SOURCES, EFFECTS
AND RISKSOF IONIZING RADIATION
United Nations Scientific Committee on the Effectsof Atomic Radiation
1988 Report to the General Assembly, with annexes

UNITED NATIONSNew York, 1988

NOTE
The report of the Committee without its annexes appears as Official Records of theGeneral Assembly, Forty-third Session, Supplement No. 45 (A/43/45).
The designations employed and the presentation of material in this publication d o
not imply the expression of any opinion whatsoever on the part of the Secretariat of theUnited Nations concerning the legal status of any country, territory, city or area. or of its
authorities, or concerning the delimitation of its frontiers o r boundaries.

UNITED NATIONS PUBLICATION
Sales No. E.88.IX.7
ISBN 92-1- 142143-8
09000PANNEX G
Early effects in man of high doses of radiation

CONTENTSParagraphs

Porogrophs
IhrTRODUCTION ........................

I . PATHOGENESISAND DOSE-RESPONSE RELATIONSHIPSC.

........
A . Cellular effects ..................
B. Tissue effects ...................
C . The radiation syndromes ..........

I11 . PROGNOSTIC INDICATORS AND

BIOLOGICAL DOSIMETRY ........ 207-287

A. Prognostic indicators ............. 207-239

I . Dosimetric data ............. 208-2 15
2. Clinical data ................ 216-221
3. Biological data .............. 222-239. Clinical and biological dosimetry ... 240-287

B

D . Effects on other tissues ...........
I . Skin .......................
2. Oral rnucosa ................
3. Eye ........................
4. Lung ......................
5. Testis ......................
6. Ovary .....................

A. Biological and other variables ...... 194-206

D

I . The prodromal phase ........
2. The neurological (neurovascular)
syndrome ..................
3. The gastrointestinal syndrome
4. Haematological and immunological effects. and the bonemarrow syndrome ...........

11. DOSE-RESPONSE RELATIONSHIPSIN MAN ..........................

............. 157-162
5. Skin ....................... 163-170
6. Lung ...................... i n - 1 7 4
7. Gonads .................... 175-179
lnterl~alenlitters ................ 180- 193

4 . LDsoJW in man

1-9

1. Dosimetry based on haematological data ................. 24 1-256
2. Dosimetry based on biochemical
data ....................... 257-265
3. Dosimetry based on cytogenetic
data ....................... 266-279
4 . Dosimetrv based on neurophysiological data ........... 280-284
5 . Other dosimetric findings ..... 285-287

I

90-206. Acute doses ..................... 90-138

IV . CONCLUSIONS................... 288-322................

.

I3

I . The LDSo/M,
90-113
2. Doses for very low and very
high mortality in man ........
114
3. Geometry of exposure anddepth-dose distributions ...... 115-1 19
4 . Dose inhomogeneity. shielding
and bone marrow distributions 120- 126
5. Radiation quality ............ 127-131
6. Modification of the LDS0/60 bypost-irradiation treatments .... 132-138
Effects of dose protraction ........ 139-179
I . Prodromal responses ......... 144- 148
2. Intestinal responses .......... 149-150
3. Haematological responses
151- 156

....

Page
Tables ...............................

598

APPENDIXACUTE RADIATION EFFECTS IN
VICTIMSO F THE CHERNOBYLNUCLEAR POWER PLANT ACCIDENT
Paragraphs
Inrroduction

A........................

. Initial diagnosis of acute radiation
sickness

1-15........................ 16-20

Paragraphs

The bone marrow syndrome and its
treatment .......................
C. Other injuries and their treatment ....
1. Intestinal syndrome ...........
2. Oropharyngeal syndrome .......
3. Lung reactions ...............
4. Causes of death ..............
5. Eye damage .................
B.

2139
50-83
56
57-58
59
60-63

64-71

Introduction

1. A review of the early somatic effects of radiationin man was published in the UNSCEAR 1962 Report[Ul]. This was supplemented in the UNSCEAR 1969
Report by two Annexes, one on radiation-induced
chromosome aberrations, the other on the action ofradiation on the nervous system [U2], and in the
UNSCEAR 1972 Report [U3] by an Annex on theradiation response of the immunological system. The
effects of high radiation doses in man were recently
re-addressed in part in the UNSCEAR 1982 Report[U4]. Annex J , which dealt with non-stochastic effects
resulting from localized irradiation of single organs o rtissues.

2. In this Annex the Committee reviews data on theearly effects of high doses of radiation delivered to thewhole human body. There is continuing interest in theeffects of whole-body irradiation because of the persistent possibilities of exposure in accidents or fromacts of warfare. Whole-bod y irradiation is also being
used in the treatment of disseminated malignancies.
However, reliable quantitative data in this field arevery limited. They are drawn.essentia1ly from isolated
accidental exposures, from information gathered on
the Japanese population exposed t o radiation fromthe atomic bombs exploded in the Second World War,and from experience with groups of patients receiving
whole-body irradiation for cancer o r prior to thetransplantation of organs.
3. This Annex reviews data o n the effects occurringin man within 2-3 months of whole-body doses ofmore than approximately 1 G y of low linear energy
transfer (LET) radiation o r biologically equivalentdoses of other radiation types. However, it also
includes mention, in some cases, of doses down to
0.5 Gy, of protracted exposures resulting in the samelevels of effect as acute doses. and of exposure tointernal emitters where the doses were sufficient tohave serious effects within 2-3 months. Gaps in theknowledge for man are filled partially by information
derived from experimental work with mammals, particularly those with a body size approaching that ofman; in general, however, large-animal data areintended to be used for interpretation of responses
rather than for extrapolation. Exposures of the wholebody resulting in doses to different regions that varyby less than lo%, apply mainly to treatments inradiotherapy. In accidents o r in acts of warfare.

I

Paragraphr

6. Treatment of radiation burns andother injuries ................ 73-83
D. Conclusions ..................... 84-89
Page

Tables ..................................

628

Refere~ces ..............................

632

whole-body doses usually are highly non-uniform (forexample unilateral), with the variation in dose fromlow-LET radiation by a factor of 2 to 3, and fromneutrons up to a factor of 10 or more (see, forexample. Figure XIX). In these cases, the dose at the
midline of the body may bear little relationship t o thesigns of injury.
4. Many accidents and some oncological treatments
involve irradiation of large regions of the body, forexample the trunk o r the chest. In these cases thedoses to specific target organs will determine theresponse of the individual. The response may differ
from that of the same organ exposed to the same dosefrom irradiation of the whole body, if there arecontributions to the expression of injury in the organfrom other irradiated tissues. for example granulocytopenia exacerbating intestinal injury.
5. Much information was gathered from the Japanese
exposed to the atomic bombs in the Second World
War. However, at distances from the hypocentre
where doses received were a few Gy, there were alsoheat and mechanical injuries. Furthermore, the radiation doses received by these individuals remain somewhat uncertain, and recent calculations suggest thatthe contribution to the dose from neutrons was muchless than considered in previous (T65D) estimates ofdose. Other groups of individuals exposed to highdoses of nuclear fallout radiation were the MarshallIslanders and 23 Japanese fishermen exposed to the
nuclear explosions on Bikini Atoll in 1954. These
groups received comparatively uniform external gammairradiation, beta-irradiation of the skin and internal
irradiation. Groups of individuals irradiated with highdoses to the whole body in accidents included those at
Oak Ridge. United States (the group is widelyreferred to as "Y-12"), at Vinca, Yugoslavia, in 1958,
in China in 1963, in Algeria in 1978, in Morocco in
1985. at Chernobyl. USSR. in 1986, and in Brazil in
1987.
6. When this Annex was approaching completion,
important information on the subject became available in connection with the nuclear accident that
occurred at the power plant in Chernobyl, USSR,
where about 100 people were exposed to external andinternal irradiation amounting to 1 Gy or more. The
delegation from the USSR has made available especiallyto UNSCEAR a report on the data gathered in thewake of the accident. The Committee wishes toacknowledge with gratitude this important contribution. Since time atas too short for a definitive study ofthe data collected and for their incorporation into thetext of this Annex. the Committee decided to present
them a s an Appendix.
7. Clinical data relate to the use of radiationdelivered to the whole body to suppress the immune
system prior to organ transplantation, to control
multiple o r systemic metastases from solid tumours.
a n d t o treat leukaemia. Although the radiation doses
are known accurately for these patients. their responses
to these treatments may be confounded to an uncertain
extent by debility and disease, by the prior orconcomitant use. in many cases. of cytotoxic or
immunosuppressive drugs and by different degrees of
medical treatment after irradiation.

8. Most of the doses quoted in the literature reviewed
in this Annex were given in rad, o r in terms of
exposure, roentgen (R). As in the UNSCEAR 1982
Report [C'4]. 100 R of exposure will be taken to beequivalent to 1 Gy absorbed dose in the case of small
animals. For larger animals, the doses at depth forequivalent surface doses become progressively less.
and this depends on the radiation quality. Doses in
the literature are quoted either as surface doses or,more commonly. as midline tissue doses. Conversions
will be made where necessary t o allow these doses tobe expressed in terms of dose in the target tissue underconsideration.

9. This Annex is intended to be a scientific compendium o n the early effects of radiation in man. It is notmeant to be a manual on the care and treatment of
irradiated persons, although the information it contains
is relevant to evaluating the radiological health consequences of accidents or acts of warfare and theeffects of radiotherapy.

1.

PATHOGENESIS AND DOSE-RESPONSE
RELATIONSHIPSA.

CELLULAR EFFECTS

10. The cellular effects that are important in the
response of tissues to irradiation have been describedand discussed previously by the Committee [U4]. The
severest injuries from radiation in most early-responding
tissues are caused by a loss of cells. This results either
from death of cells in interphase. as in the case oflymphocytes or. more commonly, from killing ofprogenitor cells at mitosis. which leads to a lack ofreplacement of mature cells lost through natural
senescence and death. hlost mature cells are radioresistant because they divide only occasionally or nota t all. In "flexible" type cell populations in tissues
such as the liver. the low rate of division of the maturefunctional cells can be increased, e.g., by partial
hepatectomy, and in this case the cells may appear
radiosensitive. In the renewing "hierarchical" typetissues [P25] which are specifically discussed in thisAnnex, such as the bone marrow, gastrointestinal
mucosa, epidermis and testis, the maturing and mature

cells are resistant because they have. respectively. little
or no mitotic potential. In contrast, their progenitor
cells have the potential for many divisions and may
die from mitotic death. The probability of mitotic
death of a cell is a function of the dose and of thenumber of divisions a cell has undergone since
irradiation. After doses up to 6 Gy. irradiated cells
have a high probability of completing one division
successfully. but a much lower probability of completing six divisions [H41]. Cells that successfullycomplete six divisions or more can form colonies ofmore than 50 cells and generally are capable of many
more divisions if the cells remain undifferentiated.
These colony-forming cells are vitally important for
the repopulation of many early-responding tissues (seebelow).
11. The dose-response curve for the survival of thesecells in some tissues (skin, intestine) shows a relatively
low sensitivity to doses up to I o r 2 Gy. followed byan increasing sensitivity at higher doses. The sensitivity
to high doses can be approximated to an exponential
curve. which is expected due to the stochastic natureof radiation action [I8. T24. U4]. This is characterized
by the parameter Do, which is the dose required toreduce survival by a factor I/e on the exponential
portion of the survival curve. Other associated parameters are the size of the "shoulder" region. which ischaracterized by the intercept of the exponential
survival curve o n the linear dose axis, Dq. or o n thelogarithmic survival axis, n. of a semi-logarithmic
plot. These are related by Dq = Do In n. Survival
parameters measured for various human clonogenic
cells assayed in primary culture are given in Table 1.
Cells that die by interphase death are often very
radiosensitive, e.g., lymphocytes [W26], and thisincreases the overall range of sensitivities. Alternatively.
the shape can be described by a continuously bending
curve when log survival, S. is plotted against dose, D.
where
S = exp - (aD + PD2)
In this case a is the parameter describing the initial
sensitivity, and the sensitivity increases at higher doses
and the dose. Thisdepending on the value of
formulation is generally considered to represent betterthe response of cells to fractionated exposures thanformulations based on Do [T24].
12. The response of cells in vitro to single doses ofradiation, in terms of their colony-forming ability, canbe modified by a delay after radiation and before thecells are induced to proliferate. This time interval
allows repair of potentially lethal injury t o occur. suchthat more cells retain their colony-forming ability.
This type of repair is likely to be important in therecovery of tissues after irradiation. The amount of
repair in the tissues under consideration in this Annex
will be smaller than in late-responding tissues, where
the rates of cell division are lower and remain low forlong periods of time after irradiation so that more
repair can occur. In the normal tissues of rodents,
where repair of potentially lethal damage has been
investigated in vivo, the effect generally does notchange the Do value but it increases all levels ofsurvival on the exponential portion of the curve byfactors of about 5 for mammary epithelium [G6], andabout 3 for thyroid epithelium [M24] and hepatocytes[J5]. Other data for hepatocytes show an increase in
Do [Fll]. In bone marrow the opposite effect isobserved; namely. a decrease in survival by a factor of 2,
which could be due to radiation-induced differentiation[HI I], specific for this cell type. The increase insurvival observed for most tissues and attributable torepair of potentially lethal damage shows a peak insurvival level by about 4 hours which remains
unchanged at 24 hours. Studies using assays in vitro
have revealed a time-related increase in Do for mouselung cells and kidney cells [U4]. With the latter, theeffect observed at 8 hours disappeared by 24 hours.
The effects of protracred doses are discussed inchapter 111.
13. The earliest effects on irradiated cells are notmediated through mitotic death but are connectedusually with membrane integrity. Examples of such
early phenomena are the effect on cells comprising theautonomic nervous system that leads to the symptoms
a n d signs of the prodromal syndrome. the interphasecell death characteristic of certain lymphocytes [Y5]a n d salivary gland cells [S32] and blood vessel injury
associated with acute erythema [P28]. When cells are
not killed after low doses, membrane injury is
generally recoverable. After high doses. these acuteeffects are often prognostic for later more serious
injuries which develop as a consequence of subsequentcell death in other cell populations.
B. TISSUE EFFECTS
14. The majority of the tissues that respond early
after irradiation are hierarchical in structure [P25]. In
these, mature cells are replenished from proliferative
cells by division, differentiation and maturation. The
proliferative cells committed to differentiation are
produced by very few ancestral stem cells. which arecapable of self-renewal and of differentiation (Figure I).
Under normal steady-state conditions, the rate of loss ofmature cells is equal to the rate of their production.

15. Clinical signs of injury will occur when the lossof mature cells has reached a critical level in a n yparticular tissue. The loss may be induced directly inthe mature cell population, as in the case of lymphopenia. Alternatively, it may occur gradually at a rate
governed by the natural lifetime of the mature cells
when their numbers are not replenished because theirprecursors are sterilized, as in intestinal mucosa [M16,P251. In the intestine, the rate of loss may be
exacerbated by other factors. such as bacterial infection, which can modify the normal rate of turnover ofthe cells [M5]. Also. there may be a variable lag
period between the time the critical level is reachedand the time of failure of the tissue or death: an
example is death due to bacteraemia and electrolyte
losses which follow cellular depletion in the intestinal
mucosa.
16. Effects that are characterized by a threshold doseand by a severity that increases with increasing doseare called non-stochastic effects 119, U4]. Thresholddoses for relatively minor effects are generally smaller
than those for severe tissue injury. The time for the
maximum effect is also usually dependent on the dose,
occurring earlier after higher doses. When doses are
relatively low and not all stem cells are killed, tissue
injury is followed by recovery mediated throughrepopulation and differentiation of the precursor cells.
The stem cells reproduce themselves and they also
differentiate into precursor cells which divide a n damplify the number of repopulating cells. Afterseveral or many divisions, these "transit" cells mature
into the functional cells in the tissue. The time courseof repopulation of the mature cells depends therefore
on the rate of differentiation of the stem cells, thenumber of amplifying cell divisions and the cell cycle
times [B16, M16. P251.
17. After doses higher than about 10 Gy, where
virtually all cells in hierarchical tissues are srerilized,
the time required for ablation of the mature andfunctional cell population is independent of dose, andin many cases it approximates the normal transit time

Figure I. Diagrammatic representatlon of cell population hierarchy wheremature cells are produced from proliferative cells. The ancestors of thelineage are the stem cells which renew themselves (left arrow) and which
also differentiate into various maturing cell llneages (right arrow).

from one of the lesser differentiated precursor cells tomaturity [M16, P8]. For the f e u non-hierarchicaltissues that respond relati\lely early after irradiation,such as the lung, the latency interval from irradiation
to failure may indeed be dependent on dose after
fairly high doses before a plateau in latency is reached[M 161.
18. After intermediate doses, where most cells in
hierarchical tissues are sterilized. the small number ofsurviving cells in a given tissue type will vary
markedly from one animal to another, for the same
dose; this results from the stochastic nature ofradiation in killing cells, which follows a Poisson
distribution. It may be expected that in some cases thenumber of surviving celis necessary for regeneration of
the tissue will have fallen below a critical number, andit may also be expected that the incidence of suchcases is dosedependent [H12, T241. This allows theconstruction of dose-incidence curves for particularlevels of effect in tissues. e.g., tissue o r organ failure,o r death of animals, as shown in Figure 11.
19. The incidence of a given level of injury is usuallyrelated in a sigmoid fashion to the dose. Many
empirical distributions have been tested for their
goodness-of-fit to a large number of dose-incidence
curves for marrow failure in various species, andoverall the logistic and probit models were the best

representations of the data [M48]. The probit model isbased on the normal (Gaussian) distribution [U4, 181.
The 50% incidence level may be estimated mostaccurately. The slope of the curve, characterized by
the standard deviation of the distribution (commonly
called the probit width), is a measure of the variationin response among individuals in the population atrisk. The dose for 50% incidence of lethality (LD,,) o r
other effects (ED,,) and the probit width (G) are thetwo parameters commonly used to describe the shapeof the curve (Figure II; see also other examples in
Figures XXI and XXII).
20. Three main sources ofvariation may contribute to
the probit width [H 121. First, there is the Poisson distribution of lethal events among the critical cells at risk.
The probit width generally is not less than the D, tSalue
for the target cells (which may be in sensitive or resistantphases at the time of irradiation), and in those systems
that the Poisson distribution adequately describes event
frequencies, the probit width is empirically about 1.2 Do[L3]. Second. there is the variation in sensitivity,
I/D,. between cells in different individuals. Third,
there is the variation in dose delivered to different
individuals. This last source of variation may relate to
the distance from the source or, in some situations,variations in the shielding of parts of the body. In
cases where the first source of variation predominates,a Poisson model can be used t o construct a dosemortality relationship, and this is not markedly
different in shape from a Gaussian curve over therange of mortalities measured from about 5% t o 95%[L3]. Conversely, a lower limit to the sensitivity of thetarget cells can be deduced from a mathematicaltransformation of the mortality probabilities versus
dose [G33.
C.

T H E RADIATION SYNDROMES

21. The lethal effects of radiation in animals reflect
failure of particular organs. These fail after different
periods of time, related to the underlying cell kinetics(see section 1.B). There is a latency period before thedevelopment of injury. and following the expression of
injury there may be a recovery phase, depending o n thedose. The temporal sequence of events is characterized
by a combination of symptoms and signs (a syndrome).
Radiation syndromes in man have been discussed in a
number of publications [e.g., A16, B31, C36, C41.
G26, L22. T23, U1, U4. U9, W13. Y7].

30SE ( I inear)
Figure Ii. Diagrammatic representation of a typical dosesurvival curve for lnadlated anlmals, uslng a linear ordinate or aprobability ordinate. The LDSoIs the dote for 50% Incidence,and the slope Is characterfzed by the standard deviation (a) of
the dlstrfbution.

22. Different organs fail over different ranges ofdose. The response of an organ is due primarily t o thedose it receives, but this can be modified by effects inother irradiated organs: for example. granulocytopenia
allows the development of bacterial invasion following
epithelial loss in the irradiated gut. These additionalfeatures will change the incidence of mortality as afunction of increasing dose by an amount that
depends on the target tissue at risk and the particularconfounding effects applicable.
23. In studies using groups of animals belonging todifferent mammalian species, the pattern of mortality
versus acute dose can be delineated into a series oftypical syndromes; namely, the bone marrow syndrome,

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A

Goats

[ R 1 5 1 (gamma rays,
unilaterally t o mixed)- .....Man (estimated) [ B 3 3 ]B o n e marrow+-Intestine++-- CNS*APPROXII4ATE DOSE (Gy)
Flgure Ill. Suwlval tlme of several mammallan specles after varlous
whole-body doses (doses are quoted as approxlmate maximum tlssue
doses).
[B16, T24]

the gastrointestinal syndrome and the neurological (orneiirovascular) syndrome. Representative data foranimals are shown in Figure 111. Doses (Gy) arequoted as approximate maximum tissue doses. Withmice a n d monkeys. doses in the target tissues, i.e.,
marrow, intestine and CNS, probably are within 10%of these doses. With swine and goats, doses in the
marrow and intestine may be less than the quoted
doses by slightly more than 10%; for swine, this figure
may be about 20% for bone marrow and could be up
to 30-40% for the intestine if the dose in the middle of
the abdomen is the most relevant dose. The percentage
for goats is uncertain, as the irradiation was unilateralusing mixed gamma rays and neutrons. Man is
expected to conform to a similar pattern of response
versus dose (dotted curve, Figure 111). Figure 111
shows that in the interval of dose from roughly 2 to
10 Gy, where the bone marrow syndrome occurs.
survival time decreases with increasing dose; survival
time remains relatively constant between roughly 10 to50 Gy. where the intestinal syndrome prevails; at still
higher doses, the neurological syndrome becomes
predominant and over this interval survival time again
becomes very dependent on dose. It should, however,be emphasized that the syndromes are idealized
clinical pictures, which are difficult to distinguish inpractice, particularly when the inhomogeneities indose are very pronounced and when injury from othercauses is present [B57, W28, W291.
1. The prodromal phase

24. The prodromal phase comprises the symptoms
a n d signs appearingin the first 48 hours post-irradiation[C36. G2]. After supralethal doses of several tens of Gy,
all individuals begin to show all symproms characreristicof this phase within five to 15 minutes. The reaction ismediated through the response of the autonomic
nervous system -and is expressed as gastrointestinal
and neuromuscular symptoms. The former symptoms
are anorexia, nausea, vomiting, diarrhoea, intestinal
cramps, salivation and dehydration. The neuromuscuIar
symptoms are fatigue. apathy, listlessness, sweating.
fever, headache and hypotension, followed by hypotensive shock. The reaction after high doses ismaximal within 30 minutes. then diminishing until itmerges closely with the neurological syndrome or, later,
with the gastrointestinal syndrome. Leukaemic patients
given 10 Gy to the whole body at 0.05 Gy per minutein many cases had a fever, occasionally associatedwith chills at the end of irradiation, but they wereusually afebrile by 24 hours [Di7]. After lower doses.
the symptoms are delayed, fewer and less severe.
comprising mainly anorexia, nausea, vomiting andfatigue. Vomiting is infrequent after doses below I Gy
[B32, D9. L8]. The responses can be produced byseparate irradiation of the head, thorax o r abdomen,
the last being the most sensitive region [G2]. Also, theregion below the umbilicus is less responsive than theregion above it, as shown by prodromal responses incancer patients receiving half-body irradiation at
3-10 Gy [FI 81. In monkeys, vomiting is suppressed
during incapacitation after high doses [M29].

-

25. Mechanisms of radiation-induced nausea andvomiting have been discussed [H34, Y33. The neuralcontrol mechanism for emesis is located in two
distinct regions of the medulla oblongata: the area
postrema containing the chemoreceptor trigger zone

(CTZ) and the vomiting centre [B34]. The latter is the
final pathway for emesis, whether the signal originatesfrom the gastrointestinal tract o r the CTZ. Ablationof the C T Z eliminates prodromal vomiting in the dog,monkey and man. Small peptides are implicated as
mediators of emesis [C23]. Inflammatory processes
could be involved in post-irradiation vomiting. assuggested by the success of anti-inflammatory agentsin controlling emesis in animals [H30] and in patients
receiving large-field or whole-body irradiation forradiotherapy [B32, S17].
26. Attempts have been made to define dose-response
relationships for the various signs and symptoms of
the prodromal phase. This has been done for casualtiesof the atomic bombs 1051, nuclear accident victims
a n d cancer patients receiving therapeutic whole-body
irradiation [M18. LIO]. The most comprehensive
studies with cancer patients involved 504 individuals
irradiated at various hospitals in the United Stares andCanada [L8]. The observations were corrected for thenatural incidence of between 8% and 19% of nonradiologically induced symptoms. ED,, values (effective dose for a given response in 50% of the irradiatedindividuals) forvarious prodromal symptoms occurring
within 48 hours are giver! in Table 2. Higher doses
were required to elicit responses within 12 hours
rather than within 48 hours. and after lethal doses theonset of vomiting in 100 pa;ients was calculated to begreatest about two hours after irradiation [L4]. Aftervery low doses, the peak incidence of nausea and/or
vomiting, if these symptoms occurred, was calculated

to be approximate1~-6 hours after exposure [GZ]. An
approximate relationship between the time of onset ofprodromal symptoms and dose is shown in Figure IV.
A comparison of ED,, values for patients not showing
signs of illness before irradiation and ED,, values for
all patients showed that the values for the former were
only slightly greater than for the latter, suggesting that
illness did not markedly predispose t o greater responsiveness to prodromal symptoms. This was also
indicated by the similarity in the dose-incidence
relationship for vomiting. when the clinical data werecompared with those for 45 healthy individuals who
were separated into four average dose groups (label 2
in Figure V) [L4. U5]. The start of the prodromal
reaction in people suffering from the bone marrowsyndrome coincides satisfactorily with the data in
Figure IV.
27. In relatively healthy Ewing's sarcoma patientstreated with whole-body irradiation [M34, R6], prodromal symptoms were observed in all those receiving
3 Gy, but not in those receiving 0.5-2.2 Gy. With
whole-body irradiation of leukaemic patients using
10 Gy to the midline delivered at 0.05 Gy per minute,nausea and vomiting began after 3-4 Gy had been
given [T19, T201. These patients were treated withhigh-dose cyclophosphamide during the week preceding irradiation, and they received sedation withbarbiturates and chloropromazine before irradiation.
Vomiting after 3 Gy had been accumulated was also
seen in another series of leukaemic patients given
whole-body irradiation [B32]. Vomiting did not occur

A Accident

A Therapy
0 Conposite
Expert opinion
0.01 i
0.5

I

I

i

1

10

100

DOSE (Gy)
Flgure IV.

Relationship between tlme of onset 01 prodromal symptoms and dose In man. Dose rates ranged from very high(accident cases) down to 0.3 Gy per minute (radlotherapy patients). Approximate mldllne doses are quoted.
(Modified from [B33].)

followed by transient periods of depressed or enhanced
motor activity leading to total incapacitation anddeath.
30. Histological studies on the brains of rhesus
monkeys receiving 100 Gy showed perivascular infiltration, haemorrhages and oedema, reaching a peak at
8 hours after irradiation [V6]: pycnosis of neurons was
maximal at 24 hours, suggesting that vascular changes
might be the initiating lesion in the brain.

DOSE TO ACDOHEH (Gy)Figure V.

Dose-effect relatlonshlp for prodromal vomltlng
wlthln two days in man.

[us1

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2 - accident cares [L4]: 6
accldent cases [TS]; 7 - therapy
patients [T17]; 8 - Rongelap natlves exposed to fallout
radlation [L4]; 9 - rnldway between the normal arithmeticaland log-normal valuer In the analysis given by Langham [L4];10 - Toronto-therapy cases (11/14) wlth Gravol pretreatment;
doses calculated for a rlsk of 0.5 of. respectively,
11
anorexla. nausea, fatigue and vomltlng (same as symbol 7) anddiarrhoea (from left to right In figure) In 163 therapy cases [Lg].
Doses are orlglnal estlmates In the cases of accidents.

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earlier than 30 minutes after doses from 2.7 to 7.0 Gy.
The effects were independent of dose rate above
0.06 Gy per minute.
28. Quite marked variations in responses are apparent
between various small series of leukaemic patients
irradiated similarly; this could be due to differences inthe severity of their illnesses and in medications
supplied. For example, only two out of eight patientswith haematological malignancies vomited during
irradiation with 10 Gy given at 0.05 Gy per minute.
One of the two vomited after 5 Gy had been delivered
and the other after 7 Gy had been delivered [C35].
Four out of seven ill cancer patients given about 1 Gy
at 0.06 Gy per minute vomited, between I and4.5 hours after irradiation, as did three out of four at
1.5-2.5 hours after about 1.3 Gy [L34]. Twenty-two
out of 30 patients with various advanced cancers given
1.3 Gy at 0.02-0.05 Gy per minute experienced nausea
but did not vomit [M 181.
2.

The neurological (neurovascular) syndrome

29. Doses higher than about 100 Gy to most
mammalian species result in death from cerebrovascular injury within two days. Survival times areshorter for higher doses, and after 1,000 Gy most
species survive only a few hours or less [B 161. The
effects of radiation on the central nervous system(CNS) were reviewed in the UNSCEAR 1969 Report[U2]. The CNS syndrome is characterized by severe
symptoms and signs of the prodromal syndrome,

31. A study of the brains of 49 casualties who died atvarious times greater than 6 days after the Hiroshima
and Nagasaki bombings revealed pathological changes
characteristic of perturbations in vascular permeability[S7]. In 10 patients surviving accidental gamma- andneutron-irradiation (average whole-body dose, 5-6 Gy;
average head dose, 8-10 Gy), cerebral lesions (disturbances in the brain circulation of the blood andcerebrospinal fluid) were found soon after irradiation[K8]. In monkeys. irradiation of the head alone
produces the CNS syndrome [CS]. One man receiving
inhomogeneous whole-body irradiation, with a doseto the front of the head of about 100 Gy of mixed
gamma and neutron radiation, died after 35 hours.
The main neuropathological finding in the brain(mean dose of about 25 Gy) was severe oedema. The
heart (dose of about 120 Gy) showed interstitial
myocarditis, which was considered the primary causeof death in this particular case [S6]. The findings
among the victims at Chernobyl, in connection with
the neurological syndrome, are described in the
Appendix.
32. High doses can result in severe cardiovascular
dysfunction [H46]. For example, in two persons
involved in criticality accidents, the inability to maintainsystemic arterial blood pressure was considered theprimary cause of death [S6, F171. Also, in a study ofcancer patients given half-body irradiation, two deaths
were attributed to myocardial infarction after an acute
hypertension episode during the first few hours postirradiation [S 171.
33. Changes in sensory perceptions are also produced by high radiation doses. Reduction of tactile
sensitivity and skin sensitivity has been reported incases of accidental irradiation in the lethal range ofdoses [Kg, S241.
3.

The gastrointestinal syndrome

34. Animals receiving doses of between about 10 and
50 Gy die with signs of the gastrointestinal syndrome.
The mean time to death after doses of about 50 Gy invarious large species of animal varies between 3.5 and
9 days [B16]. The symptoms in man follow those of
the prodromal phase, and include anorexia, increased
lethargy, diarrhoea, infection, and loss of fluids andelectrolytes. Other signs include weight loss, diminishingfood and water intake, gastric retention and decreased
intestinal absorption [B 16, B56, G3 I]. The leucocyte
count falls dramatically, and there may be haemorrhages
and bacteraemia, which aggravate the injury andcontribute to death after high doses and also afterlower doses where the gastrointestinal and bonemarrow syndromes overlap.
35. The intestinal signs that follow the prodromalphase appear as a consequence of cell depletion of theintestinal lining, as described in detail in the UNSCEAR
1982 Report [U4]. The depletion is due to loss ofreproductive capacity of the clonogenic cells in thecrypts, s o that the normal continuous flow of new
cells on to the villi ceases. The hierarchy of cell
populations in the intestinal mucosa is shown diagrammatically in Figure VI. The amount of cellsterilization is dependent on dose.
36. Histological specimens from individuals whodied with signs of severe intestinal damage after
irradiation from the atomic bombs in Japan revealed
atypical epithelial cells, an oedematous and atrophic
mucosa and petechiae, as well as ulcerative lesions
after the seventh day [05]. Similar histological findings
were observed in monkeys dying 6-8 days after wholebody gamma-irradiation [W7]. In these monkeys themost prominent findings at necropsy were gastric andcolonic ulcers. together with severe mucosal atrophy.
The incidence of colonic ulceration was independentof dose over the range tested, 15-75 Gy, but theincidence of gastric ulceration increased with increasing dose. Gastric ulceration developed after the fourthday. predominantly in regions of the stomach richestin parietal cells.

37. The time course of events is almost independentof dose between 10 and 50 Gy but is very dependent
on the species. The time course is correlated with therate of loss of the intestinal cells covering the villi. For
example, the development of the gastrointestinal

syndrome is longer in germ-free than in conventionallyhoused mice. in which the villus transit time is shorter[M5, T261. In man, the cell transit time on the villus is
3-4 days, as shown in Table 3. which summarizes
kinetic data for the intestine. The time of death is also
influenced by other concomitant factors, such as
infection, haemorrhage and fluid loss. The dose range
resulting in the gastrointestinal syndrome in man is
unknown, but it is probably similar to that observed
for large animals (see Figure 111). Gastrointestinal
signs were noted after whole-body irradiation ofleukaemic patients prior to marrow transplantation,
when the dose delivered at about 0.05 Gv. oer. minute
was increased t o 12 G y [Dl 71.

38. The time to death can be deduced from the timecourse of the frequency of deaths following the atomic
bombs in Japan. For a total of 757 documented
deaths in Hiroshima and Nagasaki [04], the timecourse of deaths showed two clear peaks in frequency.
one between days 6 and 9 and the other between days
20 and 30 (Table 4). The first peak is attributed to theintestinal syndrome and the second to the bonemarrow syndrome. One group of people dying artimes around the first peak comprised 21 documented
individuals who were in the Bankers Club in Hiroshima
at the time of the explosion [05]. Eight of themsuffered radiation injury only and died at various
times between 6 and 17 days after irradiation. On thefifth day after exposure, the leucocyte counts were
below 500 per pI in five of the seven cases in the
Bankers Club who died in the first week. The degreeof anaemia was very variable. The sample in Table 4 isa very small proportion of the people that died after
the bombing, and therefore selection procedures may
have influenced the apparent distribution of deaths.

Figure Vi. Diagrammatic representation of cell production In
Intestinal crypts, with new cells migrating on to the functional
units, the villi.
(Adapted from [P29].)

Also, there may have been a contribution frommechanical injuries. A more extensive analysis ofmortality versus distance from the hypocentre andtime after the bombing in Hiroshima was undertaken[I1 11. This revealed a peak in mortality rate slightly
before 10 days for individuals exposed at distances
between 500 m and 999 m from the hypocentre, and apeak at about 20 days for individuals1 between 1000 m
and 1499 m, after allowing for an estimated contribution to death from mechanical injuries. This isprobably the best evidence available concerning time
to death of people from the gastrointestinal and bonemarrow syndromes.
39. Deaths at these times from accidental exposures
have been rare, e.g., one person in the 1946 Los
Alamos criticality accident died at day 9. The granulocyte count was below 500 per p1 on day 6, and it
remained low until death on day 9 [H9] (see also the
Appendix for other cases of accidental exposure).
40. The gastrointestinal syndrome in all species
occurs concomitantly with various degrees of fluid,
protein and electrolyte loss, mucosal atrophy andulceration, infection and haemorrhage [B16, B56,
G311. In man. severe enteritis occurs from about day 4
after doses above 10 Gy and from about day 7 after
6-10 Gy (see Appendix). In animals, the incidence ofintestinal death can be reduced by transfusions withbalanced salt solutions and antibiotics: for example,
the LD,,, for rats can be increased by a factor of 1.4
by the use of antibiotics [Tl]. Fluid loss in thegastrointestinal syndrome can be counteracted byinfusions of electrolyte solutions [F3]. In most species,
it has been stated in general that early mortality (3-6days after exposure) after doses of 2-4 times theLD,,,,,or LD,,,, can be reduced to zero if supportive
care is employed [F3]. Such procedures, which involve
fluid replacement, parenteral nutrition, antibiotic a n d
blood-component transfusions, are effective in humans
suffering from the gastrointestinal syndrome. However,no accurate assessment of their efficacy in man isavailable even following the experience in Chernobyl(see Appendix).
4.

Haematological and immunological effects,
and the bone marrow syndrome

41. Animals die from marrow failure within 30 days
after doses between about 2 Gy and 10 Gy, dependingon the species. The LD,,,, is related to body weight, asshown in Figure VII. Death from bone marrow failure isassociated variously among species with granulocytopenia, thrombocytopenia and lymphocytopenia [B16].
In most species, anaemia is less severe than neutropenia
or thrombopenia and does not correlate well with timeof death [B 161. This is due partly to the radioresistanceand the long life span of red blood cells (109-127 days inman). The lack of a severe response indicates that
haemorrhage is not a major problem after doses in theLD,,, range, but it would become increasingly importantwith higher doses. Similarly, thrombocytopenia, occurring because of the sensitivity of megakaryocytes andthe relatively short life time of platelets in the blood(8-9 days in man [L5, C17, B16]), would not be
regarded as a major contributor to mortality in theLD,, range but would become increasingly important
after high doses.
42. Regeneration of these mature populations ofcells occurs from the surviving precursor cells after

Burro
Do9
Gerbi 1Goat
Guinea p i g
HamsterMarmoset
Flonkey
Mouse
Pig
Sheep
RabbitRat

0.01
Flgure VII.

0.1

1
10
BODY WEIGHT (kg)

100

1000

Relatlonshlp between LDSOIMand body welght for varlous mammals.
(Modlfied from [U4, U51.)

Mature c e l l s

C m i tted+

Precursor
cells

Red blood c e l l s

White blood c e l l s

Stem c e l l s
IIegaXaryocytes

T and B lymphocytes

Figure VIII. Simplilied diagrammatic representation of the haemopoietic hierarchy.
where mature cells are produced from proliferative precursor cells. Lett arrow
indicates renewal of stem cells, right arrows indicate differentiation and maturation
down particular lineages.

irradiation; the hierarchy of haemopoietic cells isshown diagrammatically in Figure VIII. The longer
the animal survives. the greater will be the contribution
to survival of cell progeny from primitive surviving
precursor cells in the marrow. Hence. in the short term,
rescue of the animal will be assisted by survival of themore mature precursors, e.g., the granulocyte/macrophage colony-forming cells (GM-CFC); and, in thelonger term, rescue will be dependent on the survival of
multipotential stem cells. GM-CFC are assayed invitro, and differences in radiosensitivity have beenreported among species (reviewed in [H 1 I]). GM-CFC
in dogs are more sensitive than in mice or in man.
However. in view of the marked differences inapparent sensitivity of human GM-CFC measured
using different culture conditions [B28], it is not clear
whether the differences reported among species areartefactual or absolute.
43. The sensitivity of haemopoietic stem cells has
been measured using the spleen colony technique inthe mouse [T8] and in the rat [C8], but not in otheranimals. The possibility exists t o measure the radiosensitivity of rhese cells in other species from theformation of foli of undifferentiated cells in irradiatedbone marrow [H48, S471. The precursor cell type thatcan be grown in vitro from different species and which
is so far known to be nearest to the stem cell in thehierarchy is a cell that is capable of forming colonies
in vitro comprising many haemopoietic cell types(Table 1). The concentration of these cells in bonemarrow is very low, as expected, so it is difficult tomeasure their intrinsic radiosensitivity. Their sensitivity
has been measured in mouse and in man, but not inother species.
In human bone marrow, the total number ofnucleated cells is reduced at day 1 by 10-20'37 after
1-2 Gy. by 25-30% after 3-4 Gy, by 50-60'35 after
5-7 Gy, and by a maximum of 80-85% after 8-10 Gy,
Resistant cells remain. such as macrophages, stromalcells, vascular endothelium and some mature granulocytes a n d eosinophils [M25]. At day 1 after doses of a44.

few Gy, resulting in the bone marrow syndrome, a
relative trebling of macrophages and stromal elements
has been reported [SZI]. Bone marrow cellularity
reaches a minimum value by days 3-4 after 5 G y or
above and by days 5-7 after 2-4 Gy. Regeneration canbe detected in the marrow at days 4-6 by the presenceof colonies of undifferentiated cells. The phase of
pronounced aplasia is characterized in the marrow byoedema, a lack of adipose cells and a cellularcomposition of mainly lymphocytes. monocytes andplasma cells. When regeneration occurs, the numberof undifferentiated cells increases to a maximum atdays 14-20. It has been reported that after doses of up
to 10 Gy cell regeneration in the marrow begins earlier
than after lower doses [B38. VIZ].
45. Various attempts have been made t o constructdose- and time-response curves for the changes inconcentration of platelets, lymphocytes and neutrophils in the peripheral blood of healthy humans
receiving whole-body exposures [A 14, B3 1. C37, PI 3,
W2]. A schematic picture of the smooth average timecourses for the various blood cell types after different
ranges of dose (Figure IX) was deduced from accidental human exposures [H9. C15, G9, H6. B29. 54.
T5, B17, S6, C l l ] . The values in these idealized
pictures are expressed as percentages of average levelsin the normal population. Control ranges ( t 2 SD)
measured in five separate studies have been summarized[T29]. The extremes are 4-1 1 lo9 WBC/I for males and
4-9 for females; 4-6 lo1' RBC/I for males a n d 3.7-5 forfemales; 34-5496 haematocrit for males and 33-48%
for females; 130-176 g haemoglobin/l for males a n d
1 13- 162 for females.
46. The patients irradiated prior to kidney transplantation showed a n earlier and more rapid decline
in numbers of lymphocytes and granulocytes than theaccident victims a t Oak Ridge (Y-12) a n d Vinca
irradiated with comparable doses. Also, in the patientsthe nadir levels (minimum values) were lower, but theregeneration of granulocytes began earlier a n d rose tohigher levels. These differences would be compatible

PLATELETSLYMPHOCYTES

0

10

20

30

40

TIME AFTER EXPOSURE ( d a y s )Flgure IX. Schematic plcture of average tlme courses for varlous cells
In the blood, after varlous doses of radlatlon In man, derlved fromaccldent cases.
(Redrawn from [WZ].)

with higher effective doses t o the patients, because
after the Y-12 accident the individuals receiving thehigher doses, compared with those receiving low
doses, had a greater fall in granulocytes but earlier
regeneration reaching higher levels by day 60 [A2].
The greater response in the transplantation patients isdifficult to explain, although it should be noted thatmany of the patients were anaemic and they had ashort expectation of life. Different marrow doses,
differences in the uniformity of dose, the contribution
from neutrons in the accident cases and the confounding influence of concomitant disease have all

been suggested as contributory factors [TIO, T11,
T121.
47. A greater-than-expected haematological response
was also observed in patients with chronic granulocytic
leukaernia [All exposed to 0.25 Gy and 0.5 Gy (rnidline doses) whole-body irradiation, in spite of the low
exposure rate of 0.0012 to 0.0076 Gy per minute (atthe midline). The rate of recovery of blood cell counts
was slower than in the transplantation cases discussed
above. These differences have been taken to indicatethat data pertaining to irradiated patients suffering

from haematological diseases are not applicable tohealthy individuals [All (except, perhaps, those data
pertaining to patients in remission) [B41].
48. Figure IX shows that the lymphocyte count is
the most sensitive index of radiation injury in the
blood, in the sense that, for the same dose, nadir levels
are reached earlier than for other cell types. Lymphocytes die in interphase, and doses of 1-2 Gy cause their
numbers to decline to about 50% of normal by 48 hours.
Decreases can also be observed during irradiation. For
example, at the end of a 4-hour period during which
10 Gy was delivered to leukaemic patients in remission, the lymphocyte count was 50% of pre-irradiationlevels, and it subsequently declined with a half-time ofabout 30 hours [D22]. A plateau was then reachedwhich is dose-dependent, remained for about 45 days
and was followed by a slow recovery over several
months. The dose-dependence of the plateau level has
been estimated in two reports from accident cases[W2. P131, and the results of the two reports are fairly
consistent, one with another (Figure X and Figure
A.1I.b).

----- Neutrophils
Lymphocytes...-......... Platelets

populations: this extends to about day 15 and isfollowed by a second decline to about day 25, due to alack of recovery in the stem-cell population. The
absence of a second rise in granulocytes is indicativeof the failure of haemopoiesis to recover permanently[B16]. The second abortive rise is not seen after doses
higher than 5 Gy (Figure A.V (left panel)).
50. With whole-body doses in excess of 6 Gy thecritical level of neutrophils is reached in 7-9 days; after
4.2-6.3 Gy, it is reached in 10-20 days. With doses
lower than 4 Gy, the critical level is generally reachedafter 20 days or more [U6]. The dose-dependence of
the white cell count is shown in Figure A.V (leftpanel), which depicts the time to the minimum
number of granulocytes; alternatively, Figure A.V(right panel) shows the time to reach the critical levelof 500 granulocytes per pl (see below). From Figure
A.V (right panel) it can be seen that after about 6 Gy,
the granulocyte level would be reduced to 10% (from5,000 to 500 per p1) in 12-14 days. In Figure X, thenadir is also 10% after 6 Gy, but it is reachedsomewhat sooner, after about 7 days (Figure IX).
5 1. The times between days 20 and 30 are criticalfor fever and infections. The period during whichagranulocytosis is observed coincides with a period offever both in animals [B17] and in man [ T l l , T12,
221. Studies of the correlation between granulocytopenia and the onset of fever showed that the latter was
better correlated with the time of the minimum
number of granulocytes (Figure XI [B37]) than withthe absolute number of granulocytes at the start of thefever (Figures XI1 [B37]). Fever and granulocytopenia
are also associated with intestinal injury [B31].
52. The degree and extent of leukocyte depression[Jl] and bone marrow aplasia [I 101 were shown to becorrelated with mortality in the Japanese exposed tothe atomic bombs. The chance of survival was verysmall in individuals having leukocyte counts of 1.000/p1

DOSE (Gy)Figure X.

ldeallzed average dose-response curves tor nadir
levels In blood cell counts.

w
2
1

49. Neutrophils show an initial increase in number
over the first few days after doses of 1-2 Gy or higher.
and this "abortive rise" is greater after larger doses(Figure IX). Immediately after the delivery of 10 Gy
in 4 hours to leukaemic patients in remission, thegranulocyte count rose by a factor of 2-4 [D22]. A
significant increase was noted as early as 10 minutes
into the irradiation, when only 1.2 Gy had been given.
The rise is probably due to a transient mobilization ofcells from marrow and/or extramedullary sites and toaccelerated maturation of precursor cells [B 161. Thisinitial phase of granulocytosis is followed by a decline
in the number of white cells, the rate and extent of
which are dose-dependent. At day 10 after doses of
2-5 Gy there is the beginning of a second abortive rise.
due to recovering haemopoiesis from precursor cell

0

4

8

12

16

20

24

28

32

36

SECOND DEPLETION HAXIMUM (day)Flgure XI. Time of the second depletion on the granulocyte
count CUNe, corresponding to the beginning of agranul0~ytOSlS
fever In man.

tf337l1O W

Y-irradiation
0 y-n-irradiation

750-

50b
250&I

I

0

8
12 16 20 24 28 32 36
BEGIN1IING OF AGRANULOCYTOSIS FEVER (day)4

Figure XII. Granulocyte count at the beglnnlng of agranulocytosls fever.
P371

in the third and fourth weeks after exposure. and thecorrelation of leukocyte counts with survival was bestin the third week. Counts of less than 3,00O/pI were
not so hazardous in the fourth and fifth week as in thethird week. The studies also showed that mortality
was greater in Hiroshima than in Nagasaki forequivalent blood count levels. A possible reason
considered at the time related to the estimated greater
contribution to dose from neutrons in Hiroshima,associated with injury in other tissues contributing todeath; this explanation is now unlikely because revisions in dosimetry have markedly reduced estimates of
the neutron components of that dose.
53. The time course of the thrombocytopenia isbroadly similar to that of granulocytopenia (Figure IX),
but there is no second abortive rise. The dose-response
relationship for the nadir of platelets shows a slightly
more sensitive response than for that of lymphocytes(Figure X). After about 1 Gy. a decrease in platelets
to 100.000 per pl is observed by day 30. The higher thedose, the earlier and greater is the reduction; after
doses greater than 6 Gy, a minimum level of 10,000
per 111is observed by days 10-15. A thrombocytopenia
below 30,000-50,000 per 111 may be associated withbleeding, which can be prevented by transfusions offresh platelets [F3]. Experience in treating patients
suffering from bone marrow syndrome indicates that thecritical level of thrornbocytes requiring platelet transfusion is 20,000 per pI (see Appendix). Haemorrhages
are also associated with the development of infections[J4, 051. Owing to the long lifetime of the radioresistant red blood cells, anaemia is observed acutely
only when bleeding has been substantial [B 161.
54. The effects of radiation upon the immune response
were reviewed by UNSCEAR in 1972 [U3]. As noted
above. lymphocytes are especially susceptible to theacute effects of irradiation. Since this cell type isan integral part of the immune system, profoundabnormalities of immune function would be expected
as a consequence of whole-body exposure. Thisappears to be the case, although data pertinent to man
are limited [C48, V19, M53J. The paucity of information is due in part to the fact that most of therelevant observations were made before many of theconcepts that underlie current thinking on cellularimmunology had been developed, in particular theconcept that lymphocytes are heterogeneous in termsof structure and function. The situation is further
complicated by differences in the radiosensitivities of
those subpopulations of cells whose co-operative
activities result in an immune response [A19. A21,
A33, M53, M54, W26].
55. An increased susceptibility to infection has been
well documented in persons exposed accidentally andtherapeutically to doses in the low- to mid-lethal range[A3]. These infections may be caused by either
endogenous (normal flora) or exogenous organisms.
However, when assessing the role of an alteredimmune response in the presence of these infections.
it is important to keep the following points in mind:(a) radiation a1 these dose levels may cause an increasein permeability of the vasculature, whch may allow
the normal bacterial flora to enter the circulation, and(b) when employed therapeutically, whole-body irradiation is generally administered to persons withhaematological disorders, often in conjunction withhigh-dose chemotherapy and bone marrow transplantation. Even with bone marrow from an identicaltwin, the confounding effects of the primary disease(often lei~kaemia or aplastic anaemia) and othertherapies on the immune response are considerable.
Despite these cautions, however, there can be little
doubt that whole-body irradiation causes marked
acute alterations in the immune response of man.
56. Support for the above statement comes fromseveral sources, the first of which is the whole-body
irradiation of experimental animals. especially mice,
whose immune response is remarkably similar to thatof man. The consequences of such exposure in miceare profound, even with whole-body doses of less than
1 Gy [A 191. The effects on the immunological system
are dose-dependent and may result in an augmented
or a suppressed response to the same antigen, dependingon the dose and the time between irradiation and theintroduction of the antigen [AZO]. This discrepancy inresponse appears to relate to differences in the radiosensitivity of effector and suppressor cells. Suppressor
T cells (CD8') are more radiosensitive than helper
T cells (CD4'). and B cells have an intermediate
sensitivity [A21, S471. In addition, whole-body irradiation with doses as low as 0.5 Gy results i n marked
impairment of the normal recirculation of lymphocytes[A22, S221.
57. The second source of evidence is the results ofgraded doses of radiation administered in vitro. With
some antigens, it is possible to evaluate the responseof immuno-competent cells completely in vitro. Thesein vitro responses are strikingly similar to the corresponding in vivo reaction. Irradiation of one orseveral of the component T- and B-cell populations
prior to introduction of the antigen results in doserelated abnormalities in function, abnormalities thatby and large would have been predicted from complementary experiments in laboratory animals [A19,A23].
58. A third source of information is the results ofpartial-body exposures administered therapeutically.

Extensive immunological assessment has been carriedout in persons given total lymphoid irradiation [TLI]
for Hodgkin's disease [M53. V19] and in otherpersons irradiated regionally. Although the extent andthe character of these changes appear to depend on
the region of the body that is irradiated [B39], theresults in genera1 correspond to what would have been
predicted from experimental animals. One of the beststudied groups of patients receiving regional irradiation
are women who have received local radiation therapy
for carcinoma of the breast. These and related studies
support the notion that lymphocyte subpopulations
differ in their depletion and repopulation after irradiation [P15. W3]. The following abnormalities werenoted in individuals who had received 45 Gy regional
irradiation over five weeks before or after mastectomy.
in comparison with individuals treated by surgery
alone [R16. W171: (a) surface markers: there was asignificant reduction in the total lymphocyte count,which returned to a suboptimal plateau by sevenmonths after irradiation. The plateau persisted for atleast 10-11 years after radiotherapy. The reduced
recovery level was due primarily to a reduction in T-cells(lymphocytes binding to sheep erythrocytes and reactingwith the monoclonal antibody Leu- l (CD5)). There wasa significant reduction in T-cells of the helper/inducer
phenotype (detected by anti-Leu-3a (CD4)). and thispersisted at one year and 10 years after irradiation.
Normal numbers of T-cells of the suppressor/cytotoxic
phenotype (stainable with anti-Leu-2a (CD8)) were
found between one year and 10 years after irradiation.
Induced IgG and IgM synthesis was also reduced after
irradiation, with later recovery. In a related experiment, Job et al. [J9] showed a reduction in thehelper/suppressor ratio in patients receiving adjuvant
radiation therapy for primary breast cancer and inpatients receiving brachytherapy and external beam
radiation therapy for carcinoma of the cervix or
corpus uteri. This change began during therapy andwas due to a decrement in helper T cells detected by
the OKTB monoclonal antibody. These alterations
persisted for at least 18 weeks after irradiation.
Similar observations have been made in patients
receiving total lymphoid irradiation for rheumatoid

arthritis [KIO]: (b) mitogen and antigen responses: no
significant changes in response of T-lymphocytes to
PHA were found. but the reactivity to PPD tuberculin
was markedly decreased after irradiation and gradually
restored during the subsequent six months. The
reactivity to allogenic lymphocytes (MLC reaction)
was also reduced, but had reconstituted three months
later; (c) cytotoxic functions: lectindependent cytotoxicity was unaffected by irradiation, but antibodydependent cytotoxicity was reduced after irradiation,
recovering by three years. Natural killer cell activity
was unaffected when tested against one tumour cell
type, but affected with another. The latter decrease
was restored by three months.
D.

EFFECTS ON OTHER TISSUES
1. Skin59. Effects in skin are important. Because they are
dose-dependent and because they are readily detectedby eye, they can provide an approximate measure of
injury with prognostic value. Attention must be paid,
however. to the type of radiation used, because withhigher photon energies, there is a build-up of dose in
the surface layers and the maximum dose may bedelivered to the dermis or deeper. In these cases,
estimates of dose in deeper tissues derived from effects
in the epidermis could be underestimated.
60. The thickness of human epidermis ranges from40-50 pm on the trunk to 370 pm on the fingertips [I6.
K15]. The average time for all basal cells to reach thestratum corneum was measured to be 17.7 4.2 (SD)days [E6]. A review of these times at different sites inthe body gave 32-36 days for the palm of the hand,
17 days for the upper limbs and 29-30 days for the
lower limbs [RIO]. The transit time through thestratum corneum is between six and 21 days, dependingon the body site [BI]. A summary of cell kinetic datafor human epidermis, averaged over various sites inthe body. is given in Table 5. The hierarchy of cell
popuiation types in the epidermis is shown diagrammatically in Figure XIII.

+

Keratinised(Mature)GranularSpinous1t(Maturing)

Stemlproliferative(Basal)Figure XI11. Dlagrammallc reprerentallon ol the hlererchy of cell population types In theepldermls, drawn from a vertlcal sectlon through normal human epidermis.
(Adapted from [P28].)

61. The effects in skin are very dependent on thedose and on the area of skin irradiated (e.g., [A34,E12, H19, P281). Erythema proceeds in waves. Afterdoses greater than 10 Gy, there may be an initial
phase, which reaches a peak around day 1, followed
by a second wave between one and four weeks. Higher
doses produce erythema of increasing severity, and thelatency interval is shorter. After very high doses,
erythema can appear and disappear several times.
Erythema was used as a biological dosimeter in theearly days of radiotherapy, and the "threshold erythemadose" varied with energy, dose rate and field size
[E12]. Erythema is less easily recognized in pigmented
skin and in exposed skin areas. The dose resulting in avisible erythema reaction within four weeks in 50% of
individuals (not the initial transient erythema appearing
within hours) after an acute single exposure with200 kVp x rays over a 10 X 10 cm2 field on the medialsurface of the forearm is about 5.7 Gy [D6, L4].
62. In patients given radiotherapy to a 3 cm diameterarea of the scalp with 100 kVp x rays the percentage
of abnormal hairs increased between days 4 and 10[V4]. The incidence of abnormal hairs rose above 10%
only after doses to the hair roots of 0.75 Gy or more.
The incidence was about 50% on day 10 after 1.5 Gy,and doses above 2.5 Gy resulted in abnormality in
100% of hairs [V4]. Temporary epilation is produced
after doses of 3-5 Gy and is most severe in the second
and third weeks [D2], as noted, for example, inpatients receiving whole-body irradiation prior tokidney transplantation [TI 1, T121. Similar time courses
were observed in the survivors of the atomic bombs,
and if regrowth of hair occurred it was observed by
12-14 weeks after irradiation [05]. Epilation may bepermanent after doses greater than about 7 Gy. Hairon the scalp is more sensitive than the beard or bodyhair.
63. Desquamation reactions appear following marked
erythema, after acute radiation doses greater thanabout 12 Gy. The severity of the reaction depends on
the anatomical location, the vascularity and oxygenation of the skin, and the genetic background, age andhormonal status of the exposed individual [R12].
Dose-time and dose-incidence relationships have beenstudied in radiotherapy patients receiving doses torelatively small fields. Moist desquamation is produced in 2-3 weeks in 50% of individuals after a doseof about 20 Gy to areas of 35-80 cm2 [A4, E2.56, L4,
P2]. The maximum reaction occurs at about three
weeks. After whole-body irradiation with such doses,
the individual will have died from the intestinal
syndrome before the desquamation reactions occur,
except when the irradiation is poorly penetrating, as in
the treatment of skin diseases or in direct skin
exposure to short-range fallout radiation.
64. Desquamation reactions in skin are due primarily
to the killing of cells in the basal layer of theepidermis and its associated appendages [PI 1, P28].
Measurements of the sensitivity of epidermal clonogenic cells in situ in man have been made after
fractionated doses [A51 but not after single doses.
However, the sensitivity has been assessed using
human skin samples irradiated and assayed in vitro[DlO]. The survival parameters were Do= 0.7-0.9 Gy,
n = 10-16 (Table 1). The keratinocytes were moresensitive than epidermal clonogenic cells assayed insitu in mice or in pigs.
65. The time to full depletion of the epidermis after
high doses corresponds to the transit time from theleast-differentiated committed progenitor cell in thebasal layer to the surface in unirradiated epidermis[P8]. This was deduced using a model applied todifferent types of epithelia, in which it was assumed
that the clonogenic stem cells were sterilized after highdoses. and also that the few divisions of committed
proliferative cells, together with the processes ofdifferentiation, maturation, and migration, were very
radioresistant and hence unaffected. The normal
turnover time of the epidermis would be expected to
be longer than the above transit time by an amountequal to the lifetime of the stem cells in the basal
layer. The time to full depletion of the epidermis after
irradiation would be shortened where there is anacceleration of cell depletion as it proceeds after
irradiation [P8, P281.
66. The degree of skin desquamation is markedly
dependent on the area of skin irradiated. This has
been studied in radiotherapy patients [C6, E2, 56. 57,
M 1, P2, V8], and some of these findings are summarized
in Figure XIV and in Table 6. Some investigations
were confounded by the use of various degrees ofreaction acceptable as "tolerance" in different fieldsizes, e.g. [J6], as discussed in [H19]. In general, theeffect of field size is similar for single or fractionateddoses and can be described by either of the formulas:
Dose = k(area)-O-I6
Dose = k(diameter)-0-33
where k is a constant [C7. V8].
67. The extrapolation of the above formulae to areas
greater than 400 cm2 is uncertain, because evidence forvery large areas relates only to the use of lightly

Flgure XIV. Relatlonshlp between Iso-effect dose for skintolerance and fleld area using rlngle doses (bottom two curves)
or fractlonated doses (top two curves) In man.
[HI91

penetrating electron beams for the treatment of diffuse
diseases of the skin, and it is not known if these
diseases predispose to increased radiosensitivity. However. it has been concluded that there is little effect ofchanges in area for areas above 400 cm2 [S15]. The
50% erythema dose was estimated to be about 3 Gyfor a single dose of electron radiation to the total
body surface [S15, W6], corresponding to about half
the dose required for areas of 100 cm2.
68. It is the dose to the basal layer of the epidermisthat determines the degree of early skin desquamation.
and concomitant doses to the dermis have little
influence. This was shown by experiments in pigs
[M21], where various isotopes were used to irradiate
to different depths a 1 cm diameter circle of skin.
Surface doses to produce transient desquamation
varied enormously with the energy of the radiationfrom the isotope but the relative doses to the basal
layer, at a maximum depth of 90 mm. were much moresimilar (Table 7). Further experiments have been carriedout with pigs, comparing irradiation by strontium-90
and thulium-170 [P32]. The percentage of the dose
reaching the epidermal basal layer was similar for thetwo isotopes, but only about 10% of the surface dose
reached the base of the dermis using thulium-170,
compared with about 50% using strontium-90. Thesestudies concluded that there was no effect of field sizefor epidermal reactions with thulium for areas between
5 and 19 mm in diameter, but a marked effect of fieldsize was observed with strontium. This was considered
to be due to the contribution to repopulation fromhair follicles, spared more by thulium than bystrontium.
69. The severity of desquamatory skin reactions may
be decreased by post-irradiation treatments using
corticosteroids, but erythema is not decreased [H26].
Standard procedures of cleanliness during the healing
period will prevent infection. Skin haemorrhages
betechiae) in monkeys can be prevented by antibiotic
treatment [S3], suggesting that infection may be
involved in their initiation. However, once petechiae
have appeared, their development continues becauseof thrombocytopenia.
70. The effects of cell depletion in the dermis are
manifested later than in the epidermis and in theepidermal-associated hair follicles, primarily because
there is a slower rate of cell turnover in the constituent
cell types of the dermis. The dermis contains connective
tissue, sebaceous glands, muscle fibres, nerve plexuses
and nerve fibres, sweat glands and blood vessels. The
thickness of the dermis varies markedly over the body,
but is generally 1-2 mm [I6]. The effects on the bloodvessels after high doses are observed initially as
erythema and later as haemorrhages. Haemorrhageson the skin appear as small (petechiae) or larger(purpura) lesions. Purpura can appear as early as day 3,
but the peak onset occurs in the third or fourth week
after irradiation, predominantly on the upper half ofthe body [05]. The duration of purpura varies
according to the severity of the injury. and in fatal
cases the lesions remain until death. Purpura occurs
concomitantly with epilation in many cases, and it has
been described in nearly all people who died 3-6 weeks

after the atomic bombings [05]. Hence, although thedose-incidence curve is not accurately known, theeffect is produced by doses of 4-6 Gy.
71. Irradiation of the dermis with high doses produces a second wave of erythema (at 10-16 nteeks inthe pig and the rat). This is dusky red/mauve incolour and is considered to be due to damage to thedeep dermal plexus of blood vessels [HIS]. I t isfollowed by dermal necrosis, ulceration and sloughingof the dermis.
72. Pain is an important feature of the exposure ofskin to high doses of radiation. particularly in the caseof deep lesions after exposure of the ex~remities.Pain
is experienced during the first few days, it lasts several
hours per day and it may persist for long periods [N I].
The period of maximum pain corresponds to theappearance of vascular lesions.
73. Effects on sebaceous glands were observed whentreating facial acne with supeficial x rays [S13]. There
are 400-900 glands per cm2 on the head. After 3 Gy,glands are reduced in size by 20% at two weeks. After
4 Gy, the glands are reduced in size by 2550% at two
weeks, with recovery by four weeks. After 8 Gy, thegland size is 50% of normal at one week. with further
reduction at two and three weeks, and recovery tonormal size by six weeks. After 15 Gy to a 2 cm circle.
the glands are severely atrophied by two weeks, andthere are only a few small glands present up to twomonths later [S13].
74. Interesting clinical information about the skinreaction after beta-irradiation is contained in reportson the Japanese fishermen irradiated on board theLucky Dragon [K4] or on people irradiated in the
Marshall Islands [C16]. The frequency and intensity ofskin reaction were highest in individuals on the islandof Rongelap, where radioactive fallout was also
highest. The period of appearance of skin lesions andepilation in these people is described in [C16]. The
skin reactions to beta-irradiation observed during theaccident at Chernobyl are described in the Appendix.

2.

Oral mucosa

75. Information relating to the effects of radiation
on oral mucosa comes from observations on atomic
bomb survivors [05] and from radiotherapeutic treatments [P12, U9]. With the former, who received wholebody irradiation, oropharyngeal lesions occurred on
all mucous membranes but were more prevalent on
lymphoid areas than elsewhere [05]. The tonsils,
pharynx, nasal passages and tongue were frequently
involved. The lesions were concomitant in many caseswith epilation and purpura. The time of onset varied
from a few days to five weeks, with a peak in the
fourth week and a mean of 22 days. The initial
symptoms were pain in the throat or gums associatedwith swelling and inflammation. This rapidly progressed to bleeding, ulceration and, in many cases
necrosis. Ten per cent of survivors had severe ulceration. Healing was generally completed in 2-3 weeks,

with the lymphoid areas being the last to heal.
Antibiotics greatly assisted healing [05]. Necrotic
gingivitis occurred i n 10% of the 20-day survivors withoropharyngeal lesions in Hiroshima and in 6% in
Nagasaki [05]. This was characterized by redness.
swelling and haemorrhage, and there was ulceration of
the gums i n fatal cases. Healing occurred slowly by
re-epithelialization. The doses needed to precipitate
these lesions are not accurately known, but areapproximately in the range that cause epilation,
purpura and some deaths, i.e., 3-5 Gy.
76. Injury to the mucosa of the mouth and throat isgreatest in the cheeks, soft palate and hypoglossal
area; it is less in the gums. hard palate, nose, posteriorwall of the throat and tongue. Other areas. including
the larynx, are less responsive [P12]. After local
irradiation, accidental or radiotherapeutic. with dosesof 5-10 Gy. hyperemia appears on day 1 and spreads
to nearly all sections of the oral and nasal cavities. By
day 4-5 there is oedema in the posterior wall of thethroat, in the soft palate and the mucosa of the cheeks
and nose. with pain in the mouth. These effects
become more marked by day 10-15 and spread to thegums. tongue, and the hard palate. If there is necrosis,
it appears at 8-12 days. followed by re-epithelialization. Recovery of the mucosal surfaces after doses up
to 10 Gy occurs by 2-3 weeks after irradiation. Afterdoses of 10-20 Gy, erythema extends to the larynx,
there is virtually no latent period, there is pain andoedema in the mouth, and extensive mucosal necrosis
begins on day 4-5. The recovery of the mucosa is slow
and lasts for 1.5-2 months. Infectious complications
occur together with local haemorrhages, and the effects
are severe if there is also leukopenia [B36. G 14. K7, K8,
V13, V141. Oral mucositis was noted at 5-7 days after
whole-body irradiation of leukaemic patients (about
10 Gy, 0.05 Gy per minute) [D17].
77. Salivary glands are very responsive to irradiation,
but recovery is possible even after high (fractionated)
doses. Parotitis was observed after the Chernobyl
accident, predominantly in those individuals receiving
more than 6 Gy (see Appendix). This was coupledwith an inability to salivate and a high level ofamylase in the blood from day I to day 4 after
irradiation. Studies in monkeys have shown that theseeffects in salivary glands are due largely to the highsensitivity of the serous cells, which undergo rapid
interphase death after irradiation [S32]. In man there
is also a loss of taste, experienced after doses as low as
2.4-4.0 Gy [C49]. In patients given daily radiotherapy,
a 50% reduction in parotid gland secretion was noted
at 24 hours after the first dose of 2.25 Gy. and thesecretion was at negligible levels 24 hours after asecond dose of the same amount [S45]. This effect was
coupled with a transient tenderness and swelling of theglands. which was more severe after high doses. Dosesof 15-28 Gy produced a dry mouth at 2.5 hours. on
average. and pain and tenderness at 4.5 hours,
reaching a maximum between 12 and 24 hours [K20].
The symptoms disappeared by seven days. In leukaemic
patients treated with whole-body doses of 6-10 Gy,
parotitis occurred in many cases about eight hours
after the start of irradiation. and it persisted to
2-3 days [B32, D 171.

78. The effects of low-LET radiation on the eyes ofvarious species of mammal. including man. werereviewed by Merriam [M 151. Information concerning
early effects in man derive niainly from the treatment ofeye turnours by radiotherapy. and they are summarizedin Table 8. For the superficial ocular tissues (particularly the conjunctiva arid cornea), 10-15 kVp x rays
were used; in other cases, 120-250 kVp x rays wereused. Eyelid skin appears to be more responsive toirradiation than skin at other sites. the minimal
erythema dose for eyelid skin was quoted as about
2 Gy, with hyperemia of the skin observed after
12-15 hours. Single doses of 3 Gy produced slight
hyperpigmentation. and doses of 4-6 Gy gave marked
hyperpigmentation in a few weeks. A dose of 4-6 Gy
led to hyperemia after 6-8 hours, oedema andhaemorrhages on day 2 and erythema by 2-4 weeks inabout 50% of cases. Partial epilation of the eyebrowsand eyelashes can occur [Zl]. After 6-10 Gy there may
be erythema after 1-3 hours, together with oedema
and pain. Partial epilation of eyebrows and eyelashes
may persist for a few weeks, the eyelid skin becomesdry and atrophic, and telangiectasia develops. Necroticchanges in the eyelid skin and underlying tissues occur
at doses above 10 Gy. After 4-10 Gy. keratitis isobserved at days 20-40 in the upper epithelial layer ofthe conjunctiva. After 15-20 Gy, there is lacrymationand pain in the eyes. with irritation of the cornea andthe iris. In the absence of infections these may last forthree to four months.
79. A decrease in tear oroduction was noted inleukaemic patients following whole-body irradiation(about 10 Gy. 0.05 Gy per minute) [D 171. The Japanesefishermen who received whole-body doses of 2-7 Gy
and much hieher surface doses from radioactive ash
after the nuclear test explosion at Bikini developed
acute keratoconjunctivitis by two weeks after irradiation [K4].
u

4.

Lung

80. The pathogenesis of radiation injury to the lungs
has been described by several authors [W4. V1, P5],
and the radiobiology of the lungs has been discussed
in [T32. U4]. The target cell population responsible
for pneumonitis after irradiation remains unknown,
but type-2 alveolar cells are implicated and vascular
injury may be contributory [D26, T271.
81. After the thymus, the lung is the most radiosensitive organ in the thorax. Because lung tissue has alower density than other soft tissue. a nominal 8 Gy
corresponds to doses 8-15% higher to lung tissue using
cobalt-60 gamma rays and 5 8 % higher using 8 MV
x rays [M9]. Hence 8 Gy becomes 8.6-9.2 Gy (cobalt-60)
or 8.4-8.6 Gy (8 MV). The earliest signs of radiation
injury in the lungs are oedema and changes in blood
circulation followed by pneumonitis, which appears
after a latent period of 1-3 months after doses greaterthan about 8 Gy. After whole-body irradiation withsuch doses, marrow failure may intervene before
severe signs of lung injury appear, unless successful

marrow transplantation is performed. In some of theChernobyl accident cases receiving the highest wholebody doses, the terminal period was characterized by thedevelopment of pneumonitis and pronounced respiratory insufficiency [U6]. Also. lung injury develops after
high doses when the lower half of the body is shielded,
as in the half-body treatment of lung metastases byradiotherapy [F12, V3].

IA

82. Threshold doses and dose-incidence relationships
for pneumonitis can be deduced from whole-bodyradiotherapy treatments of leukaemia prior to marrowtransplantation. or half-body treatments for metastases.
The effects are variously confounded by the concomitant use of cytotoxic drugs. e.g.. cyclophosphamide. A
sunrey was made of 15 centres in Europe giving
whole-body irradiation before marrow transplantation
to a total of about 400 patients [B32]. The dose rates
ranged from 0.025 to 0.35 Gy per minute, and thelung doses from 6 to 10.5 Gy. The incidence ofpneumonitis increased above 8 Gy and was dependent
on the dose rate. Included in this survey were patientsfrom the Royal Marsden Hospital in London. and aseparate report described 107 of these patients withacute leukaemia given whole-body irradiation resulting
in 9.1-10.5 Gp to the lungs at a dose rate of 0.025 Gy
per minute. Eleven (10.3%) developed interstitial
pneumonitis and five (5%) died of it [B49]. Sixty ofthem were irradiated and received a bone marrowtransplant when they were in their first remission, andthey were considered to be in a good clinical condition.

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T I M E OF ONSET OF PNEUMONITIS (months)
Flgure XVI. The frequency dlstrlbutlon of the Ume of onset ofradlatlon pneumonitis for 52 pallents who developed thecompllcatlon.

[V31

1T

83. Irradiation to the upper half of the body was
given to 245 patients for the palliation of disseminatedcancer [F12]. The dose rates ranged from 0.5 to
4.0 Gy per minute. The results of these treatments,
together with those given to a further 58 patients, wereanalysed subsequently in terms of corrected doses tothe lung. Patients with significant previous and subsequent lung irradiation, with previous lung disease orwith known tumour masses in the lung were excluded

Standard
deviationabout
the mean

Mean

DOSE TO LUIG (Gy)
Flgure XVII. Time of onset of radlatlon pneurnonltls versus
dose to the lung for 52 pallents who developed radlatlon
pneurnonllis. Error bars represent standard devlatlons.

[V31

OOSE T O LUNG (Gy)
Flgure XV. lncldence of pneumonltls versus dore to lung inman. Best 111 slgmoldal conipllcation curve uslng probll regresslon analysis. The polnt to the left of the curve was based on
only four patients and hence has a large uncertalnty. Based on
patients excluding slgnlflcant additional Irradiation, previous
lung dlsease, carcinoma In lung. Standard devlatlons do not
apply for 0% or 100% incidence.

[Valfrom the analysis. A dose-incidence relationship for
pneumonitis was presented by Van Dyk et al. [V3].
The doses to lung tissue needed to produce pneumonitis in 5% and 50%. respectively, of the cases wereabout 8.2 Gy and 9.5 Gy (Figure XV). The steepnessof the dose-response curve could be interpreted by a
Do value of
0.6 Gy for the unknown target cells
responsible for pneumonitis [T32]. The dose-incidence
data are in agreement with other data for upper halfbody irradiation [S17], where an incidence of pneumonitis of 10-20% was observed after lung doses
estimated to have averaged 8.8 Gy [V3]. The frequency
distribution of the time of onset of pneumonitis in
52 patients who developed the signs is shown in-Plasma and urinary levels of follicle-stimulating hormone increase after doses to the testis of greater than
0.1 Gy [ R l l ] , and the increase after 0.75-6 G y m a y be
as much as four times over the control level. Plasma
levels, but not urinary levels, of luteinizing hormone
are elevated after doses greater than 0.2 Gy, a n d thelevels may be two times higher than the pre-irradiation
value after 6 Gy. The levels of urinary oestrogen,urinary testosterone and plasma testosterone are notchanged significantly.

Figure XVI: in about 90% of these patients pneumonitis
appeared between one and seven months. Figure XVIlshows that the time of onset was not significantly dosedependent between 6.5 and 12.5 Gy, but this may
reflect the limited sample size. Other data for humans[S17] and dogs [M40] indicate a decrease in latencyinterval with an increase in the dose. Lung fibrosis
begins to develop at the end of the pneumonitis phase
after high doses.
5.

Testis
86. In mice, there is a correlation between the levelof stem cell killing, the sperm count at a fixed time ofrecovery after irradiation, the final plateau level ofrecovery and the length of the infertile period [M46].
In man also, the spermatogonial stem cell is considered
to be the target for long-term sterility [M46]. Doses
inducing temporary o r prolonged sterility in men havebeen reviewed by UNSCEAR [U4] and I C R P [I9].
Acute doses of u p t o about 4 Gy cause temporary o r
prolonged sterility in some men [G4. H27. H29, 011.
Higher doses may cause permanent sterility, a n d thedose inducing permanent sterility in 100% of men is
greater than 6 G y (Table 10). After 6 Gy, long-term
histological recovery has been reported at 7.5 months.
with sperm appearing in seminal fluid at 24 months[RI I]. The number of Leydig cells increased 90 days
after 6 Gy [Rll].

84. The kinetics of spermatogenesis in different
species have been described by Bianchi [Bl I], and theinformation available on the kinetics of spermatogenesis in unirradiated m a n is summarized in Table 9.
The testis is very responsive to radiation because
the early differentiating forms of spermatogonia are
extremely radiosensitive [BII, U4]. Spermatogonial
cell necrosis can be detected in man at 4-6 hours after
local testicular irradiation. with loss of these cells by
12 hours [H8].The more mature cells composing thesecond and third phases of spermatogenesis (frompreleptotene spermatocytes through meiosis and including the spermatids) are unaffected by doses below
3 Gy. These cells mature normally after such doses,
a n d they therefore maintain the normal sperm countfor about 46 days, which is the time of developmentfrom preleptotene spermatocyte to spermatozoa. The
sperm count begins to drop after 46 days, approachingazoospermia at about 10 weeks after doses greaterthan 1.0 Gy (Table 10). Oligospermia is induced bylower doses down to 0.15 Gy. The sperm count drops
earlier after doses between 1 and 4 Gy, when the
spermatids also become affected. Below 3 Gy, there
are no morphological alterations in the spermatozoa.
Changes in sperm count at various times after
different x-ray doses are shown in Figure XVIII [H8].

87. The few data for accidental exposures of thetestis are consistent with the above controlled study by
Rowley et al. [RI I]. The acute accidents include twomen who received estimated doses of 1.7 Gy a n d
1.8 Gy [H6]: one man who received about 3.9 G y of
mixed neutrons and gamma rays [OI]: one man who
received 0.6- 1 .O Gy to the testis from iridium- 192
gamma rays [R7]; and 23 Japanese fishermen who
received doses of 2-7 G y over two weeks (1.5-4.5 G y
in the first day) after the nuclear explosion on Bikini
Atoll in 1954 [K4].

85. Concomitantly with the histological changes.
changes in testicular hormone levels are also observed.

20

0

20

40

60

80

100

120

140

160 180200

r l M E (days)
Figure XVIII.

Time course of sperm-counts of normal men followlng exposure tovarlous doses of 190 kVp x rays.

[HE1

6 . Ovary

88. There are a total of about 2 million germ cells in
the human ovary at birth, of which 50% are atretic(degenerating) [B2, B4, K3]. The mean number offollicles declines from an average of 382,000 at age
12-16 years, to 150,000 at 18-24 years, 59.000 at
25-3 1 years and 8,300 at 40-44 years [B 141. This decline
is due to atresia since only about 400 oocytes are
ovulated during a reproductive lifetime of about
35 years [B4]. Germ cells killed by radiation become
pycnotic and are removed by phagocytosis within a
few days. Primordial oocytes are more resistant thanoocytes in growing follicles [B3]. The germ-cell content
and the radiosensitivity of the ovary in different
species were reviewed in the UNSCEAR 1982 Report[U4] and by Bianchi [Bl I].
89. Observations on ovaries and ovarian functions
come from patients treated locally in the past with low
doses of radiation to the ovaries to treat infertility,
higher doses to induce an artificial menopause, anddoses delivered incidentally during the treatment of
abdominal tumours. Doses inducing temporary or
permanent sterility in women were reviewed by
UNSCEAR [U4] and ICRP [I9]. Acute doses of up to
about 4 Gy cause temporary sterility in some women,
and doses of 3 Gy up to 10 Gy cause permanentsterility in an increasing proportion of women [G4,L l , P2, P3]. Older women are more susceptible,
probably because the number of follicles decreases
with age.

11.

DOSE-RESPONSE RELATIONSHIPSIN MAN
A.

produce effects that may interact with the effects ofthe diseases requiring irradiation or with the effects ofother forms of therapy, decreasing the value of theLD,, relative to its value for normal individuals. The
exposure of nutritionally-depri~~edindividuals, e.g.,
the Japanese in the Second U'orld War, might also
produce lower values of LD,. Previous estimates of theLD,,, are listed in Table 11. along with the factors that
may increase or decrease it. Thus, when data fromdifferent groups are combined. the resulting values of
the LD,will, to different degrees, depart from the value
obtained without complicating circumstances or treatments, and they will be affected by a variability larger
than that applying theoretically to the LD,, of anormal human population. This variability will tend
to lessen the slope of the overall dose-response cunle.
9 1. Ideally, data on dose-mortality relationships
should be derived from groups of individuals receiving
doses homogeneous to within a few per cent. In
practice. however, this condition is met only in thecase of radiotherapy patients, and their response may
be confounded by the underlying disease or by othercytotoxic treatments. In accidents, exposure is usuallyinhomogeneous, and this confounds the analysis of
dose-effect relationships: for example, values of LD,,,at the midline are 20% higher for unilateral than forbilateral irradiation of large animals. Most of theindividuals irradiated by the atomic bombs in Japan
received unilateral prompt exposure, accompanied by
fallout irradiation. and some of them were partiallyshielded. The population of the Marshall Islands andthe Japanese fishermen exposed in the 1954 nuclear
test explosion received substantial but non-lethal
doses of fallout irradiation, mainly in the first twodays; they are probably the largest groups of healthy
individuals exposed to near-homogeneous doses, albeit
over a two-day period.

ACUTE DOSES

90. For many purposes, particularly the planning ofprotection from accidental or other acute exposures toradiation, it is customary to think in terms of theprobability of survival following a dose of radiation
over the whole body. One would need to know theform of the dose-response relationship for death overa given time or. at least, the value of the 50% interceptof such a curve, which is most simply and reliably
defined as the lethal dose for one half of the irradiatedpopulation (LD,) over the given time; say. 30 days or
60 days (LD,,,,?, and LD,,,,, respectively). While theconcept of LD,, is quite clear and widely applicable inexperimental work, it is a difficult concept to appiy inthe context of human irradiation. For exam~le.
, thefinal effects will always be modified to a greater or
lesser extent. depending on the cause and the conditions of exposure by- the nursing or therapeutic
procedures applied after irradiation. These procedures
will presumably increase the value of the LD, relative
to its value in the absence of such procedures. Also.
the state of health of the irradiated human beings may
not be representative of the average state of health in
the population, at least not under all conditions ofirradiation. For example, the exposure of patients will.

92. Doses quoted in the literature are usually thoseat the midline, and they depend to various extents onradiation quality. Some depth-dose curves for different
types of radiation are given in Figure XIX. In thatfigure, the depth dose is shown as tissue/air ratio.
which is defined for tissue dose versus kerma at thesame point. It is, therefore. independent of theinverse-square law and dependent only on photon
energy, depth in tissue and field size. The most
relevant parameter for death following bone marrow
failure is the marrow dose, and this is usuallyestimated as the mean dose in an annulus between 0
and 6 or 7 cm below the body surface. It corresponds toabout 0.75-0.8 of the free-in-air tissue kerma for
multilateral irradiation with 60Coor I3'Cs gamma rays
[I51 (see Figure XX). The midline dose is about 10%
less than the marrow dose for ,OCo gamma rays, and thedifference is greater for less penetrating radiations, e-g.,
for low-energy x-ray beams or neutrons (Figure XIX).
Values of midline doses related to exposure for various
radiation energies and species have been published [B6].
93. The form of the dose-mortality relationship for
the LD,,, in man is expected to follow approximately
a normal (Gaussian) distribution. The relationshipwill be sigmoid on a linear plot of per cent mortality
versus dose. There is a threshold region where dosesthe hypocentre at which there had been 50% mortality,
and then converting this distance into dose. The
distance was deduced to be 892 f I 1 rn from a surveyof 201 documented individuals who died between one
day and two months after the explosion. This distancewas given later as 887 m [H44]. At the distance of
892 m, revised estimates of free-in-air tissue kerma
were used [K16], together with shielding factors [E9],to calculate a cumulative marrow dose of 1.5 Gy fromgamma rays and neutrons. Similar calculations ofdose at other distances enabled a dose-mortality curve
to be deduced. The revised dosimetry (DS86) has
caused the estimate to be increased from 1.5 Gy to
1.8 Gy [F15]. Further, a total dose of 2.4 Gy at 892 m
was quoted in an analysis using individual transmission factors [F15]. A recent re-assessment of such data
[F 151 concerning deaths versus distance at exposure
has produced a value for LD,,,, in the range 2.7-3.1 Gy(see Table 1 1 and Figure XXI).
95. The mortality in known numbers of individuals
exposed to the bomb irradiation at particular places isbeing further studied [e.g., F151. For example, a

DEPTH (cm)Figure XIX. Depth-dose curves tor dlfferent radiatlon qualities.
[BZO, S4.1 Data are tissue-air ratios (corrected for the inversesquare law) expressed as a per cent of the maxlmurn dose:
Radlatlon typeS S D (cm) Fleld rlze (cm cm)
Curve As0Co :. rays
80
20 x 20 and 35 x 35
Curve B
4 MV x rays
infinite
20 x 20 or 35 x 35
Curve C
137Cs ;. rays
40
20 a 20
50
Curve D
230 kVp x rays
20 x 20
Curve E
235U fission neutrons 500
6= 8.

cause no mortality. followed by a sharp increase inmortality with progressively higher doses, reaching aplateau at 100% mortality after still higher doses.
Doses causing very little mortality are generally
quoted in the range LD,-,,, and those causing highmortality in the range LD,,,,. To estimate these doses
directly would require analysing large groups ofindividuals exposed homogeneously to the same dose.
For example, with 100 individuals, the accuracy of
estimates for 10% and 90% mortality would be,
respectively, 3% and 30% of the mean (binomial
standard sampling error). With 1,000 individuals, theaccuracies would be 1% and 19%, respectively. Since
there is no experience with such large groups, thedoses must be estimated from dose-response relationships, where the most accurate parameter that can be
These doses apply to thecalculated is the LD,,.
average individual in a population and not to a
specific individual, who may have a response different
from the average. The LD,,,, will be considered first.
As has already been noted, previous estimates ofLD,,,
reported in the literature are given in Table 11.
94. The LD,,,, has been estimated from the data on
mortality following the atomic bombings of Japan inof 1.5 Gy
the Second World War. A value for LD,,,(marrow dose) has been deduced for people exposed
inside Japanese-style houses at Hiroshima [R20]. Thiswas calculated by first ascertaining the distance from

Flgure XX. Average dose in bone marrow per unit exposure
measured by a personal dosimeter on the front of the trunk(curves A and B) and per unit exposure measured in free air at
the position of the centre of the body (curve C). Curve A:
irradiation from the back only. Curve B: irradiation from thefront only. Curve C: rotation during exposure, simulating
irradiation from all sldes.
1151

M I D L I N E DOSE ( G y )Figure XXI. Estimates of dose-survlval curves for man, at 60 days. Curves A and 0: Standard error
llmlts (dotted curves at both sldes of curve A, dashed curves at both sldes of curve B) calculated
uslng problt analysis; Curve C: The line Is drawn assuming a coefflclent of variation of 0.24, derived
uslng several species of large animal [M28]. The left arrow extends to approximately the LD,,calculated using lower levels of survlval at the 90% Poisson probablllty level, and the right arrow Is
included speculatively for completeness. Curve D: Arrows denote standard error Ilmlts. The dosesurvlval curve estimated from the population In Hlroshima receiving atomic bomb lrradlatlon Is
expected to Ile in the range between curves A and 0 .
[L4, L11. M27. M28. M31,R203

group of 159 labourers were exposed when shielded bywooden buildings about 1,000 m from the hypocentre
at Hiroshima, and of these 58.554 died between day 20
and 38 [05]. Using the revised doses, as in thepreceding paragraph, the tissue kerma of about 2.4 Gy
multiplied by a factor of 0.79 gives marrow doses of
1.9 Gy, and possibly 2.1 Gy if prompt and delayed
radiation components are considered separately [ F 151.
.L\lso. of 193 workmen exposed unshielded at 1,000 mfrom the hypocentre. only 10 surv~veda marrou dosecurrently estimated to have been about 3.3 Gy [F15].
96. Other groups of individuals were exposed insideconcrete buildings. Ninety 15-year-old girls were
exposed in the Central Telephone Office of Hiroshima
at 550 m from the hypocentre. Of the 59 who survived
to 24 hours. 29 (49%) died between one and ten weeks
after exposure. The majority (20) died in the fourth,fifth and sixth weeks. From measurements made years
later of chromosomal aberrations in the T-lymphocytes
in the survivors [F15], the dose was estimated to havebeen 6.5 Gy. Although this is similar to the value of
6.0 Gy according to the T65D estimates, the revised
estimates of dose are lower, perhaps as low as 4 Gy
[F15]. None the less, the survival rate of these girls

was higher than that of adults irradiated in otherbuildings who had apparently lower doses.
97. A recent detailed analysis of weighted data
concerning deaths versus distance from the hypocentre, including those occurring on the first day after
exposure. has given a value for L D , , of 2.1-2.5 Gy
marrow dose, the value depending on the mathematical model used to fit the data. A probit fitting of
the data gave a value for LD,,,of 2.2 Gy, and for
LD,,,, of 5.8 Gy [F15]. It was considered that thevalue of LD,,,,, may be too low by up to 17% becauseof the contributions to mortality estimates fromdeaths on the first day and of the severely injured.
This was estimated in a separate smaller study of 184
individuals. 84 of whom died on the first day, where
was calculated using probit analysis to be
the LDso,,b~l
3.2 Gy or 2.6 Gy marrow dose when the above early
deaths were respectively excluded or included. Hencethe true value of LD,,,,,, may be around 2.5 Gy or
higher. The true value of LD,,,,is even more
uncertain. I t may also be higher, or lower down to
4.5 Gy [F15]. In view of these uncertainties. it isconcluded that the dose-survival curve for the Japanese
exposed to atomic bomb radiation in Hiroshima islikely to be similar to curves deduced for ill radiotherapy patients receiving whole-body irradiation (inthe range of curves A and B. Figure XXI).
98. There have been many radiation accidents involving single individuals or a few individuals, oftenwith very inhomogeneous doses from gamma rays or
x rays, or mixed radiation, including a neutron component. These accidents have been summarized byseveral authors [B7. B31, D24. D25, L12, M19, U4].
The most comprehensive listing is probably the
REAC/TS Radiation Accident Register [L 121. Between
1944 and October 1983. 188 accidents were recorded
involving 928 persons, 22 of whom died from acuteeffects [FIO]. One hundred and forty-four individuals
received whole-body doses greater than about 0.25 Gy,and eight of these died; 46 received, in addition, local
irradiation with doses greater than 6 Gy, and eight ofthem died; 62 received high internal doses, and fourof them died; 110 Marshall Islanders received bothinternal and external irradiation, and one of themdied. In March 1987 these numbers were updated to
284 accidents involving 1,358 persons, 33 of whomdied from acute effects (excluding Chernobyl) [L38].
99. Before the accident at Chernobyl ([U6] and the
Appendix), the accidents involving the largest numberof individuals, and therefore the most useful for
analysis. were those in 1958 at Oak Ridge. UnitedStates [02. H23] and at Vinca, Yugoslavia [H22, 11,
54, M491. The doses received by these individuals arestill a matter for debate; some recent estimates arereported in Table 12. The various estimates depend on
the assumptions about the position and orientation of
the individuals, and the dose and RBE of the neutroncomponent. None the less, there was only one death,individual V at Vinca. who received a marrow dose
estimated recently to have been approximately equivalent to 4.5 Gy of low-LET radiation (Table 12).
Although he had marked haematological responses,
these were no1 the primary causes of death. Two of
the individuals irradiated at Oak Ridge received
antibiotic treatment for respiratory infections. whereas
the Vinca cases had barrier nursing. and a series ofantibiotics. platelet and red cell concentrates, and later
marrow cells. In one report, recalculation of the doses
broadened the possible ranges of dose so that they overlap, depending on the uncertain aspect of exposure,particularly at Oak Ridge, i.e.. from the side or fromthe front [B7]. Another report concluded that the datafrom Oak Ridge were more reliable than those from
Vinca, because in the latter accident the exposures
may have been more inhomogeneous [M 191. From are-analysis of the measurements of sodium activation,it has been suggested that the doses at Oak Ridge
should be increased by about 10% and at Vinca, by
about 30% (column 8, Table 12) [M26]. This could
remove the apparent difference in clinical effect for
estimated equivalent doses in the two accidents inearlier reports.
100. In the accident at Chernobyl, described in the
Appendix. 115 persons received doses ranging fromapproximately 1 to 16 Gy (Table A.3). In most cases theindividuals received antibiotics and were hospitalized, if
necessary under aseptic conditions, and platelet andred-cell infusions were administered when considerednecessary. Thirteen patients received allogeneic marrowtransplants and six received embryonic liver transplants.
In the lowest dose group, 31 individuals received
relatively uniform bone marrow doses of gammairradiation of approximately I to 2 Gy. In thesecond dose group, 43 individuals received marrowdoses between 2 and 4 Gy: in many cases higher doses
to the skin from beta-irradiation were also received.
None of the patients of this group died up to 60 days
after irradiation, but one died at day 96. A further
21 persons received marrow doses between 4 and 6 Gy.
Seven of them died between 16 and 48 days after
irradiation, and six of these seven had severe skin
injuries, which contributed greatly to their death. In
the highest dose group. 20 individuals received doses
between 6 and 16 Gy. One person died at day 10 after
irradiation. 17 died between 14 and 48 days, and two
died at days 86 and 9 1 , respectively. The individuals inthis dose group had severe skin injuries to 40-90% of
the body that were probably lethal, as well as severe
signs of radiation sickness (Table A.7). These observations, in particular the survival of 43 individuals in thedose group 2 to 4 Gy surviving more than 60 days,
suggest that the LD,,,for this irradiated population
was at least 4 Gy.
101. Various groups of cancer patients have been
given acute whole-body irradiation. Some were relatively i l l people with advanced disseminated cancer
and others were relatively healthy individuals irradiatedwhile in remission or when bearing metastasizing solid
tumours. A group of 19 children and adolescents with
Ewing's sarcoma and one with leukaemic infiltrationof bone received 3.0 Gy from whole-body irradiation
with cobalt-60 gamma rays given in 15 minutes (dosehomogeneity to within10%) [R6]. None of these
20 individuals died within one year. They were given
antibiotics when infection arose, blood infusions at
about day 30 to replace haemoglobin, and barrier
nursing during the phase of pancytopenia. According
to Poisson statistics, zero deaths in a sample of 20
individuals might be observed 1 in 20 times (i-e.. a 5%
probability) if the true number of deaths on averageamong many such samples was 3.7: that is, if the true
mortality was 3.7/20 = 19%. Hence it is possible that.
although no mortality was observed in this particularsample, the average mortality level characteristic of
this 3.0 Gy dose could be as high as 1995, but not ashigh as 50%.

+

102. An attempt was made to extend this type ofanalysis to a total of 27 individuals, by including
subjects A, C and D in the Y-12 accident. and subjects
V. M, D and G in the Vinca accident [M28]. Estimatesof the total (n ;*) marrow doses that were usedranged from 2.8 to 3.3 Gy (colun~n7, Table 12). The
one death (case V at Vinca) was attributed to marrow
failure for this exercise, in order to provide amaximum value to the observed mortality. Using these
27 individuals, the statistical exercise in the preceding
paragraph gives virtually the same result, with thepossible average mortality being 2 1%. A further pointis that if the true average mortality was 50% at theseestimated doses of about 3 Gy, as is suggested by ananalysis of mortality in radiotherapy patients (see the+next paragraph). or more (colun~n8. Table 12), there
would be a 5% probability of as few as six deaths outof a random sample of 27 individuals, in contrast with
only one death observed. Hence the data for theEiving's sarcoma patients, with or without the inclusion of these accident cases, are inconsistent with an
LD,,,,, as low as 3 Gy. The revisions in the dosimetry
for the accident cases that increase their respective
doses [h?26] strengthens this conclusion, as does thesurvival to 60 days of all 43 individuals receiving doses
estimated to be between 2 and 4 Gy in the Chernobyl
accident (Table A.3).
103. One group of 163 relatively ill cancer patientswas irradiated to the whole body with acute doses of
low-LET radiation [Lll]. The estimated dose (with
its standard error) giving 50% deaths within 60 days
was 2.5 (+0.98 -0.51) Gy, calculated using a normal
distribution, and 2.35 (+5.06 -0.87) Gy using a lognormal distribution. The data were corrected for a death
rate of 4% in unirradiated patients, and average doses
were given for a 26 cm diameter sphere in the epigastricregion. A similar analysis of 218 patients irradiatedwithin an overall period of one day, gave an LD,,,,,,
of 2.86 2 0.25 Gy [L4]. These two calculated dosemortality curves (A and 9) are shown in Figure XXI.
104. An analysis of 110 patients receiving wholebody irradiation from I to 10 Gy, either for various
cancers and leukaemia or prior to kidney transplantation. indicated an LD,,,, of about 4.0 Gy [M31]. The
Committee's probit analysis of these data produced an
L D ,,, of 3.4 f 0.5 Gy (curve D, Figure XXI). The
data for the patients with malignancies were notsignificantly different from the data for the (fewer)
patients with kidney debilities.
105. Smaller groups of patients have also been given
whole-body doses of up to 3 Gy. without bonemarrow transplantation. For example, one patientwith metastatic bronchogenic carcinoma given about
3.8 Gy (midline dose) using 60Co died on day 20 after
irradiation, and one with generalized neuroblastoma
given about 2.6 Gy survived to 4 months after
irradiation [K 181. Of seven patients with advanced
colon and lung cancer irradiated with 2.0 Gy (midlinedose) using 60Co, two died within 60 days (at 28 and
56 days) [S27]. Three patients, in a series of 18. inremission from acute leukaemia were given 3 Gy
midline dose using '"Cs. and they survived more than
60 days [K23]. They received antibiotic therapy andtransfusions of platelets and red cells when considerednecessary.
106. Since the LD,,,for ill cancer patients is
confounded by their disease and other concomitanttreatment, it may be lower than the LD5,, for healthypeople. The data in the last three paragraphs suggestthat for ill cancer patients treated with conservative
supportive medications and blood-cell infusions whennecesFary, the LD,,,,is about 3.0-3.5 Gy (marrowdose).
107. The cancer patients considered relatively healthy
at the time of irradiation were those with Ewing's

sarcoma. Whole-body irradiation was given to thesechildren and adolescents to sterilize [he metastases.
Three patients with localized disease given 3 Gy
(midline dose) survived more than 60 days without
needing supportive medications [M34]. Ten patientswith localized disease given 3.0 Gy (midline dose)
survived more than 60 days [J17]. A larger series of
20 patients was described, one of whom was diagnosed
subsequently to have had instead a leukaemic infiltration of bone [R6]. All 20 survived more than 60 days.
This indicates that the LD,,,,, of relatively healthypeople is greater than 3.0 Gy, although it is notknown if these young people were more resilient toirradiation than adults. The apparently high doses
tolerated by the schoolgirls irradiated by the atomic
bombs [ K 171 would support this idea.
108. Attempts have been made to use experimentswith animals in order to predict the dose-mortality
relationship for man. Two similar approaches havebeen described. The first approach [L4, M28] relies on
the similarity of the coefficient of variation (CV) of
the LD,, [i.e., the inverse slope (probit width) divided
by the mean] among different species of large animals.
The CV for irradiated cancer patients was 0.58, which ismuch larger than the CVs calculated for dogs (0. 15) andmonkeys (0.21) [L4]. This greater variability was
attributed to the marked heterogeneity of responses
among patients. The mean CV for dogs and monkevs(0.18) was applied to the data for 218 irradiated cancer
patients [L4], where the LD,,
was 2.86 2 0.25 Gy, tocalculate the doses for 10% mortality (2.2 Gy) and
90% mortality (3.5 Gy). Mole [M27. M28] calculated
the weighted mean CV for five different species oflarge animal (dog, sheep, goat, pig, donkey) t o be
0.24. This value was used. together with pertinent but
sparse information for mortality in "healthy" humans,t o deduce a value for the LD,, in man of about 5 G y(Figure XXI). The information just referred t o camefrom the 27 individuals described in paragraph 102[M28].
109. The second approach was to take the ratio ofthe doses that produced measurable, very low o r very
high mortalities [B6]. The ratio of LD,,/LD, or
LD,,/LD
from 34 experiments in six species of large
animal was close to 2.0. This ratio was used, together
with the data for the Ewing's sarcoma patients, toconsider the LD,,or LD,, for man. The two approaches
are consistent with one another, and they suggest thatthe dose that would kill "few" healthy humans isabout 3.0 Gy, the dose that would kill "most" isabout 6.0 Gy [B6] and the LD, is 4.5-5.0 Gy [M27,
M28].

,,

110. Estimates of dose-survival curves for various
animal species are given in Figure XXII. Data frommany published experiments were reviewed by Baverstock [B6], and were re-analysed to obtain a mean
curve for each species [T24]. Doses in each experiment
for a given species were multiplied by the ratio of theLD,, for that experiment and the mean LD, for all
experiments. This assumed that variations between
experiments were due to dose-modifying influences,e.g., to changes in dose rate or LET. The data formice were reviewed and analysed separately [H32].

I

I

1

I

I

I

I

I

I

1

2

3

4

5

6

7

8

DOSE (Gy)Figure XXII.

Midline dose-survival curves calculated from various published experiments using
different species of animal Irradiated bilaterally.
IT241

11 1. In the data for large animals reviewed by
Baverstock [B6], lower slopes correspond with higher
values of LD,, (see curves for goat and monkey in
Figure XXII). This indicates that heterogeneity in theirradiated population is greater for species showing ahigher LDI0, possibly because variations between
individuals are greater in species with a high LDso or
because the sensitivity of their target cells is less.
Evidence for the latter possibility is that the Do
for granulocyte-macrophage colony-forming cells is
generally reported to be much lower in dogs (- 0.7 Gy)than in mice (- 1.8 Gy) o r in humans (- 1.5 Gy)[H 111. Data are not available for other species.
112. It is concluded from the preceding discussionthat the LD,,,,, for acute irradiation is likely to bearound 3.0 Gy marrow dose in the case of humans
receiving no or little medical treatment, as deduced
from recent analyses of the results of the atomic
bombings in Japan. A similar value pertains to somegroups of ill cancer patients receiving good medicalcare. The LDswmfor healthy humans receiving good
supportive medical treatment after irradiation (e.g.,barrier nursing. antibiotics symptomatically and blood
cell infusions) is likely to approach o r equal 5.0 Gy, inparticular for children. This is deduced from the lackof mortality in the young and relatively healthy
Ewing's sarcoma patients given 3.0 Gy marrow dose.
the presence of only one death out of the sevenindividuals receiving the highest doses in the Vinca
and Y-12 accidents; the survival of all 53 individuals
receiving doses of 2-4 Gy and of 14 out of 21 individuals receiving 4.2-6.3 Gy in the Chernobyl accident;
and the data on dose-response relationships available
for other large animals. It should be noted that theLD,,,, can be further increased markedly by successful marrow transplantation. probably up to about
9 G y acute single dose. After these higher doses there
may be some cases of pneumonitis occurring in thesecond month. unless the lungs are shielded. At evenhigher doses (>I0 Gy) acute gastrointestinal injury
will become more prevalent.
113. A summary of the effects and their time courses
after whole-body irradiation of man, prepared by theCommittee, is given in Table 13. The Table lists
possible therapies for the responses. More detailed
summary tables of symptoms and signs after various
ranges of dose are available, for 0.5-1.0 Gy, 1.0-2.0 Gy(Table 14), 2.0-3.5 Gy (Table 15). 3.5-5.5 Gy (Table 16)
and higher doses [Y7].
2.

Doses for very low and very high mortality in man

114. The dose-mortality curves for ill cancer patientsare shown in Figure XXI, together with a curve forhealthy humans described by an LD,,,, of 5.0 G y anda coefficient of variation of 0.24 [M27. M281. The
slope of the latter curve is consistent with theconclusion of Bavcrstock [B6], using data for various
species of large animals. that the ratio of doses(LD,,/LD ,,J or (LD,,/LD,) was about 2. Also, the probit
width, for this curve. of 1.20 Gy (i.e., 5.0 X 0.24 Gy)
would correspond to a D,, value for the bone marrowtarget (stem) cells of 1.20/1.?, or 1.0 Gy, using the
Poisson model described by Gilbert [G3]. From
Figure XXI it may be seen that a dose of 2 Gy would
be unlikely to kill more than about 1% of a healthy
population (curve C). This is compatible with theChernobyl experience (Table A.3) but not with theatomic bomb data [F15]. By contrast, a dose of 2 Gy
could kill up to 30-40% of a population of very illcancer patients (curves A , 6 and D). Similarly, a doseof 7 Gy would probably kill about 95% of healthypeople (curve C) but 5-6 Gy to ill cancer patients
could probably achieve the same level of mortality(curves A and B).

3.

Geometry of exposure and depth-dose distributions

1 15. Large animals irradiated unilaterally exhibit
greater LD,,, values than those irradiated bilaterally.
by about 20% for dog, sheep. pig and goat [M28](Table 17). Further information on the effect of
exposure geometry is that the LD,, for goats irradiateddorsally is 0.63 of the value for ventral irradiation[B7]. Also, higher values for the LD,, of goats are
obtained when parts of the vertebrae are specificallyshielded from direct dorsal irradiation [B7]. Similareffects would be expected for man. but no data exist
on this subject.
116. The interpretation of the differences in LD,
with the direction of esposure relates to the exponential
relationship between cell survival and dose. Irradiationof a cell population with a non-uniform dose is always
less effective than a homogeneous irradiation with theaverage dose of the distribution [Big]. In the case ofbone marrou,. the effects depend on the depth-dose
curve for the particular radiation used and the
distribution of active bone marrow along such adepth-dose curve. Models for these effects have been
described [ B 18, B 19, T3].

1 17. Depth-dose distributions are shown in Figure XIX
for a variety of radiation qualities [BZO, S4]. These areexpressed as percentages of maximum tissue-air ratios,
independent of the inverse-square law, and measured
for large radiotherapy fields (> 20 cm X 20 cm) andsource-to-surface distances (SSD) greater than orequal to 40 cm. No ideal comparison exists wherein afull range of radiation qualities has been used with thesame large field size and the same SSD. Hence thecurves shown in Figure XIX ~ . o u l dchange slightly.
depending on the particular irradiation set-up. For
4 %I\' s rays, the highest energy considered. thesurface dose for tvell-collimated beams and short SSD
is between 40% and 50% of the maximum dose. For
low, energies and non-collimated beams. the surface
dose is a greater percentage of the maximum dose.
With non-collimated be:~nms and \.cry long SSD. thesurface dose may be equal tu the maximum dose. For
fission neutrons, a significant build-up effect would be
unlikely.
118. The averagc dose in bone marrow per unit
esposure is shown in Figure X X [15]. These cur\.cs
were obtained by calculation and measurement usinga phantom. Similar curves are available for the
average doses in the intestine and the gonads [J 101.
119. N'ith low-energy rays there is an additionaldose at bone surfaces due to the greater photoelectriceffect with the high-atomic-number elements (e.g..
calcium and phosphorus) in bone. The greater dose
depends o : ~the x-ray energy and on the thickness ofthe bone. and the effect decays within a few hundred
microns of the bone surface. The increase in dose is as
great as 5 0 5 on the bone surface using 250 kVp x rays
[E5]. and on average about 20% for a single layer ofcells situated against the bone surface. This effect inthe mouse would increase the dose to the marrow onaverage by about 9% compared to the dose in soft
tissue remote from bone. and it should be reflected ir,

the LD,,,
if the conccntration of marrow cells criticalfor survival is constant in all regions of active
haemopoietic tissue. Since higher concentrations (about
twice as high) of critical stem cells have been detectedclose to bone surfaces in the mouse [L7]. the above
figure of 9% may be slightly higher. KO information
is available on the measurement of such effects inlarge animals, apart from the lower concentration of
granulocyte-macrophage precursor cells close to bone
surfaces in human ribs [T33].
1.

Dose inhomogeneity. shielding and boneniarroH distributions

120. The effect of dose inhomogeneit\ on the haematological response and survival in rodents and dogs
has been reported in papers submitted by the delegawastion of the USSR [D28]. In mice, the LD,,,,
about 5.5 Gy for whole-body irradiation. about 14.5 Gy
when only the front half of the body was irradiatedand about 8 Gy when only the rear half was irradiated.
The corresponding values for dogs were about 2.8 Gy
and 3.8 Gy. Different critical organs were probably
responsible for death after these types of irradiation.
Thus. for both mice and dogs, larger average doses tothe body could be tolerated when only the front half
was irradiated, and smaller average doses when only
the rear half was irradiated. compared to uniform
irradiation. Also. these average dose differences werereduced when both halves of the body were irradiated.
121. When small portions of the body containing
active marrow are shielded during irradiation, theLD, can be markedly increased. This would also
apply to some degree in the case of non-uniform
irradiation. Shielding the right legs of mice increased
the LD,,,,,,, from slightly less than 7 G y without
shielding ( 7 Gy gave 70%#nmortality) to about 12 Gy[CZ]. Shielding the right leg below the hip joint gave
7 3 5 survival at 30 days after 10.5 Gy, in contrast to
0% without such shielding [Dl]. Shielding the leg only
bclou the knee joint. or below the tibia, did not causesur\.ival to drop below 70% [Dl]. These phenomenaarc due partly to the migration to and repopulation ofirradiated marrow by progenitor cells from the shielded
marrow and partly to the ability of the shielded
marrou to increase its normal rate of producing
maturing haemopoietic cells. In mice, a persistently
reduced complen~enrof only 10-20'3 of stem cells
remaining during chronic irradiation [LZ] or after
repeated irradiation [HI41 can maintain a normal
output of mature haemopoietic cells into the blood formany months.
2 2 In dogs. shielding the skull reduced lethality
after 4-5 G from 100% to 20%. and shielding
sternum, pelvis or skull doubled the LD, [A31]. .41so.
shielding, separately. the head and neck, chest, abdomenor pelvis gave no deaths in separate groups of 20 dogs
each given 6 Gy, a 100% lethal dose if given to thewhole body [L31]. Shielding smaller volumes ofmarrow in dogs has also been shown to markedly
increase survival [D28]. Shielding one or two vertebrae
was found sufficient to protect dogs from an otherwise
fatal exposure to radiation [S41]. Shielding the limb

epicondyle resulted in 100% survival after doses threetimes the LD,,6,. but shielding only the third andfourth ribs was insufficient [C34].
123. The above data suggest that in man, theshielding of perhaps as little as 10% of the active
marrow, while the remainder of the body receives adose close to the LD5,,,, may reduce the number ofdeaths to zero. The efficacy of shielding different partsof the body in man depends on the distribution ofactive bone marrow.
124. Various estimates of the percentage of active
marrow residing in the different bones of man havebeen calculated from histological measurements using
59Fe uptake. The values for humans aged around 40
are compared with those for other species in Table 18.
Some of the values for humans were calculated fromthe absolute weights of total marrow in the bones of
1 1 cadavers [M 121. These weights separately for eachcadaver were multiplied by the proportion of marrowthat was active. This proportion has been estimated byvarious investigators on the basis of marrow cellularity
and uptake of 59Fe, and the values given by Cristy[C12] for humans aged around 40 were used by
Woodard [W8]. The absolute weight of active marrowin a given bone was expressed as a percentage of thetotal weight of active marrow. Finally, the average ofthese percentages was calculated over the six males
and five females investigated. The averages differ inmany cases from the values presented by Ellis [E4], as
used by ICRP [I61 for reference man. The largest
differences are evident in the values of 3.9% for thesternum (3.6% in females), given as 2.3% by Ellis [E4],and 7.7% for the sacrum (7.4% in females), given as
13.9% by Ellis [E4]. Also, the percentage of active
marrow in the total marrow, 27.5% (28.5% in females),was given as 50% by ICRP [16]. The values from
Woodard [W8] probably apply quite well for ages
above 20 years but not so well for younger people,
because the skull has a higher proportion of active
marrow than other regions of the skeleton [C12].
In diseased patients there may be significant extramedullary haemopoiesis, which would modify thenormal distribution.

Radiation quality

5.

127. Most accidental human whole-body exposures
to high-LET radiation have involved both fissionspectrum neutrons and gamma rays. Exposures fromthe atomic bombings also involved gamma rays andfission neutrons, but the revisions in dosimetry [K16]
have reduced the estimate of the neutron component,
particularly at Hiroshima (Figure XXIII). For example.
at 890 m from the hypocentre in Hiroshima, where
about 50% of individuals irradiated inside Japanesestyle houses have been considered to have died frommarrow failure, the contribution to the dose fromneutrons has been calculated to be only about 2% of
the total marrow dose [R20]. Thus the contribution
from doses of neutrons to early effects in the
population at Hiroshima is now considered to bemuch less than had previously been thought andapproaches the level calculated for Nagasaki.

lo4

1

HIROSHIMAI Neutrons\

Yield:
T65D 12.5 k t-\*'

GROUND RANGE (m)lo4 7

NAGASAKI

Yield:

125. The distribution of active marrow in Japanese
adults was measured by weighing the marrow in eachbone of seven male and three female cadavers, aged
between 26 and 41 years [M30]. The red-marrowcomponent of the mean weight of marrow in eachbone was assessed histologically. The values are given
in Table 18. These values are the mean for each bone,
an approach similar to that used by Ellis [E4], rather
than the mean of the proportions for each individual,
the approach preferred by Woodard [WS].

126. The less-detailed distributions in man measured
using 59Fe uptake and scanning techniques [S43, A321
are in broad agreement with an anatomically derived
distribution [M30]. A particular difference between
these distributions and others based on earlier anatomical assessments [W8] is the significant amount ofactive marrow in the lower limbs (as is found in otherspecies, Table 18); 8.7% [S43]. 7.9% [A321 and 10.6%[M30], versus 0% [W8].

GROUND RANGE (m)Figure XXIII. Comparison of 1965 estimates (T65D) andrevised 1986 dosimetry (DS86) for lnitlal nuclear radiation in
Hiroshima and Nagasaki.

128. RBE values for fission neutrons are 2-3 for
LD,,,,, in small rodents. e.g., 2.0 for guinea pigs [B5]
and 2.7 for mice [GI]. Similar values are obtained forhaernopoietic stem-cell survival [Cl]. Although in
general RBE is a function of dose. RBE values forhaemopoietic stem cells are not markedly dependent
on the dose in the range under consideration forcomponents of dose in the LD,,,,,[CI, C3]. Also, it has
been considered valid to assume that there is no interaction between doses of neutrons and doses of gamma
rays, so that the effects of combined simultaneous
exposures to neutrons and gamma rays can becalculated on the basis of the estimated separate
components of dose and RBE values measured at highdoses, as, for example. in the accident data reviewed
by Mole [M28]. There is. however, some evidence that
doses from various components d o interact. giving
greater effects than expected for cells in vitro [H16,
M I I]. and also for haemopoietic stem cells when theneutron component of dose is small [C3].
129. The RBE for exposures with fission neutronsappears to decrease with an increase in body size. For
example, the RBE for LD,, in bilaterally-irradiatedpigs has been reported to be 0.4-0.54 [W9. B25], 0.73
in goats and 0.83 for sheep [El]. There arefor LD,,,several reasons for this apparent reduction in RBEwith an increase in body size. First, neutrons areattenuated more rapidly in tissue than are gamma
rays. so the dose at greater depths is less and is due
increasingly to gamma rays. Second, in small animals,a large part of the dose from neutrons is from charged
particles, whereas with large body masses neutron
capture reactions dilute the dose from charged particles
with dose from knock-on protons. Third, the dosefrom neutrons in and near bone is less than in soft
tissue remote from bone. The dose from neutrons to a
one-cell-thick layer on the bone surface can be up to
20% less as a consequence of this effect [B22]. Whenthe doses in the experiments with sheep were expresseda s average doses in a 7-cm-thick outer annulus. theRBE value increased to 3, as expected for haemopoietic
failure [E I].

size. the RBE for the gastrointestinal syndrome does
not decrease a s it appears to d o for the bone marrowsyndrome, but remains at 2.5-3. as shown for dogs
[AIO, A 1 I] and for sheep [A12]. This is partly due tothe confounding influences on the marrow dose of the
precise distribution of active marrow and of target
cells within the active marrow. and the effect of thepresence of bone, which influences do not apply to theintestine. However. in the case of the intestine, a highdose to a small segment may be sufficient to lead todeath (this is not true in the case of marrow). Also.
because of the greater RBE values for the intestine,
the contribution of gastrointestinal injury. i.e.,
haemorrhages and infections, to the bone marrowsyndrome is greater with neutrons than with low-LET
radiation. particularly after doses slightly above theLD,,,[El, B23. B241. With unilateral irradiation.
severe injury to the skin can contribute to deaths after
neutron doses slightly higher than the LD,, [B25].

,

6.

hlodification of the LD,,,by post-irradiation
treatments

130. The doses to the individuals in the Oak Ridge
and Vinca accidents are calculated generally bysumming the three components: (a) gamma ray dose
due to emission from the source; (b) gamma ray dosefrom neutron capture in a 6 cm annulus of a 30 cm
cylinder: and (c) first-collision, charged-particle dose
multiplied by an RBE factor of 0.8-1.0 [M28]. All ofthese components have uncertainties, in particular the
RBE. None the less, when the calculations are
performed and doses are estimated for the various
individuals (Table 12), the low mortality in this small
number of exposed individuals is consistent with thatin the Ewing's sarcoma patients irradiated with similardoses of low-LET radiation [M28, B7].

132. The management of persons after irradiation o r
combined injuries has been discussed in a number ofpublications (e.g., [B57, C5O. C 5 1, W28, W291).
However. the value of routine medical treatments
after irradiation in man is uncertain because there areno suitable groups, treated or untreated, with which
the treated groups can be compared. The populationsin Hiroshima and Nagasaki received minimal medical
treatment owing to the destruction of the alreadysparse supplies and facilities [05]. The Y-12 subjects
at Oak didge were treated conservatively, and wereadmitted to hospital two hours after the accident[B29]. Prophylactic antibiotic treatment was not given.
nor were bone marrow trans~lants.Antibiotic treatment was given to two patients for mild oropharyngeal
infections. The subjects at Vinca were treated more
extensively [J2]. hey received antibiotics on the dayof the accident and thereafter when necessary. They
were barrier-nursed and given injections of packed red
cells and transfusions of platelets when necessary. The
patient who later died had received a transfusion of
foetal and later adult haemopoietic tissue. The otherfour subjects apparently showed a favourable responseto the transplants, with parallel changes in the bloodand bone marrow and clinical condition. However,
because the haemopoietic cells were given at 27-36 days
after irradiation, when endogenous recovery would be
expected t o have begun, i t is difficult to judge thedegree of efficacy of the transplants. The radiotherapy
cases [R6] were barrier-nursed. with antibiotics given
for febrile infections. Platelet transfusions were given
on two occasions. The Appendix describes the extensive treatment, including marrow transplants, given to
the victims of the accident at Chernobyl.

131. With small animals, the RBE of neutrons forthe gastrointestinal syndrome is often higher than forthe bone marrow syndrome [B22], and the ranges ofdose resulting in the two syndromes often overlap.
Thus. interpretation of the appropriate RBE values
must take into account the times of death characteristicof each of the syndromes. With an increase in body133. The use of antibiotics is reported to have been
beneficial in large animals. Monkeys, whose LD5,, is6.0 f 0.2 Gy without the use of antibiotics. were given
doses of 8.2 Gy, which would normally result in lessthan 5% survival [B30]. Antibiotics given between
1.5 days before and 14 days after irradiation increased
the survival rate to 28% (7/25), and the addition oftyphoid vaccine to the treatment protocol to hasten
marrow regeneration gave a survival rate of 36%(5/14). The estimated LD,,,
was increased to 7.5 Gy,i.e., by a factor of 1.25. The medications prevented
most of the diarrhoea and anorexia observed in themonkeys who had been irradiated but not treated.
These latter animals died between days 10 and 13 of
septicaemia due to enteric organisms.
134. Other studies with animals have combined
antibiotics with other supportive treatments such as
fluid replacement and blood or marrow transfusions.
In dogs, platelet transfusions. together with antibiotics, were successful in overcoming the critical
period of haemopoietic failure between day 10 andday 20 after doses near the LD, [S9, P4]. Mortality
after three dose levels, where the mean survival times
were about 14 days. was decreased from 9/10, 5/5,
and 5/5 to 2/10, 2/5, and 1/5, respectively [P4]. Six of
12 monkeys. irradiated with lethal doses of 8-8.9 Gy
and treated rrith autologous marrow and routinely
with antibiotics. survived to seven weeks, and five of
these survived to at least one year [S2]. All sevenmonkeys receiving the autologous marrow but antibiotics only symptomatically died between days 7
and 23. Also. six monkeys irradiated tvith 8.5-9.5 Gythen treated by autologous marrow 2.2-12.9 1 0 ~ e l l ssurvived over 50 days, in contrast with a mean
survival time of 14.5 days for six irradiated monkeys
that had not received the graft [C19]. Only three of
18 monkeys similarly irradiated but receiving 8 10'
homologous bone marrow cells survived to 30 days.
All of these monkeys de\,eloped graft-versus-hostdisease; 14 out of 18 showed recovery of haemopoiesis
from the donor cells, but only two survived to 30 days.
Another series of experimenrs with monkeys showedthat the LD,,,,,, could be increased by a factor of
about 1.8 using injections of 2-4 10' autologous bonemarrow cells per kilogram body weight. and thrombocyte concentrates, erythrocytes and prophylactic antibiotics when necessary [B23].
135. From the limited evidence available. the efficacy
of post-irradiation treatments after neutrons appears
to be similar to their efficacy after low-LET radiation.
The increase, by a factor of about 1.8, in LD, ,,for monkeys, brought about by injecting 2-4 10"
autologous marrow cells per kilogram body weightafter irradiation. was found for both x rays andfission-spectrum neutrons [B23].
136. When the platelet level falls markedly below
30.000 per ill of blood. transfusion of platelets will
help prevent bleeding. Infusions of granulocytes would
be expected to help combat infections, but the shorthalf-life of these cells (6.7 1.4 hours in man [M6.
A9, B 161) makes this procedure difficult to realize inpractice.

+137. The studies with large animals described above
demonstrate that conventional supportive medications
and transfusions of blood elements after irradiation
can increase the LD,o,3, by as much as I Gy [B30. P?,
S9]. Although this dose increment may appear small.
the corresponding survival rate would increase quite
markedly because of the steepness of the doseresponse curve (Figure XXI).

138. Clinical data on the efficacy of bone marrowtransplantation after irradiation refer mainly 10 thetreatment of leukaemia: the results are confounded by
the disease itself, concomitant cytotoxic treatment andother supportive measures. By extrapolating to man
the relatiorlship between body weight and the numberof injected autologous marrow cells required for
rescue of 50% of animals after LD,,, a value of
2 lo7 cells per kg was deduced for man [VI I]. For
100% rescue, 4 lo7 cells per kg was estimated. The
minimum cell dose for rescue after lethal whole-bodydoses to leukaemic patients using HLA identicalallogeneic bone marrow cells is approximately I lo6
per kg body weight [T6]. This is compatible with theabove extrapolations for healthy individuals, because
in mice and dogs approximately four times as many
allogeneic as autologous marrow cells are required for
rescue [V9. V 101. Foetal liver is also an importantsource of haemopoietic stem cells for transplantation
purposes, e.g., [W30]. The experience with bonemarrow and I'oetal iiver transplantation to [he t~ictimsof the Chernobyl accident is described in the Appendix.

B.

EFFECTS O F DOSE PROTRACTION

139. Protracted or fractionated doses are usually lessinjurious than are single doses, for two main reasons.
First, cells are capable of repairing sublethal radiation
damage. This process is complete in six to eight hours,
and the attending increase in survival is generally
greater after higher doses than after lower doses.
Repair of sublethal damage can also be described byan increase in the total dose required to achieve agiven level of cell killing or tissue injury. The sparing
effects of protracted or fractionated irradiation aremuch less important after high-LET radiation. becausesuch radiation produces much more irreparable damage
than low-LET radiation.

140. Second, repopulation of cells may take place
during the overall time of irradiation. The time of
onset of compensatory proliferation is specific to agiven tissue. I t occurs once depletion of the normal
complement of mature cells has been recognized. In[he intes~inc,repopulation usually commences uithina few days of the beginning of irradiation and in skin
it commences after about two weeks. The doublingtime of regenerating clonogenic cells is usually about
one day, and may be less. The doubling time is longer
than the cell cycle time because of concomitantdifferentiation of the clonogenic cells and hence theirloss from the precursor cell pool. The cycle time
during regeneration is much shorter than before
irradiation, and there can be an increased number ofdivisions in the amplifying proliferative populations.
leading to a transient overshoot in the mature cell
populations. Low dose rates, 0.4-2.7 Gy per hour, canblock cells in the cycle and prevent cell division [M36].
141. Of the main tissue responses described in thisAnnex and occurring with~na few months of irradiation. the lung shows a greater sparing effect of dose
protraction or fractionation over a week or two than
the intestine or skin CT24. U4] (the marrow shows alesser effect). Empirical formulae have been devised todescribe the increase in dose that is tolerated withprotraction or fractionation in radiotherapy. With
dose protraction, the increase in iso-effective dosewith increasing irradiation time. T, can be describedby the formula
Dose = Constant X T m
where m is the exposure-time coefficient. Alternatively.
D = constant X Rm""'-I), where R is the dose rate. The
formula is applicable over a limited range of exposure
times, which. like the value of the coefficient, varies
between tissues [TZJ]. For human skin tolerance, m isabout 0.29.
132. The most widely used description of fractionation effects is the Ellis formula [E3], in which thenumber of fractions and the overall time are variables.
According to Ellis.
Total dose = NSD X N"-'JX Tall
where NSD is the nominal standard dose and theexponents 0.24 and 0. I I apply to early skin reactions.
The formula is generally considered valid for between
4 and about 30 fractions. and it is recognized thatdifferent exponents apply to different tissues [T24].
Variations on the formula that consider partial
tolerance. time-dose factors and cumulative radiation
effects (CRE) have been described [TZJ, U4].
143. An alternative to these power-law relationships
has been described more recently; the linear-quadratic
relationship [D20]. I t is considered to be more
representative than the Ellis formula of the relationship between total dose and fraction size over a larger
number of fractions, when the overall time is less thana few weeks and does not influence the dose required
for a given effect [F4]. The effect E in a tissue of aseries of n fractions each of dose d is given by:where a (Gy-I) and P (Gy-') are constants. When nand d are changed from n, and d , to n: and dl. total
doses D l and D, resulting in the same effect E are
related by
The ratio t r / P is tissue specific. Lower values indicate agreater sparing effect of fractionation. e.g.. a//?- 2-4 Gy
for pneumonitis, and higher values indicate less of afractionation effect. e.g.. a / / ) 10-20 Gy for earlyskin reactions [T24].

-

1.

I'rodromal responses

144. Comparatively little is known about the effectsof dose rate or fractionation on prodromal responses,
but there is some decreased effect due to dose
protraction. The information comes mainly fromradiotherapy treatments, and different centres haveused different dose rates. Even when the same dose
rate is used, the severity of prodromal symptoms after
a given dose has differed between centres. For
example, only two out of eight patients with haematological malignancies given 10 Gy (0.05 Gy per minute)
had nausea during irradiation, with vomiting after

5-7 Gy [C35]. In contrast, all seven patients with asimilar condition treated by Thomas et al. [TI71
developed nausea, and six out of seven vomited
towards the end of irradiation. Prodromal symptoms
were more severe when the dose rate used to give 3 Gy
to patients with Ewing's sarcoma was 0.3 Gy per
minute [R6], compared to 0.03 Gy per minute [M34].
With whole-body irradiation prior to marrow trans~lantation.it was noted that the onset of nausea andvomiting was related to total dose. but not to the rate
at which the dose was given. except possibly in thecase of dose rates of less than 0.06 Gy per minute[B32]. The incidence of vomiting was about 10% in
the 64 Rongelap natives exposed to fallout doses
estimated to have been about 1.75 Gy. where the dose
rate decreased from about 0.055 Gy per hour at thestart of irradiation to about 0.016 Gy per hour after
50 hours [C 161; vomiting appeared in slightly less than
40% of accident cases and radiotherapy patients after
estimated acute doses of similar magnitude (Figure V).
There is no accurate information concerning highLET radiation.
145. In monkeys. the latent period to retching or
vomiting after 4.5 Gy was increased by a factor of 3
(from 30 to 90 minutes) when the dose rate was
reduced from 1.2 to 0.07 Gy per minute [H35, H36].
Most of the increase occurred between 0.5 and0.15 Gy per minute. In dogs, routine emesis during
irradiation with 18 Gy could be avoided by reducing
the dose rate from 0.18 to 0.05 Gy per minute [H38].
146. In the radiation accident in hlexico City in
1962. the individual receiving the highest dose deliveredat 3.0 Gy per day for seven days and 0.25 Gy per day
for a further 17 days, had anorexia and vomiting only
after the seven days of exposure at the higher dose rate[M3]. In the individual receiving the lowest dose ofabout 1 Gy over 106 days of exposure at 0.09-0.16 Gy
per day. fatigue was reported on day 36. but there
were no intestinal symptoms.
147. An extensive series of studies was performedon patients receiving abdominal radiotherapy with
45-55 Gy (midline dose) given in 2 Gy fractions. five
per week [B56]. Nausea and vomiting appeared after
the first few sessions. These symptoms were highlyvariable in severity and they lasted for about a week. The
effects were more frequent and intense after either theupper half of the abdomen or the epigastric region
had been irradiated. Diarrhoea occurred during thethird week when the total accumulated dose hadreached 25-30 Gy. particularly in women where thefield included the lower abdomen. Gastric pain was
experienced by men irradiated in the epigastric region.
but only rarely did diarrhoea occur in those who
received irradiation to the lower abdomen and pelvis.
The apparent sex differences may reflect technicaldifferences in the irradiations.
148. Retrospective studies on 2,000 patients receiving
whole-body irradiation showed increases in ED,
values when doses were protracted over eight days ormore (Figure XXIV) [L9]. In 1,085 patients given
small, daily whole-body exposures, 20-30 R (about
0.15-0.20 Gy to the stomach) per day for 30 days or

1.69

2.24
ABDWINAL DOSE (Gy)Figure XXIV. Changes in incidence of prodromal symptoms for fractionateddoses in man. Fractionation of total body dose over eight days increases thedoses required lo produce the same incidence of various prodromal symptoms
in the exposed population of patients by 1.5 for anorexia (A), 1.6 lor nausea (N)and 2 2 for emesis (E).
~ 9 1

more were required to cause prodromal symptoms.
Exposures from 10-20 R (about 0.075-0.15 Gy to thestomach) per day produced nausea infrequently, evenwhen these exposures were delivered rapidly at approximately daily intervals for 3-4 weeks, and exposures of
5-6 R (about 0.04 Gy to the stomach) per day produced
no symptoms [L9]. Patients irradiated at very low
rates (less than 1.5 R, about 0.01 Gy per hour to thestomach) and receiving less than 30 R (about 0.20 Gy
to the stomach) per day also showed a lack of
prodromal symptoms, except'fatigue [R5].
2.

Intestinal responses

149. Studies of human intestinal mucosa have been
made during and after x-ray therapy. using serial
biopsies from patients irradiated to the abdomen for
malignant disease [T9].Exposures of 2,000-3.300 R(15-20 Gy to the intestine) delivered in daily fractionsof about 1-2 Gy produced during the treatment a
decreased mitotic activity in the crypts, a decrease in
the absorptive surface area of the bowel, and anincreased infiltration of the lamina propria by inflammatory cells and plasma cells, with occasional
crypt abscess formation. Both the mitotic activity inthe crypts and the mucosal surface recovered by two
weeks after the end of treatment. Gastrointestinal
malabsorption was reported in patients during irradiation to the abdomen with daily fractions of 1-1.5 Gy,
to a total of about 30-40 Gy in five weeks [PI]. or
fractions of 2 Gy to a total of 45-55 Gy [B5]. Biopsiesof rectal mucosa taken from radiotherapy patients
receiving a total dose of 42.5 Gy in 10 fractions for
bladder and cervix cancer showed a depression in total
cells per crypt during treatment, with recovery tocontrol values by day 70 after the last fraction [WIO].

The number of fibroblasts in the crypt sheath wasdepressed by the end of the fractionation schedule;
this was followed by recovery, but there was asubsequent depression at days 360 to 800 after
irradiation.
150. Low-dose rate or multifractionated radiation
spares the intestine in all species quite substantially[U4]. With radiotherapy treatments, tolerable fractionated doses are in the middle of the range accepted
for all tissues in the body [R12]. The small intestine,
rectum, colon and stomach, in this order, are the most
responsive regions [F2] and will tolerate not morethan 40 Gy delivered over four weeks to large volumesof tissue. Dose-mortality relationships for man due toprotracted intestinal irradiation in man are unknown.
3.

Haematological responses

151. Protracted irradiation is generally less efficientthan acute irradiation in reducing the number ofblood neutrophils. However, this effect was notdetected when the overall exposure time was relatively
short, as in the case of the Marshall Islanders given
1.75 Gy over 50 hours, where the haematologicalresponses were those expected after a similar dosedelivered acutely [C15, C13]. With further protraction,
there is less effect per unit dose. For example. in the
Mexican accident [M3], the one survivor received
between 9.8 and 17 Gy over 106 days, and his lowest
recorded blood cell counts were 2.000 white cells per pland 70.000 platelets per pi.
152. The dependence of the nadir in WBC count on
total dose and exposure time was described by Yuhas etal. [Y2], who analysed data for 121 patients with non-

haematoiogical malignancies receiving fractionatedufhole-body irradiation over various periods of time.
The relationship was:
Per cent U'BC = I( X 100 X D-"
TT"
where K is a constant, required for extrapolation tothe ordinate at zero dose because no effect was seen
below 25 R (about 0.15 Gy to the marrow); D/0.0075
is the total marrow dose in Gy; b i is the slope of percent WBC on D/0.0075: T is the tinle of protraction
in days; and b, is the slope of per cent WBC on T. For[he patients with non-haemopoietic malignancies andwith normal initial levels of WBC. b, = 1.04, b, = 0.63.
The contribution to the observed effect from thediseases of these patients is unknown.
153. The recovery of marrow in irradiated leukaemic
patients was slower than in patients with nonhaematological malignancies [Y2]. This was deduced
from 2,000 case histories where fractionated treatments had been given. Values of the coefficient b2 weremarkedly different from the value of 0.63 for patientswith non-haematological diseases. being 0.392 forpatients with chronic myeloid leukaemia (CML), 0.221
for chronic lymphocytic leukaemia (CLL) and 0.231
for lymphosarcoma (LS). The values of b, were notmarkedly different from one another, being 0.999(CML), 0.91 (CLL) and 1.119 (LS). The analysis
indicated that the greater sensitivity of WBC levels inleukaemic than in non-leukaemic individuals was
associated more with dose protraction and recovery
phenomena than with total dose.
154. A study was made of patients in remission
receiving fractionated whole-body irradiation over fourdays prior to cyclophosphamide and bone marrow transplantation for acute lymphocytic and non-lymphocytic
leukaemia and chronic myeloid leukaemia [S5]. Frornblood samples taken during the fractionated course ofirradiation, an effective Do of 3.7-5.4 Gy was deduced
for lymphocytes and about 10 Gy for granulocytes.
This confirmed that the greater radiosensitivity oflymphocytes (relative to granulocytes) applies also to
fractionated doses. The values of sensitivity refer tocell numbers measured within a feu' hours of a dose
fraction and not to the later nadir levels. In a similar
study using 11 fractions of 1.2 Gy given over fourdays, the decline in lymphocyte numbers during
irradiation was characterized by Do = 1.2 Gy [D22].
Further, the decline was similar for B- and T-cells andfor the OKT4 and OKT8 lymphocvte subsets. Low
whole-body doses of 0.1-0.15 Gy. given twice weekly toa total dose of 1-1.5 Gy for the treatment of generali~ed
lymphocytic lymphoma and lymphosarcoma, produceda drop in the white cell and platelet counts, both ofwhich reached a nadir at 4-5 weeks after completionof the irradiation [J20, 5211.
155. A continuing decrease in granulocyte/macrophage colony-forming cells (GM-CFC) in bone marrowand blood during irradiation, followed by regeneration
after irradiation, was reported in patients treated for
malignant lymphomas using whole-body doses of
0.1 Gy delivered three times per week to a total of
1.1 Gy [L19]. In contrast, studies of the concentrationof GM-CFC in the blood of five patients receiving
whole-body irradiation (1.5 Gy in 15 days) for various
metastatic cancers showed an increase around day 10
during the irradiation [TI 81.
1.56. GM-CFC have also been measured in patients
receiving fractionaled partial-bod! irradiation. .After
irradiation of 16q-30R of the total marrow inpatients with various malignancies (carcinomas of thecervix, lung and rectum), a significant decrease in
GM-CFC per millilitre of blood took place between
days 5 and I4 after the start of treatmenf, by whichtime the cumulative doses were between 4 and I4 Gy[B48]. Between days 15 and 24 after termination oftherapy delivered over several weeks. the GM-CFC
per millilitre of blood were about 12% of normal andthereafter increased slowly to 2 4 5 on day 35. Afterdoses of 30-40 Gy (five 2-Gy doses per week) delivered
to 25-45% of the marrow of patients with Hodgkin's
disease or non-Hodgkin's lymphomas, the ablated
marrow repopulated slowly over a period of months(the repopulation was faster in larger irradiated\tolumes~[D16. M371.
4.

LD,,,,, in man

157. There have been few instances where the numberof individuals exposed to near-homogeneous protracted
irradiation has been sufficient to allow an estimate of
the change in LD,,,,, with dose protraction. The only
information relates to a few accidents. from groups ofindividuals receiving irradiation from atomic bomb
tests, and to radiotherapy patients receiving low-doserate or fractionated whole-body irradiation. Some
examples of protracted whole-body exposures are
given in Table 19. The 64 individuals exposed to dosesof about 1.75 Gy from fallout radiation received mostof their dose in the first few hours. The average
exposure rate over 50 hours was about 0.03 Gy perhour. decreasing according to t-l.:. The haematologicalresponses were those expected for similar doses given
at high dose rate. and hence any dose rate effect was
small [C15. C 131. The other individuals in Table 19
received exposures over 5-1 15 days.
158. .An accident occurred in Goiania. Brazil in 1987
[I231 which resulted in initial acute whole-bodyexternal exposures followed by low dose rate chronicwhole-body exposure from internally deposited "'Cs
chloride (from a damaged teletherapy source). In
addition, many persons received acute localized radiation injuries (beta/gamma) to the skin and deeper
tissues. Twenty-one persons required intensive medicalcare. Ten persons were critical with dose estimates(cytogenetic dosimetry) ranging from -1-7 Gy. Four
persons died as a result of their exposures. In addition
to good nursing care. antibiotics and platelet transfusions. the experimental drug granulocyte-macrophagecolony-stimulating factor (GM-CSF) was administered
to eight patients suffering from the acute radiation
syndrome. Four of the patients who received GMCSF subsequently died as a result of their radiation
insult. The efficacy of using GM-CSF was notdemonstrated.

159. Several formulae have been proposed to calculate
equivalent doses for mortality when the dose is
protracted, and these are empirical guides to changes
in dose. One of the first to be proposed involved theequivalent residual dose (ERD), which was the dose
required t o cause equivalent injury in a n unexposed
individual.
ERD = D,[f + (1 - Oe-'"1

5.

Skin

163. Information on the response of skin to fractionated doses of irradiation comes mostly fromradiotherapeutic experience. This information was
reviewed in detail in the UNSCEAR 1982 Report[U4], and is summarized here, together with more
recent information.

where D, is the dose delivered in a single exposure, f is
the fraction of the total injury that is irreparable, t is
the time in days that has elapsed since exposure andr is a constant equal t o the repair half-time in days
divided by 0.693 [L4]. The E R D during protracted
exposure at a constant dose rate is calculated as

164. Dose-incidence curves for erythema using fractionated doses (Figure XXV) have been measured usingreflectance spectrophotometry [T21]. The measurements were made on patients irradiated using twoparasternal fields, each 5 X 12 cm.

ERD = D, [ft + r(1 - f)(l - e-L/r)]

165. A dose-survival curve for epidermal clonogenic
cells in situ was measured in patients receiving fractionated radiotherapy t o an area 22-24 cm X 15-18 cm
on the chest wall [A5]. The total doses ranged between
63 and 72 Gy and were given in 34 to 48 fractions.
Cell sensitivity was characterized by Do = 4.9 t 1.5 Gy
for these fractionated doses, a value compatible withpredictions from extensive information in mice.

where D, is the dose rate and t is the exposure time indays [L33, N121. The recovery half-time in man was
postulated to be 15-35 days and f to be lo%, on thebasis of sparse clinical results a n d extrapolation fromanimal data [L4,N 121.
160. A pourer function was proposed [L9]:Iso-effective (fractionated) LD,, =LD,, ( I week exposure) X to-l6
where t (in weeks) is longer than one week. This
formula was deduced from the whole-body irradiationof cancer patients, where the LD,, (one-week exposure)was taken to be 3.45 Gy. It was suggested that theexponent 0.26 might be 2 or 3 times higher for healthypeople.
161. Another formula has been proposed more
recently for calculating accumulated iso-effective dosesu p t o 10 Gy [BlO. 821, MI91 and up to 100 days
exposure [M2, H471. The operational equivalent dose
(OED) for acute exposures is expressed by the formula
O E D (Gy) = total accumulated marrowdose (Gy) - 1.5 - 0.1 t (days)
The formula was deduced from a large number ofdose rate and fractionation experiments in various
animal species including mice, guinea pigs, sheep andswine [hf 191. The dose of 1.5 G y in the formula
represents the average amount of dose recovered in
the first day among all species, and thereafter an extra
dose per day (dependent o n species) is required tocounteract repopulation. A dose of 0.1 G y per day is
assumed for man. In view of the differences in thevalues of the constants between species. the formula isconsidered suitable only as a guide and not as an
accurate assessment [M13]. It is intended for application in circumstances where a large initial dose isgiven. The maximum value of O E D is transformed
into the expected mortality using the dose-mortality
curve for an acute exposure. Negative values have no
meaning. Also, the relationship applies only t o mortality
from marrow damage.
162. The above formulae are consistent with the data
for single and fractionated exposures in man (Tables 11
a n d 19). but they should be taken as only a very roughguide.

166. Data obtained by various radiotherapists since
about 1930 were reviewed and analysed by Cohen [C7,C211, and these data formed the basis for the Ellis
formula [E3]. The nominal standard dose (NSD) isabout 18 Gy for skin tolerance when areas of 35-100 cm'
are irradiated. The exponents of N (number of fractions)and T (overall time) also apply if the end-point iserythema, because the slopes of the iso-effect curves
are similar, but the doses are lower. Also, the same
exponents apply for different field sizes, where thevalues of NSD differ according to the formula given in
section I.D. I.
167. For early skin reactions, the n/P ratio isgenerally considered to be in the range 10-20 Gy. For
erythema on the chest wall, ratios of 8.4 Gy, 21.9 Gy
and 21.5 G y were determined at incidences of erythemaof. respectively. 16. 50 and 84% [T21].
168. The influence of dose rate on skin reactions is
known from the results of radiotherapy. Curves
relating total dose and dose rate to produce "tolerable"-

0 2 x 4 Gy per week
5 x 2 Gy per week

0

10

20

30

40

50

60

70

80

TOTAL DOSE (Gy)Figure XXV.

Dose-Incidence curves for human skln erythema.

IT211

reactions, mainly in skin, were presented by Hall [HI].
An equation describing the shape of these curves [03]has the form
where T is the treatment time in hours using dose rater (Gy per hour X 0.01).
169. The time course of skin reactions is similar after
neutrons or after x rays [FI]. The RBE value forsingle doses of neutrons (16-MeV D on Be) producing
erythema on 5 cm X 4 cm areas of thigh skin is about
3.0. with reference to 8-MeV x rays [FI]. Earlier work
using 200-kVp x rays as the reference radiation [ S l l ,S12] also gave a value of about 3.0 when the original"doses" were converted to Gy [B15] and 3.5 whenusing (8-MeV D on Be) neutrons. For fast neutrons.
the exponent of N is reduced to 0.03 [Fl].
170. Radiation-induced skin injury was evident in
19 patients involved in the Goiania accident (1987).
Lesions were present on hands, feet, legs, armpits andnumerous small areas on chest, abdomen, face, arms
a n d the anterior medical aspects of the legs. Skin
injury was due to beta radiation from contamination(external) and t o deeper underlying tissues from
penetrating gamma radiation. Beta injuries healed
within 3 months after exposure followed by expressionof gamma injuries to deeper tissues. None of the local
injuries among Goiania victims were as extensive as in
the victims of Chernobyl. The clinical interpretationof this difference was that the Russian victims sufferedfrom combined-injury disease including thermal andbeta burns while the Brazilian ones were fromradiation only.
6.

Lung

171. The lung is spared by the use of low-dose-rateo r fractionated irradiation [B32. K1, M38]. The dosefor 5% incidence of pneumonitis can be increased
from 8.2 Gy to about 9.5 Gy using 0.05 Gy per minuteinstead of 0.3-0.5 Gy per minute [Kl]. The patients
receiving low dose rate also received chemotherapy,
which may have reduced lung tolerance. Hence theeffect of reducing the dose rate may be greater thanobserved. This possibility is suggested by experimentswith mice, where the ratio of LD, values at the twodose rates was 1.8 without the use of chemotherapy[HI71 and 1.3 when cyclophosphamidc was given[L32].
172. With fractionated irradiation the total dose canbe increased even further [M38, P5]. With prophylacticlung irradiation in the treatment of osteosarcoma, nopneumonitis was seen in 40 patients given 20-25 Gy to
the lung in daily dose fractions of 1.5 G y [N8]. Thiswas in contrast to seven patients in whom pneumonitis
was observed after 30 Gy delivered at 3 Gy per day.
There was no pneumonitis in a further 14 patients
given 24-25 Gy in 13 daily doses t o the lung [N9].
173. In the Ellis formula [E3]. the combined exponents of N and T were estimated t o be 0.43, with an
NSD of about 9 Gy equivalent (7 Gy with concomi-tant actinomycin D ) [PSI. The combined exponent
was deduced from a series of 26 patients treated t o atleast one whole lung for metastatic lung disease. using
cobalt-60 gamma rays or I-MV x rays, together with aseries of fractionation data using lethality in rats after
lung irradiation. Although the separate exponents of
N and T have not been estimated for man, in mice theexponent of T is about 0.07 [U4]. The exponent of N
is about 0.39 between one and eight fractions. andabout 0.25 between 8 and 30 fractions [U4]. Alternatively, iso-effective doses for different fractionation
schedules using short overall times can be calculatedusing the a//) formulation. where a / / ] for mouse lungis 2-4 Gy [T24].
174. A recent analysis has been made of 54 patients
bvith various thoracic malignancies given irradiation t ovarious lung volumes in daily fractionated doses[M38]. No previous treatments had been given. The
incidences of pneumonitis in five groups of thesepatients are given in Table 20. The groupings weremade on the basis of biologically equivalent doses indifferent schedules. No significant differences wereobserved in the incidence of pneumonitis for patients
given irradiation to less than one quarter of the totallung volume and patients with irradiations of between
one quarter and one half of the total lung volume.
7.

Gonads175. Contrary t o what happens in other tissues.
fractionated doses to the testis are more effective thansingle doses in damaging spermatogenesis in animals[U4]. because of the progression of cells into sensitive
stages. This is also observed in man [L13]. Comparedto single doses of the same total amount (5 Gy),
20 doses of 0.25 Gy produced a more rapid drop in
the number of sperm cells, and more time was
required for recovery [L13].
176. Most of the quantitative data on the effects offractionated irradiation on the testis come from thetreatment of malignant disease by radiotherapy [19. U4].
Fractionated doses of 0.5-1.0 Gy produce temporary
aspermia beginning at about three months [Sl].
Fractionated doses of 2-3 Gy produce long-lastingaspermia at 1-2 months [SI 1.
177. The few measurements of testicular hormone
levels in accident cases receiving protracted irradiation
are consistent with the planned study referred to earlier
using single doses [Rl I]. After accidental exposure toiridium- 192 gamma rays for various periods of time in aseven-day period, the levels of serum follicle-stimulating
hormone were constantly elevated and luteinizing
hormone was variably depressed after a dose estimatedto have been 1.75 Gy to the testes [W I].
178. The total doses of fractionated radiation needed
to cause temporary or permanent female sterility arehigher in some studies than in others using single
doses [19, U4], but i t is difficult to assess accurately
the increase in the total doses. In mice. fractionation
clearly has a sparing effect on fertility [R 131. Fractionated doses of 4-7 Gy to the ovaries of older

women induced artificial menopause in the majorityof cases. Higher doses, 12- 15 Gy. were required inyoung women [A((].
179. Serum gonadotrophin levels were unaffected bydoses of up to 1.5 Gy given in fractions over 28 days
to a series of patients treated for Hodgkin's diseaseby oophoropexy followed by irradiation [T7]. A seriesof patients received pelvic irradiation for carcinoma of
the cervix, to a total dose of 60 Gy using dosesof 9-12 Gy per week in 3-5 fractions [BIZ]. Levels offollicle-stimulating hormone rose immediately following doses of 5.6-24 Gy among different patients; thelevels of luteinizing hormone rose after doses of
11-3-26 Gy. The levels of oestradiol in the peripheral
blood decreased after doses of 6-12 Gy.

C. INTERNAL EMITTERS
180. Large amounts of internal emitters are required
to produce early effects in man. Amounts this large
would be received in therapeutic treatments and.
possibly, in accidents or from nuclear fallout [D23]; inthe case of nuclear fallout, however. external irradiation might provide the majority of the dose and could
therefore be responsible for producing the early
effects. Large amounts of internal emitters have beenused to treat certain cancers. The dosimetry isconlplicated by tissue distribution, decay rates andclearance rates. More uniform distribution of dose to
the body is produced by elements that are not taken
up by specific organs (e.g., iodine by the thyroid,
phosphorus by the marrow), and the whole-body dose
depends on the circulation time before uptake. Dose
rate. cumulative doses, spatial distribution of dose andthe effects of' internal emitters on tissues in animals
were discussed in detail in the UNSCEAR 1982
Report [ i l J ] .

about 50% of patients. Bone marrow depression may
be observed after multiple doses or large single dosesof I3'I; however, this can be avoided by administering
doses with individual activities not exceeding 5.500 hlBq
at intervals of two or more months [HZ]. The
accuniulated dose to the blood can be as high as 5 Gy
[SX]. In d large series of patients, about 3 Gy weredelivered to the blood from !"I-sodium iodide; after
nausea. the most frequcnt serious complication wasdepression of the bone marrow [D9].
183. Detailed immunological studies have been performed on 34 patients treated with 1-3 doses of300-350 MBq "'I for toxic or atoxic nodular goiter[W27]. Blood lymphocyte counts were reduced to60-80% at both one week and six weeks after treatment.
and the frequency of lymphocytes expressing receptors
for C3 (EAC-rosette-forming cells) was also reduced.
At six weeks there was a small increase in thefrequency of T-cells. identified by Leu- I monoclonal
antibodies: this was due to an increased proportion ofhelper/inducer T-cells, identified by Leu-3 monoclonal~. The "'I also decreased the capacity oflymphocytes to secrete IgM when stimulated withpokeweed mitogen. Less effect was seen for IgG and
IgA. The mitogenic responses of lymphocytes to PHA
and ConA were not changed significantly.
184. Radiophosphorus (j2P)has been used widely forthe treatment of polycythemia Vera. Single or multiple
doses are given to reduce the polycythemia. and theactivity per treatment. 140-220 MBq, delivers a cumulative dose to the marrow of about 1.4 Gy [SIO]. The
dose rate decays with a half-life of 6.7 days. Overdosage was reported with a patient who received
14.8 MBq per kg body weight [C33]. This patient
showed a mild and reversible pancytopenia. Twopatients were given 1.850-2.220 MBq, which delivered
a cumulative dose of about 10 Gy to the marrow[G16]. Three weeks later there was agranulocytosis.
severe thrombocytopenia and marrow aplasia. Haemopoiesis recovered spontaneously from day 40 after
treatment. Blood counts returned to normal in one
patlent, but mild thrornbocytopenia persisted in theother.

18 1. Haematological injury has been reported in man
after the therapeutic use of colloidal gold, radioiodine,radiophosphorus and radiosulphur. Radiocolloids havebeen used to irradiate serosal surfaces follo*ing theaccumulation of fluid and disseminated tumour cells.
An activity of 550 MBq colloidal ' 9 8 A in
~ 40 ml saline
185. An immunological study was carried out on
injected into the peritoneal cavity resulted in total
16patients receiving a single dose of 150-305 MBq "Pfordoses to the retroperitoneal lymph nodes. the omentum
polycythemia [W27]. Blood lymphocytes were reduced
and the peritoneal serosa of 77.5. 67.5. and 47.5 Gy.
40% by 12 weeks after treatment. The B-cell component
respectively. Mild radiation sickness and haematowas reduced most, but lymphocytes expressing T-cell!ogical complications such as persistent leukopenia.
markers were increased. IJHA reactivity was increased,
were reported [H7]. The dose to the marrow from thisbut Ig secretion in response to pokeweed mitogen was
reduced.
treatment is unknown, but i t would have been v e n
inhomogeneous. Overdosage using 7.400 MBq of 1 9 b A ~resulted i n estimated doses of 73 Gy to the liver and
186. The treatment of chondrosarconia and chordoma
spleen and 4.4 Gy to the marrow [B40, S231, givingby j5S is limited by the latter's haemotoxicity. In
rise to pancytopenia, with a tendency towards recovery
13 patients, the cun~ulativeactivity administered asby day 60-70. However, on day 69 the patient diedsequential amounts of 185-222 MBq per kg bodyof cerebral haemorrhage, with concomitant severe
weight, was 370-1.780 MBq per kg of body weight,
thrombocytopenia.
giving a total dose to the marrow of about 9.9 Gy[M7]. The first dose had minimal effects in most
182. The use of radioiodine to treat metastatic
patients, but with each successive dose, marrow
thyroid cancer is limited generally by the dose to bonedepression increased and recovery decreased. Thrombomarrow. Doses of 3,700 MBq of ''I1 delivered in excess
cytopenia, leukopenia and, later, anaemia developedof 0.5 Gy to the plasma and caused sialadenitis inprogressively and were dose-related.

187. Severe acute injury to the intestinal mucosa has
not been reported from internal emitters in man. The
highest radiation dose would be received by the large
intestine, because the contents of the gut ha1.e a longresidence time at in this site. The critical cells are thestem cells in the crypts, the dose at this p o s ~ t i o nis themost important. Experiments in dogs indicated an
LD,,,, corresponding to 130 MBq per kilogram bodyh,delivered approximately
weight of 1 0 % ~ - l O b Rwhlch
40 Gy t o the mucosa over about 18 hours [CIS].
Comparisons were made of doses from '"Pm or
LU6R~-'06Kh
resulting in death from gastrointestinal
injury. These isotopes have widely differing beta
energies. and i t was calculated that a dose of 35 Gy ofeither isotope to the crypt cells resulted in the death of
50% of the dogs [S14]. This dose is comparable to adose of about 13 Gy of external irradiation delivered
acutely [B 161. Values of 35-40 G y in these experimentswith dogs are compatible with similar doses ofmultifractionated external irradiations in man, which
are considered to be tolerance doses in radiotherapy
IR91.
188. In the few cases where doses to the human lungfrom internal emitters have resulted in symptoms ofpneumonitis. the inhalation has been very protracted
and the doses uncertain. For example. a chemist who
had been involved in the separation of radium andmesothorium compounds and who had inhaled radioactive compounds over a long period showed signs ofradiation damage to the lungs [D5]. Pneumonitis wasreported in a man who had been employed for a longtime in the luminous paint industry [RI]. Relationships have been described between the initial dose ratein the lung following inhalation of radioactive particles
a n d their effective half-life in the lung, in relation to
the survival of different animal species from pulmonary
injury, extrapolated to man [W25]. It was deduced
that death from lung injury could be expected in all
individuals receiving as little as 7 MBq ot' an inhaledaipha emitter with an energy of about 5 MeV a n d aneffective half-life greater than 100 days.
189. Effects of internal emitters in animals have been
discussed in detail by ICRP [I71 and UNSCEAR [U4].
For example. in experiments in which dogs were
exposed to beta-emitting aerosols of fused aluminiumsilicated particles labelled with
I4'Ce, o r 'OSr,it was found that the dose to the lungs resulting indeath from pneumonitis in 50% of the dogs could be
increased by a factor of 5 (90Sr)o r 10 ("'Y) relative tothe acute dose of external radiation [M8]. The dosage
increase depends on the half-life of the isotope whichgoverns the exposure time. With long-lived aiphaemitters. the clearance rate from the lung is mostimportant.
190. Two individuals died after working with large
amounts of tritium; they had received doses whichwere estimated to have been in total about 3 G y over
six years and about 10 Gy over three years [M39.
S31]. A slow but continuously progressive anaemia
was observed, rather than changes in the white cellcount. Another individual. who received a lower
accumulated dose of about 1.5 G y over four years,
showed only a slight hypoplastic anaemia.

191. Many cases of accidental ingestion of radionuclides have been reported [FIO]. Bone marroweffects are particularly marked when the compound istaken up in the marrow (phosphorus) o r the bones(strontium. radium) and when the half-life is long.
Haemopoietic injury has been reported after theingestion of, and chelation therapy for. 37 MBq
americium-241 delivering 5.5 Gy to the bones over
five years [T22] a n d after the ingestion of radium
giving 2 Gy over six weeks and more than 50 Gy overthree years [G 141.
192. Extensive internal contamination with '"CsCI
occurred in 22 persons in the Goiania accident (1987).
Internal contamination in these 22 individuals exceeded
85 mCi (3,100 kBq). One child in the Goiania accident
had internal 13'Cs levels exceeding 30 mCi (1.100 MBq).
Extensive "'Cs internal contamination prompted theuse of Prussian Blue for the first time in radiation accident histor?. Prussian Blue was effective inenhancing the foecal elimination of 13'Cs althoughhigh levels of internal contamination remain in manyof these people.
193. The treatment 01' individuals following ingestionof large amounts of internal emitters has been
discussed in various publications [D23. 12. 13. 14.
N 151. The treatments are based on reduced absorvtion
a n d Aretention, enhanced excretion o r diminishedtranslocation. Internal emitters reaching the gut canbe removed to some extent bv the use of emetics.
lavage and precipitating agents. Colloidal ion-exchange
carriers, e.g., zirconium citrate. are effective whenadministered within hours of exposure but are themselves toxic. Decalcification therapy, designed toincrease bone resorption, enhances only slightly theelimination of radium and strontium. and i t does notaffect the non-alkaline earth elements. e.g.. plutonium.
Chelating agents such as DTPA and. more recently,
LlCAM C [M35] are efficient at complexing rareearth elements and actinides.

D.

BIOLOGICAL AND OTHER VARIABLES

194. Many biological variables are known t o affectthe response of tissues and whole animals to i r n d i a tion [U4]. In this section. only those variables will beconsidered that may contribute t o important differencesin the response of tissues i r ~ man after whole-body
irradiation, namely. oxygen concentration, previous
treatment by radiation or other cytotoxic agents. a n d
genetic disorders in the general population.
195. The radiosensitivity of well-oxygenated tissues
can be reduced by a factor of 2-3 by excluding oxygenat the time of irradiation. This was seen f o r skinreactions where a tourniquet applied to limbs enabled
the dose given in radiotherapy to be at least doubled[V16]. There is evidence of a slight natural hypoxia ina few tissues in man. particularly avascular laryngeal
cartilage, which was sensitized by about 10% by theilse of hyperbaric oxygen [H 151. and skin. which wassensitized by up to 40%. also using hyperbaric oxygen[V2]. The use of the chemical sensitizers metronidazolea n d misonidazole in radiotherapy has not produced
any sensitization of normal skin [D4], but there is one
reported case of increased oral mucositis [A6].

system and a predisposition to cancer. Death often
occurs before the age of 20, from either sinopulmonary infections o r malignancies.

196. Radioprotectors have been considered as one
means of decreasing the effects of irradiation. Theseradioprotectors include thiol compounds, which must
be administered before irradiation, and immunomodulators, which can be given afterwards [e.g.. G321.
Many studies, for example those using the Walter
Reed (WR) thiol compounds, have been carried out inanimals. Protection factors of up t o 3 have beenreported for the bone marrow in mice, and values ofbetween 1 and 2.5 for a variety of other tissues [D27].
This variation depends o n the radiation dose, lower
values being observed at higher doses. in part todifferences in intrinsic oxygenation status among
tissues. and perhaps also to their natural endogenous
thiol content [D27].

200. Three A T patients, children aged seven, nineand 10, were reported to show unusually severe
responses to cancer radiotherapy, particularly inrespect to skin responses. Gotoff et al. [G5] described
the case of a 10-year-old boy with palatal lymphosarcoma who received 30 Gy to the nasopharynx outof a total planned dose of 40 Gy. He developed
marked erythema. severe dermatitis and subsequent
deep tissue necrosis. It was concluded that an unusuallyhigh radiosensitivity was responsible for his death. A
nine-year-old boy with Hodgkin's disease received
27.5 Gy out of a planned dose of 40 Gy to themediastinum [M20]. H e developed severe oesophagitis,the skin became pigmented and desquamated and helater died of respiratory problems. Cunliffe et al.
[C20] reported a seven-year-old boy with a malignant
lymphoma in the upper lobe of the right lung. After
20 Gy, dysphagia and erythema were noted, and after
30 Gy the treatment was stopped because of theseverity of the responses. He died three weeks later. In
addition. successful treatment of medulloblastoma in
an A T patient was reported using conventional
techniques but reducing the dose to one third ofstandard, in accordance with their findings that thesensitivity of the patient's bone marrow cells wasthree times normal [H49]. In a survey in 1982 of all
known radiotherapy treatments of AT patients, fiveout of seven individuals were considered to be
excessively sensitive to radiation [S30].

197. Previous irradiation may influence the responset o a second treatment if there has not been full recoveryof the tissue. This is a well-known phenomenon in
animal tissues, particularly in the skin [B26, H131. At
times greater than six weeks after a large first dose,
the tolerance dose is reduced by about 10'3, and it canbe reduced further by repeated priming doses [HIO].
In man, there is little quantitative evidence pertainingt o skin, but some radical radiotherapy treatments tothe larynx, performed up to 30 years after moderately
high doses given for thyrotoxicosis, were tolerated
remarkably well [H21]. Intestinal tolerance to second
irradiations in man is uncertain. In mice, there is ahigher resistance [H3], which is due t o induced
hypoxia [R4]. With bone marrow in man, there is agreater response to a second irradiation given a few
months after the first irradiation [M 18. T11. TI21. In
animals, the LD,,,,, for a second irradiation can begreater than or less than the LD,,.,, for animals nothaving received any pre-treatment; this depends on thesize of the priming dose and the time between
irradiations [H 101.

201. Cultured skin fibroblasts from AT patients were
found to be more radiosensitive to gamma rays thanthose from normal individuals, by a factor of 2-3 [U4,T2]. With 14-MeV neutrons. this factor was 1.2-2[P26. P271. Heterozygotes have a sensitivity intermediate between that of homozygotes and of controls[C4. K2, T2], as detected for example between cellstrains using low dose rates [P26. P27].

198. Many cytotosic drugs decrease the radiationdose required for a given effect. The effect is achievedby the direct cytotoxic action of the drug and/or bysynergistic interaction with radiation. This information was reviewed in part in Annex L of the
UNSCEAR 1982 Report [U4]. Interaction effects are amajor confounding factor in analysing the radiation
response of ill cancer patients treated with othercytotoxic agents.

202. Peripheral blood lymphocytes from patients
whose illnesses were associated with autoimmunity,
such as rheumatoid arthritis, systemic lupus erythematosus and polymyositis. were found to be moreradiosensitive by a factor of up to about 4 thanlymphocytes from healthy volunteers or from patients
whose illnesses were not associated with autoimmunity[H43]. The increased sensitivity was associated with
deficiencies in D N A repair.

199. .4 very small sector of the population may beparticularly radiosensiti\,e because of inherited genetic
disorders. The relevant data were discussed in Annex Iof the UNSCEAR 1982 Report and in Annex A of the
UNSCEAR 1986 Report [U4, UIO]. The best documented of these disorders is ataxia telangiectasia (AT).
which is an autosomal recessive disease. In this diseasehomozygotes may be present at a frequency of 1 in
40,000 and heterozygotes at a frequency of between 0.5
a n d 5% [S42]. The signs of A T are progressive cerebellar
ataxia, conjunctival and cutaneous telangiectasia, frequent sino-pulmonary infections with sometimes
abnormal immunity, a generally hypoplastic lymphoid203. Other genetic disorders predispose t o increased
chromosomal injury a n d tumour induction after radiation. These include retinoblastoma [H4]. basal cell
naevus syndrome [T4, H4], Fanconi's anaemia [R3,
B131. Down's syndrome [T2], xeroderma pigmentosum.
Bloom's syndrome [U4] and Huntingdon's chorea[M22, K2, A7, T2]. Although the lymphocytes fromsome patients with Fanconi's anaemia were moresensitive to radiation-induced chromosome aberrations,fibroblasts from the same patients showed n o increased
sensitivity, using colony formation as an endpoint[Dll]. No accurate estimates of increases in tissue
radiosensitivity are available.

204. Other genetic factors in the general populationthat may affect radiosensitivity have been discussed in[P7]. These include familial deficiencies in glutathione
metabolism and variations in genetic constitution
mimicking the variations in radiosensitivity between
mouse strains and mutants, particularly those withhaematological disorders. Also, the radiosensitivity ofnatural killer cells in the immune system has beenreported to be controlled by X-linked genes [B35].
205. Skin fibroblasts were taken from unirradiatedsites in six patients who had an unusually severe skinreaction after radiotherapy. The fibroblasts were
irradiated in vitro. and survival cunles were plottedfor colony-forming ability. The cells from five of thesix patients showed greater sensitivity than cells takenfrom individuals whose skin response to radiotherapy
was normal [S20].
206. In conclusion, it is believed that the proportionof individuals in the general population who, becauseof genetic disorders, are likely to show a significantly
higher radiosensitivity for acute tissue effects is about
1%. While some of these individuals could of course
occur in groups of irradiated individuals being used to
calculate the LD,,,,,,
their rarity in the general
population makes it unlikely that they would have any
significant influence on the calculated values.

111. PROGNOSTIC INDICATORSAND BIOLOGICAL DOSIMETRYA.

PROGNOSTIC INDICATORS

207. In cases where persons are exposed t o highdoses, whether as a result of accidents o r of irradiations for therapeutic reasons, it is essential to determine the prognosis as precisely a s possible in order tobe able to decide on the best treatment. The prognosis
after near-lethal exposure is based on three types of
data: dosimetric, clinical and biological.
1. Dosimetric data

208. Where doses to the body in general and t o thebone marrow in oarticular can be determined with
sufficient precision, it is possible t o make a relatively
accurate prognosis. This is the case with individuals
irradiated for medical reasons or for those irradiated asa result of accidents where the distribution of the dose in
the body and the dose rate are reasonably well known.
Because all the dose-effect relationships suggested for
mortality in man have very steep slopes, a very small
shift towards lower or higher doses can cause a large
variation in the probability of death. It is reasonable
to assume that variability within a single species willbe less than, or at most equal to, the variabilitv
between different species of similar body size. For
different species of similar size, the LD,, varies by afactor of less than 2 ([U4] and Figures VII and XXII).
209. Taking estimates of LD,,,,for all classes ofindividuals (healthy and sick), situated at the extremesof a probable range of LD,,, between 2.5 and 5.0 Gy(Figure XXI), and comparing them with a n overall
average LDw,, of about 3.75 Gy, for example,
corresponds to probabilities of mortality of about
20% o r 90%. assuming the same form of dose-effectrelationship. Figure XXI illustrates these variations,
showing, for example, that the 10% probability ofdeath lies between approximately 0.5 and 3.5 Gy andthe 90% probability, between 4 and 7 Gy. The large
uncertainties preclude a formal prognosis only o n an
estimate of the dose to the bone marrow.
210. The intensive treatments to which exposed
individuals are always subjected may completelychange the prognosis. The treatments that are offeredfollowing accidental exposures are designed to combat
intercurrent infections and aplasia, and they may
increase the probability of survival. Those that are
offered to patients suffering from neoplastic disorders
often involve cytotoxic agents, and they may decrease
the probability of survival. In the first case, theindividuals are mostly healthy; in the second, thedisease affecting the patients is an aggravating factor.
In accidents, the higher the dose. the more intensive isusually the treatment; consequently, the slope of thedose-effect relationship may be less steep than theslope of the theoretical curve expressing LD,o,60 in theabsence of treatment. It is possible that, after treatment. the LD,,,,, may be increased by a factor of (atleast) 2 or (at most) 3 [L9, R6, TS].
91 1. The values of LD,,,, are influenced by a variety
of factors. The main ones are (a) sex: women appear
to be slightly more resistant than men [F15]; (b) age:extrapolation from animals to man suggests that theLD,, at birth is lower than the LD,, for adults by afactor of 2; the value for adults appears to be attainedat around puberty. with a subsequent decrease tominimum values in old age; (c) state of health: theLD,, is lower in individuals affected by other diseases,
particularly if they relate to the bone marrow o r ifthey reduce the natural immune responses; and,
finally, the most important factor. (d) the protraction
and/or fractionation of the dose with time.

212. In cases of accidental exposure, protraction a n dfractionation of the dose can have a very important
effect; when irradiation is performed for medical
reasons, whether it is whole-body irradiation o r
successive half-body irradiations. the dose is usually
given over a few days to a few weeks. This may also
be true with accidental internal exposure to long-lived
radionuclides. If the dose is spread over a month o rmore, the LD, may be increased t o 10-20 Gy (seeTable 19). The use of a model based o n cellularresponses and comparing single and multiple exposuresused in radiotherapy would give a factor of 2, o r an
LD,, of about 7 Gy for protraction over two weeks
1~91.
213. All these uncertainties make it very difficult toestablish an accurate prognosis based solely on physicaldosimetry. This is particularly true in the case of
accidents, where, except for criticality accidents, theexposure time is very difficult t o determine, giving rise
to a n additional error whose magnitude may reachfactors of 2-3 or more. Dosimetry is most valuable inthe case of very low or very high doses because.
whatever the possible error, one can ar least establish
whether the patient has been exposed in the non-lethalor the lethal part of the curve (broadly, doses up to
0.5- 1 Gy or above 6 Gy).
214. The prognosis is related to the nature of theradiation involved. In accidents. one is generally
dealing with penetrating radiation. since out of acatalogue of 98 accidents, 61 were caused by irradiatorsand 13 occurred as the result of criticality excursions
in reactors [H20]. In whole-body medical irradiations,penetrating radiarion is also usually involved, depending on which of the effects are desired. The prognosis
is particularly difficult to establish in cases of criticality
accidents with mixed gamma-neutron fields. There
are two types of difficulty in reconstruct~ngthe dose:(a) the uncertainties in assessing the values of theneutron and gamma-ray components and (b) the
choice of an RBE for the neutrons. The latter choice isparticularly difficult, because the RBE varies according
to the syndrome under consideration; in addition, theneutrons attenuate more rapidly with increasing depth
than do the gamma-rays (see Figure XIX). Also. thesimple addition of gamma doses and neutron doses
multiplied by an RBE factor, may be an oversimplification and a source of additional error, as alreadydiscussed.
215. Another important element in the prognosis is
the spatial distribution of the dose. In accidents,
irradiation is never homogeneous. Therefore, theconcepl of average dose in the bone marrow, while
useful for establishing an order of magnitude, isinsufficient for making a precise prognosis. Relatively
small volumes of bone marrow that have escaped
exposure or have been only slightly irradiated becauseof the inhomogeneity of the exposure are sufficient torepopulate sterilized haemopoietic areas through cell
migration. as long as the marrow stroma has not beendamaged.

2. Clinical data
216. An accident victim will be rapidly admitted tohospital following a reactor accident(after an accident
with an isolated irradiation source it may be later
before the symptoms and signs of radiation injury arerecognized, depending on the dose and the part of the
body irradiated). At an early stage, the critical period
may not yet have been reached, and prodromal
symptoms may be of major importance. The prodromal phase. described in section I.C.1, lasts fromthe first to the seventh day; it precedes a latency
period from about day 7 to day 20 after doses
resulting in the bone-marrow syndrome (Table 21).
The principal gastrointestinal prodromal signs areanorexia, nausea, vomiting and d~arrhoea.The average
50% incidence dose is lowest for anorexia (slightly
below I Gy) and hlghest for diarrhoea (between 2 and3 Gy). Table 22, which summarizes the results ofTable 2, may allow a quick prognosis for a patientpresenting one or more of these symptoms. Vomiting

is an easily detectable prognostic indicator, provided
that no psychosomatic factor is involved. Figure V,
which expresses incidence of vomiting as a function ofdose, allows a preliminary assessment of the dose level
and therefore of the prognosis. In addition to defining
the dose-effect relationship, the intensity of these
phenomena may have prognostic value: vomiting anddiarrhoea may be isolated or profuse, and they may or
may not increase in frequency. Their intensity andfrequency are an indication of the severity. The otherprodromal signs are indicators of neuromuscular reaction: fatigue, apathy, fever and hypotension (whether
or not followed by hypotensive shock).
217. For doses around the LD,,,, the most frequent
prodromal indicators are anorexia, nausea. vomiting
and fatigue. At supralethal dose levels, other indicators appear, such as diarrhoea, fever and hypotension[L4]. However, the prodromal indicators may occur
without necessarily being followed by the death of theindividual or by an acute irradiation syndrome. The
latency period before their appearance is also a good
prognostic feature. The earlier and more sustained isthe prodromal indicator, the longer and more difficult
is the return to normal, and the higher is usually thedose. Figure IV illustrates the times eIapsing before
appearance of the prodromal indicators: these range
from a few hours for doses of around 1 Gy down lo
about 20 minutes or so for doses of about 10 Gy[B33]. The same data are set forth in Table 23 [I12],
which also lists times of delay for the critical period(latency) and prognoses.
218. Fractionation and protraction of the dose inlluence the appearance and intensity of prodromal
symptoms and signs. Fractionation over one to sevendays increases the ED,, by a factor of 1.5-2.7,
depending on the effect under consideration (seeFigure XXIV) [L9]. Table 24 compares the ED,,, values
for the principal prodromal indicators after exposuresover one day and over about a week [L9]. These doses
are based on a retrospective study of 2.000 radiotherapy
patients (whole-body irradiation) receiving doses above
0.3 G y per day. The ED,, is estimated to be about one
quarter of the ED,,. The mean factor for exposuresover a week is approximately 2; by extrapolation. i t
could go up to 3 for longer periods.
219. The appearance of erythema during the prodromal phase is a bad prognostic sign, particularly iferythema covers extensive areas, as this indicates ahigh dose. The prognosis is poorer if the erythema
appears at an early stage, in spite of the fact that thepatient may still appear to be in good health. For
whole-body irradiations with energies of 0.1-0.5 MeV,
erythema becomes manifest after doses of 2-3 Gy;
with much higher energies, i t will indicate higher doses
at depth because of the build-up of dose in the surface
layers.
220. The absence of any prodromal symptom soonafter irradiation indicates an excellent prognosis: theaverage dose in the whole organism is probably lessthan 0.5 Gy and certainly less than 1 Gy. A few
isolated, temporary syniptoms of moderate intensity

suggest a dose below 2 Gy. From the first days after
the accident on\vards, the presence of clinical indicators and the observation of their severity allows amorc accurate prognosis, and therapeutic decisions
can be taken without wairing for the acute symptomsof the later critical phase.
221. Once the critical phase begins, the prognostic
elements are much easier to interpret than they werein the prodromal phase. An excellent indicator is thetime elapsing before the appearance of the criticalphase; the shorter the latency time. the less favourable
the prognosis. All cases of accidents involving wholebody irradiation have shown this [H20]. During thecritical phase, the appearance of new clinical indicators, an increase in their severity and persistence arebad prognostic signs. Table 25 lists the principal signs
that ma); appear, classified in order of increasing
severity, but not necessarily in chronological order of
appearance [N4].
3.

Biological data

222. The haematological syndrome presents the mostserious problem for clinicians. The gastrointestinal
and neurological syndromes appear at considerably
higher doses: 10-15 Gy in the digestive tract and
50 Gy or more in the central nervous system are
required to trigger these syndromes in one week andin a day or two, respectively. In the case of uniform
whole-body exposure, the haematological syndrome
occurs without fail below 10 Gy and down to afew Gy.
223. The earliest haematological indicator is a reduction in the concentration of blood lymphocytes. The
speed at which this phenomenon begins is directly
related to the mean .bone marrow dose. In general,once the fall has started, its rate, estimated over the
first three days, is a good prognostic indicator [H20].
Figure XXVI shows the lymphocyte reduction in six
subjects irradiated in the course of three accidents[I 131.
224. Other signs are also useful, although later,
biological indicators. The fall in granulocytes concentration in the circulating blood to very low levels is an
important feature to be monitored. because granulocytopenia is responsible for intercurrent infections,which may cause death. Also important are thethrombocytes, which help prevent haemorrhages. Daily
blood counts are the basis for the immediate prognosis
and for decisions about transfusions of blood cells.
225. An important element in prognosis is theminimum level of the various blood cells and the dateon which this minimum is reached (Figures X. A.1I.b
and A.V). In three accidents, with doses ranging from
3 to 12 Gy, the time taken to reach the nadir varied
from about 4-7 days in the case of lymphocytes andfrom 10 days to about a month in the case of
granulocytes and platelets [N5].Quantitative data are
set out in Table 26, together with the clinical outcomeor the prognosis.

DAYS
Figure XXVI. Approximate reductions in lymphocytes following
accidental exposures to inhomogeneous doses. Data from six
individuals exposed in three accidents: Brescia, Italy (1955):
12 :.; Mol, Belgium (1965): 5 :*+ 0.5 n: Vinca. Yugoslavia (1958):
3.4 :. + 0.9 n (4.38); 3.3 ;. + 0.9 n (4.18): 2 6 ;. 0.65 n (3.38);
1.6 :,+ 0.45 n. Original estimates of doses (Gy) related to
gamma rays and neutrons are presented separately. Values ofdose in parentheses are revised equivalent low-LET marrowdoses (see Table 12).
[I131

-

226. .4fter prolonged exposures it is difficult toassess the time taken for the haematological syndrome
to appear, because it is difficult to fix a starting point
for the irradiation period. The minimum values havethe same significance for the prognosis as in the caseof acute exposure; the length of time at the minimum
level is more difficult to interpret for purposes ofprognosis, since it seems to be related to the exposure
period [HZO]. Table 26 indicates minimum values ofthe same order of magnitude as those in Table 27
w51.
727. During the critical phase, the duration of
marrow aplasia is an important feature. A low bloodcount lasting for a long time is a bad sign, probably
indicating not only a high but also a relatively
uniform bone marrow dose and, possibly. a prolonged
exposure. In the case of prolonged exposure. thedepression is long-lasting and the repopulation rate isparticularly slow. a mirror image of the initial slow
reduction [H20]. During the phase of recovery, thereappearance of cells (whether mature or not) in thecirculating blood, and their gradual increase, are goodsigns. Lymphocytes and platelets are generally slower
in returning to normal than are granulocytes. Veryoften. all blood-cell types fluctuate considerably aroundtheir normal concentrations when they return t o levels
within the normal range, but this phenomenon has no
prognostic importance.

may not adequately reflect the concentration of stem
cells in the marrow. For the time being, therefore, thismethod remains qualitative and its true value uncertain.

228. The appearance and persistence of immature
cells in the circulating blood is a good sign, because it
indicates a good bone marrow response. The cells
most frequently found belong to the granulocyte
lineage: pro-myelocytes. myelocytes and meta-myelocytes. As a rule, they are present only in small
numbers. It is their continuing presence over a periodof days, rather than their absolute number, that is thebasis for a favourable prognosis. Likewise, the numbera n d variation over time of reticulocytes are important.

233. Quantitative marrow scintigraphy can be used
to evaluate the regions of the bone marrow that are
still functional: this technique produces quantitative
findings quite rapidly [I14, P161. The pattern can befollowed for about a week. I t is possible to study, ineach region of the bone marrow, the degree of ironturnover (incorporation by the erythrocytes and releaseby the reticulocytes) and its uptake. It is also possible
to distinguish extra-medullary haemopoietic regions
and to measure their relative effectiveness. However,studies such as these relate to the erythroid lineage.
not to the most important granuloid lineage. a n dtransient erythroid recovery may occur in the absenceof stem-cell recovery.

229. Other conditions such as a rare blood group,
repeated transfusion problems (shock, etc.), sudden
anaemia indicating haemorrhage, or leukocytosis
indicating an infection, are unfavourable prognostic
signs [HZO].
230. A detailed examination of the bone marrow isessential for several reasons. A number of marrow
punctures in widely scattered areas selected according
to the conditions of the accidental irradiation (that is,
the subject's position in relation to the source and thepart of the body that has probably been most
exposed) will give information about the uniformity of
the irradiation. The severity of marrow aplasia is
directly related to the distribution of the dose [I14].
hlarrow punctures give a much more reliable pictureof the bone marrow state than does the circulating
blood. However. the prognosis is not necessarily poor
if the samples all show a severely depleted marrow; it
requires only a few stem cells to repopulate themarrow, and direct examination ivith differential
counting ofthe bone marrow cell types is an insufficientbasis for a reliable medium-term prognosis. I t is not
unusual for an apparently depopulated marrow to
become repopulated to a normal level.

234. Cytogenetic dosimetry, which may be performed
in a feu, days. allows a n estimate to be made of themean dose in the body. Counting the number ofabnormalities in circulating blood lymphocytes (mainly
dicentrics, rings and fragments) and comparing thisnumber with reference values gives an accurate estimateof the mean dose. This approach has its limitations incases of highly inhomogeneous acute exposures during
which only some of the lymphocytes are irradiatedand for which the dilution factor is not known. a s wellas in cases of prolonged exposure. Study of theelectroencephalogram is equally useful but has thesame limitations with regard to prolonged exposure.
All the above techniques are discussed in section 1II.B.
235. Urine analysis is useful from several standpoints(see section III.B.2). I t evaluates the state of theirradiated indi\pidual's renal function. which is essential
to outlasting the critical, life-threatening period. I t
may confirm hidden haemorrhaging. by indicating
haematuria, or renal malfunction associated withglycosuria or proteinuria. It is not. houever, essential
for determining the actual radiological damage a n d its
consequences.

231. I t is then necessary to perform further tests on
the bone marrow cells; the cells (e.g.. CFU-MIX)
closely related to the stem cells should be cultured,
because their existence indicates the likelihood ofsubsequent bone marrow restoration. There is. however, a practical problem in that such cultures takequite a long time to grow (around one week). and theyrequire fairly elaborate techniques that cannot normally be carried out on a large scale [I14]. Furthermore, it is debatable whether they are useful inpatients with extensive aplasia, in view of the relatively
large marrow samples needed for the examination.
Since it is exactly those individuals exposed to thehighest doses who require a precise prognosis. thisculture technique has its limitations.

236. Biochemical analysis may throw some light on
metabolic disturbances. These include disturbancesthat affect the regulation of the water balance. u'hich. if
extensive. can jeopardize survival. The prognosis will
depend on the quality of the treatment utilized. anddaily checks are indispensable. A routine check mustcover (a) renal functions (urea. creatinine. calcaemia.
phosphoraemia and blood ionogram); (b) liver functions (lactic dehydrogenase, transaminase, alkaline
phosphatase and bilirubin): and (c) nutritional indicators (electrophoresis of peptides and proteins. a n dserum iron).

232. Because it is easier to take blood samples thanmarrow samples, cultures are generally made of thecirculating progenitor cells (GM-CFC). This technique
has been used in cancer patients receiving partial-bodyo r whole-body irradiation to assess injury and recovery
in haemopoietic progenitor cells [T 181. There are
difficulties here too, however. These circulating cells
have a low concentration, the culture techniques areelaborate. and the number of GM-CFC in the blood

237. A thorough bacteriological check would makeit possible, in the event that infection is discovered,to take measures that would allow a favourable
prognosis. at least in the short term. The aim here
would be to detect any latent infections (especiallydental, otorhinolaryngeal or urinary) or opportunist
infections, which are frequent in subjects with immune
deficiencies. Again, the prognosis will depend on theeffectiveness of the treatment. Septicaemia, fungalinfections and infections involving bacteria that are
particularly pathogenic and/or resistant t o antibiotics
present special problems.

plasma) and in the haemopoietic tissues, and theexaminations have to be more rigorous than routine
examinations.

238. Sperm analysis is also a useful prognostic
indicator. Changes attributable t o irradiation are
discussed in section I.D.5, and Figure XVIlI showssperm counts as a function of dose and time. The
prognostic value of a sperm count is great. because thechanges are very sensitive indicators at relativelj low
doses [I9]. A first sample must be obtained less than
40 days after the accident and a second sample, after
the second month. Table 10 shows the effects ofirradiation on spern~atogenesisand the prognosis for
fertility [LA]. It should be noted that the thresholddose for permanent sterility does not rise significantly
when the dose is fractionated over some days or a few
weeks. This is attributed to differentiation of the
spermatogonia, which pass from relatively resistantearly stages to type B, more sensitive, with a D, value
in the region of 0.2 Gy [U4].

242. The morphology of the cells can be changed byirradiation. Frequently. the number of binucleate
lymphocytes is higher than normal [H20.513. J 14. R171;
how.ever. their appearance is generally delayed. so thismeasure is of little interest for immediate diagnostic
purposes. Other abnormal features have been observedin the peripheral blood lymphocytes of persons
irradiated with high doses, including ( a ) nuclear
changes; ( b ) nuclear pycnosis; and (c) micronuclei.
which are the result of chromosomal abnormalities
but can be detected more easily and more quickly
than karyotype abnormalities. These changes can beobserved at relatively lou doses. typically 0.25 Gy invivo and 0.02 Gy in vitro [I 151.

239. As is clear from the foregoing discussion, aprognosis founded on only one parameter or one classof parameters (dosimetric, clinical or biological) isbound to be very uncertain. T o be valid, a prognosis
must be founded on an entire range of data, and thewider the spectrum of these data and the better theircoherence, the more refined will be the predictions.
Table 23 summarizes the kinds of data that are usefulin prognosis [Il?]. and Table 28 recapitulates thethreshold levels of the signs and symptoms that can bedetected by specialist teams and that appear after low
doses [N5].

B.

CLINlCAL AND BIOLOGICAL DOSIMETRY

240. The many ways of estimating dose can be divided
into two main kinds of investigation: (a) clinicaldosimetry, u.hich compresses the obsen.ation discussed
in sections 1.C and 1.D (the relative value of theseobservations is discussed in section li1.A) and ( b ) biological dosimetry, which comprises all the laboratory
examinations that might allo\v an evaluation of thedose received by the individual. its distribution in thebody, the time span of dose delivery and the quality ofradiation involved. Biological dosimetry relies onhaematological. biochemical, cytogenetic and neurophysiological examinations [ElO. 113, J 1 1, J 12, K19.
KIJ]. which have different degrees of dosimetricvalue. Some are only qualitative (biochemical examinations, for example), others have considerable
prognostic value (cytogenetic and neurophysiologicalexaminations. for example): the majority are difficul~
to interpret in cases of protracted or fractionatedexposures.
1.

Dosimetry based on haematological data

24 1. Quantitative morphological haematology (cellcount, differential count, platelet count etc.) is discussed in sections I.C.4. and 1II.A. Irradiation causeschanges in the circulating blood components (cells and243. The number of peripheral lymphocytes displaying a defective nuclear structure has been shown to berelated to dose for doses above a few Gy. administeredin vitro and in vivo [W 141. This phenomenon has beenstudied in rats and in humans. but it cannot be readily
used for dosimetric purposes because the damaged
cells are trapped by the reticulo-endothelial system
and rapidly disappear from the bloodstream; blood
samples must therefore be taken soon after irradiationand incubated in a culture medium for several hours.
243. The incidence of nuclear pycnosis in lymphocytes irradiated in vitro is also related t o dose. In
animals (rats, rabbits) there is a linear relationship up
to about I Gy, with a low threshold at about 0.05 Gy[I15]. However, this method is unreliable because
pycnotic Iymphocytes vary so widely among nonirradiated subjects. Moreover, it has been shown thatin animals, pycnosis varies tvith the size of the cell andthe nucieus/cytoplasm ratio [R18].

245. At doses between 1 and 8 Gy [115]. irradiation
reduces the uptake of tritiated thymidine in vitro by
the lymphocytes following treatment with phytohaemaglutinin. This explains the reduction in mitoses a n dcellular transformations during irradiation. Although
it should be regarded as only semi-quantitative, thismethod is sometimes used in cases of accidental
irradiation [U'lj].
246. Irradiation also affects the electrophoretic
mobility of lymphocytes and the distribution ofcellular volumes [S25]. This was noted in rabbits after
doses of 2 and 3 Gy, where there was an increase in
the number of large cells in the second week after
irradiation. At the same time, in the categories of cells
characterized by their degree of mobility, the category
showing the first changes manifested the phenomenon
only briefly, starting about five minutes after exposureand lasting for about 30 minutes. The explanations
offered for this vary: an increase in cellular metabolismthat produces functional changes in the lymphocyteor, alternatively, differences in the cell populations at
the outset, with the most mobile groups able toundergo certain alterations outside the circulation andthen to reappear with a different volume [I 151.

247. Various immunological changes have beenmeasured after regional irradiation [W17]. in surface
markers. mitogen and antigen responses and cytotoxic
functions (see section I.C.4). Some of these changes
persist for up to 10 years, but there have been no
detailed studies of their potential use as biologicalindicators of radiation dose.
248. Leucocytes other than lymphocytes also show
malformations after irradiation. There are few quantitative data. and such data as there are. are of little use
in establishing a ciiagnosis or prognosis. These changes
only confirm exposure; it is not so far possible tocorrelate them with dose or to know their relative
importance. The most common changes are ( a ) giant
polynuclear cells lhypersegmented polyploid granulocytes); f b ) cells uith small alterations in their nuclear
structure. such as small chromatin adnexa: ( c ) the)
presence of immature granulocytes; and ~ d m~totic
abnormalities in erythroblasts and granulocytes [B16.
F5, 115, 1161. Tlirse abnormalities occur only infrequently. The reduction in the number of rnonocyles
may be related to the inhomogeneity of the dose, inthe sense that when severe nlonocytopenia appears
rapidly, it is d sign that a very large proportion of thebone marrow has been irradiated [I 151. Conversely, if
a significant part of the haen~opoieticmarrow has
escaped irradiation, [here may he only a temporary
reduction in the number of monocytes. or evenmonocytosis with an increase in the number of
immature cells [I IhJ.
249. Er~throblastscan be Sound in the blood stream
after irradiation. illways in very low proportions [B16,
1 1 51. Reticulocytes are useful indicators in prognosis[H20]; a dramatic fall in reticulocyte count is often asign of early fatalit).
250. Serum glycoproteins increase in the presence of~nfcction.inflaniniation or neoplastic and idiopathic
disorders. The effect of irradiation on the conccntration and distribution of protein-bound carbohydrates
in the serum of mice and dogs has been studied [I 151.
A considerable increase has been reported in animals
exposed to lethal doses. while no notable change has
been reported in animals receiving lower doses. I t is
not possible to treat all glycoproteins as one entity to
be used as a dosimetric indicator. However. following
the separation of various elements, changes in concentration have been noted for transferrin. haptoglobulin.
the /I2 glycoproteins and the ( I : macroglobulins [E8]. A
common feature of all these proteins is their richness
in bonded carbohydrates.
251. Because the bone marrow function is extremely
important for prognosis. all tests of its proliferative
ability may a priori be regarded as useful dosimetricindicators. The analysis of bone marrow cannot in any
case be a substitute for studies of' the peripheral blood.
which are currently the most reliable biologicaldosimeter.
252. The mitotic index in bone-marrow cells is oneof the most accurate biological indicators, and also
has a certain prognostic value. Changes in the mitotic
index are related to the dose. hut doses of I Gy orlouler produce little change [K12]. After a few Gy inman, there is an initial drop in the mitotic index,
recovery at about day 8 and a further fall before it
returns to near normal by day 34 [F9]. In the Y-12
accident. the marrow of individuals who had received
estimated doses of 2.4-3.7 Gy had practically no
mitotic cells. For higher doses, the cell count dropped
slightly from day 3 after exposure. The niost comnionly
observed morphological change was the presence of'giant neutrophil precursors from day 2 to day 16.
253. Some authors have proposed a test based on the
marrow's capacity to respond to stimulation: injectionof ethiocholariolon causes granulocytes stored in thebone marrow to migrate into the bloodstream [G 18.1 15,
V151. The ethiocholanolon is a testosterone metabolite.
(5-4-androstane-3. 17-dionin. It is an androsterone
isomer, with the configuration 5P-H (X:B cis); androsterone has the configuration 5a-H (A:B trans). The
etliiocholanolon tcst was first used in patienrs sufferingfrom malignant blood disorders: given the relationshipbetween the responses to this test and the qualit? ofthe peripheral granulocytic cell pool. i t was considered
to be a good guide to the therapy of these blood
diseases [V15]. Furthermore, ethiocholanolon affects
neither the mononuclear nor the thrombocytic celllines. The granulocyte outflow starts quickly and lasts
for about 16 hours after the injection. Because of its
low toxicity and the good reproducibility of the
response, the method using ethiocholanolon is superior
to methods using other leucocyte-mobilizing agents. .4
positive response indicates active medullary production of'granulocytes.
254. Many of these niethods have now been supcrseded by cell culture techniques for bone marro\\.
These techniques are at present fairly reproducible:
mixed-cell colonies originating from cells closely
rel;ilcd to the stem cells and gran~~locyte/macrophagecolonies arising from grani~locyticprecursor cells may
appear i n cultures even using marrow punctures thathave indicated, morphologically, a lack of haeniopoiesis. Quantitative medullary scintigraphy, in conjunction with the iron-59 test, gives a picture that canbe used to assess the impairment of the marrou.
255. Because the mature cells are resistant and havea long lifetime (approximately four months), it isdifficult to use erythrocytes directly as early biologicalindicators of radiation damage. although the erythroid
precursor cells are radiosensitive. Iron is incorporated
only into the precursor cells, and the iron-59 test. inconjunction with the other tests of medullary function.
allows the erythroid cell populations to be evaluated.
256. A greater denaturation of haemoglobin in
crytl~rocytes by phcnylhydrazine was reported in
occupationally exposed persons, compared with thenor~nalpopulation [G22]. I n patierlts ~31thbronchial
carcinoma given fractionated doses (1.2-1.5 Gy perday). an increased denaturation was observed when
the cumulative dose reached 7-9 Gy [G22]. However.
no increase was noted when erythrocytes from normal
individuals were given doses between I and 8 Gy in
vitro [G23].

2.

Dosimetry based on biochemical data

257. Any changes in the blood biochemical parameters ma!, be regarded as interesting signs. Glycaemia
cannot be taken as a biological indicator because of its
high degree of stabilit! in the body. It is not unusual
to observe hyperglycaemia from day I , followed bypronounced hypoglycaemia (0.5 g/l) on about day 3
and a return to normal that takes about a w.eek. aftersome fluctuation around the normal level [J13, 514,
Jlj]. In the same way, fluctuations in plasma electrolytes and plasma proteins increase as the dose rises.
However, tne data are not accurate enough for these~ndicatorsto be used q u a n t i t a t ~ ~ e [l J\ 151. The featuresoften noted are disturbances such as hypochloraemia.
hyponatraemia o r hypokalaemia during the first week
[J13]. Electrophoretic analysis of the protein fractions
shows the largest reduction (greatest at about two
weeks) in the albumins. A dose-dependent appearanceof a humoral factor in blood serum. which inhibits
incorporation of ""VdR into cells in culture, wasreported in mice [F7]. The technique has not yet beendeveloped for man, partly because the thymidine
concentration is only one-tenth that in mouse seruma n d partly because of other technical difficulties [F8,S391.

255. Hyperamylasemia can be produced by irradiation [B51. C38, K20. T301. The pancreas is not very
sensitive (doses up to 2 Gy have n o effect), but
amylase increases are detected if the salivary glandsha\,e received more than 0.6 Gy [W18]. The increases
are m a ~ i m a lon day 1 after radiation, returning tonormal by day 3, but a clear dose-dependence has not
yet been established.
259. The variations in the chemical composition of
the urine are of more significance than those of theblood. The urinary electrolytes may reveal changes inpotassium excretion (extra-physiological fluctuations)a n d in the excretion of sodium and chlorine, which
declines during the first feu days after exposure [J 131.
The 17-ketostsroids increase substantially during thefirst few days. before returning to normal by the endof the first week [J 131.
260. After radiation exposure, there is a considerable
enzymatic breakdown of nucleic acids and proteins.
especially in lymphatic [issues [A29, H42. S381. As aconsequence. the urinary excretion of nucleosides andamino acids, as well as their metabolites, increases. A
dose-dependent increase of deoxycytidine from normal
low levels [I151 was observed in the urine of rats
during the first day after a whole-body irradiation
with 0.5-2.5 Gy [G30]. An enhanced excretion was
also found in man after radiotherapy [B55. S39].
Similar effects were reported for the excretion ofthymine in rats [ZS]; however, this was not seen inman [B55]. Thymine is n~etabolized to /&aminoisobutyric acid (BAIBA). The excretion of this substance is considerably increased in mice, rats and man
after irradiation [S39]. After accidental human irradiation, a n increase from 100-200 pmoles per litre ofurine to 250-650 pmoles per litre was observed [G19,J 141.

261. There is a general increase in the levels ofamino acid in the urine of animals and humans during
the first day after irradiation [S39]. The relative
enhancement depends on the absolute excreted amountand on the metabolism of the specific amino acids.
Because these factors are very complex and different
for each amino acid (a decrease in urinary escretion
can occur with some) no general rule is observed [S39,5141. Accordingly. the excretion of amino acids is not
usually a n appropriate indicator.
some amino acids o r their263. There are. ho~ve\~er,nletabolites that show a dose-dependent change inurinal? excretion after irradiation. One of these istaurine, which is the metabolic end-product of cysteine.
Its excretion increases 1-2 days after irradiation in theurine of rats and mice [K22. S26, S381. Excretion
increases with radiation dose in the range 0.75-2.5 Gy.
In man. a n enhanced urinary level of taurine was also
observed after accidental irradiation [X29, J14J. It has
been suggested that the increased excretion of taurine
after irradiation may be related to intracellular taurine
elimination due to changes in cell permeability [S26]and to the breakdown of lymphatic tissues [D12].
However, metabolic studies in mice show that thebiosynthesis of taurine is also altered [H41. S40).
263. Some days after irradiation the urinary excretion of taurine decreases below normal values [L30].
This effect is due to metabolic changes of vitamin
B,-dependent decarboxylases and other enzymes which
are decreased, as in the condition of vitamin B,
deficiency [S3P]. As a consequence of such metabolic
alterations, the urinary excretion of kynurenic acida n d xanthurenic acid (~netabolitesof the amino acidtryptophan) increases after irradiation of mice andrats [A29. H42. L30. S38. S39]. This effect was also
observed in man [L29]. These changes occur in a dose
range of 4-8 Gy, which, in mice and rats, causes severeradiation sickners prior to death [S39]. From thesestudies it can be concluded that biochemical indicators
may be useful for certain dose ranges. Thus, thebreakdown products of nucleic acids and taurine may
be useful indicators in a lower dose range (0.5-3 Gy)and metabolites like kynurenic and xanthurenic acid.
in a higher dose range (4-8 Gy).
164. Creatinine could serve as a measure of radiological damage to the irradiated muscles that are n olonger able to metabolize it in the normal way [G20].
The level of creatinuria has never been correlated withdose. but i t may confirm the uniformity of irradiation.
In accidents where a relatively large portion of the
body has not been irradiated, such as the Lockport
accident in 1960, the level of creatinuria (creatine/
creatinine ratio) scarcely increased. In accidents
involving whole-body irradiation, such as occurred at
Oak Ridge (Y-12) in 1958 and at Mol in 1965, the level
was significant. with three conspicuous peaks in one
instance (day 2, end of first week and end of secondwcek) [J 141.
265. In recent years a number of new biochemical
indicators of severe radiation damage have been
proposed. For example, a method has been suggested
for the quantitative evaluation of damage to themembranes of erythrocytes in the peripheral blood[M50, M51. M521. Inhibition of the incorporation oflabelled precursors of the D N A in bone-marrow cells
has been used in a method worked out by Porschen etal. [P31]; the authors used their method to monitor
irradiation even in small doses (some tenths of Gy).
There are also data on determining the total content
of desoxyribonucleotides in the blood and urine ofpatients irradiated for therapeutic purposes [S46,
T 3 11. However, due to the paucity of such studies, it isdifficult to evaluate the value of these indicators.
3.

Dosimetry based on cytogenetic data

266. The analysis of chromosome aberrations in thecirculating lymphocytes is widely used to assess thedose. Even in cases of partial-body exposure. thechromosome changes are excellent indicators of theabsorbed dose. The evidence to justify the technique iswell founded and covers various irradiated populations (in nuclear medicine, radiotherapy and accidents)
a n d very wide ranges of dose [B42, K13, L15. L161.
The technique provides a reliable indication of theacute dose, since lymphocytes are widely dispersed in
the various tissues and organs, have a reproducible
radiosensitivity and a long life, and circulate rapidly inthe body [D 131.

267. Many types of radiation-induced chromosomal
aberrations may appear in irradiated lymphocytes, but
the dicentric aberration is currently taken as providing
the most valuable information on dose. This isbecause the dicentric aberration is almost unique toionizing radiation and occurs rarely in persons exposed
only to normal background radiation. Centric rings
occur only 5-10'3 as frequently as dicentrics in control
o r irradiated Lymphocytes and are thus roo infrequent
to be used as a sole measure of dose. Some researchers
combine the centric and dicentric yields. Acentric
fragments, by contrast. have a higher backgroundfrequency, which probably reflects their induction bya large number of chemical mutagens. The confounding
effect of many environmental non-radiological insults
reduces the acentric's value as a measure of dose.
although elevated acentric yields may qualitatively
supporr dose estimates derived from the dicentric
incidence..
268. Human T-lymphocytes have a long lifetime; asmall proportion of them survives for decades. The
rate of replacement is quite slow, so that in the few
weeks after exposure the dicentric yield remains fairly
constant. After a partial or inhomogeneous acuteexposure, the lymphocytes that were in the irradiatedvolume of [he body in both the vascular and extravascular pools are rapidly mixed with unirradiatedcells. An equilibrium is reached by about 20 hours[T25]. and thereafter the dicentric yield in cells from asample of peripheral blood will provide an estimate of
the average whole-body dose.
269. The dose-response for dicentric aberrations in
the irradiated lymphocytes of normal individuals is
little affected by factors such as the donor's age o r sex.
The dose-response obtained for irradiation in vivo

does not differ significantly from that for irradiationin vitro [C46], so that the aberration yield observed incells taken from an irradiated subject may be inrerpreted by reference to the appropriate calibration
curve in vitro. In vitro curves have been established
for a large range of radiation qualities, including all
those likely to be encountered in accidents [L75].
Within any one laboratory, the calibration curves fordicentrics have proved t o be very reproducible, provided that the cells are examined at their first postirradiation mitosis. This is now reliably achieved byincluding bromodeoxyuridine in the culture medium
and staining the chromosomes by fluorescence plus
Giemsa [S37].

270. For low-LET radiations, the yield of aberrations, Y. conforms well to the quadratic relationshipY = c u D /ID2 where c is the background incidence(about one dicentric in lo3 cells), D is the dose, a n d aand ,4 are fitted coefficients. A dicentric aberration
requires the interaction of two breaks, each induced inseparate G, or G , chromosomes. An explanation of
the quadratic relationship may be that when bothbreaks are produced by the passage of a single
ionizing track, the yield is represented by the linear
term aD. The PD2 term thus represents those dicentrics
that are produced when the two breaks are caused byseparate ionizing tracks. The latter term becomes
more important when the dose increases.

+ +271, In general, high-LET radiation, such as fission
spectrum neutrons and alpha particles, give a linear
dose response relationship. Y = c + nD (Figure XXVII).
For these types of radiations the ionizing events are so
densely distributed along the track that there is a highprobability that one track will deposit energy in both
chromosomes. RBE values at low doses. calculated as
the ratios of the aloha coefficients of two radiations ofdifferent quality. may represent the relative hazards ofthe two radiations at loat routine occupational levels[I2 I]. At higher doses, such as are likely to cause overt
symptoms of sickness, the values of RBE decrease
markedly [L36]. With neutrons, as their energy
increases the average LET decreases and the linear
model requires a second (quadratic) term, e.g., with
7.6 MeV and 13.7 MeV neutrons. RBE values for
specific energies of neutrons have been proposed [B34,PlB].
272. Another feature of the dose-response curves forhigh- and low-LET radiation is the relative importanceof the dose rate. For high-LET radiation with a linear
dose response, this is unimportant. For low-LET
radiation, the equation Y = c + aD A /IG(.v)D' can beused, where the number of inirial chromosome breaks
falls exponentially with time according to the facror
G(s). In practice, the dose-squared term reduces until
the response can be considered to be linear for x- o r
gamma-radiation doses of a few Gy, if delivered at amore or less uniform rate over 24 or more hours.
273. An important problem in assessing the dose toan appropriate degree of precision is the number of
metaphase cells that have to be examined. As a rule,
evaluation of 100-500 metaphases is sufficient toestimate a dose at irradiation levels of medical

DOSE (Gy)Figure XXVII.

A series of generalized dose-response curves for dicentric chromosome
induction for human lymphocytes irradiated in vitro.

[Dl31

significance [ D l J . J15. LlS]. With a few hundred cells
scored from an irradiated subject, the statisticaluncertainty on the dicentric yield is the main component of the 95% confidence limits on the dose
estimate. It is much greater than the uncertainty
attached to the in vitro calibration curve [L17], so thatfor practical purposes the latter may be ignored whencalculating confidence iimits. An example of an invitro curie and the confidence limits for an elposure
to gamma-radiation is given in Figure X.X\-'Ill.
Examples of the use of such curves in cases ofaccidents have been described [D 15, L 181.
274. For a uniform exposure to low-LET radiation.
dicentrics in the scored cells follow the Poisson
distribution [D13]. However, in accidental irradiation,
the esposure is almost al~vays non-uniform. often
involving just part of the body. This results in an
overdispersed distribution of aberrations. The degreeof departure from the Poisson distribution may be
used to estimate the volume of blood exposed and its
average dose [D14]. This has recently been tested in
a n international collaborative experiment in which
partial-body exposures were simulated in vitro. The
resultant estimates of dose and volume irradiated were
acceptably close to the true values [L28]. The calculations require a number of simplifying assumptions[I22], but they produce values that are probably moremeaningful than the average whole-body dose for
accidents in which clearly only part of the body has
been irradiated. Hotvever, estimates of blood volume
exposed may not reflect closely the proportion ofbody mass exposed [L39].

275. Many chromosome aberrations. including breaks
a n d various exchanges of the chromosome o r chromatid

0.625

0.85

2.04

OOSE (Gy)Figure XXVIII. Estlmatlon of a dose of 0.85 Gy from a yield of
0.05 dlcentrics per cell (25 in 500) by reference to an In vltro
calibration curve for gamma-radiation using human lymphocytes. Statlstlcal uncertaintles on the curve are shown by thedashed curves. The upper (Yu) and lower (Y,) Poisson
standard errors on the yleld glve 95% confldence llrnlts of 1.03
and 0.625 Gy (D, and DL) on the dose estlmate.
11221

type, involve acentric fragments. The absence of acentromere in these fragments prevents the correct
distribution of genetic material during cell division.
a n d they are lost or incorporated in only one of two
daughter cells. In the daughter cell the fragment may
either join with the main nucleus or remain in thecytoplasm and form a micronucleus [K14. R191.
Recent data indicate that 20-30% of acentric fragments may become micronuclei at mitosis [B54,U723].
hficronuclei may also occur as a consequence ofcompletely aberrant configurations with more than
one centromere because such structures irequently
cause difficulties in chron~osomeseparation during
anaphase. They may also result from normal chromosomes which are left over because of a defect in the
mitotic spindle.
276. Counting of micronuclei has been suggested asa dosimetric method for situations which include theevaluation of damage of chemical origin and theidentification of particularly sensitive individuals withhigher than average potential risks of developing
cancer or genetic disorders. In principle, counting of
micronuclei appears easier. faster and less expensive
than the scoring of chromosome aberrations [I16,H33].
277. There is a higher background incidence of
micronuclei than of dicentric aberrations and this may
in part reflect the higher background incidence ofacentric fragments due to environmental chemicalmutagens. This means that the lower limit of dose
detection by micronuclei is perhaps 0.25 Gy, thus
making the technique less sensitive than that ofscoring the dicentric yield. The frequency of micronuclei after s-irradiation of human lymphocytes In
vitro reaches a peak after 96 hours of culture [F6.
C29]. However, by this time lymphocyte cultures havebeconle asynchronous and individual variability in cell
cycling kinetics is likely to inlpose considerable
uncertainty in the quantification of the dose response.
278. The method can be better standardized byscoring cells which have undergone a known numberof mitoses. This can be achieved by differential
staining of nuclei in cells which have incorporated
bromodeosyuridine [Pll], and scoring cells whichhave previot~sly incorporated tritiated thymidine in
S-phase o r by scoring cells which have been blocked at
the end of mitosis using cytochalasin B [F6].
279. Currently, the cytochalasin-B blocking method
is gaining considerable popularity. This techniqueensures that micronuclei are scored only in those cells
that have just completed their first post-irradiation
mitosis. The dose-effect relationship appears to be
similar to that observed with aberrations. in that the
response for low-LET radiation is quadratic and at
low doses it is linear [F6. F161. Data for exposure tohigh-LET radiation are not yet available. The micronucleus technique is far easier and faster than scoringfor dicentrics and is more amenable to automatedmethods of analysis using pattern recognition systems,e.g., in polychromatic erythrocytes (PCE). Individual
variability, particularly at lower doses, poses some
limitations. Factors such as dose protraction, frac-tionation and partial-body exposure have yet to beinvestigated. The test can be envisaged as being
particularly useful after a serious accident irhen many
people may need to be tested quickly.
4.

Dosimetry based on neurophysiological data

280. Whole-body gamma-irradiation is accompaniedby immediate functional changes in the central nervous
system, particularly with respect to spontaneous andevoked cerebral electrical activity. These changes havebeen shown in animals [B45, C30, M33] and in man[C31. C321. They appear immediatel!. after exposureand are an important indicator of the direct effect ofradiation on the optic nerve [C31]. Radiation may
also affect ( a ) the function of peripheral receptors:(b) nerve conduction; and (c) synaptic trznsmission.
High doses are required to modify the function of theretina. since more than 6 G y must be administered tocause changes in the electroretinogram. The administration of large doses (- 10 G y ) of x or gamma rays triggers
a process that lowers the excitability threshold andincreases the action pcteo!ial and, more irregularly.
the rate of conduction of the nerve impulse. Examination of synaptic transmissio:~produces results that are
harder to interpret.

281. Irradiation, e\en in small doses, may causechanges in the acetylcho:ine-chol~nesterase balance o r
in other chemical mediators, such as aspartic acid,adrenergic anlines, and gamma-aminobutyric acid
(GABA). The examinstion of vascular lesions makes
it possible to study the role of disturbances inmembrane permeability. Cell metabolism is probably
disturbed, as shown by reversible changes in the
nuclear chromatin. Furtl~ermore.whole-body irradiation is accompanied by changes in the acid-basebalance, essentially hypocapnia and acidosis, which
can be restored from the seventh hour ontvards fordoses of about 1.5 Gy. It seems likely that. even if thedevelopment of functional disorders of the autonomic
nervous system is not superimposable on the trend of
cerebral electrical activity. changes in the acid-basebalance of the blood pl?y an important role in thegenesis of the disturbances observed.
282. I t has been shown by one group of investigatorsthat whole- o r partial-body gamma-irradiation of theorganism can act as a stimulant or as an agent of
injury. depending on the level of dose, the dose rate.
the irradiated volume and, above all, the percentage ofthe body irradiated [C3 I]. There is direct stimulationof the brain and particularly of the structures in thebulbar protuberance and the hypothalamus, as well asof all the synapses in the organism. This direct
stimulation is followed by an indirect stimulation of
the brain by the convergence of impulses originatingin the spinal cord and the bulbus in the direction of
the brain. Depending on the strength of these direct o r
indirect stimuli and the number of impulses arising inthe subcortical structures, there is an immediate
defence response; the intensity and nature of this
response from the central nervous system. the modifications to the autonomic nervous system and thechanges in cerebral activity and behaviour will differ

with respect to both their general expression and theirdevelopment. These various effects combine to createan acute functional metabolic encephalopathy.
283. Disturbances in the neurophysiological equilibrium are indicated by (a) changes in excitability,
consisting of successive phases of inhibition andexcitation; (b) an increase in irritability in the form ofparoxysmal abnormalities, ranging from a burst ofslow activity through an isolated spike to a deformed
spike-wave to grouped bursts of spike-waves. withrare convulsive spasms (in the case of high doses): and(c) the impossibility, at LD,, doses, of structures suchas the hippocampus maintaining basic rhythms. On
the electroencephalogram. changes in the excitation
waves are noted: there is a slow-down in cerebral
activity (appearance of slow, regular and broad
waves), recurring spasms, slow activity or groups ofslow waves, and isolated and then grouped spikes. All
these phenomena are characteristic of radiation-induced
effects.
284. After analysing cerebral electrical activity in themonopolar, conventional and harmonic modes, it ispossible to quantify the energy changes in the power
density spectrum and thus to describe objectively theslow-down in cerebral electrical activitv. This isachieved by calculating the extent of drift and thepercentage of the recording time during which themodifications in the EEG are observed [C32]. The
dose-effect relationships obtained in animals show a
response above 0.25 Gy. This response appears at
15 minutes after exposure. A comparison of wholebody and head exposures makes it possible to separate
the effects of direct and indirect stimulation, the latterbeing under the influence of the convergence ofascending impulses from the whole body. The persistence of the effect observed above 0.25 Gy during
the hours following irradiation tends to indicate
changes in protein synthesis and the coding of
information of the neurons. This dosimetric method isa valuable tool, especially if the assessment is done
long after irradiation and in cases where it has notbeen possible to undertake chromosome analysis
immediately after transfusions of blood components.
The changes are persistent, particularly in cases ofhigh doses. In survivors of doses of near the LD,,,.,,
the normal electroencephalographic patterns seem totake several years to reappear [C30].
5.

Other dosimetric findings285. In cases of exposure to mixed gamma-neutron
fields, the dose, its neutron component and its spatial
distribution can be estimated by determining thepresence of 24Na and 32P [I9]. This radiation-induced
acrivity can be measured in the body. blood, urine andbiological or other specimens, such as hair, teeth,
fingernails, clothes, metallic objects, jewellery, etc.
These measurements are. well standardized and form
part of the physical dosimetry, in the same way as
does the reconstruction of the accident. Techniques
based on electron spin resonance [N7]. applied tobone, hair, teeth and skin after low-LET irradiation,
have shown that the signals obtained are quantifiable

at lethal or sublethal doses down to about 0.3 Gy[B46,1171. The electron spin resonance signal is stable
at more than two hours after irradiation [Tlb. S281.
The intensity of the signal is linearly related to dose
[B46, 0 7 , 117. T16, S281; it is greater for incident
radiations of low photon energies [T16, 073. but was
not detected after doses of 14 MeV neutrons [117].
The method has been used to assess doses in accidents[S28] and in survivors from the atomic bombs andcumulative doses in occupationally exposed persons[T 161.
286. Another assay described recently measures thefrequency of variant erythrocytes produced by erythroid precursor cells with mutations that result in aloss of gene expression at the polymorphic glycophorin
A (GPA) locus. A linear relationship was observed
between variant frequency and dose received 40 years
previously [L37].
287. Other techniques have also been suggested foruse in biological dosimetry but have not yet beendeveloped for man. One example is cell death in hairfollicles (dose-dependent from about 0.1 to 1.0 Gy ) andconsequent changes in hair width (dose-dependent from
1 to 10 Gy) [PlO, P201. Another is spermatogenesis,
which is very sensitive to irradiation and could be used
as a biological indicator of dose [H37]. DNAsynthesizing cells (spermatogonia and preleptotene
spermatocytes) can be measured rapidly using flow
cytometry. and their concentration i n mice shows
marked dose- and time-dependent changes [H37].

IV.

CONCLUSIONS

288. The Committee has reviewed a large body of dataon the effects occurring in man within two to threemonths of whole-body doses above approximaiely
1 Gy of low-LET radiation. These data were gatheredfrom three main sources: radiotherapy treatments.
radiation accidents and the Japanese exposed to theatomic bombs in the Second World War. Homogeneous
doses to the body are usually received only in the caseof deliberate exposures in the course of radiotherapy,
while non-homogeneous doses are usually received in
accidental or warfare situations. and the effect ofirradiating organs to different doses must be considered.
A patient's response to whole-body radiation may also
be confounded by the use of other cytotoxic agents, by
disease and by medical treatment after irradiation.
Data collected on patients exposed to external orinternal irradiation during the nuclear accident at the
Chernobyl power plant in April 1986. supplied by thedelegation of the USSR, were also examined. Thesefindings are presented in the Appendix. Finally,
information on experimental work with animals wasused to help interpret the responses.
289. Many of the acute effects of radiation in earlyresponding tissues are mediated through the death ofcells when they attempt to divide. The incidence of cell
death is dose-dependent, ar.d cells that have retained
their capacity to divide after irradiation can bestudied, using precise techniques, in vitro and in vivo.

These surviving cells contribute to the post-irradiation
recovery of the tissues. Cell death can also occur
independently of cell division. as. for example. theinterphase death of lymphocytes.
290. Tissues that are most sensitive to irradiation areusually hierarchical in organization, in the sense thatthey are structured into different compartments, eachof which feeds new cells into the next compartment.
One can describe, therefore, the compartment of
undifferentiated stem cells, that of the differentiating
and dividing precursor cells and that of the maturingand mature cells. The stem cells and the proliferative
cells undergoing many divisions are the most radiosensitive. After high doses, the loss of mature cells
from the last compartment is not compensated by thedecreased production of cells from sterilized precursor
cells in the first compartment, and this causes tissue
function to fail. After high doses, the proportion ofindividuals showing failure of a given tissue increases
as a function of dose. The relationship between dose
and the proportion of individuals affected is called thedose-response curve. I t can be characterized by thedose at which 50% of the individuals are affected andby the slope of the curve, which reflects the inhomogeneity in response among different individuals. The
inhomogeneity results from the random nature of theradiation action, from the variability in response of
the individuals in the population or from inhomogeneity in the dose.
291. Loss of tissue function produces clinicalsymptoms in the irradiated subject, and these
symptoms will differ according to \vhich tissue fails.
Also, owing to differences in the sensitivity of cells
and in the structure and function of each tissue,
organs will fail at characteristic times and doses, sothat certain symptoms will appear together at certain
times after exposure to typical dose ranges, giving riseto the so-called radiation syndromes. Ideally, foruniform whole-body exposure above some thresholdof dose. one should be able to observe a prodromalphase (common to all syndromes but of differing
probability, severity and duration, according to the dose
received) and three syndromes: the neurological. thegastrointestinal and the haematopoietic. In practice,depending on the level of dose, its distribution in
space and time and other variables. the syndromes
may often merge into each other. and it becomesdifficult to recognize them as such.
292. The prodromal phase of responses after wholebody irradiation comprises the symptoms appearing
during the first 48 hours. The reactions are mediatedthrough the autonomic nervous system and are expressed as gastrointestinal (anorexia, nausea, vomiting.
diarrhoea. intestinal cramps, salivation, dehydration)and neuromuscular (fatigue, apathy. sweating, headache, hypotension) symptoms and signs. The incidence
and latency periods for the cffects are dose-dependent.
The dose inducing vomiting in- 50% of individuals is
about 2 Gy, and the latency period is about threehours.
293. Doses higher than 100 Gy result in death from
cerebrovascular injury in the neurological syndrome

within two days. This syndrome is characterized bysevere symptoms and signs of the prodromal phase.
followed by transient periods of depressed or enhanced
motor activity, leading to cerebral coma and death.
Doses between about 10 and 50 Gy result in thegastrointestinal syndrome, with most deaths occurring
between days 6 and 9 after irradiation. The symptoms
in man follow those of the prodromal phase andinclude anorexia, increased lethargy. diarrhoea, infection and dehydration. There is also weight loss.
decreased food and water intake and decreased
intestinal absorption. Other superimposed symptoms
due to bone marrow failure include a profound dropin the leukocyte count, haemorrhage and bacterernia,
which aggravate the injury and contribute to death.
The time to death is influenced by the mucosal
turnover time in the gut and by other, secondary
factors such as infection, haemorrhage and loss of
fluid, protein and electrolytes.
294. Lower doses, of a few gray. result in the bonemarrow syndrome. The haemopoietic and lymphoidtissues. megakaryocytes, lymphocytes and precursor
cells are radiosensitive. and leucopenia is the mostimportant injury. The lymphocyte count is the earliest
sensitive index of injury in blood and doses of 1-2 Gy
reduce the concentration to about 50% of normal by
48 hours after irradiation. Neutrophils show an initialabortive increase over the first few days. A secondabortive rise is seen at about day 10 after 2-5 Gy. Thismay be followed by a further decline if the stem-cell
population fails to recover. The neutrophil count iscorrelated with the onset of fever. Thrombocytopenia
and associated haemorrhagcs are increasingly important after higher doses. The time course of thrombocytopenia is broadly similar to that ofgranulocytopenia.
but there is no second abortive rise. Thrombocytopenia
below 30,000-50.000 per jrl is associated with bleeding.
295. Persons exposed accidentally or therapeuticallyin the low- or mid-lethal dose range show an increased
susceptibility to infection. Reported changes in the
immune system of persons irradiated regionally include
a persistent reduction in T cells of the helperhnducer
and suppressor/cytotoxic phenotypes.
296. In addition to the systemic effects described,
irradiation can also cause damage to many othertissues and organs. The resulting effects and clinicalsymptoms vary in their appearance time and severity.
They may or may not be part of the syndromes
described, depending upon the dose level, the tissue
irradiated, the modalities of irradiation, and on otherphysical and biological variables.
297. Effects in irradiated skin are correlated with thedose and the area irradiated. The effects include
erythema, abnornlal hair growth, epilation, desquamation (dry or moist) and vascular and dermal injury.
The doses that produce an incidence of 50% ofabnormal hairs, erythema within four weeks andmoist desquamation are, respectively, about 1.5 Gy(3 cm diameter field), 5.7 Gy (10 cm X 10 cm field)
and 20 Gy (35-80 cm2). The dose in the basal layer ofthe epidermis determines the amount of stem-cellkilling and. hence, the degree of desquamation.

Desquamation is maximal at about three weeks after
irradiation. With larger areas. smaller doses elicit thesame level of damage. The 50% erythema dose is about
3 Gy when the whole skin is irradiated. which is about
half the dose for areas of 100 cm2. High doses to thedermis induce dermal erythema, necrosis, ulcerationand sloughing. Vascular lesions are associated withpain in irradiated extremities.

298. Injuries in the mucosa of the mouth and throat
include inflammation and stvelling, with ulcerationand necrosis after high doses. Mucosal injury is
greatest in the cheeks, soft palate and hypoglossal
area. hlucosal recovery begins by 2-3 weeks after 510 Gy, and it is assisted b) the administration of
antibiotics. Injury of the salivary glands occurs at
about eight hours after 6- 10 Gy. persisting to about
48 hours.
299. Acute effects on the eye iriclude acute erythemaof the sensitive conjunctiva (after 2 Gy), hyperemia ofeyelid skin and hyperpigmentation (4-6 Gy). keratitis(4-10 Gy), epilation of the eyebrows and eyelashes.
telangiectasia and necrosis (above I0 Gy). After 15-20Gy
local irradiation, there is lacryniation and pain in theeyes. with irritation of the cornea and iris. Even in theabsence of infection, these symptoms may last for a
few months.
300. Pneumonitis is the earliest sign of radiation
injury in the lung. appearing at 1-3 months after doses
greater than 8 Gy. The doses to lung tissue giving
pneumonitis in 5% and 50% of patients irradiatedover the whole body prior to marrow transplantation
are, respectively, 8.2 Gy and 9.5 Gy. The time of onset
is not significantly dose-dependent between 6.5 and12.5 Gy.
301. Acute doses of up to 4 Gy cause temporary
sterility in some irradiated male individuals, and thedose inducing perrnane'nt sterility in all men is morethan 6 Gy. The sperm count begins to drop after 46
days. Some of the early differentiating forms or
spermatogonia are very radiosensitive, and the progression of cells into these forms explains the higher
sensitivity of the testis to fractionated irradiation, as
opposed to acute irradiation, dose for dose. Changes
in testicular hormone levels and in Leydig cellnumbers are also induced. In women, temporary
sterility is induced by doses up to 4 Gy, and pcrmanent sterility by 3-10 Gy. Older women are more
susceptible. probably because the number of follicles
decreases with advancing age.

between days 20 and 29; in a group 1,000 metres fromthe hypocentre at Hiroshima, 58.5% died between
days 20 and 38. This peak in the death rate reflects
marrow failure. The most recent estimates of theLD,,,from the Japanese data after revision of thedosimetry have yielded values of around 3.0 Gy. Thisis thought to be applicable to the very special
conditions prevailing before and after the bombingsand to human beings receiving no medical treatment
or only minimal treatment.
304. Until Chernobyl. the two accidents involving
the largest number of individuals irradiated solely
with acute doses were those at Vinca and at Oak
Ridge. Only one out of seven individuals in bothaccidents receiving doses estimated to be between 2.7
and 4.5 Gy died. not primarily from marrow failure.
305. In the Chernobyl accident (see Appendix),
115 individuals were measured to have received
acute marrow doses above approximately I Gy of
gamma rays, as assessed by dicentric aberrations intheir lymphocytes. There was also beta-irradiation ofextensive areas of skin in many cases, in particular inindividuals also receiving high marrow doses, toaccumulated skin doses of the order of 10-20 times themarrow dose. The victims received immediate andcomprehensive medical treatment in specialist centres.
This included barrier nursing. antibiotic treatments.
and blood-cell infusions. Of 43 persons receiving
marrow doses between 2 and 4 Gy. none died before
60 days (only one died, at 96 days). Of 21 individuals
receiving between 4 and 6 Gy marrow doses. seven diedbetween 16 and 48 days. Of 20 individuals receiving
between about 6 and 16 Gy, two rejected a transplantbut survived more than 60 days after about 8 or 9 Gy.
Nineteen from the last two groups. i.e. 4 to 16 Gy. were
given either allogeneic bone marrow transplants (in13cases) or embryonic liver cell transplants (in six cases)
between one and two weeks after exposure. Fifteen of
the 19 died before 60 days (and two others at 86 and91 days). including seven from skin and intestinal injury,
the others from infections and other causes. Extensive
information was obtained concerning the effects on
different organs of acute high-dose irradiation from anuclear reactor accident, including bone marrow.
intestine. oral mucosa. and the eye.

302. In many cases, particularly when planningradiation protection for accidental or other types ofacute exposure, it is useful to think in terms of thedose at which the probability of survival 60 days after
homogeneous whole-body irradiation is 50% (LD,,,,).
The data available for deriving the \*slue of the LD,,,,,
in man come from different sources, each of which
poses difficulties: radiotherapy patients, accident cases
and the Japanese exposed to the bombs in the Second
World War.

306. Three groups of radiotherapy patients are usefulfor assessment. None of 20 children and adolescents
given 3 Gy to the \vhole body died within one year of
marrow failure. However, the LD,,,for various
groups of adults with disseminated cancers was 2.9 Gy
in one series and 3.4 Gy in another. These data indicate
probably aboutthat for ill cancer patients. the LD,,,is
3 Gy, while for healthy individuals receiving conventional supportive treatment after irradiation it may
be substantially higher, approaching or equal toabout 5 Gy. The response of Japanese irradiatedduring wartime and receiving minimal post-irradiation
medical care was more like that of the ill cancer
patients than that of the healthy groups of individuals
irradiated in accidents and receiving medical care.

303. In Hiroshima and Nagasaki, 50% of the deaths
after day 20 in a small documented sample occurred

307. Data on LD,,,for various species of large
animals have been used to estimate the probable slope

of the dose-mortality curve for man. The averagecoefficient of variation among species is about 0.24.
and the ratio of LD,/LD,, is about 2. This suggeststhat the dose that would kill few healthy humans isabout 3.0 Gy and the dose that would kill most isabout 6.0 Gy.
308. Based on experiments with animals, the LD,,,,,
would be expected to be greater for unilateral than forbilateral irradiation, by about 20%. This depends on
the penetration of the radiation used. Doses decrease
faster with depth for low energy photon or electron
beams and for fission neutrons than for higher energy
beams. In and near bone, there is a higher dose fromlow energy photon irradiation and a lower dose fromneutrons.

-

309. In large animals. the LD,,,,,, may be increased
by up to about 1 Gy through conventional supportive
medications and transfusions of blood elements. However, such a small dose increment can increase markedly
the survival rate because of the steepness of the doseresponse curve. Bone marrow grafts also increasesurvival. After a lethal dose in man. 2 10' bonemarrow cells per kilogram is needed to rescue 50% of
individuals, based on experiments with different animal
species, and 3 10' cells per kilogram for 100%. rescue.
More allogeneic than isogeneic marrow cells are
required for rescue. The shielding of perhaps as little
as 10% of active marrow in man may reduce themortality to zero after doses near the LD!,,,,.
310. It is concluded from the various groups ofindividuals discussed in this Annex that the LDwm forhumans receiving no or little medical treatment after
exposure is likely to be around 2.5 Gy marrow doseand possibly higher. A similar value may pertain tosome groups of ill cancer patients receiving good
medical care. For healthy humans receiving good
supportive medical treatment after irradiation, theLD,,,,,, is likely to be approaching or equal to about
5 Gy. The LD,,,6,, can be further increased by successful marrow transplantation, probably up to around
9 Gy. After these higher doses, there may be somecases of pneumonitis occurring in the second month.
unless the lungs were shielded. After even higher doses(> 10 Gy) acute gastrointestinal injury will become
more prevalent.
31 1. Neutrons are more efficient in causing acuteinjury than low-LET radiations, by a factor of 2-3.
using single doses. However, because of the IOU,
penetration of neutrons. values of LD,, for large
animals can be apparently smaller for neutrons thanfor low-LET radiation. There is little experience inman of mortality after neutrons, except in a few
isolated accidents. The neutron component of thedoses to the Japanese survivors from the bombs isnow considered to be much smaller than had previously
been thought. probably less than 3% of the total doseat distances where acute early effects were seen.
312. In radiobiology. a protracted dose or a fractionated dose is known to have less effect than thesame total dose given singly. The early effects of highdoses in man also follow this general rule. Thus,

prodromal responses are somewhat alleviated by dose
protraction or fractionation; for example, small dosesof 0.2 Gy can be delivered daily for several weeks
without inducing nausea. Low-dose-rateor fractionatedirradiation markedly reduces injury to the intestine inall species, including man, but dose-mortality relationships for man due to protracted intestinal irradiation
are unknown.
313. The relationship between the lowest concentration of leukocytes and the total dose and exposure
time has been measured. There is less effect withprotraction of the dose. I t has also been found thatmarrotv recovery during irradiation is less in leukaemic
patients than in other patients with non-haematological malignancies. The greater radiosensitivity oflymphocytes, as compared to granulocytes. applies tofractionated treatments as well as to single doses.
Various types of quantitative formulae have been
proposed to estimate changes in the LD,,,,,, as afunction of protracted irradiation. As the data base issparse, these are to be taken as very rough guidelines
for assessing the effects of changes in dose-time
relationships.
313. The tissue responses are also markedly dependent on the mode of delivery of the dose with respect
to time. The responses of the bone marrow and theskin to protracted and fractionated doses are fairly
well known from radiotherapeutic experience. The
lung. too. is spared by protraction. In contrast with allother tissues, protracted doses are more injurious to
the testis, owing to the progression of cells into
sensitive phases. In women, a larger dose is generally
required to cause infertility when fractionated doses
are used, but an accurate assessment is not available.
3 15. Large amounts of internal emitters are required
to produce early effects in man. Bone-marrow depression is observed after large, single doses of iodine-131;
5 Gy is the maximum total dose that can safely bedelivered to the blood. Radiocolloids have produced
mild radiation sickness and haematological complications, as have radiophosphorus and sulphur-35. Setrere
acute intestinal injury in man from internal emitters
has not been reported, and lung injury has been rare.
Treatments for intake of radionuclides by ingestion
are based on reduced retention, enhanced excretion o r
diminished translocation. Emetics, lavage and precipitating agents may help prevent gut toxicity. Decalcification therapy and chelating agents continue to bestudied.
3 16. The radiation response of tissues can be modified
by physical or chemical conditions or treatments, suchas the removal of oxygen, the use of protective or
sensitizing chemicals. drug adjuvants or previous
treatments with cytotoxic drugs that produce residual
tissue injury.
317. A small section of the population may beparticularly radiosensiti\~ebecause of inherited genetic
disorders, such as ataxia telangiectasia (AT). Children
with A T are more radiosensitive, and cultured skinfibroblasts taken from them are similarly sensitive.

Estimates of the frequency of hereditary conditions
that are likely to render individuals particularly
radiosensitive are of the order of one per cent in thegeneral population.

of immature granulocytes and ery~liroblasthand theappearance of reticulocytes are also indicative of
irradiation but are not suitable for accurate dose
assessments.

318. I t is difficult to establish a prognosis forindividuals irradiated above the threshold doses for
acute effects solel!. from an estimate of the dose,
because of the steepness and uncertainty in the doseresponse curves, including uncertainty of the value ofthe LD,,,, for man. Also, there are many confounding
factors, such as the presence of intercurrent disease.
the effect of shielding and protraction and the qualityof the radiation. The type, severity and duration of the
prodromal symptoms. including the presence andextent of erythema, may assist in the prognosis.
Haematological signs, particularly the lymphocyte
count, are good prognostic indicators. The lowest
concentrations of the various blood cell types and thetime at which such concentrations are reached following irradiation are important inputs for the prognosis.
as is the duration of marrow aplasia after high doses.
The appearance and persistence of immature cells inthe blood is a sign of marrow regeneration and is afavourable sign. Marrow scanning can give an indication of erythropoiesis in different regions, but for
estimating the likelihood of long-term recovery. it isnecessary to culture very immature cells in the
marrow. Urine and bacteriological analysis may assist
in prognosis; sperm analysis is important for assessing
the dose and subsequent likelihood of fertility. However, to be valid, a prognosis must be founded on
many different data and constantly updated.

320. Tests of the proliferative abilitl of the marrobr.
may also be regarded as useful dosimetric indicators. A
drop in the mitotic index, for example, is a sign of doses
higher than I Gy. The migration of granulocytes into
the bloodstream after the injection of ethiocholanolon
suggests the active production of granulocytes by thebone marrow. Cultures of mixed-cell colonies andgranulocyte/macrophage colonies give some indication of the concentration of precursor cells in the
marrow, as a function of the dose. By contrast,
erythrocytes are relatively radioresistant and longlived. and hence their concentration in the blood is apoor indicator of dose; however, marrow scans forerythropoiesis may be used to estimate marrow doses.
Biochemical analyses of the urine are more indicativeof dose than similar analyses of the blood, but no test
provides a better estimate of the dose than haematological and cytogenetic measurements.

319. Biological dosimetry relies on many prognostic
indicators, as well as on laboratory tests, for whichcorrelations between effect and dose have been reasonably well established. Changes in lymphocytes that areclearly related to dose include the appearance of
nuclear abnormalities, pycnosis. tritiated thymidine
uptake and electrophoretic mobility. These measurements should be regarded, for dosimetric purposes, as
only semi-quantitative. Leucocyte malformations. thelevel of serum glycoproteins, the presence in the blood

32 1. Cytogenetic measurements of chromosomr dicentrics, rings, fragments and micronuclei provide themost accurate assessment of the average dose. ofimportance for acute effects, over the body. The linear
or linear-quadratic relationships are well established
for irradiation of lymphocytes in vitro, for many
radiation qualities and dose rates. With neutrons.
linear relationships apply, and the relative efficiencies
of different energies of neutrons have been measured.
Protracted doses are, however, more difficult toestimate.

322. Changes in a number of neurophysicllogicalparameters have been observed after irradiation. andthese have good potential for development as dosimeters. The radiation-induced activation of biologicaland other materials. as well as electron spin resonancemeasurements, are quantifiable signals at lethal or
sublethal doses, down to about 0.3 Gy, that could also
be used as dosimetric techniques.

T a b l e

1Survlval parameters for human c l o n o g e n l c c e l l s
a s s a y e d In prlmary c u l t u r e a f t e r slnqle d o s e s o f low-LET radlatlon

Cell t y p e

Do
( GY

Ixtrapolatlon
numberRef

H a e m o p o l e t lc progenl tor cel IS produclng
MIxed-cell c o l o n l e s
C o l o n l e s of g r a n u l o c y t e s
and macrophages

C o l o n l e s of g r a n u l o c y t e s andm a c r o p h a g e s In d l f f u s l o n chambers
Erythrold colonles
C o l o n l e s of s t r m l c e l l s
1 - l y m p h o c y t e precursor c e l l s
Skln keratlnocytes
Skln flbroblasts
S k l n a n d lung flbroblasts
Mamnary flbroblasts
Uamnary eplthellum
Thyrold eplthellum

T a b l e

2lo50 estlmates for prodromal s y m p t o m s
o f q a s t r z n t e s t l n a l lnlury for lrradlated p a t l e n t s a/
(181

Response

Prevlous
estlmatesb/
N =-163c_/

Oak Rldge
Assoclated
Unlversltles
N = 104

Other
hospttals

Allhospltals

N = 400

N = 504

All. slx
nurslng
notes
requl redd/Anorexla

0.97 (10.31)(-0.26)
Nausea1.39 (b0.72)( -0.33)
Vomltlng 1.83 (11.18)(-0.53)Dlarrhoea 2 . 3 8 (tl.22)(-0.55)

a_/

b/
C/

a/

In t h l s Table. d o s e s a r e g l v e n In Gy t I Sf; t h e y a r e t h e a v e r a g e d o s e s
to a 26 c m d l a m e t e r sphere ln t h e eplgastrlc reglon. I r r a d l a t l o n w a s to
the w h o l e body, and In 8 4 of t h e 163 patlents ( c o l u m n 2 ) t h e d o s e rate w a s
The calculations a s s u m e a log-normal
about 0.01
Gy per mlnute.
d l s t r l b u t l o n of lncldence versus dose, w l t h a n a l l o w a n c e m a d e for t h e
The r e s p o n s e s r e f e r t o anorexla.
l n c l d e n c e In non-lrradlated patlents.
nausea a n d v o m l t l n g wlthln two days and d l a r r h o e a w l t h l n s l x weeks.
S p a c e R a d l a t l o n Study Panel Report [L4].
N = n u m b e r o f patlents.
Cllnlcal h l s t o r l e s not havlng thls m l n l m u m n u m b e r of c o n r e c u t l v e
p o s t - I r r a d l a t l o n notes w e r e discarded.

T a b l e

3Cellularlty and klnetlcs In human lntestlnal mucosa[ P 9 , W24]

Small lntestlne
Cells per vlllus
Cells per crypt
Crypt cells In cycle
Cell cycle tlme
Total number of crypts
Total cells produced per day
Translt tlme (crypt to vlllus tlp)-- 4000-8000
300- 500< 300
36-60 h6 100
1011
3- 4 d--Cell cycle tlmes (hours)
Stomach
Ileum
Colon
RectumHucosal turnover times (days)
I 1 eum
Colon
Rectum

T a b l e

4

Dlstrlbutlon of deaths amonq a small sample of documented lndlvlduals
who dled after the bomblnqs In Hlroshtma and Naqasakl[041

Days after
bomblng
to death

Number of Indlvlduals
Hlrashlma

Naqasakl

345

41 2

0- 1
2- 3
4- 5
6- 7
8- 9
10-1 1
12-13
14-15
16-17
18-19
20-29
3 0 - 39
40-49
50-59
60-69
70-79
> 80
UnknownTotal

T a b l e

5

C e l l k l n e t l c d a t a f o r human e p l d e r m l s[ P l l . P301

Number o f c e l l l a y e r s
Nucleated ( l n c l u d l n g basal)
Corneocytes
Transtt tlme
Basal t o g r a n u l a r
Granular t o surface
Llfetlme surface c e l l s
Basal c e l l s p e r mn2
Labelling lndex ( 1 8 - h average)
H l t o t t c lndex ( 1 8 - h average)
L e n g t h o f S phase
Cell cycle duratlon
C e l l s produced p e r h o u r
p e r 100 b a s a l c e l l s a/&/

14 + 6 (SO)I 8 i 6 (SO)2
(20-30) l o 3
4.7
0.63
9 i 2 (SO)
213 i 84 (SD)-

Assumlng g r o w t h f r a c t l o n = 1 . 0

T a b l e
S k i n " t o l e r a n c e ' doses--b( G y ) and f i e l d s l z e s[HI91

F l e l d s i z e (cm x cni)
Treatment

I P2l
S l n g l e dose
3 weeks
5 weeks

6 x 4(Small)8 x 1 0

70.0
50.0
58.0

14.5
37.5
43.5

15x20
(Large)11 .OO
29 .O
33.5

L/S

(x)

55
58
58

F l e l d s l z e (cm x cm)
Treatment[vai

S l n g l e dose
3 weeks
5 weeks

7 x 5(Small)8 x 1 0

25.0
52.5
60.0

17.0
45.0
50.0

T a b l e

15x20
(Large)

L/S
iX)

30.0
35.0

57
58

7

Doses t o a 1 cm c l r c l e o f p l g s k l n c a u s l n q d r y d e s ~ u a m t l o n(modlfted from [ M Z l ) ]IsotopeAverageenergyThreshold surface
dose f o r d r ydesquamatlon
(GY)

(MeV)
Sulphur-35
Cobal t - 6 0
Caeslum-137
Yttrlum-91
Strontlum-90
Yttrlum-90

0.17
0.31
0.55
1.53
0.61
2.20

200
40
20
15
)
)

15

Dose a t
90 w( GY

Earlv effects of radlatlon on the human e y e[nis]Oose (Gy)
TlssueEffectLatent perlod
SlngleLid skln

frythemd, second wave
Plgmentatlon
Molst d e s q ~ a m a t l o n
Epllation (Incomplete)
Epllatton (complete)
Hyperemla
Conjunctlvltls
Punctate keratltls
Edema
Hlld ulceratlon

Lld margln
ConJunctlva
CorneaIrls
Ret lna

IrltlsEdema

2-4 weeks
2-3 weeks
2-8 weeks
1 - 2 weeks
2-5 weeks
Imnedlate
1-3 weeks
Several weeks
1 - 3 weeks
Several(3-6) weeks
Several d a y s
Several weeks

T a b l e

fractlonatedb
4-6
50-b0/5-6 weeks
10
20-30/2-3 weeks
>5
10

20

-

=50/4-5 ueeks
30-50/4-5 weeks
40-50/2-3 veekr
30-40/2-3 weeks>b0/5-6 ueeks
20-35/3-4 ueeks

9

Klnetlcs of spermatoqenesls In man
181 1 I

Ouratlon ofStages t r macrosome
development

Spermatogonlal
types

Cellcycle

Spermatogenesls(dl

Number ofstagesNumber of
types

<384
384
209

64

6

b

T a b l e

10

(h)

I -V1
VI-V
VI-I

A-darkA-paleB

Spermatlds

Cffectr of slnqle-dose Irradlat_l_on ( low-LC11
on spermatoqenerls and fertlllty

Cffect on
Oose
(GY)

0.15
0.20
0.50
1.0
2.0
> b

a/

Spermatogenes ls

fertll\tyModerate ollgospermla
Moderate ollgospermla
Pronounced ollgospermla
Severe ollgospermla
Azoospermla
Azoospermla

Temporary sterlllty ( ? )Temporary sterlllty a/
Temporary sterlllty
Prolonged sterlllty
Prolonged sterlllty
Prolonged sterlllty

Type B spermatogonla are exceptionally sensltlve.
with Do
0.2 Gy.

-T a b l e

11Prevlous estimates of L050/60 ln man(acute doses of low-LET lrradlatlonl

Data source

All groups

Japanese bomb casualtles

Radlotherapy patlents
Accldents, withrupportlve treatment

Accldents, 4 t h successful
marrow transplantattona/Mldline or
marrow dose
(GY)

Year

3.0
3.0
2.6-4.0
2.5-2.9
3.15
3.0
3-6
5.0
2.6
1.54
2.1-2.5
2.4 a/
2.7-3.1
4 .O
2.4
3.6
3.4
5.1
3.5
5.25
5 -0
4.5-5.0
4.5

1950
1950.1957
1960
1961
1974
1979
1984
1956
1969
1986
1981
1987
1981
1964
1966
1960,1962
1975
1975
1919
1919
19 79
1983,1984.1985
1985

11.0

1985

Reference[W13](L14. GI51
IN31
IL41
1 Nb 1
[Kg1
in131
1051
(181
[R201
[f151
[FlS]
If151
1 ~ 3 I1
[Lll]
[C13.U1]
[R221
[R221
[Kg1
1~91
[021 .T28][H2,M27.H28]
[us]
[us]

Revlslon of above value of 1.54 Gy.

FACTORS WHICH MIGHT CAUSE THE LD50/bo TO BE:
LOWER
Pre-1986 doslmetry for A-bomb data
Contrlbutlon of extenrlve burns
Pre-exlstlng lllness
Chrontc nutr\tlonal deprlvatlon
Concurrent lnfectlons
Contrlbutlon of hlgh-LET radlatlon
HIGHER
Young. female
Radlatlon poorly penetratlng
Unllateral lrradlatlon
Partlal marrow shleldlng
Good medlcdl support
Protracted lrradlatlon

Sect lon
II.A.lII.A.lII.A.1
II.A.lII.A.lII.A.5

T a b l e

I2

n a r r o w d o s e s (GY) for selected accldent c a s e s( ~ 2 8 ,8 7 )vlnca
V (dled)

2.14

1.33

0.89

4.3

0.68

M

2.09

1.30

0.81

4.26

0.66

0

1.92

1.36

0.91

4.19

0.69

G

1.89

1.35

0.90

4.14

0.68

H

1.58

0.99

0.6

3.24

0.50

(2.30-3.10)
2.73(2.30-3.10)
2.61(1.80-2.50)
2.11(1.80-2.50)
2.16( 1 .lo-2.30)
2.01

3.28

4.53

3.20

4.32

3.14

4.05

3.09

3.99

2.42

3.21

E / Not stated.

Columns:1
G a m - r a y e m l s s l o n by s o u r c e : leakage d o s e = first-colllslon dose.
Y-12: [H23]; vlnca: [H22].
2
G a m - r a y d o s e for neutron capture In t h e s u r f a c e o f t h e body.
Y-12: [H23]: Vlnca: [Ht?].
3
F l r s t - c o l l l s l o n charged-particle dose. Y-12: [H23]; Vlnca: [H22).
4
Total d o s e a s published (columns 1 t 2 t 3). 7-12: [H23]; Vlnca: [H??].
5
C a m - r a y d o s e f r o m neutron capture In 6 - c m annulus of 3 0 - c m cyllnder.
6
M a r r o w d o s e [Bl].
Y-12. flrst flgure: m a r r o w dose If exposed f r o m t h e f r o n t ;Y-12. second flgure: If exposed f r o m t h e slde;
Vlnca: uncertalnty range ls i 15% of the mean.
M a r r o w d o s e [M28].
7
Values a r e for Y-12: 0.8 (column 1)
0.8 ( c o l u m n 3) + column 5:c o l u m n 5.
For Vlnca: 0.8 (column 1 ) + c o l u m n 3
8
A further r e v l s l o n of t h e dorlmetry o n t h e basls of lower body sodlurnlevels. results In increased estimates of d o s e uslng s o d l u m actlvatlon
by factors o f 1.06-1.20 at Y-12. and 1.29-1.41 a t Vlnca [MZb. WZl].
+

T a b l e

13

Total-body lrradlatlon In man: rchematlc clasrlflcatlon o f dose ranges: symptoms, therapv and outcome

Prcdromal symgtoms

Cllnlcal characterlstlcs

Therapy. cllnlcal course and outcome
If lnJury. . ls fatal

Acute
dose

Inctdence

Latency

Syndromeor organlnvolved

Characterlstlc symptoms

(GY)

> 50

100

Mlnutes

5-10

2-5

1-2

100
100

50-90

0-50

0.5 h
0.5-1

1-2 h

> 3 h

h

Therapy

Prognosis~cthallty
(X)

Death
wlthlnUsualcause of death

1-48 hCerebral oednna

Cramps. tremor. atarla.
1-48 hlethargy. lmpalred vlslon.
Co m

Symptomatic

Hopelesr

100

lntestlnal
syndrome

Diarrhoea. fever,

3-14 dPalllatlve

Ve-y poor

90-100 2 weeks fnterocolltls
shock

Bone marrowsyndrome

Thrombopenla. leucopenla,h a e m r r h a g e . lnfectlons.
epllatlon

2-6 wrtkS

Bone m a r r w transplantatlon. transfusionso f leukocytes andplatelets. optlmal
care (lsolatlon.
antlblotlcs, fluldr)

Uncertrln

0-90

Ueets

Infectlons and/or h a t m r r h a g e

Thrombopenla. leucopenla.
h a m r r h a g t . lnfcctlons.
epllatlon

2-6 weeks

Transfuslons of leukocytes and platelets.
optlmal care (lsolatlon. antlblotlcs.
flulds). bone mdrrou
transplantatlon

Uncertrln

0-90

Ueets

lnfectlons and/o r haelnorrhage

on successof therapy

Mlld leucopenla andthrombopenla

2-6 weeks

Symptomatlc

Excellent

0-10MonthsInfections andlo r haemorrhage

Neurologicalsymdrome
10-15

Crltlcalperlodafter
exposure

Bone marrowsyndrome

Bone marrowelectrolytic Imbalance
dependingon successof therapy

dependingT a b l e

14

Symptoms f o r m l d l l n e dose ranqe 1.0-2.0
[Y71

Hours
Synip~on~Anorexia
D I J R ~ ~(crclnlph)"
J

0

4

8

12

16

20

(GY~

Days
1 2 3 - 1 5 6 724
1

H'rrks
2

3

4

5

6

-30-70%
mildro rncwleratc-20-50%
mildlo rndcmle-50-903-30-609mild
to modemre-30-60%mild
ro m d c r a r e------.--------------hlilJ------------------------------------------hlil~----------------------

Hypolension
Dizziness
Disorlcn~auon+,,+ -1Wrmild

-(I

-1

10-508
mild 11)n~trlcrarc

Frvcr
Infccr~on

Fluid lasc/clccrrolyre
inlb~lsnce
lic~dachc
Fa~n~ing
Prosrra~lon

a/ References f o r t h l s group o f symptoms:

A25. A26, A27, 817, 829. C10. C14.
CIS. C39. C42. C43. C44. E l l . 626, G28, G29. H39. H40, 32, L20, L24. n l 8 .
U42, M44. N10, N11. N13. 05. 06, P24, R23, 533, 534, 535, 536, 15. Vl8.
W19. W21. 24.
b/ 10% o f t h e H a r s h a l l e s e v \ c t l m s exposed t o 1.75 Gy e x p e r l e n c e d d l a r r h e ad u r \ n g t h e f \ r r t day a f t e r I r r a d t a t l o n . a c c o r d l n g t o [ A 2 5 ] .
R e f e r e n c e s f o r t h l s group o f symptoms: A27. H39. K21. N13. 06. P24. 533.
U8. U9.
d_/ References f o r t h l s group o f symptoms: A2b. A27. 816. 829. C10. C14. CIS.

c/

S l l g h t t o moderate d r o p I n p l a t e l e t s :f / S l l g h t t o moderate d r o p I n g r a n u l o c y t e s :e/5f r o m 3 10 /ul t o 1.8-0.8
3
f r o m b 1 0 - / u 1 t o 4.5-2.0

510 /ul.
3
10 / u l .

q/ S l l g h t t o moderate d r o p l n lymphocytes:

o l2.0-1.0
f r o m 3 l ~ ~ / tu

1 0 /ulh/ References f o r t h l s event: A25. 816. L4. 06.

3

T a b l e

15

Svmptoms f o r m l d l l n e dose range 2.0-3.5
(Y71

(Gyl

Postcxpusurc unic
Hours
1
Syniptorn
Nausea"Von~itingiretching)Anorexia
D~anhea(cramps)

0

4

8

12

16

20

1

3

Days
4 5

\VccLr6

7
1

24-70-90%
modcraic5 0 - 8 0 % modcratc-901005;- + 10'Z moderate

2

3

4

5

6

-ms -----------------(c)-(1

Infeclion
Ulceration(L)-lo-80%
motitrate
3 0 5 + - .

-----moderate

Fluid loss/elcc~rolytc~rnbalancc
Headache
Fainling
Prosiraiion

-a /
b/
c/
-

d/

'

R e f e r e n c e s f o r t h i s group o f symptoms: A25. A2b. A27, 817. 829. 852.
C14, C39, C40. C47. 019. E l l , G2. G25. G2b. 627. G28. H39. H40. 120. 52.
K21. L20. UlO, M42. H l l . N13. 05. 06. P24, Rb. R23, 533. 534. 535. T5.
T23, W19, W20. W21, W22, Yb. 23, 24.
R e f e r e n c e s f o r t h l s group o f symptoms: A24. A27. 816. G2. L10. M42. 06.
U9. V18, Yb. 23.
References f o r t h l s group o f symptoms: A26. A27, A28. 816. 817. C14.
019. F14, Ill. 52. K21. L10, L20, L22. U l o , U42. NlO, 05, Ob. P24. R6,
534, T23, U9. W19, W20, 23.
cC

Moderate d r o p I n p l a t e l e t s :f r o m 3 1 0 ' / v l t o 0.8-0.1
10'/~1.
3
3
U o d e r a t e d r o p I n g r a n u l o c y t e s : from 6 1 0 /PI
t o 2.0-0.5 1 0 / P I .
3f / Moderate t o s e v e r e d r o p I n g r a n u l o c y t e s : f r o m 3 1 0 3 / p 1 t o 1.0-0.4 10 / u 1$/ I p I l a t l o n .
-h / References f o r t h l s e v e n t : A25. A21, 816, L4. 06.

-e /T a b l e

16

Symptoms f o r m l d l \ n e dose ranqe 3 . 5 - 5 . 5[y71

Vorniring (re~ching)Anorexia
Dlarrhcd (crdrnps)-80- 100%
severenidcmrc-lW%- t 10% rnodsrarc

-

(Gv)

-60-

10 bCVCIC-lC@%--1 IN%--nluderare
10 severe

Fcvcr
lniccrion

Flurd losr:clecrrt~lyrc
lrnbaI~nie'
Hcad~chc

a/ Reference's f o r t h l s group o f symptoms:

A24. A25, A26, A27. 816. 817. 829,
C14. C39, C40. E l l . 625. G26. H39. H40. 120. JZ. J19, L20, U42, U43. N10.
N11. 05, 06. P24. R12. R23. 533. 534, T5. T23. W19. WZO, U9. 23. 24.
b/ R e f e r e n c e s f o r t h l s group o f symptoms: A24, A26, A27, 816. G27. H40. 120.
U18. 06, P24. 533, U9.
c/ R e f e r e n c e s f o r t h l s group o f symptoms: U43. R12.
R e f e r e n c e s f o r t h l s group o f symptoms: A24, A26. A27. 816. 817, C14. C41.
~ 4 7 . 019, 111. ~ 1 9 . LO. LIO. LZO. ~ 2 2 , nio, n42, 1443, 06. ~ 2 4 . ~ 2 3 . 533.
534. U9. W19. W20. WZ1. 23. 24.
55g/ Severe d r o p I n p l a t e l e t s :f r o m 3 10 / u 1 t o 0.1 10 - 0 / p 1 .
3
3-f / Severe d r o p I n g r a n u l o c y t e s : f r o m 6 103 / u 1 t o 0.5 10 -0/ 1 .
/ Severe d r o p I n l y m p h o c y t e s : from 3 10 / u 1 t o 0 . 4 - 0 . 1 10 /ul.
/ Cpllatlon.
I / R e f e r e n c e s f o r t h l s group o f symptom%: A27. 816. L10. 06, R12. U9.
U l l d I n t e s t l n a l damage.
K/ R e f e r e n c e s f o r t h l s e v e n t : A25. 816. 14, 06.

d/

i

I/

5

T a b l e

17Modlflcatlon of LO50/30 for slnqle doses. accordlnq to dlrectlon of the beam
I~ 2 I8

Dog

Sheep

Plg

32-57
7-13
1 MV x rays. I nv x rays.
polnt source polnt source

Body mass, kg
Radlat lon

Source to mldplaneof anlmal (m)2.1
Olameter of trunk (cm)14
Irradlatlon condltlons
Conscious
Mortallty perlod (days)
0-30
LOSO mean t SE ( G y ) a/
Unllateral exposure
3.37 t 0.09
Bllateral exposure
2.80 i 0.08
0.57
Dl f ference
1.20
Rat loCoefflclent of varlatlon
Unllateral exposure
0.15
Bilateral exposure
0.25

2.0
20-25
Consclour
0-60

Goa t

60-95
av. 62
2.5 Mev
2 nv x rays.
polnt source C a m rays.
planar source
0.25
30
Sedated
0-60

2.14
28
Consc lous
0-30

a/ Alr kerma at mldplane of exposure volume In absence of anlmal.

T a b l e

18

lxdmpler o f adult erythropoletlc bane-marrow dlrtrlbutlons
In several m m l l a n specles(per cent)

HumansSkull
HandlbleTuo clavicles
Tuo scapulae

)
)

nlce
[czzj

Rats
1vi71

Dogs

19.1

4.1
2.6
0.21
1.5

1.0
0.1

Ice]

5.1

Monkeys
[TI~I

Men
[we]

Women
1w81

IM~OI

8.7
2.7
0.7
3.9

8.3
1.0
1.0
3.8

9.4
0.7
0.9
2.8

7.3
0.5
0.7
2.2

-

(3.7)
3.7
0
0

Upper llmbs(5.7)
Two humerl
4.1 /Tuo radl l
Two ulnae
Two urlsts (hands) 1.6

(8.6)
7.0
0.4
1.0
0.2

(11.1) (12.2)
10.8
9.2
0.1
1.5
0.1
1.3
0.1
0.2

Vertebrae
CervicalThorac tc
Lumbar

(29.7)
2.4
9.9
7.6(42.6)
6.7
17.6
15.0

(33.1)
2.2
12.3
17.0

(35.9)
4.1
9
13.9

3.3

1.6

7.7

7.4

7.9

8.9

12.9

19.7

21.3

20.7

(7.9)
7.2
0.0
0.6
0.0
0.1

(20.0)
13.3
0.1
5.9
0.5
0.2

-

(10.6)
10.6

Sacrococcygeal(38.1)

8.2 b/

15.5 c/Tuo h\p bones
Lower llmbs(12.8)
Two femurs
6.0
Two patellae
Two tlblae
Two flbulae
4.2
Two ankles (feet) 2.6

a/b/(39.4)
16.9
13.5
8.6
0.4

Includes clavlcles and scapulae.
Pelvls.
c/ Includes caudal vertebrae.

(36.6) (24.4)
5.1
4.0
18.0
9.9
13.5
10.5

0
0

T a b l e

19

A c c l d e n t a l human t o t a l - b o d y p r o t r a c t e d e x p o s u r e s
g l v l n q marrow doses h l g h e r t h a n 1 Gy

Approximate

Accldent

Person(s)Rongelap

Exposure
duratlon(days)

marrow
dose(GY)

OutcomeRef.

64

A l l survlved

[CIO]

Male
Male
FemaleMale
FemaleDled
OledSurvlved
Survlved
Survlved[yll'Lucky Dragon'

23 f l s h e r m e n

A l l survlved[Kb]

A l g e r l a a/

FemaleFemaleFema 1efemaleGrandmother

Survlved
Survlved
Survlved
Survlved
Dled

[J31

MexlcoSon
Wlfe
DaughterGrandmother
Husband

Dled
Dled
Dled
Died
Survlved

Morocco c/

GrandmotherGrandfather
Cous l n

Survlved
Survlved
Survlved

Chlna

a/
b/
c/

d/

a/

Very lnhomogeneous doses.
Two t h l r d s o f dose on f l r s t day.
E l g h t o t h e r members o f t h e f a m l l y and t h e l r r e l a t l v e s r e c e l v e d exposureso v e r 15 and 45 days. and a l l o f them d l e d . However, assessments o f t h e l rdoses a r e n o t a v a l l a b l e [US].
Ten l n d l v l d u a l s r e c e l v e d h l g h doses and f o u r o f them d l e d( s e e paragraph 150).

T a b l e20

l n c l d e n c e o f D n e u m n l t l s l n man a f t e r F r a c t l o n a t e d l r r a d l a t m
L I438 ILung dose ( G y ) /number o f f r a c t l o n r

Number o fpatlents

lncldence ofpneumonltls

33
42

67

90
86

Prlmary dlagnosls
o f tumour~ung.
Hodgkln's d l s e a s e
Lung,
Hodgkln's d l s e a s e
Lung,
Hodgkin's dlsease.
Hemangloperlcytoma.
1h ymoma
Lung, B r e a s t .
ThymomaLung. B r e a s t ,SarcomaT a b l e

21

C l l n l c a l course a f t e r dosesr e s u l t l n u l n t h e bone-marrow syndrome

Phase

Approxlmate d u r a t l o n

Prodromal
LatentCrltlcal1- 7 days
7-20 days
Second o r t h l r d weekt o 7 weeks
8-15 weeks

RecoveryT a b l e

22

G a s t r o l n t e s t l n a l prodromal SYmptoms
a t 48 h o u r s I n Ill cancer ~ a t l e n t s[LEI

Doses (Gy)
Symptoms

Anorexld
HausedVomltlng
Otarrhoea

a/

D 10%

D 50%

0.3
0.4
0.5
0.6 a_/

0.6
1.2
1.8
3.0

By s l x weeks.

T a b l e

23

S u m r y o f symptoms. t l m e c o u r s e and p r o g n o s l s
I n t h e bone marrow syndrome I n man(adapted from [ 1 1 2 ] )

Dose
range

Prognosls(GY)

Approprlatetlme ofdelay fornausea andvomlt l n g

0-1
1-2

Excellent
Excellent

3 hours

2-6

Uncertaln

2 hours

6-10
10-15

Uncertaln
Poor

1 hour
0.5-1 h> 60

Hopeless

0.5 hourTlme ofdelay forcrltlcalperlodMa\nsymptoms

Moderateleucopenla
4-6 weeks Leucopenla.
haemorrhage
infectlon
4-6 weeks Leucopenla
5-14 days D l a r r h o e a .
fever.
electrolyte
imbalance
1-48 hours A t a x l a .
lethargy

Time o f
recoveryTlme o fdeath

S e v e r a l weeks-

6 - 8 ueeks < 2 months
1 - 1 2 months
Prolonged< 2 months< 2 weeks< 2 days

T a b l e

24

ED 50 (Gy) f o r p r o d r o m a l symptoms I n 1 1 1 c a n c e r p a t l e n t s
a f t e r whole-body a c u t e o r p r o t r a c t e d e x p o s u r e[L91

Exposure p e r l o dSymptom
1 day(504 p a t l e n t s )Anorexla
NauseaVomltlng
Fatlgue
Olarrhoea

7 days(103 p a t l e n t s )

0.97
1.4
1.8
1.5

2.0
2.6
4.9
2.6 ( ? )

2.3

5.3

T a b l e

25

Vain s l g n s and symutoms i n t h e c r l t l c a l phaseo f t h e bone marrow syndrome I n man( a d a p t e d f r o m [NS])1:

Anorexia
NauseaVoml t 1n g
Weakness, f a t l g u e
Prostratlon

2:

Sweatlng, f e v e r
PurpuraHemorrhage, e p l s t a x l s , g l n g l v a l b l e e d l n g ,haematemesls, melaena, haemoptysls
Infectlon

3:

Erythema. e p l l a t l o n . s c a l p p a l n

4:

Abdomlnal p a i n
Abdominal d l s t e n t l o n
Olarrhoea

5:OllgurlaHyperaesthesla. paraesthesla
AtaxlaDlsorlentatlon
Shock
coma
Death

T a b l e

26

Hlnlmum values of blood cell counts
after three accidents lnvolvlnq elqht Indlvlduals
IN51(Acute doses from mlxed fields In cases 1-7.)

Dose (Gy) y + n

Lymphocytes

Neutrophlls

Platelets

Dose 1

Dose 2b/c/

Cells/ Tlme
Cells/ Tlme
Cells/
ul(days)
111(days)
111

Case

a/

OutcomeTlme(days)
Death (day 32)
favourable
transplantationof bone marrow(day 29)
As In case 2
As In case 2
As In case 2
favourable
Favourable
Death (day 12)

a_/ Cases 1-6: Vlnca. Yugoslavia (1958).
Case 7: Mol. Belglum (1965).
Case 8: Brescia, Italy (1975).
b/ Dose 1: orlginal estimated doses.
c/ Dose 2: Revlsed equlvalent low-LET marrow dose (see Table 12)-

T a b l e27

Hlntrnurn values of blood cell counts
after two accidents lnvolvlnq several lndlvlduals
where the lnhomoqeneous Irradlatlon was prolonqed over a few weeks
lh.51

Lymphocytes
Case
a_/

15
16
17

Dose
(Gy) yNeutrophlls

Cells/ TIme
Cells/ TIme
Cells/ Timeu1
(days!
v1(days)
u1(days)
!
!
I
b/
b/

6-7
416
2-3
560
Acute
1.9. 486
chronlc 4.0

18
50

c/

63
858
1200

8
44
c/

9-12: Algerla. 1978.
-a/ Cases
Cases 15-17: Horocco. 1984.

b/c/Platelets

After t h e end of exposure.
Ourlng t h e ftrst week of hospItallzatlon

35000
Normal1000002

E/

T a b l e

28

Representattve effects and related acute doses
after whole-body lrradlatton In man(adapted From [N5])Threshold for detectton of the effect

Dose ( G y )a_/Chromosome aberrattons and sperm-count depression
flectroencephalography modlflcatlons
Vomltlng tn 10% of exposed lnd\vlduals
Translent dlrablllty and easlly detectablehaematologlcal changesa_/0.05-0.25
0.25-0.5
0.5 -1.5
1.5 - 2Whole-body dose. u h t c h may vary by as much as i 50%;
expressed a s mldllne doses.

APPENDIX
Acute radiation effects in victims of the Chernobyl nuclear power plant accident

Prepared, under the editorial s~~pervisionof A.K. Guskova, by:
A.K. Guskova
A.V. Barabanova
A.Y. Baranov
G.P. Gruszdev
Y.K. Pyatkin
N.M. Nadezhina
N.A. Metlyaeva
G.D. Selidovkin
A.A. Moiseev
I.A. Gusev
E.M. Dorofeeva
I.E. Zykova

l n troduction

1. This Appendix sets out the essential findings ofthe clinical observation of a group of patients sufferingfrom acute radiation sickness following the accident at
the Chernobyl nuclear power plant o n 26 April 1986.
The observations were conducted at the specialized
treatment centre in Moscow over a period of two
years.

2. An initial report on the accident was submitted by
the Soviet representatives to the Post-Accident Review
Meeting held at the International Atomic Energy
Agency in August 1986 and was summarized in IAEA
Safety Series Technical Report No. 75 [I 181 and in[G33]. The proposal to present this information in its
present form was endorsed at the thirty-sixth sessionof UNSCEAR in March 1987.
3. The basic information on the radionuclide releases
a n d the types of exposures of the irradiated persons
coincided with the expected pattern for an accident at
a nuclear power plant of similar type: as much as
100% of gaseous fraction of the noble gases andnuclides may have escaped from the plant; caesium,
iodine and tellurium isotopes accounted for up to
10-2070 of the nuclide inventory, and other radionuclides for up to 30% [I 181.
4.; The plant personnel and auxiliary staff present at

the industrial site in the immediate vicinity of theaccident zone were subjected to the combined effect ofradiation from several sources: (a) short-term external
g a m m a h e t a radiation from the gas emission cloud (inthe case of persons in the immediate area of theaccident zone at the time of the explosion); (b) external
gamma/beta radiation of decreasing intensity, fromfragments of the damaged reactor core scattered overthe industrial site; (c) inhalation of gases and aerosol
dust particles containing a mixture of radionuclides;and (d) deposition of these particles on the skin a n dmucous membranes at the time of the intensive
generation of steam or dust and the wetting ofclothing (as a result of them being blown or washed
off contaminated objects).

5. However, the most significant factor was thegeneral, external and relatively uniform whole-body
gamma-irradiation and the beta-irradiation of extensive body surfaces, coupled (except in two cases) witha very small intake of nuclides through inhalation.
predominantly of radioiodine and caesiurn isotopes.
Thus, the basic clinical picture was that of a distinctive acute radiation sickness caused by gammairradiation of the whole body and by beta-irradiationof extensive areas of the skin surface.
6. Direct and indirect dosimetry methods were used
to determine the nuclide content in the body. A great
many tests were carried out, both while the victims
were alive and (in 28 cases) after they had died, so that
it was possible to estimate the nuclide content in the
body and the resultant dose levels. An example ofthese types of analyses is shown in Figure A.I., giving
the distribution of various radionuclides in the lungs.

7. The iodine isotope content in the thyroid gland
was determined repeatedly (as many as four t o six

1

2

3

4

15

5

6

7

8

9

10

11

12

13

LUNG SAMPLE (as numbered on diagram)
Figure A.I. Location of lung samples taken a1 the time of autopsy and distribution of the mainradionuclides in lung samples. The number above each sample group indicates the approximate
relative average value.

times) from the second day after the accident. These
measurements showed that "'I accounted for 80 f 20%of the total activity of all iodine isotopes, "31 for
15 i 10%. and the remaining isotopes ('231, '*'I, IZ6I,
and "'I) for not more than 2%.
8. The calculations for estimating intake quantities
from the thyroid measurements were performed according to the recommendations of the International
Commission on Radiological Protection [I19]. On thebasis of the distribution of thyroid doses in exposed
individuals (Table A.I), it may be stated that in the
overwhelming majority of cases the thyroid doses were
below the levels likely to cause direct injury to thatorgan (< 3.7 Sv) o r of significantly influencing theclinical picture during the onset of acute radiation
sickness. Low radioiodine dose levels were alsosuggested by the post-mortem nuclide measurementsof the 28 persons who subsequently died.

9. Internal dose values according to post-mortem
measurements for 6 patients are shown in Table A.2.
The maximum amount of "'Cs and 13'Cs incorporated
activity was 7.4 MBq, except for two patients withextensive steam burns, which allowed intake of nuclides
through the wound. The post-mortem dosimetry gave
40 and 80 MBq of "'Cs plus '-"Cs. and 350 and
1,100 MBq of "'I. for these two patients. respectively.
The whole-body internal doses in these two individuals
from these nuclides were estimated as approximately
1 Sv and 2 Sv during the two to three weeks before
they died, which are commensurable with their external
gamma doses. This fact was taken into account during
the interpretation of clinical data. Internal doses forother patients did not exceed 1-3% of the external
irradiation doses.
10. The transuranic elements (e.g., 239Pu)were studiedin urine specimens from 266 persons (635 analyses),
including. in some ofethe cases. analyses conducted
before and after the administration of pentacine. The
urine activity values and a negative finding afterchelation treatment confirmed the absence of a significant plutonium contamination of all the patients
tests by alpha spectrometry forobserved. Post-n~orten~transuranic elements showed their presence (74-300 Bq
per organ) only in the lungs; curium accounted for asmuch as 90% of the specimen activity, and plutonium
a n d americium for 10%.
11. Gamma-spectrometric analysis of the first specimens within 36-39 hours of the accident failed toreveal any sign of 22.24Naactivation, which confirmedthat neutron irradiation of the victims was not
significant.
12. For most of the victims, the energy peaks ofmore than 20 radionuclides were detectable in the
spectrum of their whole-body gamma measurements;
however, apart from the iodine and caesium isotopes
pre~.iouslymentioned, the contribution to the overall
dose from the others (q5Nb, j4'Ce, lJOLa etc.) was
negligible. These measurements, performed while thevictims were still alive, were also confirmed throughthe analysis of autopsy specimens (approximately
35 specimens from each deceased person) (Figure A.1).

13. The dose levels from external irradiation werereconstructed from the indication of several measurements on the basis of previous experience. Subsequently. in three cases with a lethal outcome. thesefindings were refined using methods earlier proposedby Kraytor for clothing fabrics [B31] and according to
the electron spin resonance technique for dental
enamel [T16]. These measurements agreed within
20% with the dose estimates based on clinical andbiological criteria.

+

14. The total number of affected individuals among
the persons present at the reactor site in the earlyhours of 26 April 1986 was 203, as given in the reportpresented by Soviet representatives at the PostAccident Review Meeting in August 1986 [I 181. Of
these, 115 were treated, beginning on day 2, at the
specialized treatment centre in Moscow; it was thisgroup that provided most of the scientific analytical
data discussed in this report. At other hospitals in Kiev
there were only 12 patients with a clearly defined
clinical pattern of second-degree acute radiation sickness and one person with fourth-degree acute radiation
sickness. a fact that cannot in any substantial way alter
the overall assessment of the data for the entire groupof victims.
15. The increase in the total number of affectedindividuals from 203 to 237, announced in November
1986. was due solely to persons suffering from firstdegree acute radiation sickness. There were 3 1 persons
suffering from first-degree acute radiation sickness
at the special treatment centre in Moscow and
109 persons in Kiev. The task of establishing a diagnosis
distinguishing between first-degree acute radiation
sickness and ordinary somatic diseases according to
generally accepted criteria is a complex one, and onethat continued throughout 1986. On the whole, acritical analysis of the data shows a decrease in thenumber of persons suffering from first-degree acuteradiation sickness in comparison with the number
given originally. At the time of writing this report. up to
three quarters of these persons are for all practical
purposes healthy. Their clinical signs of reaction to theaccident during the first three months were neither
individually significant nor typical of a reaction t oirradiation. Table A.3 shows the distribution ofpatients with acute radiation sickness according to its
degree of severity [B31] in the group selected forscientific analysis.
A.

INITIAL DIAGNOSIS O F ACUTE
RADIATION SICKNESS

16. The medical unit sewing the plant was informedof the accident within 10-15 minutes of its occurrence.
First aid to the affected individuals was provided bymiddle-level medical personnel and emergency teams
over a time period from 30-40 minutes to 3-6 hours
after the accident. First aid consisted in the evacuationof the victims from the industrial site, the simplest
forms of medical attention, the administration ofantiemetic and symptomatic (sedative, cardiotonic)
drugs, the distribution of potassium iodide a n d thetransportation of persons suffering from a pronounced
primary reaction to the medical unit. During the first12-24 hours after the accident. other persons who werein satisfactory condition were urged to go to the medical
unit for examination; a total of 132 persons were
hospitalized there during the first 12 hours. One personwith severe thermal burns died during the first hour.
Another, a reactor operator, could not be found; hisworking station was located in the collapsed highactivity zone.
17. Within 12 hours, a specialized emergency teamarrived at the site and began work. Within 36 hours,
this team, together with the on-site medical unit,
examined more than 350 persons and carried out
approximately 1.000 blood tests, each person undergoing two to three such tests. The treatment withpotassium iodide was continued.
18. Within the first three days, 299 persons suspectedof suffering from acute radiation sickness were sent tothe specialized treatment centre in Moscow and to
hospitals in Kiev, and over the subsequent days some
200 additional persons were admitted for examination.

19. The primary diagnostic criteria for assessing thepriority for hospitalization were the presence. time of
onset and intensity of nausea and vomiting and ofprimary erythema of the skin and mucosae, and adecrease of the lymphocyte count in the peripheral
blood to below 109/1 during the first days following
irradiation.
20. The diagnosis of acute radiation sickness was
subsequently confirmed in 99 of the 128 persons(firemen. Unit 4 operators, turbine-room duty officer
and auxiliary personnel) admitted to the specialized
treatment centre in Moscow during the first two days
and in six of the 74 victims hospitalized during thefollowing three days. This is an indication of the highspecificity of the screening methods used. An additional 10 cases of minor acute radiation sickness werediagnosed among persons present at the site at thetime of the accident, who were later admitted to thehospital facility for a variety of reasons. In thereception area the patients were monitored again forcontamination and, if necessary, subjected to decontamination measures (washing under a shower withordinary soap and change of underwear). Blood andurine samples were taken for a quick test of thepresence of radionuclides; the patients also underwent
measurements (repeated a further 4-6 times during thefirst 6-10 days) of the radioactive iodine content in the
thyroid. Measuring devices consisting of a scintillation
detector or a semiconductor detection unit were used
for the whole-body counting of radionuclide activity.
B.

THE BONE MARROW SYNDROME
AND ITS TREATMENT

21. Dosimetric data, together with an analysis of thecircumstances of the accident and the presence in aconsiderable number of the victims of obvious primary
reaction symptoms (nausea, vomiting. diarrhoea, hyperaemia of the mucosae and skin, lymphopenia), confirmed that the principal modes of irradiation had been:(a) by external, relatively uniform gamma-radiation;and (b) by deposition of beta/gamma-emitting nuclides

on the skin. Radionuclide ingestion was below thelevel likely to cause acute radiation injury. As alreadynoted, two patients suffered from all three of these
irradiation modalities, in combination with extensive
steam burns.
22. The important diagnostic task during the first few
days after the accident was the assessment of the degreeof severity of the bone marrow syndrome resulting fromthe external gamma-irradiation dose. This was possible
through the use of previously devised methods, which
are based on the number of lymphocytes and on
chronlosome aberrations in peripheral-blood lymphocytes or on the incidence of chromosome aberrations
in bone marrow cells [B31, B5O. G241. These data
were later transformed into a prognosis of the overall
dynamics of the blood picture. A subsequent reassessment of dose levels involving a larger sample ofcells scored revealed not more than 5-10% changes inthe estimated doses.
23. Dose-effect relationships for these indicators had
been derived earlier through the analysis of relatively
uniform accidental or therapeutic irradiations ofhuman subjects having normal initial haematologicalcharacteristics and exposed to well established doses[P22]. Figure A.11 shows the curves (and analyticalexpressions) for the relationships between the dose
and the blood lymphocyte count for each of the firstnine days and the average lymphocyte count on days
4-7 and days 1-8 after irradiation. The radiation dose
received by each person was estimated according to
the number of chromoson~eaberrations (dicentrics) ina blood-lymphocyte culture, using a dose-effect curvefor 100 first-mitosis cells that had been obtained after
whole-body gamma-irradiation to treat acute leukaemia
patients during a period of full clinical and haematological remission [P23].
24. The formula for calculating of the dose is asfollows:
D = (-a + I/' a2 + 4by)/2bThis assumes that the yield of dicentrics shows a linearquadratic dependence on dose:y = (a t 2.24)D + (b t 0.56)D2
where D is the average gamma-irradiation dose in the
body (Gy), y is the dicentric count per 100 cells;
a = 8.36: b = 5.70.
25. Up to day 7 after the accident, the estimates of
the average dose of total gamma-irradiation wererefined, mostly on the basis of the peripheral-blood
lymphocyte counts but also, in the more severe cases
and to a lesser degree. on the chromosome aberration
count. This made it possible to divide the patients into
various prognostic groups [B31]. according to theseverity of the bone marrow syndrome as follows (seeTable A.3):
(I)
(11)
(111)
(IV)

slightintermediate
severeextremely severe(1-2 GY)(2-4 Gy)(4-6 GY)(6 Gy and above)

It was also possible to separate those persons who
received doses of less than I Gy.

IDore = a - b log(1ymphocyte count)0

2 4 6 8 1
CAMHA DOSE (Gy)0

I tjinirnal count on days 1 t o 8

0.01

010-.
1
0

2

4

MEAN BODY DOSE (Gy)

6

0

2

4

6

rlEAri BODY DOSE (Gy)

Estimation of the total gamma dose according to the blood lymphocyte counts. Upper
Figure A.II.
panel: Dose-effect relationships for lymphocyte counts at the days post irradiation shown on the
curves; analytical expression and coefficients of these relationships. Lower panels: Curves showing
the dependence of average lymphocyte counts on days 4-7 and the minimum lymphocyte count ondays 1-8 as a function of the irradiation dose.

26. Particular attention during the first days was
directed at identifying persons with a n extremely
severe and irreversible degree of myelodepression, forwhom a n urgent decision was required regarding abone marrow transplant. Additional signs providing
further evidence that a patient belonged to this groupwere (a) vomiting during the first half-hour and of
diarrhoea during tne first 1-2 hours from the start ofirradiation; (b) a swelling of the parotid glands during
the first 24-36 hours: and (c) the ascertainment of an
irreversible degree of myelodepression using a diagnostic table previously devised (Table A.4).

TIRE (days)
Figure A.IV. Example of the changes in neutrophils, lymphocytes and platelets observed in a patient (case 39) sufferingfrom acute radiation sickness (estimated dose 2.4-3.3 Gy) andthe predicted neutrophil curve for a total gamma dose of
3.0 Gy.

27. The results of numerous biochemical, immunological and biophysical indicators are undergoingprocessing and analysis at the time of writing thisreport. None of these indicators is as informative a s
the signs described above. However, it may be noted,
for example, that hyperamylasemia was used as asupplementary prognostic test.

T I E AFTER EXPOSURE (days)

28. On the basis of the estimated dose, a prediction
was made using standard curves [P22], of the overall
trend with time in the neutrophil and platelet counts(Figure A.111). By way of example, Figure A.IV shows
the real and predicted neutrophil curves for one
patient (case 39). The total gamma-irradiation doses
estimated according t o the average lymphocyte countfrom day 4 to day 7 and according to the dicentric
yield totalled 2.4 and 3.3 Gy, respectively. The patient's
measured neutrophil curve a l m o s ~coincided with thepredicted neutrophil curve for 3.0 Gy of total gammairradiation.

29. The calibration curves of neutrophil counts as afunction of dose were also used for a final assessmentof the magnitude of the total gamma-irradiation dose.
The dose calibration curve was chosen that coincidedwith the measured second depletion phase. Also. use
was made of the dose dependency of the second
depletion phase, such as the time required for theneutrophil count to decrease to 0.5 IOy/l or the time
to reach the minimum of the second depletion phase(Figure A.V).
TIHE AFTER EXPOSURE (days)
Figure A.III. Standard curves showing the changes of theneutrophil and platelet counts after various doses (numbers on
the curves indicate the dose in Gy) in the case of relatively
uniform whole-body gamma irradiation of human subjects.
[831]. (The broken segments of the curves at doses of 5-6 Gy
indicate that recovery may not occur at these times in all
patients.) Upper panel: Neutrophils. Lower panel: Platelets.

Gy), the diagnosis
30. For relatively low doses ( 1.0-1.5
was finally established over time periods of up to threemonths only in those cases that showed typical postirradiation neutrophil and/or platelet time courses
with distinct second depletion and restoration phases.
The latter generally developed beginning in the fourth
to the fifth week after irradiation. In order todetermine these changes, it was necessary to carry out
blood analyses not less than two or three times a weekover a period of two to three months. Examples ofthese curves are shown in Figure A.VI: (a) case 48:
doses, estimated according to the lymphocyte counton days 4-7 and the dicentric yield were 1.1 Gy and
1.4 Gy. respectively; and (b) case 97: doses, estimatedaccording to the lymphocyte count on day 9 (the firstblood analysis was made at this time because of latearrival) and the dicentric yield were 0.3 Gy and
0.9 Gy, respectively. It should be noted that in thecase of low doses, the minimum level for neutrophils
occurred later (day 30-50) than for platelets (day 20-40).
and the reduction in the number of platelets and theirrecovery were more clearly pronounced than forneutrophils.
31. On the basis of all these data. a diagnosis ofacute radiation sickness with the bone marrow syndrome of the first, second. third and fourth degree ofseverity was definitively established for 31, 43. 21 and20 patients, respectively (see Table A.3). The analysisof the observations carried out on these patients is the
subject of the exposition that follows.
32. Clinical manifestations of the bone marrow syndrome corresponded to the level and duration of postirradiation pancytopenia (neutrophils 0.1-0.5 109/1,
platelets 10-20 109/l). The main signs were fever,infectious complications and petechial haemorrhages
in the skin and oral mucosa.
33. Treatment was based on the principles of supportive therapy, including isolation, antimicrobial
decontamination of the intestine, administration ofsystemic antibiotics and replacement transfusions ofblood cells. In cases in which there was a prognosis ofirreversible myelodepression, transplantations of allogeneic bone marrow and embryonic human liver cells
were performed.
34. All patients suffering from a bone marrowsyndrome of the second, third or fourth degree wereindividually accommodated in ordinary hospital rooms.
These were adapted to ensure (a) barrier nursing; (b) air
sterilization by means of ultraviolet lamps; (c) strict
observance by the attending personnel of hand disinfection on entering and leaving the room; (d) mandatory
use of individual or disposable gowns. masks, andcaps; (e) antiseptic decontamination of footwear:(0 changes of underclothing for patients at least oncea day: (g) use of antiseptic agents for washing thewalls and floor of the room and the items of use; and(h) individual assignment of antiseptically treatednursing items in the room. This regimen made it
possible to maintain the micro-organism population atless than 500 mb3 in the room air. Ordinary food wasserved, with the exclusion of raw vegetables. fruits andcanned products.
35. Prophylaxis against endogenous infections wasby means of the internal administration of biseptol380 and nistatin in amounts of six tablets and fivemillion units per day, respectively. for one and 2-3
weeks prior to the development of agranulocytosis(leucocytes 1.0 109/1, neutrophils 0.1-0.5 109/1).
36. With the onset of fever, intravenous administration of two or three broad-spectrum antibiotics wasprescribed, one of them being from the aminoglycoside

Time after exposure

Time after exposure
0
0

I

I

I

1

I

2

4

6

8

10

MEAN BODY DOSE (Gy)Figure A.V.

0

0

I

I

I

I

1

2

4

6

8

10

IlEAN BODY DOSE (Gy)

Estimation of the total gamma dose according to two neutrophll counts: Left panel: time to the minimum of the second
phase of depletion; Right panel: time to the "500 neutrophll day" or lo the middle of the second depletion.

used prophylactically; experience has shown that thisshould be the case with high-dose whole-body irradiation. An ointment containing acyclovir proved effective in the treatment of skin lesions involving herpes
virus.

-------- Neutmphils..*.....*.

Lymphocytes-.-.-.-.Platelets
10
0

10

20

40

30

50

TIHE (days)

39. Blood screenings carried out while the patientswere still alive or, in the case of those who died, posthumously, most often revealed epidermal staphylococcus. I t will only be possible to evaluate the roleof this form of bacteria as an agent of terminal
septicaemia when these results have been compared withthe histological data from analysis of various organs
that have not yet been completed.

-------- Neutrophi1s..........Lymphocytes
Case 97m

0

38. The regimen described above for the empiricaltreatment to combat infection proved to be highly
effective: there was no evidence that deaths werecaused by bacterial infection alone in patients suffering from the bone marrow syndrome. This was soeven among those with a severe or extremely severe
form of acute radiation sickness, provided it was notcomplicated by burns, radiation-induced enteritis oracute secondary syndromes as a result of a bonemarrow transplantation.

Platelets-.-.-.-a---- Leucocytes

I

I

I

I

I

10

20

30

40

50

TlNF (days)

Figure A-VI. Changes in neutrophil, lymphocyte, platelet andleucocyte counts after whole-body gamma irradiation. Case 48,
estimated dose 1.1-1.4 Gy. Case 97, estimated dose 0.3-0.9 Gy.

group (gentamicin or amicacin), the cephalosporins(cephzol, cephamecin, cephobide) and the semi-synthetic penicillins with activity against pseudomonas
aeruginosa (carbenicillin, pipracil), all in maximum
doses. This treatment reduced the fever in more thanhalf of the patients. If within 24-48 hours there was noeffect, extensive use was made of gamma globulin(Sandoglobulin), made available by the Sandoz Company (Switzerland). Six grams were administeredintravenously every 12 hours, three or four times. The
policy adopted was one of early empirical prescriptionof 1 m u k g per day amphoterricin-B given intravenously, if the fever had not disappeared within aweek of the above mentioned antibiotics, in combination with the intravenous administration of gamma
globulin.
37. In this situation, acyclovir was used for the firsttime, and with good effect. in the treatment of patientswith acute radiation sickness suffering from a herpes
simplex infection. Not less than one third of thepatients with third- and fourth-degree acute radiation
sickness were affected by this virus. Acyclovir was not

40. One of the undoubted successes in the treatmentof the bone marrow syndrome in patients with acuteradiation sickness was the rational use of fresh donor
platelets for the prophylaxis and treatment of bleeding.
To make these measures possible, the collection of thethrombocytes was organized on an urgent basis, using
the method of fourfold thrombocytopheresis fromindividual donors at seven blood transfusion centres.
For one transfusion, platelets obtained from a single
donor (on the average 300 lo9 platelets in 200-250 mlof plasma) were used. Transfusions were carried out
when the platelet level in the blood fell to 20 109/1 orlower, with appearance of the first signs of bleeding.
The infusions were repeated every 1-3 days. As aprophylaxis against acute secondary syndrome. thethrombocytes as well as the other blood components
were irradiated with IS Gy before infusion in order toinactivate the immunocompetent cells originating fromthe donor.
4 1. Platelet transfusion prevented life-threatening
bleeding, even in patients with protracted (more than
2-4 weeks) and severe thrombocytopenia. The majority
showed no signs of bleeding at all, although autopsies
disclosed microcirculatory failures and porosity of thecapillaries in a number of organs. I n this situation,
successful use was made of cryo-preserved allogeneic
and. what is particularly important. autologous
thrombocytes. The latter were obtained from patientswith second- or third-degree bone marrow syndromeduring the first days following irradiation (1-2 sessions)-this had no effect on the post-irradiation behaviour of
their platelet counts-andwere used with great
effectiveness when the patients developed criticalthrombocytopenia. No cases of refractoriness tothrombocytes transfusion were observed. On the
average, from three to eight transfusions of standard
amounts of thrombocytes (300 lo9 cells) were required
for the treatment of a single patient with second- andthird-degree acute radiation syndrome. Leucocytes42. Figure A.VII illustrates the clinical record of one
patient (case 21), showing the typical extent andduration of substitutive and supportive therapy for thebone marrow syndrome. In the case of this patient
there were n o life-threatening acute radiation injuries
to the other tissues.

were not used for the prophylaxis o r treatment ofagranulocyticinfections. Requirementsfor erythrocytes
turned out t o be considerably greater than expected,
even for patients with second- and third-degree acuteradiation sickness uncomplicated by severe radiation
burns.

DAY AFTER EXPOSURE
0 ! 2 3 4 5 6 1 8 9lOU~Ul4fil6Yl8!92021ZZ252~~26272S29JOj1QDR3536a3839~uQ~w~~~@a~

,

40-

O
-

g 393
k
g 330.

x

P 37
36:~IIIIII~IIIII~IIIIIIII~II

INFECTION
Blood
Lungs
Intestine
KidneyOral c a v i t y
BURNS
Hands
Shins
Buttocks

0

0
l

l
0
l

0

0

0

e o o

0

0

e
0

0

0

0
l

0
0

0

l

l

eee

me

0
l

0
l

0

0

0

.

e m

0

0

0

0

0

0

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@ @ a e r n e

1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 3 3 3 3 3 32'2'2'2'2'2'2'2'2'2'1'1'1'1'1'1'r
1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 3 3 3 3332'2't'2'2'1'1'1'1'1'1'1'1'
1 1 1 1 1 1 1 I 1 1 1 i 1 1 1 1 2 2 2 2 2 1' 1' 1' 1' 1' 1' 1' 1' 1' 1' 1' 1' 1' 1' 1' 1' 1' 1' 1' I'

TREATtlEfIT
Isolation
Gut s t e r i l i z a t i o n

Biseptol-480: 2880 ng d-'

ANTIBIOTICS(9)
Cepari n
Gentamycin(mg)
Carbenicillin (g)

240.0
20.0

N i s t a t i n : 6 lo6 u n i t s d-'

0 1 2 3 4 5 6 7 8 9101111U1415161718!9;1021Z1U2ciX262728BD31R~%3536~~39~~~~lur1F,~Wla~~

DAY AFTER EXPOSURE

Figure A.VII. Clinical record of a patient (case 21) suffering from acute radiation sickness with bone marrow syndrome of an
average degree of severity; whole-body gamma dose of 3.9 Gy, estimated according to the chromosome aberrations i n blood
lymphocytes. The circles i n the infection section indicate the results of bacteriological tests of biological samples (blood, mucus.
faeces, etc.); empty circles indicate absence of growth; solid circles indicate the presence of bacteria or fungi. The numbers i n theburn segment designate the three degrees of radiation-induced burns.

43. The indication for an allogeneic bone marrowtransplantation or an embryonic liver cell transplantation was the whole-body gamma-irradiation dose,
estimated according to the peripheral-blood lymphocyte
count and the chromosome aberrations at about
6.0 G y and above. At these dose levels the prognosis
expected was for irreversible or extremely protracted
severe myelodepression.
44. A total of 13 allogeneic bone marrow transplantations and six embryonic liver cell transplantations
were performed. The latter contains haemopoietic
stem cells and a minimum of immunocompetent cells,
which sharply lowers the risk of an acute secondan
syndrome.
45. Seven patients who received allogeneic bonemarrow transplant died between two and 19 days
(15-25 days after irradiation) from acute radiation
injuries to the skin, intestines and lungs.
46. Of six patients who did not suffer fatal skinburns and intestinal injuries and whose total doses
had been estimated at between 4.4 and 10.2 Gy, twosurvived allogeneic bone marrow transplants (gammaray doses of 5.6 and 8.7 Gy). Both had haplo-identicalfemale donors (sisters), rejected the partially functioning transplant (at days 32 and 35) and experienced arestoration of their own myelopoiesis, beginning at
day 28.
47. Four patients who received allogeneic bonemarrow transplantation died between 27 and 79 days
(34-91 days after irradiation) from mixed viral-bacterial
infections. Two of them had effectively functioning
HLA-identical transplants (cases 6 and 28: total
gamma-ray doses 5.2 Gy and 6.4 Gy, respectively),a n d two had early rejection (day 16 and 42) of"haplo + 1" and haplo-identical transplants, but during
times when their own myelopoiesis was restored (cases 5
and 16: gamma-ray doses 4.4 and 10.2 Gy).
48. Similarly, all the patients who received embryonicliver cell transplants died from skin and intestinal
injuries within a brief period (14-18 days after
irradiation), with the exception of one woman of
63 years (case 8, embryonic-liver cell transplant froma n 18-week male donor), who lived 30 days, having
received a dose of 8-10 Gy. At death (17 days after
transplant), numerous mitoses were discovered, against
a background of severe marrow pancytopenia, and all
the cells had a female karyotype, i.e., regeneration of
the host bone marrow had begun.
49. This experience confirms that in an emergency
situation like the one described, the group of persons
for whom bone marrow transplants would be indicatedwith a reasonable prospect of success is extremely
limited. Seven of 13 patients died as a result of skinand intestinal injuries before bone marrow engraftment could be expected. In Table A.5 a comparison is
given of survival or cause of death of patients
reiceiving bone marrow transplantations and of patientsin a control group.

C.

OTHER INJURIES AND
T H E I R TREATMENT

50. The extensive skin lesions caused by beta-radiation
represented a distinctive feature of the injuries sufferedin this emergency situa~ion. Radiation-induced skinburns in firemen and personnel from the plant wereobserved only in combination with radiation injury tohaemopoiesis and were therefore an integral part of
the general acute radiation sickness.
51. This situation may be regarded as one in which
there is an extremely non-uniform distribution of doseas a function of the depth of penetration within thebody; the skin doses are estimated to be 10-20 times
greater than the bone marrow doses. There was adefinite correlation in the severity of the injuries inboth tissues.
52. Table A.6 and Figure A.VIII show the distribution of cases involving radiation-induced skin burns ofvarious degrees in patients with acute bone marrowsyndrome of different severity. Skin injuries wereobserved in more than one half of the patients and in
virtually every patient suffering from third- or fourthdegree bone marrow syndrome.
53. The aggravating contribution ofradiation-induced
skin injuries to the overall clinical picture arose not
only from their severity. but also from the duration of
the injuries, characterized as they are by recurrencesof the pathological process. As a rule. the burns
occurred at different times on various parts of the
body. The most frequent locations during the early
period were the wrists, the face. the neck and the feet;later, lesions appeared also on the chest and back, andstill later o n the knees, hips and buttocks. Exceptions
to this sequence were encountered in individual cases.
54. The development of the injury was similar tothat described by Cronkite et al. [C16], but in a more
severe form. The diffuse hyperaemia in the first few
days (primary erythema) was followed after 3-4 days
by a period of latency. Secondary erythema in the
more severe cases developed after 5-6 days and in the
majority of patients from day 8 t o day 21. Dependingon the degree of the injury, it reached a level of dry(first-degree radiation burn) o r moist desquamation
with the development of blisters (second-degree burn),or the formation of vesicular-ulcerated and ulceratednecrotic dermatitis (third- to fourth-degree burn).
The re-epithelialization of the desquamated surfaces
continued for two or three weeks from the occurrenceof the visible injury to the skin. In six patients, thehealing of the burns over skin areas involving deep
necrosis did not begin until the end of the second
month. A characteristic feature in the time course of
the burns, and one which could be monitored throughout in this group of victims, was the appearance ofrecurrent waves of erythema, beginning by the end of
the fourth week a n d continuing up to days 45-60.
These changes were characterized by hyperaemia on
the previously unaffected skin areas o r by the increase
in clinical signs of injury a t the foci of the primarylesions then in the process of healing. For example.
late secondary erythema appeared in the area of the

50

I

I N T E R S T I T I A L PNEUMOliITISI ENTERITIS

d

I

!I

1-2 Gy2-4 GyIV
4-6 Gy6 - 1 5 Gy

DEGREES OF BOliE IlARRO'nl 5YliDRO:IE AND DOSES TC THE BONC FIARROW::i:r:eath

non-haetnopoieti~)p
J Nonsevere( f o r death haenopoietic)

Flgure A,VIiI. Frequency of deaths and non-bone marrow syndromes forvarlous degrees of bone marrow syndrome In accldent victlrns suHerlng
from acute radiation slckness.

ankles and feet, or on the hips and buttocks. of thosepatients who during the first three weeks displayed"flowering" burns on their knees. By the time of
appearance of this late erythema, the lesions that had
occurred earlier in many instances had already been
repaired. As a rule. late erythema was accompanied byoedema of the subcutaneous tissues, which wasparticularly noticeable when located on the knees:
pain was experienced in walking; palpation of the skina n d underlying tissues (muscles. tendons) caused
discomfort. The most severe cases involved fever anda general worsening of the patient's condition. Latesecondary erythema was successfully resolved within
two weeks by purely topical treatment, although in the
more severe cases it was necessary to resort toadditional therapeutic means. such as the prescriptionof glucocorticoids, a form of treatment that fairly
rapidly eliminated all manifestations of epidermatitis
a n d subcutaneous oedema, both general and local.
55. As may be seen in Table A.6. the burns sufferedby the patients with acute radiation sickness coveredfrom 1% to 100% of the body surface. I t may be noted.
in this connection, that if there were relatively early(from day 5-6) second-.or third-degree burns over an
area of even 30-40% of the body. followed by the spreadof hyperaemia, these burns were life-threatening. In
19 of the 56 patients suffering from burns, the burns
proved fatal (Figure A.VII1). I t was found that patientswith early secondary erythema over a body area ofmore

than 40% first developed a febrile-toxemic syndrome.
followed by renal-hepatic insufficiency and encephalopathic coma with cerebral oedema, resulting in deathat 1 3 3 8 days after irradiation. A causal link connecting
the fatal renal-hepatic insufficiency and the encephalopathic coma to the skin injuries is confirmed by the factthat a similar development of such fatal syndromes
was observed in several patients who had neither
severe bone marrow syndromes nor intestinal syndromes. However. in the majority of cases. burns werecombined with an extremely severe bone marrowsyndrome and severe acute enteritis. and in some cases
the burns may have been the primary cause of death.
1. Intestinal syndrome

The intestinal syndrome was one of the morethreatening manifestations of acute radiation sickness.
In 10 patients, diarrhoea was observed from day 4 today 8. This suggested that these persons had received
total gamma doses of about 10 Gy or above; all thesepatients died during the first three weeks following
irradiation. The occurrence of diarrhoea after eightdays in seven other persons was an indication thatthey had received lower doses. The presence ofradiation-induced enteritis lasting from day 10 todays 18-25 in spite of intensive water-electrolyteprotein supportive treatment suggests that the intestinal
syndrome was not the main cause of death.
56.

2.

Oropharyngeal reactions

57. Acute radiation-induced inflammation of the oral
and pharyngeal mucosa was observed in 82 patients. Its
more benign manifestations (first and second degreeof severity) were characterized by desquamation an3
oedema of the rnucosa in the area of the cheeks andtongue and by tenderness of the gums. These wereobserved in 42 persons (dose range 1.7-4.0 Gy) fromdays 8-9 to days 20-25. The basic signs of a more acuteoropharyngeal reaction were observed in 40 patientswith third and fourth degree acute radiation sickness(dose range 4.5-16.0 ~ ~ ) , ; n dthese were erosions andulcers of the oral mucosa, sharp pain, and a large
production of rubber-like mucus occasionally blocking
the throat and causing breathing problems. The firstsigns appeared as early as days -3-4, attained theirmaximum intensity by day 10 and then subsided afterdays 18-20, when there was also granulocytopenia. The
Drocess involved no selective localization. as is characteristic of the ulcerated lesions in the area of thetonsils and gums when there are infectious complications. However, in a significant number of cases, theradiation-induced inflammation of the mucous membranes was complicated by secondary microbial andviral infection, which prolonged its course.
58. Another typical finding was the early (days 3-4)
appearance of herpes-like rashes forming massive
crusts on the lips and facial skin; this was observed innearly 30% of the patients with severe bone marrowsyndrome. Within this group of patients, primarily
those suffering from fourth-degree acute radiation
sickness, a pronounced radiation-induced parotitis
was observed. coupled with an inability to salivate anda high level of amylase in the blood from days 1-4. The
swelling of the parotid glands disappeared without
special treatment, whereas recovery of salivary glandsecretion was slower.
3.

Lung reactions

59. Lung reactions were observed in seven patients
suffering from third- and fourth-degree acute radiation sickness. Its characteristic signs were a rapidly
intensifying dyspnoea together with respiratory insufficiency progressing over a period of two to threedays culminating in death. Autopsies revealed large,
blue lungs with pronounced interstitial oedema, without
destruction of the mucous membranes of the trachea
and bronchi. As a rule, interstitial pneumonitis developed several days before death, generally in combination with extremely severe lesions of the skin and theintestine. The times to death were 14-30 days after
irradiation.
4.

Causes of death

60. The frequency of non-haemopoietic injury increased as a function of total dose (Figure A.VII1).
Clinical observations indicated the essential role ofskin injuries in pathological processes prior to death.
Among the patients that died, in two thirds of them
there was extensive and severe radiation and thermalskin burns, which were considered life-threatening. In

five cases skin injuries were the sole cause of death.
because there was neither radiation enteritis or irreversible myelodepression. Deaths were observed between
10 and 96 days after exposure. The clinical picture in
all fatal cases was characterized as following a difficult
course. because in every case two or three radiation
syndromes had occurred with complex toxicity, infection and circulation disorders. A summary listing ofpatient identification and causes of death is given in
Table A.7.
61. A detailed clinico-morphological analysis madeit possible to identify the predominance, within
specified time periods, of particular lethal syndromes.
Up to day 24, a total of 19 patients (65%) died. In one
half of these patients the competing causes of death
were skin and intestinal reactions (cases 3, 4, 10, 14,
15, 17. 20, 23, 26. 2097: in all the cases the gammaradiation dose in the bone marrow was estimated to
be greater than 10 Gy). Four patients showed acuteradiation injury in the lung (cases 2, 9, 12 and 27; thedoses were, respectively. 9.2, 9.7, 9.3 and 8.3 Gy), and,of these, two (cases 2 and 9) suffered also severe
injuries to the skin. Two patients died of combined
thermo-radiation burns (cases 24 and 25: the gammaradiation doses in the bone marrow were estimated tobe 3.7 and 5.7 Gy, respectively. in combination withinternal irradiation doses. Within this time-frame, onepatient (case 62, dose about 6 Gy) died almost
exclusively from severe radiation burns at a time whenhaemopoiesis had begun to be restored. Three cases(cases 17, 26, 62) had involvement of mycobacterial
sepsis. One patient (case 30, dose about 5.5 Gy) diedof bleeding caused by mechanical injury to the subclavicular vein during catheterization. and another(case 7. dose about 4.7 Gy), suffering from severe radiation injury to the skin, died of post-transfusion shock.
Characteristics of the deaths on days 11-34were marked
circulatory problems during the terminal period. Thiswas shown by the relatively high frequency of signs
indicating cerebral oedema and focal haemorrhaging
into the brain and spinal cord.
62. Six patients died during the period fromdays 25-48. All six cases were characterized byextremely severe complications of a toxic or infectious
nature. Two patients (cases 31 and 34) involved subtotal skin injuries (bone marrow doses about 6.7 and
5.8 Gy, respectively, with death occurring on days 32
and 48, respectively), coupled with practically restored
haemopoiesis. The immediate cause of death in thesecases was severe respiratory insufficiency and cerebral
oederna. In one patient (case 28, dose about 6.4 Gy;
death on day 48) the cause of death was severe, graftversus-host disease and fungal and viral infections.
One additional patient (case 5. dose about 4.4 Gy)
died on day 34 of severe pulmonary and renal
insufficiency, caused, most likely, by the transplantation of HLA-non-identical bone marrow and by posttransplant immunosuppression using cyclosporin andmethotrexate. Two patients (cases 1 and 8. doses
about 6.6 and 8.3 Gy) died on days 25 and 30.
respectively, with symptoms of severe toxicity andpulmonary insufficiency. In nearly all six cases there
were marked circulatory disorders in the lungs,
intestines, brain and myocardium.

63. At a relatively late stage. days 86-96. threepatients died. One patient (case 6, dose about 7.5 Gy)
died on day 56 of graft-versus-host disease complicatedby cytomegalovirus (CMV) infection. Cytomegalovirus
infection was also the cause of death for another
patient (case 16. dose about 10.1 Gy) on day 91. A
female patient (case 33. dose about 4.1 Gy) died onday 96 displaying marked disruptions of cerebral
blood circulation against a background of renalhepatic insufficiency and foci of mycococcal infection(pneumonia). This patient suffered also skin injuries
from beta-radiation which extended over one third ofher skin surface and underwent a severe recurrent
wave of erythema with oedema of the subcutaneous
tissue.
5.

Eye damage

64. Eye injuries were characterized by the early andsubsequent involvement of all eye tissues in thepathological process (Table A.8). In this group ofpatients. damage to the skin and eyelid conjunctiva
was caused, to a considerable degree. by betaradiation.
65. At doses not exceeding 1 Gy there were no visible
alterations in the structure of the eyes. In the case ofpatients suffering from first-degree acute radiation
sickness, changes were noted only in the front segmentof the eye: there was in individual cases a slighterythema in eyelid skin during the first two to four days
and an intensification of the vascular pattern in the lid
and conjunctiva of the eyeball. In 40% and 100% of
the patients suffering from second- and third-degree
acute radiation sickness, respectively. the eyelid skinshowed a first wave of of erythema within 6-12 hoursof irradiation. and within 2-3 weeks there was asecond wave. These cutaneous alterations disappeared
without trace, leaving'hyperpigmentation and scaling.
In all patients suffering from fourth-degree acuteradiation sickness, the times to the appearance of thefirst and second wave of erythema were 1-2 hours and8- 10 days, respectively.
66. Microscopy of the bulbar conjunctiva revealed anumber of alterations in the microcirculation: there
was a dilation of the venules and capillaries (morerarely the arterioles), and an increase in the number offunctioning vessels coupled with a reduced blood flow.
67. Two patients suffering from combined radiationand thermal second-degree lesions on the lid skin andconjunctiva experienced ulcerations on the skin aroundthe eye that did not re-epithelialize for a long time.
Epilation of the eyebrows was noted at days 15-17 in
16% of the persons with second-degree acute radiation
sickness. and in 67% and 100% of those with thirdand fourth-degree acute radiation sickness, respectively.
The epilation was partial and transient. Hair growthon the head was fully restored. All patients retained
their eyelashes.
68. Corneal damage was manifested in an early
reduction in corneal sensitivity coinciding with thefirst wave of erythema. although first-degree patients

did not show such an effect. At later times (days 35-55).
superficial radiation-induced keratitis was observed inpatients suffering from second-. third- and fourthdegree radiation sickness in 5%. 5257 and 100% of thecases. respectively. Also noted were focal defects on the
superficial epithelium of the cornea; these defects, which
often merged. stained with fluorescein. The radiation
keratitis regressed over a period of 1- 1.5 months, leaving
no opacification of the cornea.
69. Signs of disturbances in the haemodynamics of theretina were related to the dose and the degree of setverityof radiation sickness. From a few days after irradiation,a reduction was observed in the level of diastolicpressure in the central retinal artery. followed later bysigns of hypotonic angiopathy of the retina. Coinciding
in time with the peak of the sickness. other injuries
appeared. e.g.. retinal oedema along the vessels andincreased permeability of the retinal vessels (plasma
discharge and haemorrhaging). The low diastolicpressure in the central retinal artery persisted over theentire acute phase.
70. In one severely ill patient (case 29. dose about
8.7 Gy) with fourth-degree acute radiation sickness.
who survived the acute phase. the symptoms ofangioretinopathy with haemorrhaging and plasma
discharge recurred within 4.5 months, accompanied bya persistently low diastolic pressure in the central
retinal artery (up to 5-10 mm Hg).
71. In the acute period, the treatment consisted in
the topical application of ointments to the scaling
surface of the eyelid skin and the instillation of 20%
albucid, sophradex and vitamin solutions as eyedrops
into the conjunctival cavity.
72. Within observation periods of up to one year, no
obvious radiation-induced alterations of the lens werenoted.

6.

Treatment of radiation burns and other injuries

73. The treatment of radiation burns and other nonbone-marrow syndromes and their complications posedcomplex and multifaceted problems [J18]. From day 2
through day 8. 15 haemosorption sessions (purification
using activated charcoal) were conducted for 13 patients
suffering from the most severe skin lesions. Threepatients who had been exposed to a total dose rangeof 2.0-4.6 Gy survived: they underwent haemosorption
on a single occasion at days 5-8. i-e.. considerably
later than the time at which this might have affected
the treatment of the bone marrow syndrome. Thismethod of treatment did not change the outcome of
the illness by modifying the haemocytopenia.

74. During the haemosorption process, and particularly towards the end of the session. many patients
experienced a short-term improvement (lasting from a
few hours to a single day), a reduction or disappearance of the pain in the extremities, and also adecrease of the oedema in their tissues. In thisconnection, contributory effects from the medicationaccompanying the procedurecannot be totally excluded.

75. A more widely used technique to combat thedevelopment of renal-hepatic insufficiency and fatal
encephalopathic coma was plasmapheresis. Lesions
induced by beta-irradiation over 30-40% and more of
the body surface served as an indication for theapplication of this procedure. Plasmapheresis sessions
were conducted for 17 patients from days 18-37. For anumber of patients, daily sessions were conducted, up
to six times.

76. The positive effect of repeated plasmapheresis
was shown by a reduction of bilirubinemia andtransaminasemia and a lowering of the nitrate level inpatients suffering from renal-hepatic insufficiency
caused by skin burns. On occasion, the plasmapheresis
sessions uere accompanied by reactions of minor
severity such as chills and fever; there were no fatal
complications. Another method used to treat toxicosis
due to skin injuries was the injection of 1,000 ml offreshly-frozen plasma, accompanied by round-theclock administration of heparin (1,000 active units/hour) with a liquid load (2-6 litres/day) and forced
diuresis adequate to the intake volume. A precondition for this treatment was the presumption ofdisseminated intravascular clotting (DIC) syndrome(no typical anomalies in respect of coagulation were
present) as a possible cause of encephalopathy andrenal-hepatic syndrome. In its most strictly appliedform, the heparin treatment method was used withtwo patients over a period of 7-15 days. The impression was that these patients survived longer than didpatients whose condition was s ~ m i l a r in terms ofseverity and extent of their burns. Their renal-hepatic
insufficiency was less pronounced; however, a death
due to encephalopathic coma was not averted.
77. The topical treatment of the burns required the
involvement of a group of surgeons and nurses. A
broad range of preparations and agents having ananti-inflammatory, bacteriostatic and regenerationstimulating effect was used. Good results were achieved
with lioxanol aerosol, an anti-burn ointment based onhydrocortisone with locally acting antibiotics, as well
as BALIZ-2 solution and collagenous coatings. In
each individual case the treatment varied in accordancewith the stage of the lesions. Experience gained in theuse of bactericidal fabric, both as a dressing materiala n d for supplementary bedding, for patients withextensive burns deserves a particularly favourable
comment in this connection [Z2].
78. Treatment of pain. as is typical of radiation
injuries, was rather ineffective. At present. there areclearly no suitably effective local anaesthetics.

79. In patients suffering from severe radiation-induced
inflammation of the oral mucosa, and enteritis, total
parenteral nutrition had a positive effect: this was
based on alvesin hydrolysate or an aminoacid mixture.
aminone and a 40% glucose solution as the energy
material. The treatment was carried out according to
the principles and rules described by Dudrick et al.
[D18]. This method was tested over a number of years
with good results in patients receiving whole-bodytherapeutic gamma-irradiation at a dose level of
10 Gy for allogeneic bone marrow transplantation.

The danger, which has possibly not been fully
evaluated, is the probability that certain severely
injured, comatose patients may enter a state of
hyperosmolarity. Data on plasma osmolarity thatwould appear to be necessary in a programme of total
parenteral nutrition were not provided for all patients.
80. For the majority of patients suffering from firstand second-degree bone marrow syndrome, the periodof clinical convalescence was con~pletedby the thirdor fourth month. A longer period of treatment was
required by persons suffering from severe radiation
burns and the sequelae of third- and fourth-degreebone marrow syndrome. A1 the present time, the bulkof the patients have resumed work with the exclusionof any contact with radiation sources.
81. O w r the period from the fourth month t o one
year after the accident. the specialized treatment
centre was periodically visited by patients with skinlesions (dystrophic a n d ulcerated areas and alsooedema of the subcutaneous tissues, mainly o n theknees and feet). These patients are being treated withagents designed t o improve local blood circulationand tissue trophism. Five patients ~vith deep andextensive ulcers o n their arms and other areas of the
body underwent repeated plastic surgery. and anumber of them will require more extended treatment.
82. Immunological examination data, acquired
0.5-1.5 years after the accident, haire shown that in the
peripheral blood of the patient groups with a historyof acute radiation sickness of the second, third a n dfourth degrees a decline was observed in the numberof T-lymphocytes with helper activity along with anincrease in the number of T-lymphocytes with suppressor activity. This led to a considerable reductionin the normal ratio between these immunoregulatory
lymphocyte sub-populations. At the same time, there
was no reduction in the general lymphocyte level o r intheir T- and B-sub-populations. As an average for thegroups, the level of class A, M and G immunoglobulins
in the patients' blood serum corresponded to thephysiological norm. Similar changes ivere not observedin the case of patients with a history of acute radiation
sickness of the first degree. During this time theyexperienced no severe o r life-threatening infections. In
a number of cases an effort \vas made at immunocorrective therapy using T- and B-activin.
83. Within these same patient groups. an estimate of
the number of respiratory illnesses over the same
period of time was conducted retrospectively. It was
found that the incidence of illness in the group of
19 patients with a history of first-degree acute radiation
sickness did not differ from the incidence of illness forthe group of persons for whom no acute radiation
sickness diagnosis had been established, and that it
averaged 0.3 cases per person per year. During thesame period, this indicator approached I for 22 patients
who had experienced second-degree acute radiation
sickness, and 3 for 8 persons with a history of third- tofourth-degree acute radiation sickness.

84. This comparison underlines the importance of
the immune system in maintaining anti-infection

resistance in radiation convalescents and raises thequestion as to the usefulness of conducting supportive
immunomodulating therapy courses, long after theincident, for persons who have undergone severe
forms of radiation sickness.
85. The experience of the specialized treatment
centres in Moscow and Kiev in the organization of
medical care of persons exposed in this nuclear reactor
accident has been described [N16]. For the surki vors.
a plan of scheduled follow-up observation is in effect,a n d decisions as how best to arrange their living andworking condirions are being taken.

D. CONCLUSIONS
86. The analytical data presented in this Appendix
and derived from clinical observations of the victimsof the accident at the Chernobyl nuclear power plant
are in agreement with the data in Annex G .

87. However. the fact that such a large group of
115 patients, who had all received uniform wholebody irradiation. was treated simultaneously for acuteradiation sickness of varying degrees of severity,
represents a unique event that makes i t possible toclarify numerous aspects of earl? effects in man. A
complicating factor was the presence of severe andextensive beta-radiation skin injuries in 58 patients
which aggravated the course of the sickness in 19 of
the 28 who died. Two more patients died during thefirst days as a result of severe combined injuries(trauma plus thermal burns plus irradiation).

88. The analysis provides a basis for describing theprincipal clinical syndrome, the bone marrow syndrome.
with various degrees of severity in all 115 patients. In
the case of some of them the bone marrow syndrome
was combined with intestinal and oropharyngeal
injuries and radiation damage to the skin, the foreward segment of the eye (keratitis), and the lungs.
89. The treatment provided was in accordance withinternational practice and proved highly effective forthe patient group exposed to doses of 2-3 Gy and for
two thirds of the patients who received doses of
4-6 Gy. In the group of patients receiving 6-16 Gy.
two patients who received doses of 8-9 Gy survived
past 60 days.
90. The average bone marrow dose and the prognosis
regarding the further course of the illness were
determined on the basis of biological criteria. During
the early period, most information was obtained fromthe karyological analyses, the lymphocyte counts andthe primary reaction periods; later, from the granulocyte
counts. The remaining indications were of an auxiliary
nature. In three cases, the dose value coincided withthe electron spin resonance study of dental enamel
after death.
91. There is a need for further analysis of the timecourse of the early effects for a more accurate
understanding of the nature of lung and neurologicalinjuries, and for more detailed data on the relevanceof biological dose indicators and the reasons for
disparities between them. I t is hoped that these data
will be of use in the preparedness to respond in theevent of an accident of a similar type in the provisionof medical treatment.

T a b l e

A.l

Thyrold doses received by exposed persons

Range ofthyrold
doses

Numberofpersons(Sv)

T a b l e

A.2

Ooses of vlctlrns recelvlnq hlqher Internal exDosuresCase
numberThyrold
dose
a/
(Cy)

Lung
dose
a/

Whole-body dose (Sv)

(Cy)

Internal

Externala/ Ooses accumulated until tlme of death.

T a b l e

A.3

Dlstrlbutlon of patlents with acute radlatlon sickness
treated at the spectallzed treatment c e n t r e

Degree ofseverlty

Number ofpatlents

Bone marrowdose range( GY)

Number ofdeathsTime t o death(days)

a/ In addltlon to t h e patlents w h o dled of acute radlatlon slckness, one
person died at t h e plant slte and another wlthln t h e flrst 1 2 hours
followlng t h e accldent. as a result of thermal burns. at t h e In-patlent
cllnlc ln Prlpyat where he had been glven flrst ald.

T a b l e

A.4

Assessment of lrreverslble mvelodepresslon
accordlnq to diaqnostlc scores
In cases of acute radlatlon slckness
Slgn

Time to the onset of vomttlng

Lymphocyte count on the second day

Olagnostlc
score a/(hours)(109/1)

Lymphocyte count on the thlrd day(109/1)

Lymphocyte count on the fourth day(109/1)

Lymphocyte count from day 4 to day 7 (109/1)

Average retlculocyte countfrom day 3 to day 5(lo9/l)Hlnlmum neutrophll countfor d a y b to day 7(l09/l)0.00- 0.4
0.41- 0.8
0.81- 1.2
1.21- 1.bl.bl- 2.0
> 2.010.00- 0.2
0.21- 0.4
0.41- 0.6
0.61- 0.8
> 0.610.00- 0.1
0.11- 0.2
0.21- 0.3
0.31- 0.4
> 0.410.00- 0.1
0.11- 0.2
0.21- 0.3
0.31- 0.7
0.11- 0.8
0.81- 0.9
0.00- 0.1
0.11- 0.2
0.21- 0.3
0.31- 0.4
0.41- 0.5
> 0.51
0.0 - 8.0
0.1 -10.0
10.1 -14.0
14.1 -18.0
18.1 -20.0
0.00- 0.3
0.31- 0.6
0.61- 0.9
0.91- 1.2
1.21- 2.4
2.41- 3.0

8
4
+ 2
- 2
- b
-10
+

+

+ b

+ 2

- 2
- 8
-15
+ 8
+ 2
- 2
- 9
-10
+ 4
+ 2

0
- 2
- 3
- 8
+ 5
+ 2
1

- 5

-13
-15
+ 2
0
-4
- 6
-10
+12
+ 5
0
-3
- 6
- 8

a/ The dlagnostlc slgns are used to determine the dlagnostlc Scores, uhlch arethen added together. A sum of +10 I s the basls for a prognosls of
lrreverslble myelodepresslon; a sum of -10 for a prognosls of nolrreverslble myelodepresslon. If after the dlagnostlc coefflclents of all
the avallable slgns have been added no postttve value has been reached, theanswer i s lndetermlnate (the avatlable lnformatlon Is lnsufflclent for adlfferentlal dlagnosls, wlth an error probablllty of not more than t 10%).

T a b l e

A.5

Survival or cause of death o f patlents receivlnq bone marrow transplantat\ons
and of patlents In control q r o u D

Bone marrow transplant patlents
Dose
range

NumberDeathsControl patlents(Gy)patlentsa/b/survlvors

patlentsa/

Numberofsurvivors

Total

13

7

4

2

14

8

6

0f

- ---- - - - - -NumberNumber0f

0fDeathsa/ Skin and intestinal injuries.
b/ Bone marrow rejectlon (graft-versus-host dlsease) plus Infection.
PosltIve graft-versus-host disease post-mortem histology.

g/

T a b l e

A.6

DlstrlbutIon of cases of radlatlon burns of different deqree
In the Dresence of acute botle marrow syndrome

Degree ofseverltyof bonemarrowsyndrome

Total

Total
number ofpatients

Number of patients w i t h radlatlon burns
t o v a r i o ~ s percentages of t h e body surface
0-1 OX115

10-SOX

56

50-100%T a b l e

A.7

Patlent Identiflcatlon, estimated dose. cause and day of death

Degree ofseverity
of
ARS

Case
numberTreatment

Day o f
death

a/

b/

(GY)

II I

.

a/
-

Bone
marrow
dose

5

4.4

7
24
25
28
30

4.7
3.7
5.7
6.4
5.5

34

5.8

1
2
3
4
6
8
9
10
12
14
15
16
17
20
23
26
27
31

6.6
9.2
12
11.8
7.5
8.3
9.7
11.1
9.3
10.9
>10
10.1
10
12.4
13.7
12.5
8.3
6.7

62
2097
(Klev)

6.1
10.2

Cause of death96

Infectlon, renal-hepatic lnsufflclency
and skln lnjurles

BUT

34

BUT
BHT

18
23
16
48
21

Infectlon. post-transplantatlon
lmnunosuppresslon
Skln lnjurles, post-transfusion shock
Thermal and radlatlon burns
Thermal and radlatlon burns
Infection, graft-versus-host dlsease
Bleeding from mechanical Injury durlng
catheterlzatlon
Respiratory lnsufftclency, cerebral
oedema

48
BUT
BUT
BUT
BUT
BUT
LCT
LCT
LCT
LC1
BUT
BUT
LCT
LCT
BUT

Toxicity. resplratory lnsufflclency
Skln and lung lnjurles
Skln and intestinal Injuries
Skln and lntestlnal lnjurles
Infection. graft-versus-host dlsease
Toxlclty. resplratory lnsufflclency
Skln and lung lnjurles
Skln and lntestlnal lnjuries
Lung injuries
Skln and lntestlnal lnjurles
Skln and lntestlnal Injuries
Infectlon. graft-versus-host dlsease
Skln and lntestlnal lnjurles
Skln and lntestlnal lnjurles
Skln and Intestinal lnjurles
Skln and lntestlnal lnjurles
Lunglnjurles
Respiratory lnsufflclency.
cerebral oedema
Radlatlon burns (skln lnjurles)
Sktn and lntestlnal lnjurles

25
15
17
18
86
30
23
14
24
18
14
91
18
17
15
20
24
32
21
10

BHT = bone marrow transplantatlon; LC1 = llver cell transplantatlon.

T a b l e

A.8

Type of eye changes and per cent Incidence
In t h e vlctlms of the accldent

Degree of acute radlatlon slckness
Nature of the changes

Flrst wave of erythemaSecond uave of erythema
Reductlon In cornea sensltlvlty
Epllatlon of t h e eyebrowsKeratltls
FundusDllatlon of blood vessels
Decreased dlastollc pressureof the central retlnal artery
Retlnal oedema
Haemorrhaglng
Plasmorrhaglng

6.1

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