy in head and neck cancer. Radiology 117:469-471 (1975).
W30 Willoughby, D.A. The vascular permeability in the rat's
intestine following abdominal radiation. J. Physiol.
148: 42-43 (1959).
W31 Wende, S. Tierexperimentelle Untersuchungen uber die
Strahlenschadigung der Blut-Liquor-Schranke. Strahlentherapie 134: 529-532 (1967).
W32 Wordsworth, O.J. and P.W. Dykes. A functional andmorphological study of liver radiation injury following
intravenous injection with colloid gold (198Au). Int. J.
Radial. Biol. 14: 497-515 (1968).
W33 Wilhelm, D.L. The mediation of increased vascularpermeability in inflammation. Pharmacol. Rev. 14:
251-280 (1962).
W34 Warren, S. Effects of radiation on normal tissues. XIII.
Effects on the skin. Arch. Pathol. 35: 340-347 (1943).
W35 Weeks, P.M. Irradiation effect on collagen degradation.
Surg. Forum 20: 498-499 (1969).
W36 Wagner, B.M. Hyalin and librinoid: current status in:
The Connective Tissue (B.M. Wagner and D.E. Smith,eds.). Williams and Wilkins, Baltimore, 1967.
W37 Homsey, S., C.C. Morris, R. Myers et al. RBE fordamage to the central nervous system by neutrons. Int.
J. Radiat. Oncol. Biol. Phys. 7: 185-189 (1981).
W38 Wells, J. and M.W. Charles. The development of
criteria for limiting the non-uniform irradiation of skin:
the rationale for a study of non-stochastic effects. RB/
B/N4565 (1979).
W39 Wall, P.G. Effects of x-irradiation on the adrenal
glands of immature rats. J. Endocrinology 34: 69-80(1966).
W40 Walton, R.J. and W.K. Sinclair. Intracavitary irradiation with radioactive colloidal gold in the palliative
treatment of malignant pleural and peritoneal
effusions. Brit. Med. Bull. 8: 165-171 (1952).
W41 Webb, F.W.S., J. Lowe and R. Bluestone. Uptake ofcolloidal radioactive yttrium by synovial membrane.
Ann. Rheum. Dis. 28: 300-302 (1969).
W42 West, J.E. and W.J. Bair. Plutonium inhalation studies.
V. Radiation syndrome in beagles after inhalation of
plutonium dioxide. Radial. Res. 22: 489-506 (1964).
W43 Woodard, H.Q., K.S. PentlO"'., K.S. Mayer et al.
Distribution and retention of hS-sodium sulphate inman. J. Nucl. Med. 17: 285-289 (1976).

653

W44
\V45
W46

YI

Y2
Y3
Y4
Y5

Wolf, N.S. The haemopoetic environment. Clinics in
Haematology. Vol. 8, No. s. 469-500 ( 1979).
Walinder, G. and E. Walinder. Effects of IJIJ on thecellular survival in mouse thyroids. Acta Radio!. Suppl.
310: 235-237 ( 1971).
Walindcr, G. Radiationsinduced neoplasia andimpairment of epithelial regeneration, two anrngonistic
effects. p. 33~3 in: Radionuclide Carcinogenesis. U.S.
AEC Symp. Ser. 29 (1973).
Yamaguchi, T. and J. Tahachnick. Cell kinetics of
epidermal repopulation and persistent hyperplasia in
locally beta-irradiated guinea pig skin. Radial. Res. 50:
158-180 (1972).
Yoffey, J.M. Bone Marrow Reactions. Arnold, London,
1966.
Yukawa, 0. and T. Nakazawa. Damages in the microsomal drug metabolizing enzyme system after partial xirradiation of rat liver. Radial. Res. 58: 101-110 (1974).
Yuhas, J.M., A.P. Li and M.M. Kligerman. Present
status of the proposed use of negative pi mesons inradiotherapy. Adv. Radial. Biol. 8: 51-83 (1979).
Yuile, C.L., F.R. Gibb and P.E. Morrow. Dose-related
local and systemic effects of inhaled plutonium-238

11nd plutonium-239 dioxide in dogs. Radial. Res. 44:
821-834 (1970).
ZI

Zaruba, K. Renal functions in acute radiation sickness.
Radial. Res. 25: 1-8 (1965).

22

Zeeman W . . Radiosensitivity of nervous tissue, p.
176-199 in: Fundamental Aspects of Radiosensitivity.
Brookhavcn Symposium in Biology, Vol. 14, 1961.

23

Zollinger, H.U. Die Strahlenvasculopathie. Pathol. Eur.
5: 145-163 (1970).

Z4

Zeeman, W. Disturbances of nucleic acid metabolism
preceding delayed radionecrosis of nervous tissue.
Proc. Nat. Acad. Sci. 50: 626-630 (1963).

Z5

Zaitzcva , R.N. Comparative characteristics of radiation
damage to rats after partial irradiation , p. 127-130 in:
Biological effects of inhomogeneous irradiation.
Atomizdal, Moscow, 1974 (in Russian).

Z6

Zedgenidze, G.A., Bardychev, A.F. Tsyb et al.
Condition of the regional lymphocirculation in lateirradiation induced ulcers of the skin (according tolymphography data). Medical Radiology 17(6): 3-10
(1972) (in Russian).

back

to
first page654