REPORT OF THE

UNITED-NAXI-ONS .

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EFFECTS OF !iit}ifffHiADIATION.. : . . .

·'GENERAL ASSEMBLY
OFFICIAL RECORDS : SEVENTEENTH SESSIONSUPPLEMENT No. 16 {A/5216}

New York, 1962

NOTE
Throughout the present report and the annexes thereto, references to theannexes are indicated by a letter followed by a number: the letter denotes the relevant
annex and the number the paragraph therein. Within each annex, references to its
scientific bibliography are indicated by numbers.
Symbols of United Nations documents are composed of capital letters combined with figures. Mention of such a symbol indicates a reference to a United
Nations document.

h we ut··m,.

SOMATIC EFFECTS OF RADIATIONCONTENTS
ParlS{JraN.s

ParlS{JrapJu!. PHYSICAL FACTORS INFLUENCING SOMATIC EFFECTS 1-18
1-2
Introduction ........•.....•••.......••.••..••
Definitions ...•....••••..•....•......••••.••.• 3-9
4
Short-term exposure ..........•.....••...•.
5Long-term exposure •.••..•...•......•..••.•
Cumulative dose ......••••..•.......•.•..•• 6-7
Consequences of exposure •....•.....•.....••• 8-9
10Type of radiation ....•...•.......•.......•..••
11
Time distribution of dose ..................... .
12
Early effects •...••••..•..••.....•••..••.•....
Late effects .•...•......•.•.•..•••••...•...••. 13-14
15
Anoxia ..................................... .
16
Temperature .•.•..•••••••.••.•••••.•••••.••.•Nature of radiation injury ................... .. 17-18
18
Chromosome damage •.••.....•.•.••.•.....•

Partial-body exposures .. . . . . .. . . . . . . . . • . . 130
Role of genetic constitution and physicalstatus •...•...••..•.....•............•• 131-138
Life-lengthening •••.•....................
139
Nature of the lesion in life-shortening ..... . 140
Radiation carcinogenesis .••.•.....•.••.••... 141-165
Relation to rate of mitosis ............... .
145
Relation to age .....•....•...•..•.•.•.•.• 146
Relation, to radiation dose ............... . 147
Mechanisms of carcinogenesis .•.•......... 148-150
Somatic mutation theory ................. . 151-153
Chromosomal changes and carcinogenesis •. 154-158
Radiation leukaemogenesis •.•...•..•••••.. 159-163
Vrrus theory •....•..............•.•..•..• 164
Risk of carcinogenesis from low doses ..•••• 165
Recovery and the concept of irreparable injury .. 166-169
Early and late effects on embryos and foetuses •. 170-192
The mammalian embryo ................•... 170-180
The human embryo ...•...•.....•.........• 181-185
Recovery and protection in irradiated germ
cells and embryos ........................ 186-192

I!. LETHAL AND LESSER DAMAGE IN CELLS, TISSUES,ORGANS, NEOPLASMS, AND ORGANISMS ••••••••••••

Introduction ..•••...••.•...•.......•.....•...
End-points .•...•..•....••..•....•.••.•..••...
Death of cells as end-point. ................. .
(a) Law of Bergonie and Tribondeau •.•...
( b) Radio-sensitivity of cells in the adultmammal .........................•••(c) Radio-sensitivity of tissue in the adultmammal ..••••......•.•..••.....•...
Age and radio-sensitivity ..................... .
Mammalian cell survival curves ..•...........
Radio-sensitivity of malignant tumours ...•...•.
Factors influencing radio-sensitivity •..•........
LD.. values for mammals ................... .
LD,.and age .•..•••••••....••.•..••......••.
LD,. in man .....••...•..•••.....•••.•...•••LD.. and dose-rate ...••••.....•.•...•••.....
Radio-sensitivity •••.•.••.••.•...••••..•.••••.

19-47
19
20-24
22-24
22

IV. ACUTE RADIATION INJU11.Y IN MAN •••••••••••••• 193-231
Acute radiation syndrome ..............•..... 193-206
Sources of information .................... . 194
Total body response ....................... . 195
Radiation sickness •...•..•...••.•...•.•••.•• 196-197
General clinical picture .................... . 198
CNS form ••..••••.••.••....•••.•.••••..•• 199
Gastro-intestinal form •....•..•..••.•.••..•. 200-201
Haematopoietic form ..................... .. 202
Prognosis •..•....•.••..••..••..••••••...••• 203-204
Prognostic value of the leukocyte count ....•• 205-206
Analysis of past accidents ................... . 207-229
First and second Los Alamos accidents ••.•.. 208-213
Argonne accident ........•.........•..•.... 214
USSR accident ........................... . 215
Oak Ridge accident ................•.•..... 216
Yugoslavian accident ...................... . 217-220
Third Los Alamos accident .......•.....•... 221-223
Lockport accident ............•..•....•..... 224-229
Assessment of injury ........................ . 230-231

23
24
25-28
26-28
29-34
35-46
36-40
41-42
43-45
46
47

Ill. SoMATIC RADIATION INJU11.Y AND ITS REPAIR, PAR·
48-191
Modes of death with TBR ......•....•..•...... 48-54
Partial body irradiation .................... . 51-54
Early and late organ effects ................... . 55-112, B~ood .and blood-forming organs •.........•. 55-60
D1gesbve tract ........•..•......••...••.•.. 61-64
Reproductive organs ....................... . 65-87
Male animals ..........•.......•....•.•... 66-75:r.,,fan ................................... .
76
Female animals •••••........••.•••......•. 77-81
Sexually immature animals •.....•......... 82-87
Nervous system ..........•...••....•.....•• 88-90
Eye ..............•............•........... 91-93
Liver ..................................... . 94-95
Kidney ................................... . 96-97
Circulatory system ........................ . 98-99
Endocrines ................•.......•....... 100-101
Skin ..........•............................ 102-108
Bone ........•............................. 109-112
Late effects ................................. . 113-164
Life-shortening .••.•........................ 113-140
Introduction .....•....................... 113-121
Liie-shortening by single doses in animals .. 122-126
Life-shortening by multiple doses or protracted irradiation in animals ...•........ 127-128
Age effects •..........••...••.......•.... 129
TICULARLY IN MAMl!Al.S . . . . . . . . . . . . . . . . . . . . . . .

V. LATE EFFECTS OF IRRADIATIOS IN MAN, INCLUDINGCARCINOGENESIS • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 232-327
Life-shortening . . • . . . . . . . . . . . . . . . . . . . • . • . . . . . • 232-239
Effect of long-term radiation on life-span inman •...................................• 232-239
Carcinogenesis in man . . . . . . • . . . . . . . . . . . . . . . . . 240-286
Leukaemogcncsis •...•............••...••... 241-286
Situations in which a relationship between
radiation and leukaemia has been established ......................••..•...... 241-244
Situations in which a relationship between
radiation and leukaemia has been suspected but not established .............. 245-247
Leukaemia in the Japanese survivors of theatom bomb ............................. 248-253
Leukaemia in ankylosing spondylitis . . . . . . . . 254-262
Leukaemia in children . . . . . . . . . . . . . . . . . . . . 263-273
Leukaemia in radiologists . • . • . . . . . . . . . . . . . 274-276
Pelvic irradiation and leukaemia in children .....••...•..............•••.•..•.. 277-286

118

CONTENTS (continued)
Paragraphs

Parograp/ss

V. LATE EFFECTS OF IRRADIATION IN MAN, INCLUDINGCARCINOGENESIS ( contiimcd)
Malignant neoplasms in the Japanese survivorsof the atomic bomb ........................ 287-288
Local effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . • • 289-327
Radiation cataract . . • . . . . . . . • . . . . . • . . . . . . . . . 289-307
Radiation effects on fertility . . . . . . • . . . . . . . . . 308-310
Sterility doses for men and women .......•.. 311-315
Degenerative diseases and histopathologicalchanges ..•.............................•. 316-323
Effects on growth and development . • . . . . . . . . 324-327

Lanthanide and actinide rare earths (including
yttrium) ................................. 392-396
Caesium-137 .•.............•.......•....... 397-401
Iodine-131 .........................•....... 402-404
VII. DOSE-EFFECT RELATIONSHIPS ..............••... 405-491
Early effects ......••..........•....•......... 405-442
Immediate.. • . . . . . . . . .• . . . • . • • . . . . . • . . . . . . . 405
Early death ...•.•.•..•.•.•...............•• 406-407
Body weight loss and organ atrophy .•.•...... 408-412
External irradiation • . . . . . . . . . .. .. . . . . • . . • 411
Internally-deposited radio-isotopes ...... : . 412
Intestinal atrophy ....•..................... 413-416
The atrophy of spleen and thymus .......... 417-421
External irradiation . . . . .. . . . . . . . . . . . . . . • • 418
Internally-deposited radio-isotopes ..••..•. 419-421
Testicular atrophy ....... ."................. 422-425
Lymphatic tissue • . . . . • • • .. • . • • • • . • . . . . . . . • . 426
Depression of mitotic activity .•.•....•..... 427-433
Depression of iron uptake by erythrocytes anderythrocyte-forming tissues . . • • . . • . • . • . . • • 434
Quantitative studies ..•...•.•••••..•...... 435-439
Suppression of immunological mechanism • . . . 440
Leukaemia transplantation ••.•••.....•...... 441-442
Late effects • . • . . . • . . . • . . . . . . • • . . . • . . . . • . . • . . . 443-490
Induction of lens opacity • . . . . . . . . . . • . • . . . . . . 443-455:Methods ..••.......•............•........ 445-446· Human studies .......................... 447-451
Experimental studies . . . . . . • . . . • . . . . • . • . . • 452
RBE • . . . . . . . • . . . . . . . . . . . . . . . • . . . • • . . . . . . 453-454
Dose-effect correlation . .. • . .. . . .. . . . .. . .. . 455
Shortening of life-span .••••.•..••.....•••• 456-470
Induction of tumours •.•..•................. 471-490
Quantitative studies •......•..•...••.....• 477-4i9Radiation-induced leukaemia in man ..••..• 480-482
The Hiroshima and Nagasaki surveys ...... 483-484
Children irradiated for thymus enlargement................................... 485
X-ray treated ankylosing spondylitis ......•. 486-489
Concept of threshold . . . . . . . . . . • • . . • . . . • . . . 490
VIII. PROI'ECTION AND MODIFICATION OF RADIATION
INJURY .....•..•. , ....•....•.••.••.•••••....• 491-527
Introduction . • . . • . . . • • . . . . . • • • • • . • • . • • . . • • . • • 491
Protective agents ............................ 492-524
Anoxia . • . . . . . . . . . . . . . . . . . . . . . . . . • . • . . . . . . . 492-493
Protective chemicals . • . . . . . . . . . . . . . . . . . . . . . 494-503
Modifying treatments • • . . . . . . . • . . . . . . . . . . . . 504-524
Internal decontamination . • • • . • . . • • • • . . • . . . • • . 525
Treatment of acute radiation syndrome • . . . . . • • 526-527
SUMMARY . . • . • . . . . . . . . . • . • . . • • • • • • . . • . . . . . • . . . 528-539
TABLES

Vl. SPECIAL FEATURES OF INTERNAL AND EX~"IAL
CONTAMINATION •.....•.•..•...•....••...•• , .. 328-402
Physical consideration . . • . . . . . . . • . . • . . • . . . . . . • 328-333
Special problems associated with internal emitters 334-347
Localization of radiation • . . . . . • . . . . . . . . • • • • • 334-335
Concept of RBE .. . • . . . . . . . . . . . . . . . . . • • • . • 336-337
Modes of entry of radio-isotopes into animals
and man . . • . . . . . . • • . . . . . . . • . . • . . . . . . . . . . . 338-347
Ingestion . • . . • • • • • • . • • . . . . . . . • . . . . . • . . . . • 339-342
Inhalation . . . • . . . • . . . . . . . . . . . • . . . . . . . • . • . 343-346(a) Size of inhaled particles............ 344( b) Radio-activity of inhaled particles. . .
345( c) Solubility of inhaled particles. . . • . • . 346
Skin absorption . . • • • . . . . • .. . . .. . . . . • . • .. . 347
Effects of radio-isotopes after absorption ......• 348-382
Early effects •........•...........•.....•.. 349-350
Late effects ........•...•................... 351-382
Effects of internal emitters on the lung,including cancer of the lung . . . • . . . . • • . . 352-365
Long-term effects of internal emitters inanimals . . . . • . . . . . . • . . . . . . • • • • . . . • . . . . 354-355
Effects of internal emitters on the lung inanimals . . . . . . • . . . . . . . . . . • . . . . . . • • . . • . 356-364
Effects of internal emitters on bone ..••.•.• 365-380(a) Histological damage in bone ........ 365-367(b) Histogenesis of bone tumours ...... 368-370(c) Relationship between the pattern ofradiation dose in space and time, histological bone damage, and bonetumour induction .................. 371-372(d) Accumulated radiation dose to the site 373-377(e) Radiation dose-rate to the site •.•..• 378-380
Dose and dose-rate in carcinogenesis byinternal emitters ........................ 381-382
Internal emitters and leukaemia . . . . . . . . • . 383
Internal emitters and life-shortening . . • . . . 384
Metabolic characteristics of particular isotopes . • 385-404
Alkaline earths (calcium, strontium, barium,
radium) •.•.•••.••...........•.......•..• 385-391
Radiurn-226 . . . • . . . . • • • . . . . . . . . . . . . . . . . . . . 386-387
Strontium-90 ................•........... 388-391

REFERENCES

The inhomogeneity of dose in man, particularly after
accidental exposure, raises an important practical difficulty in assessing e.'Cposure in man : one can ascribe nosingle meaningful value for the dose delivered.

I. Physical factors influencing somatic effects
INTRODUCTION

1. The present anne.x summarizes lmowledge of thebiological effects of ionizing radiations on animals andman; the object is to assess the effect of radiation on theindividual.

DEFINITIONS

3. To facilitate prospective and retrospective classification and study, definitions used by the United States
National Academy of Sciences-National ResearchCouncil Sub-committee on Hematologic Effects ( 1961) 1
are recommended. Some terms cannot be defined precisely. Others, because of ambiguity, e.g. "acute" and"chronic", are best avoided in describing e.'Cposure andeffects and reserved for use in their usual medical sense.

2. The principal physical factors determining thebiological effects of ionizing radiation are the absorbed
dose (rad), its distribution in time (instantaneous doserate, fractionation, short-term or long-term e."<posure),
its spatial distribution (anatomical region, fraction of
total body, organ depth, distribution, etc.) and the qualityof radiation (energy: a-,{3-,y-, X-rays, neutrons, etc.)119Short-term exposure
4. Short-term exposure includes: (a) total or substantial body exposure to radiation over a short time(e.g. in nuclear warfare from direct exposure to initialradiation from the detonation of nuclear weapons andnuclear reactor or accelerator accidents), and ( b) exposure of limited yet substantial body areas in which theradiation is given either as a single dose or fractionatedover a few days or weeks (e.g., in therapeutic radiation,
diagnostic radiology, or tracer or therapeutic use ofradio-active isotopes). A dose > 50 rad is defined, forthe purposes of the present report, as a high dose, < 50
rad as a low dose.

there are possible differences at the microscopic level;
but superimposed on this uniformity they may have a
different relative biological effectiveness ( RBE), e.g.
densely ionizing particles (a rays, neutrons) are more
efficient in producing most forms of cellular damage
than y- and X-rays giving lower ion densities. The RBE
quoted for a particular kind of radiation depends on thespecific biological effect observed, the tissue irradiated,dose, and rate at which it is given. Annex B details theconcept of RBE; difficulties in its application to internal
emitters are described in section VI of the present annex.
TIME DISTRIBUTION OF DOSE

11. A dose which is lethal if given in a short time
may, if spread over a long time, produce effects difficult
to relate to the exposure or. especially when recovery
intenrenes, to detect at all. This poses the key questionin assessing somatic effects in man : what are the effectsof low doses, single or long-term?

Long-term exposure
5. Long-term e..xposure refers to continued or repeated exposure to radiation over months or years. Such
exposure is greatest in certain occupations and in persons
containing radio-active isotopes with relatively longeffective half-lives. X-ray examinations repeated frequently over a long time also constitute long-term exposure, as do exposures to cosmic radiation, naturallyoccurring radio-active isotopes, and fall-out.

EARLY EFFECTS

12. The early effects in man of large doses are fairly
clearly known from the therapeutic use of X-rays andof radio-nuclides such as Ra226 (used in teletherapy)
and I1 31, from atomic energy workers in nuclear accidents and from clinical studies on atom-bomb survivors.
The acute radiation syndrome is detailed in section IV
below.

Cumulative dose
6. Although the total dose of radiation is important inlong-term exposure, it is sometimes useful and convenient to indicate degree of exposure as dose per unit
time, usually cumulative dose per week:(a) Very low weekly dose< 100 mrad.
( b) Low weekly dose : 100-1,000 mrad.
( c) High weekly dose > 1, OOO mrad.
7. The very low weekly dose is less than that impliedby the 1960 maximum permissible dose (MPD) recommended for occupational exposure by the International
Commission on Radiological Protection (ICRP) 2 andthe United States National Committee on Radiation
Protection and Measurements ( 1958). 3 The dividing
line between low and high dose corresponds to the first
MPD recommendations of these groups in effect between
1936 and 1948.

LATE EFFECTS

13. Late effects in man are inferred from knowledgeof specific effects produced in animal e..xperiments, fromlarge-scale observations on population, and from occupational and medical exposures in man. Late effects
comprise:(a) Many, if not all types of neoplasm, including leukaemia;( b) Local effects on tissues, e.g. skin changes, precancerous lesions, cataract and sterility;( c) Changes in life-span;(d) Effects on growth and development, e.g. irradiation of the foetus can produce abortion, still birth anddevelopmental abnormalities;( e) Effects on subsequent generations, covered inannex C.

Consequences of exposure
8. The initial effects produced by radiation may leadto observable alterations expressed promptly or months
or years after irradiation. The development of clinicalfindings depends not only on the nature and extent of theinitial radiation injury, but also on the operation of
secondary factors, e.g. the influence of hormonal secretions on the development of radiation-induced mammary
tumours. A distinction should also be made between
those effects that produce only a cytologic abnormality,e.g. binucleate lymphocytes, and those that produce a
serious disease, e.g. leukaemia.
9. It is not possible to distinguish sharply between
early and late effects since effects observed soon afterradiation may persist. Nevertheless, it is convenient toconsider as early, effects observable \Vithin a few weeks
after exposure. Late effects are those that appear later
not obviously re1ated to the early effects. Late effects
include cataracts and tumours; they may not appear until
many years after exposure.

In general, the late effects are not unique to radiation;
for the most part they are indistinguishable from diseasestates induced by other causes commonly present in the
population.
14. Although the main late effects are known-indeed
familiar-the possibility of other effects being produced
cannot be excluded, notably in the foetus. Not enoughis known about the relationship between dose and incidence of late effects. Accurate measurement of dose andincidence may be very difficult.
AKO XIA

15. Reducing the oxygen concentration inside cells
during irradiation with X- or y-rays diminishes cell sensitivity by a factor of 2-5, as measured in several ways.
This effect of anoxia in the active bacterial cell is independent of eYents later than 0.02 seconds after irradiation." Analysing such phenomena within such time limits
is not easy. 5 The effect of oxygen is re\·iewed in an-

TYPE OF RADIATION

10. Different kinds of radiation produce essentiallysimilar biological effects at the macroscopic level, though120nex B and anoxia is discussed further in section VIII
belmv (Protection and modification of radiation
injury) because of circumstantial evidence suggestingthat many protective agents act by interfering with oxygenation of the cell.
TE~1PERATURE

16. Lowering temperature soon after irradiation, thus
temporarily slowing metabolism, promotes recovery inmicroorgMisms. In amphibia and mammals, loweringbody temperature after irradiation may delay the onsetof symptoms, but there is so far no evidence of an increased degree of recovery.
NATURE OF RADIATION INJURY

17. A big bar to understanding the nature of radiation
injury arises from the difficulties in discerning the immediate processes in the interaction between radiations
and living cells: (a) the low concentration of the reaction products between initial interaction and final expression of damage after biologically effective doses ofradiation, makes characterization of these reactions difficult by present physico-chemical techniques ; ( b) thevery rapid completion of these interactions allows little
time for detection of the intervening events. 5 • 6 • 7
CHR0:).!0SOME DAMAGE

18. Much evidence points to chromosome damage as
the central mechanism of radiation-induced cell injury
and death. This and the considerable effort to explain
effects biochemically are reviewed in annex B.

ral blood . by F e59 incorporation in bone marrow and byblood cells, by degree of aplasia, or by the likelihood ofleukaemia being induced years after radiation.
Death of cells as end-point(a) Lcrw of Bergonie and Tribondeau
22. In 1906, Bergonie and Tribondeau 9 proposed a"law" of cellular radio-sensitivity which on the ·whole isvalid in radio-therapy: the most radio-sensitive cells arethose which ( i) have the highest mitotic rate, (ii) retain
the capacity of division the longest, (iii) are the leastdifferentiated.
(b) Radio-sensitivity of cells in the adult mammal
23. Cells in the adult mammal can be arranged approximately in the order of decreasing sensitivity on thebasis of clinical and experimental data with death ofcells as end-point: lymphocytes, erythroblasts. myeloblasts, megakaryocytes, spermatogonia, egg cells, cells of
jejunal and ileal crypts, epithelial cells of cutaneous appendages, cells of eye lens, cartilage cells, osteoblasts,
endothelial cells of blood vessels, glandular epithelium,
liver cells, epithelial cells of renal tubuli, glia cells, nerve
cells, alveolar lining cells of lungs, muscle cells, connective tissue cells, and osteocytes.10( c) Radio-sensitivity of tissue in the adult nz.ammal
24. The body's organs reflect differences in the radiosensitivities of their cells, usually of those in the generative compartment. The radio-sensitivities of different
cells, tissues, and organs of mammals are detailed in
section III and quantitative relationships between effectand dosage in section VII of the present annex.

II. Lethal and lesser damage in cells, tissues,organs, neoplasms, and organisms
I~TRODUCTION

19. Knowledge of the comparative radio-sensitivity ofdifferent cells and organisms is significant in studying
somatic effects. A theory e..'<:plaining the large differencesin radio-sensitivity among different cells and organisms
would be decidedly valuable in understanding radiobiology. Differences in the radio-sensitivity of organs are
the principal factors defining the organ whose damage
by a gi~en radiation dose impairs the body most.

AGE AND RADIO-SENSITIVITY

25. Man's sensitivity depends on age at the time of
exposure. Embryonic neuroblasts are killed by a muchsmaller dose of radiation than that which kills adult nerve
cells. Children are more susceptible than adults in a
number of respects. For example, the child's growingbone is more sensitive than the adult bone. These are but
a few examples of the relation between age and susceptibility to radiation. The radio-sensitivity of embryos andfoetuses is discussed more extensively in section III, andof children in subsequent sections covering effects onman.
klammalian cell survival curves

END-POINTS

20. Various end-points are used to determine comparative radio-sensitivities: (a) death of cells ; ( b) doseto inhibit mitosis; ( c) alteration or loss of functions ;( d) time taken to regenerate; ( e) time taken to atrophy;(f) LDso· In general the morphological end-points
hitherto used cannot be regarded as satisfactory anddetermination of radio-sensitivitv is better based onfunctional criteria, e.g. the concept of radio-resistanceof nerve tissue based on morphology has proved incorrect, since functional transient changes in synaptic transmission result from doses of ,...., 0.025 r. 8

26. Puck et az.n- 1 ~ plotted the first survival curves for
mammalian cells cultivated in vitro ; they measured the
reproductive potential of each individual cell after radiation. They found that human squamous carcinoma(HeLa) cells responded with a two-hit type inactivationcun•e, and that the logarithmic fraction of surviving
cells was linear with increasing dose beyond the initialshoulder of the curve. The D 37 was only ,...., 100 rad incontrast to ,_, IOS rad for virus inactivation. They suggested that the more sensitive mammalian cells may havemore unit targets vulnerable to inactivation.
27. Estimates of D 37 by Puck for various normal andneoplastic cells in vitro have been very close to one another. This may reflect the high rate of growth of normal
cells in tissue culture ; indeed there is strong evidence ofmalignant transformation in many types of cells in vitro.

21. The apparent radio-sensitivity of a cell or tissue
thus depends on the method of observations. e.g. lymphocyte damage may be measured by structural changes in
the cell nucleus, by change in DNA content, or by degreeof lymphopenia; bone marrow damage may be measured
by examination of bone marrow smears, blood counts.
haemoglobin and haematocrit estimations in the periphe-

28. Hewitt and Wilson 13- 14 and Till and McCullough 1 5-16, in ingenious extensions of the Puck tec~que121to in vivo conditions estimated the sensitivity of mouse
leukaemia cells and haematopoietic stem cells irradiatedin vivo in mice. In both experiments survival curves werevery similar to those obtained with human tumour(HeLa) cells irradiated in vitro. These observations areimportant for radio-biological theory, but much work
remains to be done to determine how far the results
apply to cells in their normal in vivo environment. The
sigmficance of the shapes of the survival curves for thebasic mechanisms involved is still obscure. Elkind's
work11 underscores the considerable significance of repair mechanisms in the response to fractionated or protracted exposure.
RADIO-SENSITIVITY OF MALIGNANT TUMOURS18

29. Radio-sensitivity of a tumour depends primarilyon the radio-sensitivity of the cell of origin. Gross reduction in tumour size depends on the proportion of cells
immediately affected by radiation. A lack of immediatevisible response does not necessarily indicate radioresistance. Radio-sensitivity is not synonymous withradio-curability.
30. Therapeutic irradiation of malignant neoplastic
tissue may induce almost immediate inhibition of mitosis
followed soon after by increased abnormal mitoses andcell death. 19 If new radiation reinduces this effect, complete tumour destruction may be expected; but in many
tumours intensive radiation may not induce this response
and the tumours keep growing.
31. Cells within a tumour may differ widely in susceptibility to radiation. In tumours of predominantly
radio-sensitive cells (lymphosarcoma, myeloma) a small
dose of radiation destroys immediately most cells withevident reduction in tumour size, although the growth
may recur rapidly. In tumours havings cells in different
stages of differentiation ( epidermoid carcinoma), evena large dose of radiation may not visibly affect the mostdifferentiated cells : no gross effect may be seen for days
or weeks, yet destruction of basal cells eventually causes
complete disappearance of the tumour. In tumours ofradio-resistant cells (malignant melanoma, rhabdomyosarcoma), a most intense radiation may not cause any
immediate or late effect.
32. Misunderstanding of response of tumours to radiation has resulted in semantic confusion about radiosensitivity (see discussion of this situation by Stewart
and Warren 2 0-21 ). The number of mitoses or the proportion of undifferentiated cells may indicate the immediate
response of radio-sensitive malignant tumour, but anaplasia and reproductive activity are not per se signs ofradio-sensitivity in any or all malignant tumours.
Marked differentiation in an epidermoid carcinoma may
imply a lesser degree of radio-sensitivity, but no epidermoid carcinoma merits the description radio-resistant;nor does a basal-cell carcinoma simply because it fails todisappear as rapidly as others.
33. Clinical observation has established a scale ofradio-sensitivities of malignant tumours, in order of decreasing radio-sensitivity: malignant tumours arisingfrom haemopoietic organs ( lymphosarcoma, myeloma) ;Hodgkin's disease; epidermoid tumours of the upper air
passages; seminomas and dysgerminomas; Ewing's sarcoma of the bone; basal-cell carcinomas of the skin; epidermoid carcinomas arising by metaplasia from columnar epithelium; epidermoid carcinomas of the mucous
membran~s, mucocutaneous junctions, and the skin;adeno_carcrnomas of the endometrium, breast, gastroin122

testinal system, and endocrine glands; soft tissue sarcomas ; chondro sarcomas ; neurogenic sarcomas ; osteosarcomas; and finally, malignant melanomas. Evenamong the latter radio-resistant tumours there may berare instances which show unpredictably a higher degreeof radio-sensitivity (fibrosarcoma and melanoma). Onevariety of liposarcoma is definitely radio-sensitive and iseven radio-curable; this is an exception to the experiencethat radio-sensitivity of malignant tumours depends
upon radio-sensitivity of their cell of origin. This list
represents only average radio-sensitivity in each group ;individual tumours may show more or less radio-sensitivity than their place. Rare tumours of uncertain radiosensitivity are omitted.18
34. Oinically it has been known for a long time thatinterference with blood supply of a radio-sensitive tissue
diminishes its radio-sensitivity22 and the important effectof anoxia on radio-sensitivity has already been discussed.
FACTORS INFLUENCING RADIO-SENSITIVITY

35. Factors influencing radio-sensitivity are reviewed
in annex B as are the radio-sensitivities of viruses,bacteria, protozoa, and other unicellular organisms.

LD so values for mammals
36. The data on LD 50 values (table I) 23 permit tentative generalizations. Other references to LD 50 values
are: mouse and rat, ~ hamster, 29 monkey, 3 0-32 dog, 3 a- 35
burro, swine, sheep and cattle. 36 Additional LD 50 values
for guinea pig will be discussed below.
228

37. There is a clear demarcation of LD 50 values (expressed as midline absorbed dose) between small andlarge animals. Air doses do not reveal this relationship.
The LDr;o for large species is ,...., 250 rad or less for
X-rays with uniform dose distribution in tissues, that forsmall species is approximately double this value orgreater.
38. The tissue-dose LD 50 values for small animals
presently available are all ,...., 400-800 rad for X-radiation, and between ,...., 550-800 rad if the guinea pig is
excluded. The differences might be smaller if different
species were irradiated with identical relative dose distributions. The monkey (Macaca mulatta) cannot be
considered, radio-biologically or haematological!y 37 any"closer" to man than any other small species. Man isdifficult to simulate quantitatively in total body radiation
TBR studies with smaller animals (table I). 38 The dog
is not large enough for direct comparison.
39. The data on guinea pigs given by several previous
investigators 24• 3 - 1 are often difficult to evaluate owing
to dosimetric and statistical difficulties; possible effects
of animal strain; possible disease in some animals. 24• 42 • 43
40. Large animals exposed under similar geometricalconditions have rather uniform LD 50 's (again, the higher
LD:;o values for animals given y-radiations should becorrected for RBE, and dose rate factors before strict
comparison 'vith X-rf.y data), perhaps partly because
large animals, unlike small, provide their own constant,maximum scatter.

LDso and age
41. The average or median acute lethal dose (LD 50 =30 days) for young adult mammals is within ,..., 300-900
rad. ·while it is customary to give the LD 50 for a given
strain independently of age, age causes variations.

42. In the mouse susceptibility is maximal at 30 days,
decreases rapidly to that in young adults, remains constant until advanced age and then increases rapidly. In
the rat the LD50 at age 3 months is ,_, double that at 3
weeks; beyond 3 months it diminishes approximately
linearly with age. More study of this relationship isneeded, but it is now evident that susceptibility of awhole population cannot be adequately denoted by asingle LD 50 • Published values are usually obtained fromyoung adults and are therefore maximal or nearly so forthe strain. This age-dependence must be taken into account in estimating the LD 50 for man.
LD 60 in man

43. Several sources of data are relevant to the LD 50
in man, but each has serious limitations. There are dataon large animals, and also on Japanese at Hiroshima andNagasaki, on Marshallese, and on patients given therapeutic TBR.

44. If the data for large animals apply also to man,the acute LD 5o for man should be ,_, 250 rad for uniform total body radiation, dose expressed as absorbed
dose at the midline. This accords with the low value estimated from the Marshallese exposed to fall-out y-radiation 88 • ... and indicates that the true value probably lies
well below the 450 rad air dose commonly quoted. From
the Marshallese data, the near sub-lethal dose for man
could be estimated; this fixes the lower part of the survival curve at ,_, 200 rad. In dogs and swine an increaseof 100 rad over that received by the Marshallese would
be well within the lethal range. If one uses the same slope
for man as for dogs, the 90 per cent mortality dose isabout 500 rad. By splitting the difference, the LD 50 forman, in the absence of complicating thermal injury,
trauma or therapy, is ,_, 360 rad. 45 Recent data on patients treated with TBR also indicate this low value.'-'• 46 •4 1
200 r TBR depresses haematopoiesis severely but one
must recall that these subjects are already infirm. Blair 48
extrapolating from the same Marshallese data, concludes
that the LD 1;o (air dose) for man probably is not below

400 r. Both authors, using the Marshallese findings,

extrapolate from data in animals, and emphasize thelarge uncertainty in the quantities deduced. Conflicting
facts of trauma, thermal injury, poor nutrition, high andlow neutron component in the Hiroshima and Nagasaki
bombs, and incomplete knowledge of the position ofindividuals and surroundings, complicate calculation of
the LDM for man from the Hiroshima and Nagasaki
data.
45. Recent data on large doses of radiation on
man 49 • 54 do not suffice for accurate estimation of the
LD 50 •53• 55 Difficulties in evaluating complicated dosage
situation in reactor accidents have been reviewed elsewhere, 54 and are discussed later in sections IV and VIII
on effects in man and on treatment.
LD so and dose-rate

46. Figure l 5 6 summarizes data on the relation between LD 50 and dose-rate. For all species the LD 50 increases with decreasing dose-rate.
RADIO-SENSITIVITY

47. This discussion has dealt with only certain aspectsof radio-sensitivity. A survey of the different radiosensitivities of cells, tissues, organs, neoplasms, and organisms indicates that radio-sensitivity is a complicatedconcept: theory is incomplete (para. 20) and radiosensitivities of isolated cells may apparently differ fromthose of the same cells fo viva. Investigators should beaware of these differences and not use radio-resistantorganisms in their study of radiation effects from fallout or for those circumstances in outer space where low
dosages are to be expected. Different radio-sensitivities
of cells, tissues and organs underlie the hierarchy ofdeaths in the different lethal dose ranges and also thedifferent patterns of recovery after radiation below thisrange. This is discussed in section III.

ID. Somatic radiation injury and its repair,particularly in mammals
MODES OF DEATH WITH TBR

48. Acute total-body and regional exposure may cause
various syndromes or modes of death depending on doselevel time after e.'\:posure, type of radiation, and species.51-59 Very high doses (tens of thousands of rad)cause death in mammals in minutes or hours ; this syndrome61l-61 depends on irradiation of the brain. The
marked symptoms of brain dysfunction suggest thatdeath may be from neurological damage. This type of
death can also be produced by radiation of the head
only.6~a

0.1

0.5

I

5

10

DOSE RATE r /MIN

50 10049. The order of events preceding death are dosedependent. As dose is reduced.. survival time increases
until the 3-4 day "gastrointestinal" type of death isseen. This familiar dose-survival time-curve 58 has been
examined for X-rays, thermal neutrons, and fission
neutrons. 64
50. In the "bone-marrO\v" syndrome, in the low-lethal
dose ranges, no doubt the sequelae of pancytopenia(infection and haemorrhage) cause death; the precise
mechanism of death remains open. 6 s-a 6 Sporadic deaths
occur in the few weeks after the bone-marrow death
period, when the marrow has essentially recovered. The
cause of these deaths remains obscure.

500

Figitre 1. Dependence of LDso/30 on dose-rate•s
X Rats (SPRAG-DAW) Logie, Harris et azm
o Chicks (LDso/21) Vogel and Stearner771
0 Mice (CF-1) Vogel, Clark and Jordan 775
Co&O'Y• Mice (CF-1) Thomson and Tourtellotte 7Sl
250 kvp{l:;. Mice (WR-BAGG) Dacquisto and Blackburnm
X-ray O Rats (WR-CF) Dacquisto and Blackburn1110Mice (CBA) Neal'97l12356. Levels of cells in the peripheral blood reflectchanges in number and maturation time of precursors
a.'ld their own life span and changes in their distribution
throughout the body. With some species variation,
lymphocytes decrease most rapidly, granulocytes a little
more slowly; later, platelets decrease and much later,
erythrocytes. Usually an overwhelming bacteremia accompanies profound granulocytopenia; germ-free animals die of anaemia. 92
57. Leukopenia appears faster and is more severe in
irradiated weanling rats and hamsters than in adults, but
recovery is more rapid, indicating a more labile homeostasis.s3-94

Partial body irradiation
51. Quastler et al. 61 have reported deaths two weeks
after irradiation of the head, jaw or tongue of the mousewith 1,500 r or more. The mechanism remains obscure.
Similar deaths have been reported after 1,500 r to thehead of rats. 68 Dogs given 1,750 r to the head only survived five months or longer. 69 In the "total head" (brain)studies of Mason et al judging from survival time, theeffect described by Quastler 67 probably caused death.
52. The gut syndrome is identical if caused by
TBR or by local irradiation of a large segment ofbowel. 5 1-S"ll, n-12 Re-section of irradiated intestine increases survival beyond the time when death from thegut syndrome would otherwise be lethal. 73 Depletion of
fluids and electrolytes contributes greatly to the immediate cause of death since massive fluid repla~ement
prolongs survival. 74 Death from this syndrome can beprevented in some animals by shielding only a small
portion of the duodenum or ileum, but not by shielding
the caecum or stomach ;75 the authors feel that protection
operates through protection of some bowel function
rather than by repopulation as in spleen or bone-marrowprotection. 76
53. The bone-marrow syndrome and shielding havealso been studied by Lamerton et al. 7 7-7 9 They showed
clearly by weight changes two phases of radiation injury,
and confirmed that shielding of even a small portionof bone-marrow minimized haematopoietic depression.
They also emphasized the importance of anaemia in theacute bone-marrow syndrome in the rat. The remarkableprotection given by marrow shielding and the degree towhich this may be masked by bowel damage have beenshown by Swift et az.sa
54. Maisin et al. in Belgium have studied shielding indetail 81 -s 3 and concluded that :(a) There are at least two syndromes after TBR;
( b) Shielding of bone-marrow or bowel prolongs survival; and( c) Protection of bowel and bone-marrow by shielding acts synergistically.
These conclusions agree with those of many workers. s•. 5B, 1s, s4, ss

58. Extracellular fluid and plasma volume increase
after irradiation in dogs, 95 rats. 96 mice, 97 and rabbits 98 at
the e..xpense of intracellular fluid. An initial decreased
plasma volume of rats accompanies radiation diarrhoea. 99
59. In rodent spleen, as in marrow, LD 50 irradiation
inhibits mitosis and damage to lymphocytes is evident
within an hour. In survivors regeneration begins on days
9-10 but in lymph nodes, destroyed follicles may not be
restored for three weeks. As in bone-marrow, injury
increases with dose within certain ranges. In different
species, a particular dose-level damages lymphatic tissue
similarly, regardless of lethality. 99
60. Cell destruction shrinks lymphoid tissues. The
dose-dependency of the weight response of spleen andthymus is discussed in section VII (dose-effect relationships). Weight loss is in part directly due to radiation
damage and in part indirectly mediated through theadrenal has a stress effect.iao
Digestive tract
61. Sensivity of the epithelium of the small intestine
is second only to bone-marrow in deciding survival after
TBR with X- and gamma rays. After irradiation at highLET, the intestine may be the critical organ determining
survival at the LD 50 in mice.101 In mice, doses below
1,000 r damage the intestinal mucosa but animals do not
generally die from this cause but rather between days
10-14 from bone-marrow damage. From 1,000-10,000 r,
mice die 3-4 days after irradiation with complete denudation of intestinal epithelium :71 death is due to failure offood absorption, dehydration from diarrhoea, and bacterial invasion, and toxaemia.1020 103
62. The radio-sensitivity of the various parts of thealimentary system varies greatly: stratified squamous
epithelia are of the same sensitivity as the epithelium inthe skin ;1a. intestinal mucosa is much more sensitive
than gastric mucosa; small bowel more than large. 105 • 100"Oral" radiation death has been described in mice. 67
Death does not resemble that from intestinal or bonemarrow damage.
63. The stomach and esophagus are more radio-resistant than the intestine.1 n7 • 1 ns Two effects may be seen in
the stomach : (a) functional and degenerative morphological changes with subsequent repair: ( b) developmentof gastric ulcers in man several weeks after 1,600 r tissue
doses given to the gastric fundus over ten days in divided
doses via anterior and posterior fields. 109 Destructive
changes seen as early as thirty minutes after moderate
doses in rabbits exposed to LD 50/30 days of X-rays,_, 800 r are most pronounced after eight hours andrepaired within four weeks.110 Similar effects are seen inmice after 350 r, in rats after 400 r, and in chickens after
800 r total body radiation. There is hyperplastic regen-

EARLY AND LATE ORGAN EFFECTS

Blood a11d blood-forming organs

55. Haematopoietic tissue is one of the most radiosensitive tissues with cell death as end-point. In general,
the sensitivity of bone-marrow of different species increases from rat, rabbit. mouse, chick, man, goat, guinea
pig to dog. 86 After an LD 50 dose the mitotic index falls
and erythroblasts decrease within an hour. \Vithin a few
hours there are many dead cells and cellular debris.
Myeloid elements regress increasingly with cytoplasmic
and nuclear disintegration. After 9-10 days, the marrow,filled with a gelatinous, relatively acellular mass containing degenerating cells, has only the relatively radioresistant fibroblasts, blood vessels. and primitive reticularelements. Animals which will survive. regenerate normoblasts and myeloblasts from spared haematopoietic
precursors, and eventually the marrow may be completely
regenerated. In rats and rabbits, after doses in the lethalr~nge, e91:hr?poiesis regenerates earlier than myelopoies1s ;61- 88 m mice both types regenerate at the same time,or myelocytes first. 81 - 99 The effect of radiation on bonemarrow has been reviewed extensively. 8 s- 91
124erative activity with continued degeneration of manycells for the first few days. At twenty-one days all
mucosae, possibly with the exception of duodenal crypts,
are normal. Damage is greatest in duodenum, least incolon and rectum.
64. Doses of 1,000-1,200 rad given locally 111 • 112
diminish gastric acidity and gastric ulcers may develop
after several weeks.11 a-i 16 Although radiation increases
intestine tone and contractions, gastric emptying isdelayed.117- 119 In dogs, gastric emptying time is prolonged only after three or four times the LD M,120 but
after as little as 25 r in rats.
Reproductive organs
65. Acute doses of radiation causing only marginalchanges in the gut or blood-forming tissues may induce
permanent sterility and endocrine dysfunction in thefemale. Males may become temporarily sterile, but theacute doses required to produce permanent sterility in themale are above LD100 in all species that have been studied. Understanding the effects of radiation on the reproductive organs is important because those germ cells
which survive to form gametes can transmit the genetic
changes induced by radiation. Since genetic damage isqualitatively as well as quantitatively dependent on the
germ-cell stage in which radiation was received 89• 121 - 124
it is obviously important to know the relative radio-sensitivities of various germ-cell stages over a wide rangeof doses and dose-rates.

Male animals
66. In the male, the various stages in the developmentof spermatozoa, from the earliest spermatogonia to themature spermatozoa, have very different sensitivities toradiation. An understanding of normal sperrnatogenesis
is, therefore a prerequisite in understanding radiation
effects on the testis.
67. The spennatogonia of monkeys can be divided
into type A 1 , A 2 , B1, B2 , B3.123 In rodents spermatogonia
can be divided into type A (dusty) and type B (crusty)
by cell morphology and developmental potentiality; atransitional type between A and B, designated as intermediate spermatogonia, can also be identified in rodents.
In mammals, type A spermatogonia are the true stem
cells and through stem cell renewal form an unlimited
number of spermatocytes while maintaining a constantcell population. This wave of activity leading to newspermatocytes is cyclic. In the monkey, type A spermatogonia undergo mitosis and transform into type A2
spermatogonia and so on until type B3 spermatogonia
divide to form resting primary spermatocytes. In themouse and rat type A spermatogonia undergo a series ofmitoses, and most of the products of the final divisiontransform into intermediate spermatogonia. The intermediate spermatogonia divide to form type B cells, which
in tum divide to form resting primary spermatocytes.
Determination of the developmental potentiality of individual spermatogonia takes place before the last divisionof type A cells, in which certain spermatogonia form thestem cells for the next multiplication cycle.127 • 128 This
basic process is essentially the same in all mammals
studied including the monkey and man, 125• 1~ 6 variation
is associated with differences in the number of identifiable spermatogonial types and duration of spermatogenesis.
68. Because of the similarity in normal gametogenesis,
the radiation response of the testis is basically the samefor all mammals, but modifications are required in extrapolating from the response of laboratory animals to thatof domestic animals and man. Thus species may differin: (a) duration of spermatogenesis (i.e., the time fortype A spermatogonia to develop into mature spermatozoa), e.g. spermatogenesis takes 35 days in mice, andaccording to Arsenyeva and Dubinin ,..., 70 days inmonkeys. 1 ~ 9 It is probable that duration of spermatogenesis in man is nearer that of the monkey than that of
the mouse; ( b) time for spermatozoa to travel from thetestis to the ejaculate; ( c) regeneration rates, which area function of (a) above; and ( d) possibly, intrinsic
sensitivity.
69. Adult male mice given acute doses of 200 to 1,000
r either to the testes only or to the whole body (highdoses, of course, are limited to partial-body exposure),
are initially fertile, owing to continued development andutilization of gametes irradiated as mature spermatozoa,
spermatids, and possibly spermatocytes. An infertile
period follows owing to destruction of spermatogonia.
A few type A spermatogonia, however, survive and repopulate the seminiferous epithelium, and almost normal
fertility eventually is regained. Doses of 100 r cause
temporary sterility in the monkey for,..., 2 to 3 months.129

70. Sensitivity of the different stages in spermatogenesis has been most thoroughly investigated in themouse. Intermediate spermatogonia and early type B
spermatogonia have LD 50 's in the range of 20-24 r.128
Type A spermatogonia show a wide range of sensitivities. At doses below 25 r, survival is comparable tothat of intermediate spermatogonia; but, at higher doses,
survival is relatively much greater. 128 A few type A
cells survive doses as high as 1,500 r. Thus the paradoxof high sensitivity of spermatogonia, which results inthe temporary sterile period coupled with high resistance,
which leads to return of fertility, is readily e.'Cplained.128
The primary effect leading to depletion of spermatogonia
is cell death, mostly in interphase or early prophase,before cell division. 130 With doses of 100 r or more, somecells die after cell division, probably because of chromosome imbalance ; a few cells appear to divide several
times before degenerating, but these effects involve only
a very few cells. As a result of extensive necrosis, particularly in interphase and early prophase, it is difficult toestimate the amount of spermatogonial depletion arisingfrom mitotic inhibition; this inhibition is probably comparable with that seen in other germinative tissues. 131
Doses of 100 r caused the death of all Bi, B2, and Ba
spermatogonia in the monkey.1 :?S
71. In mice, spermatocytes show no immediate damage even after radiation doses of 1,000 r, but degenerate
during meiotic division. From the number of spermatids
formed, LD~ 0 's ranging from 205 r for preleptotene to837 r for diakinesismetapbase I have been obtained.132
In the monkey, resting spermatocytes are damaged after
100 r.m Spermatids formed by irradiated spermatocytes
show anisocytosis, indicative of aneuploidy and heteroploidy; this later results in many abnormal spermatozoa
in the ejaculate.
72. Spermatids and spermatozoa show no morphological changes after irradiation nor is the rate of spermiogenesis altered. Mature sperms may be motile after
50,COO r. 133 Such sperms, however. have such severe
genetic damage that normal development of a resulting
zygote is precluded.
73. The efficiency of fractionated vs. single doses isinfluenced by size of the fractions, intervals between
12579. In the adult mouse, all oocytes, except those about
to be ovulated, are in dictyate stage. Dictyate oocytes inearly follicles are the most radio-sensitive cells in theadult ovary, and are completely destroyed by SO r. 1 • 3
As the follicles mature, resistance of the contained oocyte
increases, and at least one litter usually is obtained fromfemales given 400 r.1 u A similar increased resistancewith development of the follicle has been observed in
the rat,1"" but the dose required to sterilize the female
rat is higher. Resistance of mature follicles also is shownin women, since there are a few ovulations after 300 r;
early follicle stages must be resistant, however, because,
after a period of amenorrhea, ovulation begins again. 145

doses and total dose. In the mouse, fractions given
withi~ a 4-day period act as a single dose.m Maximum
effectiveness of fractionated doses in different species
depends on duration of normal spermiogenesis and reproductive potential. Because information is scarce on
the dynamics of spenniogenesis in species other thanmouse and rat, contradictory assumptions have been
made, in planning experiments and in interpreting data.
In dogs, a single total body dose of 300-375 r results inonly a partial and temporary reduction in spermiogenesis, with return to normal within a year. This contrasts with complete aspermia after 375 r given overtwenty-five weeks at 15 r/wk, there being no sign ofrecovery within a year after irradiation. 45 In the dog,
long-term radiation gradually reduces the number, motility and viability of sperm. Such damage is one of themost sensitive indicators of chronic damage seen so far
in dogs given 3.0 r/wk, i.e. 30 times the average ma.ximum permissible dose-rate (occupational).
74. With prolonged exposure at low dose rates, anequilibrium is established between the cell death, mitotic
inhibition, and regenerative activity of the seminiferous
epitheliurn,135 this equilibrium being dependent on dose
rate rather than total dose. If dose rates are low enough,e.g. 10 r/wk in the mouse or 0.1 r per day 136 in the
dog and some other species, fertility remains unaffectedeven after thirty weeks' exposure. Histologically, however, a decrease in cell populations can be demonstrated
after 100 rat this dose rate. 187 At 90 r/wk, cell populations are severely depleted, and if doses of 300 r or moreare given, temporary sterility is comparable to that following the same dose of acute irradiation.188

80. Species comparisons are very difficult in thefemale, since meiotic prophase stage, relative frequenciesof resistant and sensitive oocytes, rate of follicle growthand number of oocytes required for normal fertility undoubtedly vary widely. Valid comparisons of intrinsic
sensitivities require more information on the cytology
and dynamics of normal oogenesis.
81. In mice lowering the dose rate decreases thesterilizing action of a given dose of radiation. The shortening of the breeding period-the characteristic effect ofradiation on female fertility-is dependent on dose rate.
Fractionation and even more directly, long-term administration of a given total dose postpones the onset ofsterility. The greater the fractionation and the more protracted the long-term dose, the longer is the onset ofsterility postponed. These results indicate that some radiation damage to oocytes can be repaired, and that repair
is greater at lower dose rates.141 Conflicting conclusions
in the literatureHs-Hs are due to the use of the first postirradiation litter, not length of breeding period, as theindex of effect.

75. Testis weight as a biological indicator of radiation
damage is discussed later under "Dose-effect relationships" (section VII).

Sexually immature at1imals
82. Studies in laboratory mammals show that germ
cells may change sharply in radiation-sensitivity as theanimal develops. In the female mouse, for example, thelate foetus 141H 51 and the newbom152 are relatively moreresistant than the adult; but, only two days after birth,a two-week period of extreme sensitivity sets in, during
which sterility is much more readily induced than in theadult. 152

Man

76. A single dose of 400-600 r to the testes may cause
permanent sterility.139 Temporary sterility of twelvemonths' duration usually follows 250 r; even 30 r to thehuman testis may be injurious. 140 In relating studies onlaboratory animals to the response in man, it is of primary importance that corrections be made for differences in time-sequence arising from differences in therates of normal gametogenesis. Such a correction factor
would for example explain the slower recovery in man.

83. The fertility of animals irradiated in utero or inearly post-natal life can be understood only in terms ofthe normal development of germ cells and the sexual
dimorphism which exists in this respect. During mitotic
divisions of the primordial germ cells or their precursors,
males and females are about equally sensitive to radiation-induced depression in fertility. In the mouse, both
sexes, when irradiated with 200 r as 70 or 90 day
embryos, show somewhat depressed fertility throughout
their lives.153 In the female, the fertility depression becomes greater following irradiation at a later stage, day
110 postfertilization, and even greater for day 130.163
Similarly, the developmentally corresponding stage inthe rat. day 15 is, by histological criteria, the most sensitive of the foetal stages.154 It should be noted thatmitosis of the primordial germ cells in the female is at a
ma.ximum at this stage. In the male rat, on the other
hand, sensitivity continues to increase and is highest on
day 19.m

Female animals

77. Since there are no cells comparable to type A
spermatogonia (stem cells) in the adult mammalianovary, females of some species are more easily permanently sterilized than are males. The supply of oocytes
if once destroyed is not replaced.
78. The adult female mouse given 300 r acute TBR
produces, on the average, 1.4 litters as compared with
14.9 in controls. A dose of 100 r TBR produces complete
sterility in twelve weeks, 50 r in twenty-two weeks. 141
Even 30 r, given in three divided doses at weekly intervals, produces sterility in some animals. 142 The mouse
ovary tends to develop invaginated tubular downgrowths of germinal epithelium and ovarian tumours.
These changes, which are readily increased by relatively
low doses of radiation, are, however, not the cause ofsterility: sterility results from the killing of oocytes indeveloping follicles. Since oogonia are no longer present
in the adult, there can be no repopulation of germ cells.

84. With the onset of meiotic prophase, sensitivity isfound to decrease, well in accord with the relative radiation-resistance of this stage demonstrated in a wide variety of organisms. In the female mouse and rat, meiotic
126prophase begins about four days before birth. In malefoetuses of the same age, however, the germ cells present
are still in a primordial stage and undergoing mitosis.
This sexual dimorphism in development explains theapparent reversal from the adult situation of differential
sensitivity of the sexes that has been observed for latefoetal stagesull-151 when males are more sensitive thanfemales.
85. Shortly after birth, when the progress of meiotic
prophase ceases in the female, and the oocytes assume theearly dictyate phase, a period of extreme sensitivity
sets in. This has been demonstrated by fertility studies 152
and histologically156 in the mouse, and histologically inthe rat. 1« In the mouse, an LDM of 8.4 r (95 per centconfidence limits: 7.2 and 9.7 r) has been observed for
oocytes in the smallest follicles of ten-day old females 161
and even long-term irradiation has severe effects on
fertility. 152
86. It may provisionally be assumed that the mouseand rat results here summarized can be e.xtrapolated toequivalent germ-cell stages (rather than equivalent ages
in other species. In particular, the existence of periodsof extreme sensitivity at certain stages in the development of the human ovary is a possibility of the utmost
importance.

Eye
91. The lens of the eye is highly susceptible to irreversible damage by radiation. Sensitivity varies withsubjects and with type of radiation. Doses of 15-30 r,
X-rays and possibly 1 rad of fast neutrons11• induce
minimal lens opacities in the mouse; the threshold sensitivities of rats, rabbits, dogs and man decrease progressively for X-rays, {3-rays and neutrons.
92. The retina is more resistant than the lens. In themonkey, 2,000 r destroys the rods; 30,000 r inducesmorphological change in all retinal elements. 11 s-170
Retinal haemorrhages, retinitis, choroiditis, and iridocyclitis developing days to weeks after TBR are due tosystemic alterations. 177

87. The effect on foetal cells is discussed further
under the section on embryos in this chapter.

93. Some very low doses-0.5 to 1.0 mr-give thesensation of light in man. 178 In frogs, electroretinograms(ERG) and the discharge of nerve impulses by retinal
ganglion cells in response to retinal irradiation have beenmeasured.17° Less than 11 r caused an immediate temporary rise in the light threshold, and 0.7 r caused an
immediate temporary rise in the X-ray threshold 5 X
greater than the rise in light threshold caused by athreshold light stimulus. Doses of 5-100 r, after temporary intensification of the electrical response of theretina to light depress it down to complete loss evenafter the lowest dose. 180 The conclusion that high-energy
irradiation of the eye produces effects with doses as low
as 0.5 mr needs further study. 179

Nervous system
88. The brain is more radio-sensitive than generally
supposed. Although no morphological change has been
seen at LD 50 doses, transient functional changes havebeen reported at low doses. Doses of 100,000-200,000 r
kill almost instantly, probably by destruction of medullary centres. 1 G7 With lower doses that kill hours after
exposure, there is a question how much brain damage iscaused directly by radiation and how much is secondary
to vascular destruction. The effects of 2,500-10,000 r
have been described in rabbits 15s-i 59 and monkeys. 1 eo-u 2
Doses in the LD 50 range163 cause no EEG changes inmonkeys but these are induced within 1-2 minutes after
rradiation at 1,000 r/min. 1 0. Single exposures of 1,0001,500 r of X-rays may quickly kill a few oligondendroglia and some neurons. 165 The developing nervous
system is much more susceptible to radiation injury.
Single doses of a few 100 r kill the most primitive embryonal neural cells, and as little as 20-30 rare damaging
in animals.166 This is discussed later in this section(paras. 170-192).

•

radiation to the abdomen of 54-108 r induced avoidance ·similar do~e~ to other areas of the body failed to do so'.
but such hm1ted exposure was not as effective as TBR.
Changes in the conditioned refie.xes of dogs have beenreported after single TBR and local head irradiation at
5, 10 and 20 r. 171 vVork in the USSR on effects of radiation in the central nervous system11z and on its sensitivity to low-level radiation was recently reviewed. 1 n
Some effects of low doses, interpreted as effects on the
nervous system, are based on the concept that the CNS
controls all reactions in the organism. Thus, postirradiation pancytopenia is considered an effect mediated
via the CNS. 112

Liver
94. Judging by morphology, the liver is radio-resistant as compared with other organs although minor
cytological changes have been seen.181- 185 A low (6 percent) casein diet tends to result in cirrhosis several
months after rats are given 500 r.1 ss-u 7 Liver regeneration, as measured by weight recovery, is not impairedby 20,000 r. 188 On the other hand, sublethal TBR greatly
increases the frequency of abnormal mitoses in regenerating liver of the rat for at least 250 days.189 Decreased
incorporation of P 32 into DNA of irradiated regenerating liver190 may, in part, be due to decreased uptake byreticulo-endothelial cells.

89. In contrast to the brain, the spinal cord and peripheral nerves are highly resistant. No alteration in
structure or function of monkey spinal cord was foundafter twenty-four hours y-radiation at 135 r/hour. 167
Damage of the spinal cord blood vessels by doses of
3,000 rand more can induce occlusive disease leading toischemia of the cord, i.e., radiation myelopathy as a lateeffect.

95. Changes in liver mitochondria were found in mice
6-8 hours after 500-1,200 r; their structural stability decreased; they became vesiculated, globulated, and fragmented; and were also decreased in number. 191 These
alterations are not specific for radiation.

90. Radiation can condition the behaviour of rats,
mice and cats so that they avoid identifiable stimuli previously associated with radiation exposure. 16s-11° Fastneutrons as well as y- or X-rays can condition such
behaviour. A TBR dose of 7.5 rad given animals was
sufficient to alter preference for saccharin. Animals
learn to avoid a compartment in which they had been
irradiated, and this avoidance is more pronounced whentaste cues are coupled 'vith radiation exposure. Localized

Kidney96. Because impairment of renal function does notcontribute to mortality after TBR, the kidney is considered radio-resistant; this is supported by clinical127

zation of the collagen. The skin reactions generally are
more severe after exposure to less penetrating radiation.
104. From extensive studies on the effects of locallyapplied radio-isotopes on the skin, it has been found that
exposure of the skin to external /3-irradiation may induce
severe skin lesions.
105. According to Moritz and Henriques~ 18 /3-irradiation of pig skin produced epidermal atrophy, appearing
one to two weeks after exposure and lasting for two to
three weeks, often with ulcerations and transepidermal
necrosis. Healing was slow, and often a chronic radio
dermatitis persisted.
106. Presumably the late deleterious changes in irradiated skin are the direct result of radiation damage toepithelial cells and indirectly the result of starvation andanoxia of these cells due to ·vascular radiation trauma.
Radio-sodium clearance measurements have, however,led to the startling observations that the effective bloodflow in these densely fibrotic, scarred, and atrophiedtissues is functionally unimpaired at any time up to years
after irradiation.m This indicates that vascular damage
plays little role in the deleterious changes after skinirradiation. Some of the changes in the skin after irradiation may be secondary to infection in radiation-induced
ulcerations.
107. The skin is more resistant to tumour induction
by irradiation than most internal organs. Cutaneous
tumours, however, were the first noted in man, owing to
the relatively soft X-radiation used earlier and lack ofadequate filtration.
108. In animals. tumours of the sJ...-in have been induced mainly by /3-radiation, and co-carcinogenic or promoting effects have been observed from application ofchemical carcinogens 215 or croton oil216 respectively.

radio-therapeutic experience. Only if several tlmes 0elethal dose is given the kidney are marginal changes mrenal function seen in dogs 192 and rats. 198
97. Nephrosclerosis developing several months after
exposure has been described in mice given 50~ r ;194 mi~esurviving doses of 800 r after treatrn~nt wit!; spl~ruc
homogenates died probably of renal failure. 19 a Similar
lesions (radiation nephritis) have been seen in dogs andman after local irradiation of the kidney region ·withlarger doses. Avian kidneys are much more sensitive
than mammalian kidneys.196
Circulato1·y system
98. "Within a few hours after exposure to single dosesof X- or y-radiation in the LD 50 range, arterial bloodpressure drops. It usually soon returns to normal an.cl
remains so until a few hours before death. Although thts
initial decrease has been reported in every species examined, death from circulatory collapse may be inducedby LD 50 doses in the rabbit, chick, duck and burro.
99. Although only massive doses of radiation induce
histological change in the heart, ECG changes have beenfound in dogs,197 hamsters, 1118 and rats199 after LD50
doses. ECG changes are at least in part due to change inpotassium concentration in serum ;200 radiation causes
release of potassium from the isolated rabbit heart andfrom the heart irradiated in situ.199 Doses of 1,0002,000 r produce slight vasodilation in the per!us~d isolated rabbit ear; doses of 2.500 r and above brmg immediate vasoconstriction ;201 - 202 after 8,000 r flow is completelv inhibited for fifteen to twenty minutes ; the bloodvessels are damaged at all those doses as indicated by theappearance of increased amounts of protein in perfusion
fluid.
Endocrines
100. In general, doses in the LD:;o range induce few
signs of damage in endocrine tissue. The normal a.dult
thyroid gland is fairly radio-resistant: 17,200 r given
locally causes negligible changes in rats ;203 10,000 r _may
cause histological change in dog thyroid. 2 G4 Local tr~a­diation of the thyroid of young or mature rats with
5 OOO r X-rays does not cause morphological change,~edified basal oxygen consumption, or loss in bodyweight. 205 In tadpoles more than 20,000 rare needed toalter the thyrotropic function of the pituitary. 206
101. Doses of 5.000 r alter the alpha cells of the islets
of Langerhans in the pancreas ; beta cells show littlechange below 20,000 r. 207 Adrenals show degenerativechanges after heavy local irradiation ( > 5,000 r) but
after 1,000 r only minimal morphological change in cortex and medulla. 208 ; 209

Bone109. Bone tissue is generally believed to be relatively
radio-resistant. Some observations, however, indicatethat bone tissue damage may follow even a rather low
dose. This is especially so in young individuals. The
foetal skeleton is highly radio-sensitive; the system responsible for bone growth may be especially severely
damaged by irradiation. The growth of long bones may
be inhibited. This is seen in rats after a dose of 600 r.m
A single dose of 400 r TBR of rats reduced the numberof osteoclasts.
110. The retardation in osteogenesis is permanent andirreversible after 2,000 r local irradiation in rats, and
5. 000 r to the femurs of guinea pigs caused a complete
osteonecrosis.
111. A characteristic feature after irradiation of bone
tissue is the absence of any demarcation between normal
and irradiated parts. Irradiated bone is more easily infected than normal bone, especially if necrotic spots arepresent but healing of fractures is not significantly
altered after moderate doses.
112. The effects of internal irradiation on bone aredescribed in section VI below.

Skin102. Degree of skin damage after irradiation depends
on the dose received and also on the species of animal.
Individual differences in sensitivity are fairly large.
Furthermore. the various structures of the sJ...-in havelarge differences in sensitiv-ity.
103. Epithelial changes in the skin of the mouse ear
have been described after a dose as low as 35 r. 210
Epidermal mitoses are much reduced. After 600-800 r
TBR some inflammatory reactions with slight hyperemia
and some oedema are seen. 89 • 10•· 211 • 212 After higher
doses the epithelial cells become swollen and vacuolated.
Vascular changes presumably play a great role. Aftersevere irradiation the inflammatory changes may be followed by sclerosis \Vith loss of elastic fibres and hyalini-

LATE EFFECTS

Life-shortening 218
lntrodttction
113. In mammals radiation in substantial doses towhole- or part-body shortens life-span. In part-body128•

exposure, the life-shortening effect is variable dependingon the kind and amount of tissue irradiated as well as
dose. Radiation may shorten life-span by: (a) damaging
a specific tissue (e.g., dermatitis followed by skin cancer) ; ( b) inducing a specific disease (e.g. leukaemia) ;( c) producing more generalized changes (e.g. lowered
immunity, damage of vasculo-connective tissue and premature aging).
114. Data for man are yet inadequate to assess theeffect of radiation on life-span. From animal data andthe increased incidence of leukaemia in man after totalbody or marrow irradiation, some life-shortening is to
be expected.
115. Comparisons of mortality rates of United Statesradiologists with other physicians and the general malepopulation indicate that occupational exposure may haveslightly increased mortality rates of radiologists in past
decades. The cumulative doses are not known for individuals; the dose-life-shortening relationship cannot
therefore be measured. British radiologists showed noclear increase in mortality rates. This subject requires
further study.
116. In animals, the survival time for given dose rates
is generally shorter the more energy absorbed. Lifeshortening is less for a given dose absorbed over a longtime than over a short one. Some evidence suggests thatradiation-induced life-shortening depends on genetic
constitution, age, and clinical status at exposure.
117. Animals irradiated with substantial but sublethal
TBR, after recovery from the acute early illness, dieprematurely. They develop the diseases of their species
earlier than usual and deteriorate sooner than nonirradiated controls, with various physiological and histopathological changes suggestive of senescence. At a first
approximation, comparison of mortality curves of survivors of acute radiation mortality and controls suggeststhat radiation causes premature aging in an actuarial
sense.
118. Some premature deaths after radiation are due tothe increased incidence of such diseases as malignant
neoplasms. This is especially tme after localized irradiation from external sources or from locally depositedradio-active materials. After TBR the number and variety of diseases induced are greater than after localized
irradiation. At their respective median death times, animals whose lives are shortened by single TBR and controls usually have approximately the same diseases,
although not necessarily the same proportions. Irradiation may separately induce each of the diseases of advanced age or cause a general deterioration of bodytissues that advances the onset of most diseases toroughly the same extent. Some animal species or strains
are unusually susceptible to certain diseases, e.g. ovarian
tumours and lymphatic leukaemia in mice, and mammary
tumours in rats.
119. In general, irradiation increases the incidence
and severity of recognizable diseases at given chronological ages. When these cjiseases appear rarely or not at
all in controls, or are thought to have different pathogeneses from similar diseases in controls, they are regarded as having been induced by radiation. Diseases
common to the population which appear earlier in irradiated animals than in controls are regarded as having been
advanced by radiation. In many experiments both effects
may be combined, with induction relatively greater after
local radiation and advancement relatively greater after
TBR.

120. The life-span of animals often falls short of thepotential because infectious diseases kill many well before senescence. In man, the counterparts of these lifelimiting diseases have been largely eliminated in countries with adequate medical services; non-infectious
diseases associated with senescence are prominent. In
animals, diseases of long latency may rarely or neverdevelop spontaneously within the life-span observed.
Consequently, it is possible that some, if not all, diseases
considered induced by irradiation may be diseases oflong latency whose onset has been advanced. When intensive, localized irradiation causes a high incidence of
certain diseases, induced or advanced, to the irradiatedpart, the incidence depends on the latent period of thedisease relative to the development of other terminal
diseases to which the animals are susceptible. This, inturn, depends on the age of the animals.
121. These considerations on the effects of irradiation
on life-span, mortality curves, cause of death, and timeof onset of disease. together with available information
on clinical, physiological and histopathological effects ofirradiation. indicate a resemblance between the pathological events underlying radiological life-shortening andpremature aging processes. Whether the two processes
are similar is not clear, and whether they are identicalcannot be decided until the causes of radiological lifeshortening and physiological aging are better understood.
Life-shortening by single doses in animals21 8122. Recent data demonstrating life-shortening ofmice and rats by single TBR with X- or y-rays have been
given.21 0- 231 Data on rodents indicate that the lifeshortening effectiveness of single TBR \vith X- or y-rays
increases as dose increases. The life-shortening can be
expressed either as an absolute time interval or as apercentage reduction of life span. The use of the latter
definition in the following paragraphs does not imply thata value obtained for one strain or species will necessarily
hold for another of different life-span. For doses up to
300 rad, the reduction per 100 rad is constant or slowly
increases with dose, but increases rapidly for doses approaching the LD 50 • Other data are not inconsistent witha linear relationship. 232 At doses from 200-500 rad ( i'),the reduction is 2-4 per cent per 100 rad depending on
dose. As one approaches the LD 60 (600-800 rad) etc.,
reduction of life-span is accelerated about 25-50 per cent(5-10 per cent per 100 rad).

123. Doses < 200 rad do not usually significantly
shorten life in the numbers of rodents tested to date.
On the assumption that effect remains proportional todose down to the smallest doses, extrapolation from present data gives an upper limit of ,_, 1-5 per cent per 100
rad to the life-shortening effect of single doses below
200 rad. It is possible that effectiveness falls below thisvalue for 10 rad or less.
124. Female mice show more life-shortening thanmales at all dose levels, presumably due to endocrine disturbance after radiation damage to the ovary. The extraordinary radiation sensitivity of mouse ovary has no
known parallel in other species, nor is there evidence ofdisproportionate life-shortening in female rats or guinea
pigs. There is no basis for expecting a large sex differential in life-shortening in man.
125. The RBE of fast neutrons for shortening life iscompared to X- or gamma-radiation ,...., 2-3 at the LD 60
level. The RBE for life-shortening is thus about thesame as that for acute lethality. Although survival data129

after a wide range of neutron doses are !lot yet ava~labl~,
accumulating evidence suggests that hfe-shortemng isnearly proportional to dose, rather than an acceleratedfunction as after X- and gamma-rays. Consequently, theneutron RBE for life-shortening increases as dose decreases. If the X- and gamma-ray effectiveness becomes
proportional to dose, at sufficiently small doses the RBE
for life-shortening by fast neutrons may approach alimiting value. The highest value so far experimentallyseen is,...., 10.

found that exposure of mice 730 days old did not reduce
life-span. An explanation for this decrease in effect withage is perhaps found in experiments 240 in which mice
435 days old exposed to 500 r of TBR had an increased
death rate over controls twenty-four weeks later in malemice and sixteen weeks later in females. Thus the damage which induces premature death evolves slowly andsince twenty-four weeks are an appreciable fraction of
normal life-span, irradiation of animals late in life does
not allow sufficient time for damage to express itself.

126. Several studies are in progress 220 • ~ss, 234 on lifeshortening after a wide range of dosages; data fromOperation Greenhouse194 remain the most extensive. The
conclusion235 that life-shortening is a non-linear functionof dose, with an accelerating rate of loss of life withincreasing dose, has been challenged. 236 The data ofGowen and Stadler2 31 covering a wide dose range indicate a curvilinear relationship ; and the data of Storer
and Sanders226 compatible with a linear relationship, do
not permit a choice between the alternatives. No studies
to date provide direct evidence for or against a thresholddose below which radiation is ineffective.

Partial-body exposures130. Partial-body exposure of mice and rats is far lesseffective in shortening life-span than TBR. 2281230•:2 4 0- 243
The extent of life-shortening depends on area irradiated,size of field, and total dose. Maisin et al. m found that inrats survival curves had different shapes depending on
body part exposed. They concluded that the TBR survival curve is a composite of partial-body curves andthat injury to various body regions summates to produce
the total-body effects. Lamson et al. 240 reported that lifeshortening was roughly proportional to the percentage
of body radiated. But no clear-cut relationship allows
direct extrapolation of TBR information to partial-body
exposure.

Life-shortening by multiple doses or protracted irradiation in animals 218

127. Small animals given comparatively small daily
doses of X- or y-radiation for several months or more
have about 11 per cent life-shortening per 1,000 rad.
The effect is proportional to dose, or nearly so, for accumulated doses of 500-2,000 rad or more. This factor isconsistent with the rough estimate given for life-shortening by small single doses.
128. The dose-effect curve for exposures over days
and weeks falls between those for single doses and thosefor highly fractionated exposure ; the slope of the curve
diminishes as exposure time lengthens. But, there is no
sharply defined point on one side of which response issimilar to that with a single dose and on the other response is similar to that for continuous exposure. Effects
intermediate between single and continuous exposure
have been shown. 235 At present, data are insufficient forformulation of empirical relations to predict responses
for all conceivable fractionation schedules. One difficultyis the variable response of different strains of mice.
Appropriately timed fractionated exposures are clearly
more leukaemogenic than single exposures 231• 2 ss for certain strains with a high susceptibility to radiationinduced lymphatic leukaemia. In such mice if leukaemia
is a major cause of death, fractionated exposures may be
more potent in life-shortening than single exposures 238
even though the incidence of degenerative diseases, suchas nephrosclerosis, decreases with increasing fractionation. Such data can be corrected for the high incidenceof leukaemia, or other strain or sex specific tumours toevaluate life-shortening from other causes. 224 Corrected
data, unfortunately, are not usually reported. Data onlife-shortening effect of a long-term protracted radiation
with fast neutron compared to X- or gamma-radiationsuggest an RBE of around 10.

Role of genetic constitiition and physical sfatus218
131. Information on the influence of genetic constitution on long-term survival after radiation is meagre but
permits preliminary discussion. Most work on genetic
constitution in radiation-sensitivity of mammals examines differences in response of genetically homogeneous(inbred) mouse strains and their hybrids. Susceptibility
to early, acute death differs by somewhat less than afactor of 2 between the most sensitive and the mostresistant strains. Resistance to acute death is apparently
correlated with general vigour; most radiation-resistantstrains are longer-lived and less susceptible to spontaneous infectious disease. A short life-span, if due to highsusceptibility to leukaemia does not appear to influence
susceptibility to acute death.

132. Lifetime follow-up of several inbred strains andtheir hybrids after radiation indicates that the number ofdays lost varies less between strains than does acutesensitivity. Most strain differences in life-shortening isdue to strain difference in susceptibility to radiationinduced leukaemia; when leukaemia mortality is excluded, life-shortening due to all other causes varies
comparatively little between strains and is independentof normal life expectancy. Thus, in the mouse, a major
component of life-shortening is independent of genetic
make-up, aside from the variable susceptibility to leukaemia and ovarian tumour. The contribution of thesestrain-specific diseases to total mortality is greater inthe mouse than in other species for which data are available; nevertheless, the range of variation in over-all lifeshortening between strains is less than a factor of 2.
133. These results only partially answer the role ofgenetic constitution on life-shortening even in the mouse.
Inbred mouse strains are highly selected genetic material
from which many genes that could alter viability may
have been eliminated. These genes are maintained in wild
populations by various mechanisms, some of which could
make an additional contribution to life-shortening byradiations. Furthermore, several of the most widely usedmouse strains are genetically related, and are therefore
unrepresentative of the genetic potentialities of thespecies.

Age effects218

129. Kohn and Guttman 229 studied the important
problem of the effect of age at time of radiation on lifeshortening in mice. Mice given single X-ray exposuresat ages 160, 435 or 535 days had less life-shortening thanmice irradiated at later ages. Total gross tumour incidence was also decreased. In another study, Kohn 239
130134. Human populations are genetically heterogeneous. There is as yet no way to determine the influence of
this heterogeneity on radio-sensitivity from individual toindividual. Ethnic differences in spontaneous leukaemia
incidence suggest that, in man, as in the mouse, genetic
constitution plays a role in susceptibility to radiationinduced leukaemia.

presently recognized genetic apparatus. Statisticaltheories based on fluctuations in mean physiologic
state 234 • 256 point to whatever the investigator is familiar
with as potential areas for study. Theories based on
irreparable levels of injury 257 • 258 point out methods formeasuring the level wiiliout achieving its identificationand similarly the hypoiliesis of progressive loss of ability
to repair damage 259 does not tell anything about the
repair function itself. Life-shortening probably summates so many insults that one must be careful not tosingle out any particular lesion as of primary importance-at least not without ovenvhelming new evidence. The
only clear candidate as an especially vulnerable site ofradiation damage is the replication of DNA as noted
earlier.

135. A fraction of the human population may have
hereditary traits giving e.x.traordinary susceptibility toradiation-induced malignancies. E..x.istence of such a trait
can only be established from data on familial tendency
towards such susceptibility or from a demonstrated correlation between such malignancy and some other genetically determined trait. Large numbers of presumptive
radiation-induced cases would be required; may they
never become available.

Radiation carcinogenesis

136. Vigour or fitness probably correlate with acuteradiation-sensitivity in man-as in e.x.perimental animals. Study of the influence of nutrition, e.'Cercise, disease, and other environmental and physiological variables
on radiation effects has only begun; present judgements
must therefore be based on incidental clinical and e-'\.perimental observations.

141. Data from irradiated animals and man indicatethat enough radiation to almost any part of the body increases the incidence of malignant neoplasia. 89
142. Radiation-induced tumours often take long todevelop, not beginning necessarily· immediately after
obvious changes in ilie cells. Obvious tissue disorder need
not e.'Cist at the site of origin of the cancer: radiation can
induce malignant disease ilirough physiological mechanisms as with e.g., ovarian, thymic and pituitary tumours
in mice which are clearly indirect (i.e., where irradiationof ilie cells of origin of the neoplasm is not the criticalfactor).
143. Most animal experiments, usually with relatively
homogeneous populations, have shown that there aredose levels iliat induce no detectable increase in incidenceof certain neoplasms. Some investigators construe suchdata to mean that there is a ilireshold dose of radiation
below which certain neoplasms cannot be induced or theirage-specific incidence increased. It must be recognizedthat no dose-incidence experiment can prove the existence of a true threshold dose since, however large thenumber of animals used, ilie tumour incidence at a givendose may be too small to be demonstrated. On the other
hand, a linear dose-effect relationship e.'Ctrapolating backto zero dose would strongly suggest the absence of athreshold dose. This has been demonstrated in a few
experiments for certain types of tumour.
144. A major difficulty in short-lived laboratory
animals is iliat at low doses the latent period for tumour
induction may exceed the life-span and hence no effectmay be seen.

137. Stresses may activate chronic or latent diseases.
Radiation may so act in certain disease; e.g. inactive
tuberculosis in monkeys and man and diseases caused by
Bartone/la or Salmonella in rats. The nature of activation is unknown, but is probably due to impairment of
immunological response.
138. In contrast, a therapeutic or prophylactic effectof irradiation on certain infectious diseases can mask
the life-shortening effect in e.'Cperimental animals. The
observed life-span of animals is sometimes greater withdaily doses of 1 rad or so throughout adult life than thatof their controls.

Life-lengthening
139. Data on rodents exposed to small accumulated
doses (about 100 to 400 rad per lifetime) at low dose
rates were puzzling because such animals frequently
survived longer than controls. 2 H,m Although sampling
errors and bias in experimental conditions may have contributed, some recent findings suggest this effect may bereal. us In many experiments showing increased survival,
there was considerable intercurrent mortality early inlife in control animals, presumably from infectious
disease, whereas irradiated animals had less mortality inthe same period. There is no evidence the maximal Ii fespan is extended in t11is situation, or that the incidenceof cancer or degenerative disease is decreased. Since thecause of ilie prolonged survival is unknmvn, the significance for man is unknown.

Relation to rate of mitosis260
145. Aliliough neoplasia arises most commonly in proliferating tissues, in ilie long-term effects of Operation
Greenhouse (mice exposed to atomic bomb radiationtable II) tumours of lung, liver, mammary gland stroma,and anterior hypophysis-sites of relatively slow cell
turnover-were more frequent than iliose of skin, bonemarrow, and intestinal mucosa-sites of more rapid cell
turnover.

Nature of the lesion in life-shortening
140. The primary lesions responsible for non-specificlife-shortening in irradiated animals have not been
identified. Casarett and co-workers 2 n,us view arteriolocapillary fibrosis as ilie major radiation effect. If iliey
are correct, it should be possible to show deficits in circulation in various organs and decide whether these
deficits go with normal aging. Such findings would notprove a cause-and-effect relationship, but would at least
show an association. Various hypoilieses and models to
explain aging and life-shortening by radiation have nothelped as guides for histological or physiological studies.
Information theory and somatic mutation 249- 255 do notindicate experimental approaches going beyond theRelation to age
146. In the same study 260 ilie incidence of all tumours
increased wiili time after irradiation, wiili one exception.
This was lymphoma of thymus, which reached a ma..x.imum early in life in heavily irradiated populations.
Tumours arose earlier in irradiated mice and ilien advancement in onset corresponded to reduction in mean
age at death of the entire population. As regards theinfluence of age at the time of irradiation, diverse effects
131

have been seen. Osteogenic sarcomas and tumours of thegastro intestinal tract have shown a higher incidence inanimals irradiated when young, whereas the reverse
occurs with leukaemias and tumours of the mammary
gland.261
Relation to radiation dose
147. The relation between tumour incidence and dose

varied from one neoplasm to another. The incidence ofsome increased with increasing amounts of irradiation(e.g., thymic lymphoma), the incidence of others was
maximal at intermediate dose-levels (e.g., hepatoma,
ovarian tumour, pituitary adenoma), and some usuallycommon, decreased in frequency with increasing dose(e.g., non-thymic lymphoma, sarcoma of breast, adenoma of lung) .260 In no instance did tumour incidence
vary as a simple linear function of dose, and extrapolation, therefore from the high doses in this experiment
to doses near those from natural environmental radiation
is not possible, and the question of whether or not very
low doses of radiation cause some slight increase in theover-all risk of malignancy (so-called threshold) remains unsettled. As a general rule, single-dose irradiation is more effective in producing cancer than greatly
protracted e..xposure with the same dose.
Mechanisms of carcinogenesis
148. Of the various neoplasms induced by radiationsome may be caused indirectly without irradiation of tl1e
tumour-forming cells themselves. Thus in certain strainsof mice, presence of the thymus is necessary for induction of lymphomas 262 although the thymus itself neednot be irradiated. Strong evidence that induction isindirei:t is given by the neoplasm arising in a normal
thymus transplanted to an irradiated host. 263 In otherstrains, thymectomy shifts the site of origin of thetumour to other lymphoid tissue. 264 Repeated radiationin proper sequence causes a higher incidence of lymphoma in mice than do single exposures to the same total
dose. 237• 264 •265 Inoculations of normal bone marrow or
spleen,1 95 partial shielding 265 • 267 • 268 and certain radiation-protective agents,7° decrease incidence. There isdose-rate dependence in response 269 • 271 that, together
with the incidence after various radiation dosages 255
suggests a curvilinear relationship between dose andresponse.
149. Indirect carcinogenesis also appears responsible
for the development of thyrotrophic pituitary tumours
in mice thyroidectomized by I1 31 • 272 Such tumours may
possibly be more readily induced if the pituitary is also
irradiated. 273 .m Other pituitary tumours are as readily
induced by local radiation of the pituitary as by TBR,
suggesting that their pathogenesis is direct. 214 For theseas for many other types of radiation-induced tumours,
the relative importance of direct and indirect causes is
not yet understood. In certain instances, both causes
seem to operate; e.g., the induction of ovarian tumours
depends on destruction of ovogonia and ovocytes bydirect irradiation and on gonadotrophic stimulation ofremaining ovarian stroma by pituitary hormones. 275

the greatly increased incidence at 400 r depends on intact
ovarian function and direct radiation injury to the breastis necessary for an increased incidence of radiationinduced neoplasia. These results indicate that primaryradiation damage to the breast tissue is necessary, but
this primary damage can be dormant and not result in
neoplasia unless an additional mechanism is operative.
Somatic mutation theory
151. Under a broad definition of mutation, generally
used by geneticists, as including all sudden heritablechanges in a cell line, the somatic mutation theory ofcarcinogenesis can embrace almost all currently proposedmechanisms (e.g., gene mutation, chromosome breakage
or loss, mutation or loss of cytoplasmic particles, or evenvirns infection). Under such circumstances the theory
is reduced to a truism and merely serves to describe
well-known characteristics of malignant disease. As a
special case of this, simple gene mutations or othersingle-hit changes have often been invoked as a single
basis for radiation-induced neoplasia, and incidentally asa basis for predicting effects under conditions that preclude direct observation. The simple point mutation
hypothesis remains to be substantiated, as does thetheory that naturally occurring point mutations cause"spontaneous" cancer.281•m A widely held view has
been that, if a single hit on a gene or other cellular structure were the basis for radiation-induced neoplasia, thenthe dose-effect relationship might well be linear withno-threshold. The rat mammary tumour data and others
indicate both a primary and secondary mechanism inthis type of radiation-induced neoplasia. The neoplasms
themselves were seen only when both mechanisms wereoperative. The secondary mechanism in the present situation (normal ovarian function) could not reflect asomatic mutation. Even if the primary event were asomatic gene mutation (or a single-hit chromosome
break), the dose-effect curve 278 would not have been
linear with no-threshold unless the secondary mechanism
were operative. It follows therefore that lack of linearityand of an apparent threshold does not rule out somatic
mutation as the primary event. Lack of such a response
might simply indicate a non-operative necessary secondary mechanism.
152. Furth 3311 concludes from the findings of several
authors that radiation-induced rat mammary gland neoplasia ''are best interpreted by supposing that radiation
causes a subtle, irreversible change in the mammary
gland which remains latent until the organ is subjected
to proliferative stimuli".
153. The demonstration of a two-stage mechanism in
the induction of some neoplasms throws doubt on theuse of dose-response curves as arguments for or against
the point mutation theory (or any simple one-hit theory).
No "one" experiment even if the animals are numerous
can settle this question for all types of malignancy andall circumstances. If the dose-effect cunre is not linear,nothing would have been necessarily proved about the
primary mechanism. If a linear no-threshold response
obtained down to the lowest doses, the somatic mutationinterpretation, if it could be made under these circumstances, would apply only for the particular neoplasm inthe particular strain and species. Extrapolation would
not be valid.

150. _Studies on radiation-induced mammary glandneoplasia in the rat 276•::so have shown that a single sublethal dose of X- or y-irradiation in young male or female
rats res?lts in an increased incidence of mammary glandneoplasm. The dose-effect relationship appears linear
over 25-400 r, and the curve within limits oi error, e.xtrapolates to zero. No data are obtained below 25 r; above
400 r, etc., the curve was either flattened or declined, since

Chromosomal clza11ges a11d carcinogenesis
154. The role of chromosomal changes as an inter-mediate cause in carcinogenesis has been widely de132

irradiated. Here radiation probably merely favours selection of spontaneous carcinogenic mutants, possibly byexcessive growth stimulation during recovery.

bated.m,m Malignant tumours often have aberrant(usually aneuploid) chromosome numbers and a highdegree of instability in chromosomal constitution.~ 56 It
by no means follows that the chromosomal changes are
the cause of the malignancy; inaccuracy in the transmission of genetic information may be merely the priceof proliferation at unrestricted speed. Association ofchromosomal variation with tumours therefore does notof necessity imply any cause-effect relationship.
155. Chromosomal aberrations can be induced in
norlllal human and monkey cells cultured in vitro by
X-ray in doses as low as 25 r~ 81 • 288 and such aberrations(presumably of mixed 1-hit and 2-hit origins) in in vivo
monkey bone marrow cells show a rough proportionality
with doses from 50-100 r. Blood cells cultured from twopatients given radiation for ankylosing spondylitis
showed numerous chromosome structural abnormalities
but these rapidly declined in number. 289 Similar changes
have been seen in patients with chronic myeloid leukaemia after X-ray treatment.
156. The persistence of chromosome aberrations inperipheral blood leukocytes,....., 2.Vz years after accidental
whole-body irradiation of eight men by mixed gamma
and fission neutrons has recently been reported. 781 Fivemen received doses > 230 rad; three others, < 70 rad.
The frequency of cells with chromosome counts differingfrom 46 ranged from 4-23 per cent in the irradiatedcompared to 2 per cent in controls. In the five cases withhigh doses, there were grossly altered chromosomes suchas rings, dicentrics, and minutes; these were often in cellswith abnormal count with a frequency of 2-20 per cent.
No polyploidy was seen. A detailed karyotype analysis
of some normal-looking cells from irradiated individuals
revealed the presence of pericentric inversions, translocations, and deletions. A comparison of the frequency of
induced chromosome breaks in tissue culture preparations suggests that the frequency of aberrations diminishes with time, and that polyploid cells are eliminatedmore quickly.
157. There is increasing evidence of an association of
specific types of leukaemia with chromosomal anomalies.
In many cases of chronic myeloid leukaemia there is a
specific abnormality (possibly a deletion) in one of thechromosomes of pair-21 or pair-22 (the Philadelphia
chromosome). Variations in the proportion of cells withthis Philadelphia chromosome in blood-cell cultures fromdifferent patients with myeloid leukaemia and its absencein skin cultures from the same patients strongly suggest
the presence of a somatic chromosomal anomaly in thesepatients' leukaemic cells. Moreover, the incidence ofacute leukaemia is greatly increased in mongolism, adisease 2111 now known to be associated with trisomy-21.
These observations suggest that either a deficiency orexcess of genetic material of chromosome pair-21 may
result in different types of leukaemia. For other types ofleukaemia, no such consistent associations have been
established as yet. 290• 782• 783 • 7 8-1
158. These chromosomal aberrations and especiallythe possibility of a specific chromosome abnormality inmyeloid leukaemia and the hereditary nature of theneoplastic change in subsequent cell generations suggestthat cancer reflects a genetic change in the cell. But thecourse of evolution of malignancy in certain tumours
argues against a one-stage cause, such as single point
mutation or chromosomal aberration.~ 85 • 292 • 293 Moreover,induction of neoplasia by indirect effects on the hostcannot be due to the mutagenic action of radiation on thecancer-forming cells, since the cells themselves are not

Radiation leukaemogenesis

159. Studies of radiation leukaemogenesis use themouse because of ease of leukaemia induction and theavailability of different leukaemias associated with various inbred strains. Mouse leukaemia is not a single
disease; much confusion arises because precise classification is often lacking.za..,m The most studied mouse
leukaemia is lymphatic arising in the thymus, classified
variously as thymic leukaemia, thymic lymphosarcoma,
malignant lymphoma, and "mouse leukaemia''. In themouse, the thymus normally atrophies in early adult life
instead of in early childhood as in man. Extensive studies
by Upton et al.2 84 show that factors inducing this neoplasm differ from those inducing myeloid or granulocytic
leukaemia. Since most radiation-induced leukaemias in
man are granulocytic, thymic leukaemia of mice havelittle relevance to man. 294 Myeloid leukaemia in mice,possibly more analogous to human radiation-induced
leukaemia, has been shtdied less.
160. In spite of these reservations about the comparability of human and murine leukaemias, the leukaemia
responses of the two species share certain features. 296
Both species show an increased incidence of leukaemia
after TBR. In mice, the leukaemia incidence in irradiatedgroups returns to or near control levels 18-20 months
after exposure. 223 • 291 The Hiroshima and Nagasaki
survivors 298 had still some excess leukaemia mortality
over their unirradiated controls by 1959. By adjustingtime scales. human and murine experiences can be superimposed ; for comparable radiation exposures, thefactor of in~rease in age-specific leukaemia mortality
over control is nearly identical for the two species. 296
161. Data of Kaplan et al. 263 indicate that lymphoma ta
in thymectomized irradiated mice can appear at the siteof transplantation when the thymus from non-exposed
mice is transplanted into the irradiated animal. The
origin of the neoplastic tissue has been studied ':!ea, 299 • 301
and although in some instances the cells may be derived
from the donor cells, in others they are derived definitely from recipient cells.
162. Radiation-induced myeloid leukaemias of themouse are uninfluenced by the thymus but are reducedby splenectomy.264 They are more effectively induced byrelatively lower radiation dosages than is the thymic
form and their induction is apparently not similarly enhanced by fractionation of the exposure. 264 Partial
shielding reduces incidence 264 as does prophylactic administration of mercaptoethyl guanidine, 302 a radioprotective agent. The incidence reaches plateau at radiation doses above 150 r. 264 The shape of the dose-response
curve is not definitely known, but data after doses of 16
and 32 r 1 ~ and after 128 or more254 • 303 suggest curvilinearity in the low-dose range. In rats and mice injectedwith strontium-90, more differentiated forms of leucosis
predominate when the accumulated dose to the bonemarrow is small and less-differentiated forms when thedose is large, i.e., of the order of 6,000 rep or above. 304
163. Variables besides radiation dose affect the probability of an animal developing leukaemia, e.g., strain,
age at time of irradiation, sex, and endocrine status.
Leukaemia incidence can be modified by endocrine status
and genetic inheritance (by selection, hybridization, etc.),
or by removal or implantation of tissues. 2 1H, 3os- 311
133

Virns theory
164. Evidence that viral agents cause vari~us types ofcancer in mices12- 315 stimulated the search ror filtrable
leukaemogenic agents in mice with radiation-~nduced
leukaemias. 31G-318 Results as yet are not conclusive, ~ut
they suggest viruses a.s J?Ossible eti~logic agents. in rad~a­tion-induced leukaemia.- 93 Depression of host immumty
by radiation may promote infection by a!l ~"\".ogeneous
carcinogenic virus or radiation may activate. a lat;nt
carcinogenic virus infection analogous to the. mduct10nof lysogenicity in bacteria. To ~h~~e hypoi;hetical mechanisms must be added the poss1bil1ty of viral transduction of carcinogenic substances from one cell toanother. 312 ' 3u

no higher than that of certain a.ctiyely :fividing and ~f­ferentiating adult tissues. Irradiation ot an embryo with
5-25 r causes evident changes; similar exposure of adulthaemopoietic or epithelia~ tissue~ is likewise follow~d bymorphological and functional disturbances. The difference between embryonic and adult response to lo~ dosesof radiation is that an over-all effect in embryos is evenmore extensive than in the adult probably because aminor irreversible injury in embryo, particularly after
the blastomeres have lost totipotency, is amplified indevelopment: morphogenetic relations are upset t;hroughdeath of cells in various precursor fields, and this leads
to faults-in the formation of adult structures.
171. Radiation effects in embryos may reflect two
mechanisms: developmental alterations through cell
destruction in the embryo and physiological disturbancesin the mother.

Risk of carcinogenesis from low doses
165. Carcinogenesis is the most imp~rtant late .e~ectof radiation. Knowledge of the mechanism of radiation
carcinocrenesis is a prerequisite for the accurate assessment of risk at low doses. Since the mechanisms of carcinogenesis are unk11own, any such assessment of risk
must be purely speculative, although possibly of somevalue in estimating upper limits.
RECOVERY AND THE CONCEPT OF IRREPARABLE INJURY

The mammalian embryo
172. l\fammalian pre-natal development can bedivided into three periods with respect to radiation
effects : (a) pre-implantation when early deaths are
induced but survivors are mostly normal; (b) majororganogenesis. yielding neonatal deaths and abnormalities; ( c) the foetal period when sensitivity to death ar:dgross malformations decreases. The general pattern mmice is given in figure 2.

320166. Radiation injury, like other injury, immediat~ly
sets off the classical reactions of homeostasis and repair;
to some extent, radiation affects the repair processes
themselves.
167. In the weeks after a single sub-lethal dose,
damage gradually is repaired. Many, if not all, cells
destroyed by radiation are replaced by regeneration fromsurviving cells. Irradiated organisms may resume anormal or near-normal appearance. With time there isrecovery of resistance to lethality from furth~r radiat~on.
:Most radiation injury from X- and y-rays is thus irequently reparable. Animals, therefore, survive a prolonged dose several-fold larger than a single dose.
168. Despite apparent recovery residual damage (e.g.,incomplete regeneration or residual defects in cells andtissues) and late effects seen after maximal recovery
show that some injury is irreparable. Certain specifici11juries associated with the formation of bone tumours
caused by radiation are reparable. Recovery is more
likely with injuries which are caused by {3- than bya-radiation. 2G1, 3o4, 321

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Figure 2. Incidence of pre- and nee-natal death and of abnormal
individuals at term after irradiation at various intervals(separated by 24 hours) pre- and post-fertilization. Abnormal
individuals may have more than one abnormality 3 2 4169. Life-shortening by radiation implies that an
irreparable component of injury is detectable. This component is detectable as premature aging in an actuarial
sense. But how closely this process parallels and contributes to that cumulative injury called natural aging is
unclear in the quantitative sense. Likewise, it is notknown whether the irreparable component represents
abrupt aging at the time of injury or initiation of gradualaging. Limited observations in rodents, dogs. and swine
indicate that irreparable injury is measurable, after aninterval of presumed complete repair, as a reduction inacute lethal dose. This suggests that irreparable injury is
at least partially sustained at the time of radiation and ispotentially observable as a persisting tissue change; thedistinction between reparable and irreparable injury has
not yet been related to morphology.

173. When females are irradiated after fertilization
but before implantation, high and rapid mortality of thefertilized ovttm is the main effect. Studies by the
Russells m, 323 indicate that deaths are maximal for radiation given during the first two post-copulation days, andthat one-third of total deaths are in the pre-implantation
period. Most deaths, especially among embryos irradiated later after fertilization and closer to the expected
implantation time, ensue shortly after implantation. No
deaths in excess of controls occurred after day IO}'S.
174. Survivors of irradiation in the pre-implantation
period were free of obvious defects 322 had normal birthand post-weaning heights, exhibited normal fertility andshowed no evidence of decreased survival throughout
life. 153 The all-or-none response to irradiation during
cleavage stages which has also been observed in rats andguinea pigs 323 has led Russell to suggest that mammalian
blastomeres are totipotent. 3 : 3 , 3 :~ On the other hand, Rughand Grupp 325 showed that a dose as low as 50 r to a pre-EARLY AND LATE EFFECTS ON EMBRYOS A:\D FOETUSES

170. Ionizing radiations profoundly disturb developing embryos. Their susceptibility while very high may be

134

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implantation embryo might induce cerebral abn~malie~.
This result has not yet been confirmed by other mvestlgators.
175. The pre-implantation mouse embryo is highly
radio-sensitive. Earlier studies indicated that 200 r prevented about 80 per cent of all embryos from reaching
the tenth day of gestation. It was recently shown that25 r killed 38 per cent of embryos exposed before firstcleavage. A dose of 5 r increased resorption. 325 However,the degree of radio-susceptibility of an. embryo ~y bespecies specific: the rat embryo before 1mplantat10n can
withstand a dose of 300 r. ~1

3

176. Mouse embryos given 200 r or more between
gestation days 6.5-13.5 developed but had a high incidence of abnormalities. A certain proportion of theabnormal foetuses died at birth. The proportion of prenatal deaths was much lower than in animals exposedin the pre-implantation period. The LD 5o for neo-natal
death was > 200 r for irradiation in the pre-implantation
period and through day 8.5; decreased to between 100200 r for days 9.5 and 10.5 and then increased to 200-300
r for day 11.5 and finally to > 300 r for later periods indevelopment. 323 • 324 'With 200 r the incidence of grossly
abnormal new-horns is 100 per cent for irradiation ofmost stages during major organogenesis. Doses as low
as 25 r have been shown to be effective in causing morphological changes. 326
177. Neo-natal mortality is greatest in embryos irradiated between gestation day 83/i to day 12. Exposure in
the same period decreased the weight of new-born
mice124 • 323 • 324 comparable quantitative studies have notbeen made in other mammals but there are frequent
reports of marked decrease of size among rats andrabbits irradiated during development.
178. Several investigators have tried to decide
whether specific developmental abnormalities depend on
the stage of development at which radiation is given.
Early work by Kosaka 327 indicated that the brain andspinal cord are the most sensitive tissues at the beginning of major organogenesis, while at later stages thymus
and, to a lesser degree, liver and spleen, become the mostsensitive. A more detailed description of "critical
periods" has been given by Job et al. 328 The peak incidence of abnormalities was reached with embryos irradiated between gestation days 8-11. Hydrocephalus
was easily induced in embryos irradiated at day 9, eyedefects at day 10, jaw defects at day 11. According toKaven s29 the structure of the tail was most affected inembryos e.."<posed on day 11, brain hernias on day 8, andskin defects on days 13-14. The results of Russenm.sso
and others on critical periods are given in figure 3. Ma.ximum susceptibility to defects was between days 7-13
the beginning coinciding with the appearance of manydifferentiating centres. Irradiation at day 9 caused anencephal~, at day 10 ~ye defects, at day 11 hydrocephalus
and spmal anomalies, and at day 12 anomalies in thefore-brain.
179. Embryonic neuro-blasts are particularly susceptible to radiation. Within two hours after 100 r, there arescattered areas of necrosis. and necrotization of individual neuro-blasts after doses as low as 40 r. With increasing exposures, more areas of developing neuraltissues are affected. Intermitotic neuro-blasts are more
susceptible to radiation than those in mitosis. 331 Cells
during active differentiation may well be more sensitive
than completely differentiated cells. Further studies areneeded, and the radio-sensitivity of erythro-blasts, myelo-

blasts, and spongio-blasts should be compared withcorresponding mature cells.
180. The existence of "critical periods'' in development has thus been demonstrated, but the use of the term
must be properly qualified. 3 ~ 4 For some anomalies, thecritical period is greatly e.xtended, e.g. e.."<encephaly canbe induced by radiation at any time before neural differentiation. 332 Sometimes induction of a specific anomaly
does not coincide with an apparent period of increased
developmental activity, e.g. induction of polydactyly.l 24
Also, the limits of periods of sensitivity seem to dependon the dose 323 • 3 ~ 4 and how it is fractionated ;153 however,stage of maximum sensitivity is usually revealed by theuse of low-dose single exposure.
The human embryo
181. The first harmful effects of ionizing radiation onhuman embryos were recorded in 1901-1904. Soon afterwards, reports drew attention to serious hazards in irradiating pregnant women. Earlier clinical literature has
been reviewed extensively. 33 ~ 36 Table III summarizes
observed malformations. Malformations specifically reported for human embryos are marked with an asterisk.
The most frequent abnormalities are in the central
nervous system, then eye defects and skeletal malformations.
182. Malformations among children irradiated in
1ttero have been reported. In a 1929 survey of 75 children
born of 106 irradiated women, 38 were abnormal, andin 28 of those the likeliest cause of malformation wasradiation. 337 The dose was estimated to be 30-250 r.
183. The frequency of malformations in man, as inother animals, depends upon developmental stage.
184. The marked qualitative similarities between radiation-induced abnormalities in man and other mammals make extrapolation of e.xperimental studies to man
apropos. For that purpose, a graph correlating development of mouse and human embryos constructed by Otis
and Brent is useful3 38 (figure 4). The correlation between the appearance of some morphological featuresin the mouse and in the human embryo is given intable IV. Since mouse experiments have shown that

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137

irradiation dunng the period of ~ajor organogenesi~ ispotentially most hazardous and smce part of that penod
occurs at a time when pregnancy may still be unsuspected
Russell and Russell have suggested that whenever possible pelvic irradiation of women of child-bearing age
be restricted to the two weeks following the menses. 339 • 340
185. Besides abnormalities in embryos, foetuses, andin early childhood, several effects of irradiation durU;ggestation have been reported, appearing at a later age 111
children. Stewart and collaborators341 concluded that
there was an increased incidence of leukaemia and cancer
among children irradiated in ·utero, and also an increased
incidence of mongolism. 342 Children of Japanese mothers
exposed, during gestation, to atom bomb radiation tended
to show stunting343 and some mental retardation, especially among boys, 344 but neither observation has been
supported by other studies. m, 346 Among children who,
while in utero, had received an average of 3-5 rad during
maternal diagnostic X-ray, 15 of 1,101 had phenotypicchanges involving colour sectors in the iris of the eye.
The incidence was only 11 in approximately 7,092 nonirradiated control siblings and parents. The differenceis highly significant. This somatic effect is only seen in
the children of women irradiated at 6 to 6~ months ofpregnancy. It is not yet known whether the effect is due
to genie chromosomal or other changes. These studies
are discussed further in section V under the heading"Late effects".
Recovery and protection in irradiated germ
cells and embryos
186. In the sea-urchin egg, as time elapses between
irradiation and fertilization, there is the increased proportion of cleavages pointing the possibility of recovery. m The effect was described by Miwa348 for
Pseudocentrolus depressus irradiated with a:- or y-rays.
This does not imply recovery to pre-irradiation stage. 349
The delay between irradiation and fertilization counteracts the delaying effect of irradiation upon cleavage, butdoes not increase the number of embryos capable ofnormal development. In frogs Rollason 350 found no evidence for this kind of recovery.
187. Recovery was seen when an organ from an irradiated embryo was transferred to a normal one. The
irradiated organ, e.g. of a frog 851 or chick embryo 352 developed further and survived longer than it would havein its original environment. This does not necessarily
denote recovery; it is perhaps better explained by assuming that the transfer of the organ removes it fromthe noxious environment of a dying embryo.
188. Recovery in embryonic tissues has been postulated by several authors from the observation that irradiation of embryos at an early stage brings early death,but survivors develop normally. Recent experiments 825
have shown that exposure to radiation, even almost immediately after fertilization, caused marked abnormalities (brain hernia) ; survivors that developed without
big abnormalities nevertheless showed stunting and some
impairment of the ability to learn. 353
189. After radiation-injury the embryo as a whole
rr:a~ show a _certain recovery in that survivors of rad1at10n continue to develop despite morphologicaldamage. 354 This does not imply that the injured tissues
have ~ecovered; the survivors are usually stunted andthere is some topographical reorganization of undamaged tissues, which might indicate that the maintenanceof viability and shape is due to some of the cells fromsurrounding areas invading the lesion. 332 Recovery ofan embryo is more the outcome of a regenerative process,aided by the remarkable powers of reorganization ofembryonic tissues and scavenging actiYities of macrophages, than recovery of the cells actually damaged.
190. Expected radiation injury may be prevented tosome extent by several factors; hypoxia, lowered temperature, and various thio compounds. Lowering theambient temperature protects against immediate radiation effect in frogs, an effect lasting only as long as a
low temperature is maintained ;855 in salamander larvae,
protection appears to persist. 356 Also in chick embryos
Goffinet357 protected against radiation by lowering temperature.
191. The effects of hypoxia were studied by Russelland collaborators :m, 35s mouse embryos e..xposed todoses 100-400 r had a lower percentage of abnormalities
if irradiated in 5 per cent o:x-ygen in helium. Allen,
Schjeide and Piccirillo359 showed that the proportion ofcells injured by radiation was reduced if irradiated cells
were maintained afterwards in mildly anoxic conditions ;anoxia reduces cell division.
192. Cysteamine as well as several other compounds
protects to some extent against radiation if given before
irradiation. The survival of chick embryo was llnt:>roved
after giving cysteamine, cystamine, and methylamine ;the efficacy of these compounds was highest when thecirculatory system began to function. 357• 360 It has been
observed that mercaptoethylamine can protect the rat
foetus if irradiated on days 15-18, 301 and that cysteamineand similar compounds permit mouse foetuses to maintain a higher growth rate and lower mortality than irradiated untreated controls. 362 • 863
IV. Acute radiation injury in man
ACUTE RADIATION SYNDROME

193. The acute radiation syndrome differs from ordinary injuries since there are integrating patterns ofsymptoms after higher doses, or a latent period at lower
doses during which hidden histological changes are taking place from the time of exposure until the recrudescence of symptoms and frank danger of death.
Recovery from the initial symptoms does not signify real
recovery. Review of reactor accidents (see below) emphasizes the problem of inhomogeneous irradiation of
the body in man and the inHuence of the part irradiatedupon the symptoms that follow. Effects of localized irradiation on individual organs are discussed in earlier
sections of the present annex.

Sources of information
194. There are four sources of information on acuteradiation effects in man: (a) the largest, but studied
under obvious difficulties, is the experience of theJapanese at Hiroshima and Nagasaki: ( b) the less serious and smaller experience of the Marshallese, American
servicemen, and Japanese fishermen to fall-out radiation
during atomic tests in 1954; ( c) exposure of a few people to reactor and radiation accidents in the UnitedStates, the USSR and Yugoslavia; (d) exposure of patients to therapeutic radiation. Some shortcomings ofsuch information have been discussed earlier in paragraphs 43-45 above. Information on atomic bomb, fallout, reactor accident, and \Vhole-body radiation injuries
has been summarized. so, 364, 312, s;3, 3ss, 393, ;02138

Total body response 365

Gastro-intestinal form 53 • 69

195. The total body response in man to radiation in
sufficient doses includes: (a) radiation sickness beginning during or very soon after acute e..xposur~, and overlapping with other responses; ( b) degeneration and. repair of proliferative ti~sues; ( c) l<?cal and gen~rah~ed
toxaemia; ( d) changes m homeostas1s ; ( e) deteriorationin physical and mental fitness.

above given to whole-body, symptoms have appeared in
1-2 hours. The onset, duration and severity of all symptoms varies depending largely on dose and partly on
susceptibility. 366 Symptoms may include :367 (a) general:
headaches, vertigo, debility and abnormal sensations oftaste or smell; ( b) gastro-intestinal : anorexia, nausea,
vomiting, diarrhoea; ( c) cardiovascular: tachycardia,
arrhythmia, fall of blood pressure and shortness ofbreath ; ( d) haematological: leukopenia, thrombopenia,
and increased sedimentation rate; and ( e) psychological :increased irritability, insomnia, and fear.

200. The gastro-intestinal form predominates withlower doses (500-2,000 r). The prodromal nausea andvomiting begin promptly and do not subside. For somepeople these symptoms develop within 0.5 hours after
e..'Cposure ; in others not for several hours. Gastro-intestinal symptoms may continue (anorexia, nausea, vomiting, and diarrhoea). Sometimes these symptoms disappear after 2-3 days and recur ,__, day 5 just when thepatient's condition seemed to have improved, owing toinjury of intestinal epithelium, leaving bare villi. Rather
abruptly, malaise, anorexia, nausea and vomiting prevent
normal food and fluid intake, leading to serious electrolyte imbalance. Simultaneously high fever and persistentdiarrhoea-rapidly progressing from loose to watery tobloody stools-appear. The abdomen is distended andperistalsis is absent. Rapid deterioration leads to severe
paralytic ileus. Exhaustion, fever and perhaps delirium
follow ; dehydration and haemoconcentration develop ;the circulation fails, and the patient becomes comatoseand dies a week or so after e..'Cposure from circulatory
collapse.

197. The incidence of radiation sickness is affectedby the part of body irradiated. 368 • 369 Exposure over thewhole trunk and partly over the upper abdomen causes
more radition sickness than does exposure of comparable tissue volumes in the extremities. Explanations forradiation sickness include : (a) release of toxic substances from disintegrating cells ;370 ( b) disturbance of
pituitary-adrenal cortical function ;311 ( c) tissue destruction giving rise to histamine and mildly toxic histaminelike products.

201. After doses where regeneration is possible, fluid
replacement during days 4-6 keeps dogs alive. 74 The
epitheliµm regenerates and vomiting and diarrhoea subside. This is only a temporary respite as evidence ofmarrow aplasia and panctyopenia begin within 2-3
weeks. After doses that cause this severe intestinal damage, marrow regeneration is unlikely, so that even if
there is spontanous recovery or successful treatment,
individuals have yet to experience the effects on haematopoiesis.

General clinical picture

Haematopoietic form

198. Although the different organs have widely different radio-sensitivities for the acute radiation syndrome in man, three are important :n• 372 • 373 the central
nervous system (CNS), small intestine, and bone marrow, together with lymphoid tissue (table V). The acuteradiation syndrome may therefore take three primaryforms---cerebral, gastro-intestinal, and haematopoietic,
depending on the dose. To induce acute effects in thecentral nervous system requires several thousand r; damage is seen within minutes to hours. The dose for theacute small intestine form is 300-500 r, with a latent
period of ,__, 5 days. For severe haematopoietic changes,
the dose is > 200 r and the effect takes ,__, 3 weeks todevelop.

202. In the haematopoietic form, after lower doses ofradiation, e.g., < 500 r, the haematopoietic symptoms
are due to different origins and appear in two successive
phases. Leucopenia, thrombocytopenia and haemostatic
abnormalities are a direct consequence of lesions of thehaematopoietic organs. Symptoms such as haemorrhage
and anaemia may be secondary to the visceral lesions andassociated with ulceration of mucous membranes. Anorexia, apathy, nausea, and vomiting, and some diarrhoea
are maximum 6-12 hours after exposure. The symptoms
may subside so that by 24-36 hours individuals feel well,
but their bone marrow, spleen, and lymph nodes areatrophying. The patient enjoys apparently normal health
until,..., days 19-20 (many Japanese soldiers returned towork only to die later in the pancytopenic phase), when
the patient has chills, malaise, and fever, headache,fatigue, anorexia and dyspnoea on e..xertion. and at thistime partial or complete loss of hair is likely. Within a
few days the general condition worsens, hospitalizationis needed. The patient then develops sore throat andpharyngitis, accompanied by swelling of gingiva andtonsils and petechiae in the skin with a tendency to bruise
easily, followed by bleeding from gums and ulcerations
on gingiva and tonsils. Similar ulceration in the intestines causes a renewal of diarrhoea. The patient has highfever with complete anore..xia. Weeks 5-6. with agranulocytosis, anaemia, and infection, are critical. The increased susceptibility to infection is caused by the dose
dependent decrease in circulating granulocytes and lymphocytes, impairment of antibody production, impairment of granulocyte and RES function, lessened resistance to diffusion in subcutaneous tissues, andhaemorrhagic ulceration permitting entrance of bacteria.
Thereafter, if the patient recovers, fever, petechiae andRadiation sickness

196. After a single dose of radiation of SO rad and

CNSform

199. The clinical picture of the CNS form must be
extrapolated from animals and a few accidents in man.
The onset is prompt and death may occur in minutes tohours. After the initial phase of radiation sickness, thereis swift progression from listlessness, drowsiness, andlanguor to severe apathy, prostration, and lethargy probably caused by small non-bacterial inflammatory fociappearing throughout the brain in 1-2 hours; this development of vasculitis or encephalitis gives rise to cerebral
oedema. After > 5,000 r, one deals with seizures ranging
from generalized muscle tremor to epileptoid convulsions similar to grand mal. This convulsive phase lasts a
few hours and is followed by ata.'Cia from vestibulocerebellar disturbance. Convulsions and ataxia probably result from the degenerative pyknosis in the granule layerof the cerebellum within two hours after exposure,concomitant with brain oedema. TBR causing the CNS
syndrome is fatal.

139

exposure; a fall in white count beginning within the firstweek denotes a rather high exposure whereas late falls,
such as observed in Marshallese, indicate a less serious
e.xposure;(iv) The platelet count, while being of some prognostic value, is of more importance in the general management of the patient. In general, the fall in platelet
count would parallel the change in neutrophils, althoughoccurring somewhat later, and the neutrophil count ismore readily available, particularly in accidents awayfrom hospital centres;(v) The reticulocyte count would sen•e as a guide as
to the extent of erythropoietic damage. Fe59 turn-overstudies would be of little value; to be meaningful, theywould have to be done serially and even then would add
little information beyond that derived from the reticulocytes.
( d) Recovery potential
The type and extent of injury following radiation represents a spectntm and it is not possible to divide injury
into clear-cut syndromes. In general, however, at higher
doses, the predominant injury would be cerebral and theoutcome uniformly fatal. With doses lower than this, themajor injury would be to the gastro-intestinal andhaematopoietic systems. Judicious use of fluid. electrolytes, and treatment of the haematopoietic injury as
outlined below provide hope for recovery. In the socalled lethal dose ranges with X- and y-radiation, theinjury is primarily to the haematopoietic system. At
doses of approximately S0-100 rad, symptomatology ismild, and below SO rad, symptoms are virtually absent
even though there is some injury, particularly to haematopoietic tissues.

ecchymoses subside; ulcerations heal and convalescence
begins about the end of the second month after exposure.
These symptoms tend to merge into one another.
Prognosis
203. Early symptomatology in the diagnosis of radiation injury is a useful guide to management.H, 375 • 316
Subjects with intractable nausea, vomiting, and diarrhoea
will generally die-the survival-improbable group. Thosein whom nausea and vomiting is brief, 1-2 days, followed
by well-being. have a good chance to survive.
204. After initial symptoms, the effects of haematopoietic damage predominate. The survival-possible groupare in the lethal dose range. The survival-probable group
includes those with no initial symptoms or only mild andfleeting ones disappearing within a few hours. Practicalexperience on the Marshallese, Los Alamos, Argonne,
Y-12, Vinca and Lod"Port accidents demonstrate thatphysical measurements to compute probable doses takemore time than do several haematological procedures.
The dose must be judged on the basis of symptoms. Thisis especially important in determining management andprognosis when physical measurements are not available,or when radiation exposure has been non-uniform.

(a) Na us ea and vomiting
In general, if nausea and vomiting are absent, it may
be assumed that the dose was relatively low. Nausea andvomiting warrant hospital admission for observation.
The rapidity of onset of nausea and vomiting provides
some notion as to the severity of the exposure: usually,
the earlier the onset and more protracted the vomiting,the higher the dose.
(b) Erythema
Much depends on the type of radiation as to whether
erythema will result. It is difficult to make judgementsof the dose on the basis of erythema but its presence isevidence of a serious exposure.

Prognostic value of the leukocyte count
20S. At Operation Crossroads depression in leukocyte count correlated with distance from the bomb. 377
At Operation Greenhouse 378 there were four groups ofdogs with mortalities of 100 per cent, 100 per cent, 80
per cent, and 10 per cent. In the group given 800 rad,the total leukocyte count fell to zero; all the animals
were dead by day 10. Group 2, given about SOO rad,had a smaller fall in leukocycte count. Group 3, with
80 per cent mortality, received ,...., 400 rad, and group 4,
given 200 rad with 10 per cent mortality, had a smaller
decrease in leukocyte count.
206. Extrapolation to man directly is difficult, because
the rate of change in leukocytes in man as shown in the
Marshallese and various clinical experiences is muchslower.H• 372• 373 Jacobs, et al., 379 re-analysed the leukocyte counts done in Hiroshima and Nagasaki after the
explosion ; despite the limitations of the data depression
in total leukocyte count at different times correlates
well with survival. The treatment of the acute radiation
syndrome in man is discussed in section VIII.

( c) H aematopoietic and bone-marrow picture
Where casualties are few it is simple to carry out all
haematological procedures and other studies that might
be of value. In a radiation disaster, extensive studies
would be impossible, although many leukocyte counts
would be practical with modern electronic counting
devices:(i) Lymphocytes are valuable as an early criterion for
judging radiation injury. In normal individuals, a fall in
lymphocytes is seen within the first 24-48 hours. If at
48 hours the lymphocyte count is 1,200 or above, it isunlikely that the individual has received a fatal exposure ;if the lymphocyte count is in the 300-1,200 range, a dosein the lethal range may be suspected ; counts below 300
indicate an extremely serious exposure;(ii) Early bone marrow examination is advisable fordetermining whether the patient was haematologicallynormal at the time of exposure and might give someinsight to the extent of damage. Some workers consider
that multiple bone marrow examinations would be no
more helpful than peripheral blood examinations andhave the disadvantage of being potential sources ofinfection. Cronkite and Bond have proposed a determination of the mitotic index in bone marrows on day 4
as a measure of dose exposure--a mitotic index of zero
indicates an exposure of 200 rad or more.
(iii) The total white-cell count is of particular value
for following the patient throughout the course. In general, the drop in neutrophils will reflect the degree of

ANALYSIS OF PAST ACCIDE!\TS

207. There have been at least eight major radiation
accidents:
Los Alamos I ......... 21Aug.1945 Criticality (experimental
assembly)
Los Alamos II ........ 21 May 1946 Criticality (experimental
assembly)
Argoooe ............. 2 June 1952 Criticality (reactor)
USSR ............... ?
Criticality (reactor)
OakRidge ........... 16June1958 Criticality (processing)Yugoslavia ........... 15 Oct.1958 Criticality (reactor)
Los Alamos III ....... 30 Dec.1958 Criticality (processing)
Lockport, New York .. 8 Mar.1960 Radar X-radiation

140

Several isolated cases of pericardia! effusion and constrictive pericarditis have been reported in patients given
radiation therapy to the chest. aso-as~

The Idaho SL-1 reactor accident on 3 January 1961 is
not discussed because the three fatalities were caused byblast from the nuclear excursion. The immediate dose
calculations in the above accidents were of necessity very
uncertain and probably not too meaningful. In the studyof reconstituted accidents more accurate dosimetry has
been obtained particularly from the point of view of nonuniformity of the exposure. Even here, there are important practical difficulties in assessing e."Xposure when with
the neutron component significant dosimetry is further
complicated by considerations of distribution and RBE.
In the present state of knowledge the doses presented
should be considered as approximate orders of magnitude rather than exact measurements.

211. The second fatality received an estimated average dose to his torso of about 2,000 r of soft and 150 rof penetrating radiation, with considerably greater exposure of his hands. The patient vomited on his way tothe hospital. Both hands were swollen within an hour<:fter the accident. His temperature, pulse. and respiration rose abruptly on day 6 and increased until death on~ay 9_. His hospital course was characterized by severe
mtestmal symptoms, with almost complete paralytic ileus
and extreme abdominal distention. Continuous 0CTastricsuction was required. He had no diarrhoea. Both arms
packed in ice, were in effect amputated. The most strik~
ing features of the patient's blood count were the initialhigh white count, the complete disappearance of all
lymphocytes from the peripheral blood by day 2, and theabrupt fall of the total white count on day 6. Thesefindings are similc:r to those in the first case. At autopsy,
am<?ng other findmgs, there was severe damage to intestmes.
212. Case 4, a 34-year-old man, received an average
estimated dose to the entire body of 400 r of soft and
40 r of penetrating radiation. His head and upper chest
are believed to have received a larger dose than the restof his body. On day 5 he developed fever, along withlethargy and somnolence for no clear cause at the time.
The fever may possibly have been associated with damage to the CNS like that in the Lockport accident. His
lymphocyte count fell to below 1,000 cells/mm 3 by thesixth hour after exposure.
· 213. This patient had severe fatigue 15 days after exposure on discharge from hospital, and at first had 16
hours bed rest per day, improved gradually and wasback to normal in 10 weeks. Although completely aspermic for several years after e."Xposure, he recovered completely, lived an active normal life, and became the fatherof an additional t\vo normal children. The patient had
mild hypertension at the time of e."posure. In the ne."tseveral years his blood pressure rose but ''tas treated successfully with reserpine. In 1955, aged 43, the patient had
a severe posterio-lateral cardiac infarction. (It is difficult
to relate this to his radiation exposure. The patient's
coronary vessel probably received a relatively small dose.
Patient's father died of a heart attack in his early 40's.)
Within a year after the heart attack a diagnosis of acute
myxedema was made. From clinical findings and laboratory tests this condition had undoubtedly been present
for several years, and contributed to the coronary thrombosis. Whether radiation exposure to the neck was responsible for the thyroid damage is uncertain.

First and Second Los Alamos accidents
208. The first nuclear accident occurred at Los
Alamos on 21 August 1945 and the second on 21 May
1946. 380 • 381 The accidents occurred during experimentswith critical assemblies of a fissile core surrounded byneutron reflector material. In the first accident the reflector was tungsten carbide; in the second beryllium.
In both accidents the man doing the experiment wastouching the reflector at the time of the reaction. Exposure of these two fatally injured operators was nonuniform; hands and arms received the largest dose,abdomen and chest somewhat less, and head and legs thesmallest. All others were presumed uniformly exposed,e."'Ccept for case 4, whose body from mid-chest down waspartly shielded at the time of the second accident. The
head, upper chest, and left arm of this patient received
the highest dose.
209. Dose calculations are uncertain and probably notparticularly meaningful; e.g., if 5 per cent of neutrons
had an energy exceeding 5 mev the dose ·would havebeen increased by 45 per cent; the choice of RBE wascritical. 'With these reservations, five cases received an
estimated dose of less than 100 rem of soft radiation andless than 10 r of penetrating radiation. Case 6 (dose unavailable) had no symptoms of any kind after exposure.
:r~~ on~y l~boratory findings of significance were an
1mtial nse m granulocyte count and a lymphopenia ofless than 1,'?00 cells/mm 3 from day 40. The lymphocyte
count remained low for two years. In 1959 the patient
retired, aged 68, with no signs of injury and a normal
blood count.
210. Case 1, received an estimated average body doseof 840 rem of soft radiation and almost 500 r of y-rays.
His hands and arms, especially the right, received many
thousand r. His hands and arms were tensely swollen
30 minutes after the accident, and soon thereafter hebegan to vomit and retch almost continuously for - 24hours. His temperature rose gradually reaching 41.7° C
re~tally on. the day of death 24 days after e.xposure.
His pulse increased abruptly on day 6 and remained
high with an episode of acute paroxysmal tachycardia
on day 15 following a blood transfusion. Cardiac symptoms, abnormal electro-cardiograms, low blood pressure,enlargement of heart with friction rub were related at
the time to his known congenital defect (WolfeParkinson-White syndrome). The patient had e.xtreme
necrosis of the tissues of hands and arms, and extensive
third-degree bums of the body extending to the precardial region. The underlying heart undoubtedly received a high dose. At autopsy, the heart showed extreme
fibrinous pericarditis with no microscopic evidence ofdamage to cardiac muscle. At the time this response wasrelated to his known cardiac defect but in retrospect thisprobably represented radiation injury to the heart.

Argonne accident
214. A reactor criticality accident occurred at Argonne Laboratory on 2 June 1952. Four persons were
exposed to a mixed field of radiation, y-neutron dose
ratio - 10 : 1. Clinical and dosage details were reported. m, ass There were no deaths. The calculated doses
range from 10.8-159 rad.
USSR accident
215. One reactor accident has been reported in the
USSR causing "short general external e.."posure" of two
people to neutrons and y-rays. 386 Doses of 300 r and
450 r were assigned but no y-neutron ratio was given.
Since fuller data are not available these dosages are
uncertain.
141

slavs showing generally more severe injury; (c) haematological recovery occurred at about the same time after
exposure in the two groups of patients ; this and the factthat the bone-marrow was given just at this time to the
Yugoslavs, makes enluation of its therapeutic effectdifficult.
219. An international group under the auspices of theInternational Atomic Energy Agency studied the dosimetry of the Vinca accident in a reconstitution of theaccident. 396 The recalculated doses, still under discussion,
were between ,_. 320 to 440 rad in the five treated.

Oak Ridge accident

216. A criticality accident occurred on 16 June 1958
in the Y-12 plant at Oak Ridge. Enriched uranium component was drained ~nadve.rtently into a w'3:ste d~u~387
causing a chain reaction. Eight persons recetYed s1gmficant TBR; five were exposed to 236-365 rad including aneutron component of slightly more than one quarter.
There was no associated trauma, the whole body was
fairly uniformly exposed, and the radiation dose wasrather accuratelv determined. Three persons received
between 20-70 r'ad. In the five higher-dose patients thehaematological values emphasized that TBR in man
causes clearly defined symptoms. Blood and bonemarrow changes appeared over several weeks in welldefined stages : early and persistent lymphopenia andvariable transient leukocytosis ; mild leukopenia during
the first ten days; abortive rise in white cells, and someincreased erythropoeisis at about two weeks ; severe depression of neutrophiles and platelets greatest at weeks
4-6; rapid recovery of platelets and neutrophiles; andanaemia maximal at week 7, with recovery accompanied
by reticulocytosis. This sequence is uniform in different
persons and similar after radiation over a wide rangeof dose. The patients showed the greatest depression ofleukocytes and platelets between days 24-37. All fivepatients recovered from the early post-radiation effects
and have now no visible damage. 888- 890

220. In the follow-up 397 on the Yugoslavs the patients
continued to have slight reticulocytosis, 0.5-1.7 per cent,for several months. Electro-encephalograms showedslight abnormalities characterized by low voltage andinstability ; the tracings lacked the usual individuality ofpatterns expected in five patients and all looked remarkably alike. At 2 years, basal metabolic rates are normal.
Lens opacities developed, decreased, and are no longer
present. The female patient has had persistent menstrual
difficulties with excessive bleeding. In the male patientssperm counts are still very much depressed 2 years later.
The peripheral blood shows light lymphopenia. The patients complain of fatigue and neuro-circulatory instability-evaluation of both symptoms is difficult.
Third Los Alamos accident

Yugoslavian accident

221. A third radiation accident at Los Alamos on
30 December 1958 of a critical e..xcursion, during a routine plutonium salvage operation caused massive overexposure of one man. 398 • 399 The average TBR exceeded
3,000 rad; the dose to the anterior chest was ,_. 12,000
rad, that to the front of the h@ad ,_. 10,000 rad. The victim went into a state of profound shock within minutes.
The outstanding finding was right-sided heart failure
with resulting renal ischemia and nitrogen retention. The
patient died 35 hours after injury.
222. Less than 30 seconds after the accident the patient was ataxic and disoriented, needing support toremain erect. He complained of "burning up" and appeared flushed at this early time. Within 5 minutes hewas virtually unconscious and was admitted to hospital
25 minutes after the accident. At this time, he was semiconscious but disoriented and clearly in general shockwith depression of blood pressure. Vigorous efforts toreturn the patient's blood pressure to a satisfactory level
and to maintain it were made by giving pressor aminesin heroic doses. Five hours after the accident the patient
appeared to be in a satisfactory condition, he was relatively comfortable and mainly at ease. By this time it
was obvious from dosimetric studies that his radiation
exposure had been supra-lethal. His leukocyte count rosesteadily to a peak of 28,000/mm3 but lymphocytes had
virtually disappeared from the circulating blood in < 6hours. He had marked oliguria, voiding a total of < 600
ml of urine onr 22 hours with a total fluid intake of
14 litres in the same period. More than 30 hours after
the accident the patient abruptly became worse. developed increasing abdominal cramps, became more cyanotic, and despite oxygen. lapsed into coma. His heart,that had received nearly 12,000 rad, stopped 34-M hours
after the accident.
223. At autopsy. the picture was that of acute rightheart failure caused by right-side myocarditis complicated by e..xcessive fluid intake. The most striking histological findings were in heart muscle : severe oedema
and beginning degeneration of muscle fibre with cellular217. On 15 October 1958, the zero-energy reactor at
the Boris Kidrich Nuclear Science Institute, Vinca,
Yugoslavia, became super-critical, injuring eight people,
The reactor 'vas constructed with natural uranium rods
suspended in a large tank that could be filled to various
depths with heavy water. Six received significant dosesof neutrons and y-rays. 391- 393 Following a brief hospitalization in Belgrade, the six patients were transferred to
the Fondation Curie in Paris under the care of Dr. H.
Jammet. The early dose estimates described by Jammet,
et al., 391 on the basis of local information from Vinca
were 1,000-1,200 rem for the highest exposure and 300500 rem for the lowest, placing five of the six in a range
considered to be above the LD 50 • All six had the acute
TBR syndrome: nausea, vomiting, anorexia, asthenia
beginning after the first hour and lasting 2-3 days ;thereafter their general condition was relatively good,in contrast with the progressive evolution of haematological and cutaneous changes: fall in lymphocytes, thengranulocytes, thrombocytes, and erythrocytes. Towards
the end of the fourth week and during the following
weeks there was a worsening in general condition withfever and clinical evidence of haemorrhagic disease. The
individual originally believed to have received the highest dose was given foetal bone-marrow on 11 November,and the four patients having the next highest exposure
were given homologous bone-marrow from adult donors
at various times between 11 and 20 November. The man
who received the foetal bone-marrow died as a result ofradiation with no immunological reaction. Extensive
clinical studies have been detailed. 391 • 394
218. Comparison of the haematological and otherclinical effects of the four YugoslaYian accident victims
who survived after bone-marrow infusion with the fiye
men exposed to 236-365 rad at the Y-12 plant, leads tothe following conclusions :395 (a.) the effects of injury
suggest a somewhat higher dose in the Yugoslavian thanin the Y-12 accident; ( b) haematological patterns in thetw"o groups of patients are remarkably similar, the Yugo142

exudate between fibres showing the presence of true
interstitial myocarditis. In short, this could be termed a
cardiac death. It should not be regarded as representativeof all kinds of radiation injury to the heart, as in aslightly different position he could have received mostof his e.xposure to the left side of the heart. In otheraccidents, other parts of the body might receive thegreatest dose and other mechanisms of quick radiation
death are possible.

Lock port accident
224. On 8 March 1960 nine technicians were exposed
to pulsed X-radiation from an unshielded klystron tube
at Lockport, New York.~ 00 Two of the exposed wereseriously injured, five others less seriously damaged,
while two remained asymptomatic during observation.
Shielding of greater or lesser areas of the body in men
working closest to the tube was critically important indetermining the outcome. To date, satisfactory integrated dose estimates of the entire body in any of themen are not available. Clinical e.xposure appeared tohave been greatest over the right side of the head, rightarm, and axilla of A, the man most seriously injured.
Exposures of the nine varied with their individual activities. The best present estimates are that doses to A
could have been as high as 1,200-1,500 r over certain
parts of the body. Since even a few inches back andforth would result in major changes in e.xposure there
is considerable uncertainty. B's e.xposure is slightly lessthan A's due to his smaller stature and slightly different
position. C's position on the floor limited his e.xposure
largely to head and upper chest. The ne.xt four, D, E,
F, and G, were exposed over greater portions of theirbodies for 60-120 minutes at 6 inches at 4-6 feet, and
H and J were minimally e.xposed for ,...., 120 minutes
at 8 feet. Nevertheless, because of the pulsed nature of
PLATE.
10-3

x

WBC

x 10-3 ·400-10350

9B

INITIALERYTH.
2nd WAVEERYTH.

l

3rd WAVEERYTH.

K.S. HEMATOLOGICAL CHANGES300(MODIFIED CURVES, REPRESENTATIVE POINTS)

7250

the radiation, the actual e.xposure time was only 7.2
secondsjhr.
225. A was exposed from head down to mid-thigh,B from head to pubic symphysis. C was e.xposed largely
above the shoulder level. Throughout e.xposure the men
were unaware that they were being irradiated. Nevert11eless, symptoms appeared during e.icposure, severe
enough to make B and C seek medical aid on their way
home. Headache was the first complaint, beginning during exposure and described as severe, deep within thecentre of the head, and unlike any headache ever experienced before ; even walking around caused intolerable pain. The headache persisted for several hours after
exposure. Nausea and vomiting began in the most seriously injured shortly after the beginning of the headaches. Vomiting persisted throughout the first day;nausea subsided very slowly. The most seriously injured
man continued to have morning nausea for a week after
exposure and sporadically for several weeks. Of all thesymptoms, nausea and fatigue were the most persistent.
With the exception of F all the e.xposed developed conjunctiva! reddening. In A conjunctivitis and acute eyepain was followed by the development of haemorrhage
and exudates in botl1 eyes, with severe interference ofvision in the right eye due to macular involvement. His
eye difficulty has continued to be present and has changed
only in that the acute symptoms have subsided. Visionin the right eye did not improve and that in the left
eye remained stationary. Parotid swelling was the most
severe in A. Both A and B had temporomandibttlar
tenseness and pain on moving the jaw. Treatment wasconservative throughout the patients' hospital course.
In A an initial wave of erythema was present during thefirst 7 days after exposure, a second wave between days
13-19, and a third wave, also seen in B, D and C, between
days 24-29. These waves are shown in figure S that also

6

200-5

•

• (

TOTAL WBC/mm3

•
0

150

3
100
2
3
/YMPHS./mm

50""-MoNOS./mm3

30

40
50
60
DAYS POST EXPOSURE

70

80

90

100

Figure 5. Graph showing the periods of erythema and levels of leucocytes, platelets, lymphocytes,
and monocytes in K. S. (A) injured in the Lockport accident•o 0143

shows changes in the total white count, platelets, lympho·cytes, and monocytes.
226. A's total leukocyte count fell from the time ofadmission until approximately the sixth post-exposure
week. At that time minimal counts of,.., 1.400/mm3 wereseen. Monocytosis was a prominent feature of the peripheral blood during acute stomatitis present days 7-15.
Lymphopenia was severe in this patient and was an important indication that A had sustained major radiation
injury. Platelets reached minimal level of 35,00040,000/mm3 cluing the fifth post-exposur<: week. There
was no evidence of abnormal bleeding, with the exception of a few petechiae on the palate and one foot during
the fourth post-exposure week.
227. At day 38, A became febrile, somnolent andmentally depressed ; these symptoms increased, so thatat day 44 he was moderately ataxic with transient paresthesias of the right arm and left hand, and mild transientreflex changes. These neurological symptoms varied over
12 days. Electro-encephalograms showed multiple, large
and small focal abnormalities. The records improved
gradually, until a normal record was first obtained on
12 September 1960. Mild fatigue with improvement inover-all symptoms continued at day 210.
228. In A there was complete aspermia by the sixth
month, with complete return to better than normal values
at the end of one year. Sperm samples of the others
showed at most only the minimal depression during theacute phase.
229. Follow-up examinations on A, B and D at one
year showed all observations on B were normal, progressive deafness in D-apparently traumatic-but no othersignificant findings, continuation of the eye symptoms
in A, complete correction of aspennia, secondary loss ofhair over the right temple and eyebrow, and mild
asthenia.
AssESS:MENT OF INJURY
230. At present, the severity of illness following radiation damage can only be assessed by comparing the
response of the patient with that of others previously
exposed under similar conditions, who have survived orhave been fatally injured. For this reason, detailed information concerning radiation dose, exposure conditions, and the clinical course of each patient injured byradiation should be available to all likely to be concernedwith these conditions. There is need for further biological indicators of radiation damage, other than theexisting methods, of which the early rate of fall andultimate depression of lymphocytes appears the mostsensitive. A number of patients from reactor accidents
showed a high urine level of amino acids 380 •" 01 and it was
hoped that this might serve as an inde.x of tissue breakdown.381 The metabolism and re-utilization of aminoacids by the body is so rapid that their release fromproteins being quickly broken down after irradiation canbe shown only by the use of special research techniques402"403 not yet applicable to clinical diagnosis.
231. Creatine excretion in the urine is a good indicator of muscle break-down. Patients with muscular
dystrophy excrete large amounts of creatine. It is possible that the weakness of irradiated patients might also
be reflected in e.xcretion of excess creatine. Radiationinduced creatinuria has been studied. •04-ti0s There is acorrelation between large integral doses of radiation tomuscle and creatinuria. Since creatine estimations are
simple and accurate this would appear to be a promisingline for further study. Similarly the excretion of betaamino isobutyric acid is an index of the break-down ofcell nuclei but the analytical method is less simple.
V. Late effects of irradiation in man,
including carcinogenesis

LIFE-SHORTENING
Effect of long-term radiation on life-span in man
232. The problem of extrapolation of animal lifeshortening data to man is difficult because of the lack ofdata on life-shortening for large animals with life-spansintermediate between man and rodents. TBR of rodents
shortens life-span; this effect has not been shown unequivocally in man. Three studies have compared mortality of radiologists with other physicians or with thegeneral male population.
233. Dublin and Spiegelman409 investigated 2,046
deaths of United States medical specialists age 35-74,
1938-1942. Mortality in all specialist groups was lessthan that for all physicians, but mortality of radiologists
and dermatologists was l 6 per cent and 25 per cent respectively above that of all specialists combined. Fromtheir data, the mortality of radiologists and dermatologists, combined or separated, differs from that of specialists not using radiation routinely by an amount bordering on statistical significance. Dublin and Spiegelman
did not calculate occupational risk in differences in life
expectation, but estimated from their data and life
tables for physicians that the difference between radiologists and dermatologists and other specialists is 1-3
years.
234. 'Warren 410 used 82,441 obituaries of physicians
reported 1930-1954 in Journal of the American Medical
Association to compare the mean age at death of UnitedStates radiologists (60.5 years) to that of other physicians not exposed occupationally to radiations ( 65.7
years) ; he concluded that radiologists died 5.2 years
earlier.
235. Court Brown and Doll 411 • 41 " compared the mortality of British radiologists 1897-1957 ·with those of all
physicians and of men of equivalent social class (definedby the Registrar-General). Correcting for age distribution and various biases in vital statistics, they concluded
that British radiologists show no eYidence of lifeshortening. They attribute this to early adoption ofeffective safety measures.
236. These studies suffer from uncertainties and limitations that bedevil evaluations in man. Dublin and Spiegelman did not intend an analysis to apply to mortality
in radiologists specifically. For this purpose their work
suffers from small sample size. Warren's data were notcorrected for age distribution of groups at risk. Seltzer
and Sartwell 413 found "the difference between radiologists and other physicians as to average age at deathcan be accounted for simply by differences in age composition between the two groups". The differences foundby Dublin and Spiegelman included consideration of age
distributions. These data were analysed in annex G of
the 1958 report. 414
237. Vvarren has compared the survival of radiologists averaged over five-year periods ·with survival of
the general population. 415 The latest report giving survival of the general population and radiologists (Warren,
personal communication) suggests that the slope of the144radiologists group is approaching that of the general
population, i.e., the survival of radiologists has increased
from 1930 to 1957 at a more rapid rate than that of thegeneral population. This suggests in retrospect that theevidence of life-shortening in American radiologists
should not be dismissed out of hand. The fact that nolife-shortening was found among radiologists in the
United Kingdom probably reflects not only differences insafety procedures, but also in practice. In the United
Kingdom, most radiology is done in hospitals, and therefore many examinations are made by radiographersrather than radiologists themselves. In the United States
the private practice of radiology is much more extensive,
and the radiologist tends to do this himself. Fluoroscopy
is much more extensively practised in the United States
than in the United Kingdom and probably the numberof X-ray films used in radiographic examinations islikewise greater.
238. A lower limit can be set for life-shortening of
United States radiologists by considering leukaemia incidence only. A statistically significant excess of leukaemia among those radiologists has persisted for years,
decreasing recently;ns-m This is equivalent to a lifeshortening of 3-12 months, depending on assumptions.
239. In conclusion, occupational exposure of UnitedStates radiologists increased mortality in past decades,
but the radiation doses and distribution are unknown.
The exposures must have been heterogeneous withhands, arms, and upper body receiving the most. A lifeshortening effect in man after substantial TBR is to
be expected from animal data. Despite uncertainties,
data on radiologists and other medical specialists represent one of the best available means for studying lateeffects of radiation in man.
CARCINOGENESIS IN MAN

240. It was early known that skin cancers were common in radiologists and dermatology patients. Later,
radiation-induced tumours were seen in haematopoietic
tissue, bone and thyroid. Increased leukaemia has beenreported in United States radiologists, in Japaneseatomic bomb survivors, in children irradiated in infancy
for benign conditions (usually thymic enlargement) andin ankylosing spondylitis patients. Some retrospective
studies have reported that a greater proportion of children with leukaemia and other malignancies were e.'Cposed to X-ray in utero than selected controls \vithout
malignant disease.

fifteen-year period, is about 100 cases per 105 persons
per 100 rad for each year at risk. This estimate is probably too low in children and too high in adults. Additional data are needed for selected age groups.
242. Large amounts of e.xternal radiation, protracted
over a long time given to the entire body or a large segment of bone marrow, are leukaemogenic in man. Nevertheless, present uncertainties about the influence of doserate, fractionation and total dose make it impossible toestimate the probability of leukaemia other than undershort-te~ exposures to high doses. l\foreover, long-term
exposure 1s probably less leukaemogenic than short-term
e.xposure for the same total dose.
243. !1 31 given in high doses, e.g., therapy of carcinoma of the thyroid has in some cases caused leukaemia. •55
244. Cases of leukaemia in which a relationship toradiation exposure was shown' 27 • 428 indicate that withfew e.xceptions the leukaemia was either acute or chronic
granulocytic. In the United States and United Kingdom,
the commonest chronic leukaemia is lymphocytic; its
increasing incidence has not been correlated with irradiation.
Situations in which a relationship betwee!I- radiation andleukaemia has been suspected but not established245. It is not known whether short-term e.""<posure todoses of less than,...., 100 rad given to the entire body or a
portion is leukaemogenic. In particular there is a question about an increased incidence of leukaemia amongchildren exposed in utero, during diagnostic pelvimetryof the mother.' 28431
246. There are no documented cases of leukaemia as alate effect of radio-isotopes such as Sr89• 90 and radium
at any body burden. With thorium while there are ninerecorded cases, the relationship between thorium andleukaemia is hard to gauge because of scarce clinical anddosimetric information.
247. Since leukaemia has been seen after irradiationin Japanese, British and sporadically in other nationalities, there is no reason to believe there is any outstanding
racial sensitivity to radiogenic leukaemia.
Leukaemia in the Japanese survivors of the atom bomb
248. The increased leukaemia incidence in Japanese,e.""<posed to nuclear explosions in Hiroshima and Nagasaki, is inversely related to the distance from the hypocentre. Dose-estimates are uncertain even after the results of recent tests which simulated an actual nuclear
explosion with extensive shielding. Heyssel et a/., 425
summarizes studies by the Atomic Bomb Casualty Commission since 1951 on the increased leukaemia in the
Hiroshima survivors and relate incidence to calculated
dose from y-rays and neutrons combined in the open air
at various distances from the hypocentre. In these calculations, they used an RBE of 1 for neutrons. They
estimated that 60 per cent were indoors at the time ofthe explosion, reducing the air dose by 30-70 per cent.
With leukaemia cases diagnosed up to 1957 they postulated a linear relationship between incidence and calculated open-air dose of 177 rad or more. The point, representing the leukaemia incidence of 3,605 persons receiving a mean estimated air dose of 77 rad, falls almoston the line drawn through points at higher doses. No
cases of leukaemia were seen in 3,512 and 1,305 persons
receiving an average estimated air dose of 34 and 19
rad respectively.

Leiekacmogenesis
Sitt1atio11s in which a relationship between radiation andleukaemia has been established
241. Single doses of external radiation to whole bodyat
100 rad or more and irradiation of an appreciable
portion of the bone marrow with ,.._, 500 rad or more.
slightly increase the incidence of leukaemia in man.
There is no evidence of an increase in the first fifteen
months after exposure. In the Hiroshima data, limited
to 2 km from hypocentre, the incidence increased to a
maximum between years 4-7, declined thereafter but was
still above the e.xpected incidence in 1959. The Japanese
data00428 shows that with short-term exposures to doses
greater than ,...., 100 rad, the incidence of leukaemia integrated over fifteen years increases with dose. The exact
quantitative relationship between dose and incidence ofleukaemia is unknown. Assuming proportionality, theincrease over the natural incidence. averaged over the
,-J

145

249. These authors also show that the latent period
between exposure and development of leukaemia depends on dose. They report that nearly all cases in the
exposed and non-exposed persons were acute leukaemi2.
or chronic granulocytic leukaemia. Among the Japanese,chronic lymphocytic leukaemia is very rare ; a very few
cases were found in exposed and unexposed groups andtheir significance, if any, is hard to evaluate. Heyssel
et al., estimate that radiation increased the incidence ofleukaemia rather than accelerated the appearance of
spontaneous cases.
250. For several reasons, individual dose values canbe appreciably in error. At least 200 survived where themean open-air dose was calculated to be 2,620 rad. 488
Allowing for shielding and assuming that they were at
the edge of zone, the doses received, by these calculations, must have been > 100 per cent lethal. In the lowdose region, the accuracy of the calculated doses may beseriously questioned since many victims in the 2,0002,499 metre zone, where the calculated average dose wasless than 10 rad, had symptoms ( epilation, oropharyngeal lesions, and purpura) 427 suggestive of severe radiation dosage. The calculated dose is far below that producing radiation sickness after TBR and it may be thatthe quoted doses are a serious underestimate because of
the contribution of induced radio-activity. On the other
hand, since victims even farther away were also said tohave similar symptoms it is the consensus of opinion of
the observers 438 who interviewed these patients that their
symptoms were complicated by malnutrition and factors
other than radiation exposure.
251. These studies by Heyssel et aJ,.;m suggest astraight-line relationship between doses above __, 100 rad
and the incidence of leukaemia among bombed Japanese.
Considering the large variation inherent in incidence anddose estimations, the data could also have been represented by a straight line with a different slepe, or by acurved line.428 Although the data are not enough to say
whether the relationship is linear over the entire dose
range, they do allow a conservative estimate of theprobable incidence of leukaemia in a population of allages over the first 10-15 years after a single exposure tohigh doses. A reasonable estimate might be an averageof 100 additional cases per 106 persons per 100 rad foreach year at risk during that period.
252. It is not possible to demonstrate an age-incidence
relationship because of the small number of cases ofleukaemia in Japan although there is some indication ofa higher rate among bombed children than bombed
adults. Hence, prediction of incidence in selected age
groups or calculation of the probability of leukaemia
among the individuals exposed may be speculative.

data of all suspected of dying of leukaemia or aplastic
anaemia ; they calculated from dose records mean doseto spinal marrow and whole-body integral dose of a large
sample. There were thirty-two proved and five probablecases of leukaemia and four cases of aplastic anaemia ;the number e..xpected from national vital statistics was
2.9 for leukaemia and 0.3 for aplastic anaemia, a significant increase in mortality from these causes.
255. They estimated the annual incidence of leukaemia for the general male population not therapeutically
irradiated to be 50/106. The annual incidence in man
given a mean dose of over 1,750 rad to only spinal marrow was 1,600-1,700/106 • For all patients regardless ofsite of exposure, the. annual incidence was 7,200/106,
with a mean spinal marrow dose of over 2,250 rad.
256. Classifying cases by mean spinal marrow andintegral dose shows a correlation between dose and leukaemia incidence. The shape of the incidence-vs-dose
curve depends upon whether mean spinal marrow or
integral dose is used, and whether the cases given e..rjraspinal radiation are excluded. However, whatever the
method of analysis, the relatively small number of casesof leukaemia and the dose parameter used make it impossible to decide whether the dose response relationship is or is not linear (figure 6).
25.0

i!!"'

fj

r:..

.

•

l!ll,0i5§

a 1.5.oe;"":s~ 10.0l!s~eu s.o:;;2.0

MEAN DOS£ lO SPllW.. IMRRO\V, Crl

Figure 6. Incidence of leukaemia in relation to mean spinal
marrow dose of therapeutic irradiation. The regression line
was obtained after weighting the rates according to theirreliability and is given by Y 0.00586X 0.380; the 95 percent probability limits of the value of Y for each value of X
are shown by the curved lines. Redrawn from Court Brown
and Do111ss=+

257. The single point below 500 rad is based on twocases of lymphatic leukaemia, one chronic that developed
after a mean marrow dose of 471 rad, and the other inwhich the spine received 113 rad but extra spinal regions
received additional larger doses.

253. There are some data which suggest an increasein leukaemia incidence in Hiroshima among persons who
were not directly exposed to the atomic explosion but
who entered the area very soon aftenvards. These data
should not be overlooked, although there is great difficu~ty, at the present time, in making any accurate calculation of the dose received from the induced radioactivity.439

258. There were ten cases of leukaemia within five
years after a single course of therapy. 0£ the thirtyseven leukaemias, including those with multiple courses
over years and those with a single course in a month,
the diagnosis was made in thirty-five within five yearsof the last treatment. Of the fifty leukaemias in spondylitic patients after X-rays, including those reported by
Court Brown and Doll, thirty-eight were acute and only
eight were chronic-with only one of the latter being
chronic lymphatic leukaemia. Data in the remainder wereinsufficient to establish clinical type.

Letlkaemia in ankylosing spondylitis
254. Court Brown and Doll 412 • 440 in the United Kingdom reviewed 13,352 patients, presumed to have anh.7Josing spondylitis give;i X-ray treatment to theirspmes, from 1January19;,3 to 13 December 1954. They
reviewed death certificates and clinical and pathological146

259. Some leukaemia patients showed a sequence of
pathological changes : a persistent damaged or aplastic
marrow was a precursor rather than a consequence ofleukaemia; other cases of aplastic anaemia were seen
after the same dose range.

mus glands of normal size at birth. The radiation factors
were uniform; 88 pe~ cent were giv~ 75-300 r (usually
150 r) to the manubnum ; the remarnder were restudied
11-18 years after therapy. Four cases of malignant disease, including one of leukaemia, were expected in thisgroup; none was found. There was no significant difference between the number of expected and observed casesof cancer and leukaemia in untreated siblings.

260. In attempting to e."'{trapolate the incidence data
to low doses, use of the incidence of spontaneous leukaemia in the general population as a control is questionable since there appears to be a strong hereditary
factor in ankylosing spondylitis.441 This is underscoredby the report of Abbott and Lea4 ·12 showing an association between untreated rheumatism and leukaemia. The
only available control group of 399 untreated spondylitic
patients is too small to be useful.

267. The failure to find the four expected cases ofneoplasia is not significant, since one-tenth of the group
was not located. One can conclude, nevertheless, that
there was no evidence of an increased cancer rate intreated children or of a greatly increased leukaemia
frequency.
268. To avoid variables due to considering children
given X-ray therapy to the mediastimal region only, a
study was made of 6,473 children in Rochester, New
York, treated with X-rays for various benign conditionsin the past twenty-five years. 434 The difference between
the eight leulrnemia cases observed and the two e.xpected
is significant. There were five leukaemia deaths in 2,750
children treated for thymic enlargement; two were inseventy-five children treated for pertussis and one in
1,073 children given X-rays to the head and neck region,
mainly for lymphoid hyperplasia of the nasopharynx.
There were no leukaemia deaths in 2,460 children treatedwith superficial X-rays for benign skin lesions.

261. Because of limited data in the lower dosi;! range
and lack of an adequate control group, this study does
not provide evidence on leukaemia incidence after doses
below 500 rad.
262. Leukaemia is a rare disease; cases after radiation represent only a small portion of its incidence.
Nevertheless, in a single case where the onset of leukaemia associated with radiation exposure occurs within
an appropriate interval after a known single exposure
to over 100 rad, the probability that the disease is due toradiation is high. It is possible to estimate this probability by considering the normal incidence in the population and the probable increase in the incidence of leukaemia after a single high dose.Ha, H 4 This probability
will increase to a ma..ximum around the fourth-seventh
year after e."'{posure and thereafter decrease perhaps ultimately diminishing to the level of the incidence expectedin the general population.

269. Similar surveys of children treated for thymic
enlargement and other benign lesions are now being
made in the United States. Latourette and Hodges 450
reported the incidence of neoplasia in 861 children
treated for thymic enlargement, 1932 to 1951. Most children were treated with 200 r or less, through a large
10 x 10 cm port. The two cases of lymphoma (one being
leukaemia) were more than expected, but not significantly so. One child had a carcinoma of the thyroid andothers had various benign tumours. Snegireft4 51 found
two thyroid tumours in 148 children followed out of
1,131 children treated for thymic enlargement; Moloney,
in a discussion of Simpson's work4 47 mentions sevencases of thyroid neoplasias including two malignancies
in 125 of 700 children so treated.

Leukaemia in children (table VI)
263. Some investigators found an increased incidenceof leukaemia in children given radiation to the thymus;
others have not. There is no satisfactory control groupfor a conclusive statistical evaluation. Simpson, Hempelmann, and Fuller,4'15 Simpson and Hempelmann 446 andSimpson 4 H found in 2,393 such cases in upstate New
Y ork-87 per cent traced ·138-twenty-one cases of malignancy instead of 3.6 e.xpected, and nine confirmed and
one unconfirmed leukaemia deaths instead of one exexpected. Most other malignancies were thyroid carcinomas. There was no significant difference between
expected and observed incidence of cancer or leukaemia
in 2,722 untreated siblings of children in this study.

270. Saenger et al452 reported on 1,644 out of 2,230
children treated for various benign conditions. Of 675
given treatments e.xclusively to the chest, mainly forthymic enlargement, only 124 received more than 200 r.
Eighteen cases of thyroid neoplasia (eleven diagnosed
as malignant) and one case of leukaemia were found in
the entire group. They also report a striking incidence ofmorbidity of all types of non-fatal illnesses in thesechildren, indicative of the selected nature of the group.

264. Exposures measured in air were known or calculated from radiation factors for all but 299 children.
Four of the IH1own leukaemias were in 1,050 children
with a cumulative exposure of less than 200 r, 5 were in
1,025 children given 200-600 r. All other malignant neoplasias were among children given 200 r or more. Average survival between irradiation and death from leukaemia was 5.3 years.

271. From these studies it is clear that an association
between radiation e.xposure and subsequent leukaemia
has been established only in one group of children treatedwith X-rays for thymic enlargement. Further epidemiological studies are needed to establish the true incidenceof leukaemia in children given thymic irradiation, andespecially the relation of incidence to dose, port size, andpart of body treated.
272. Numerous studies of children given radiation to
the thymic region showed an increased incidence of thyroid neoplasia; in contrast, an increased leukaemia incidence was found only in one study.
273. Long-term exposure to radiation will increaseslightly the incidence of leukaemia in man. This opinion
is based mainly on the reported increased incidence of

265. Since the state of the thymus gland in the siblinggroup is unknow-n and is, in general, normal in childrenof the general population, this study does not differentiate between the association of leukaemia and (a) X-ray
e.xposure, or ( b) thymic enlargement. Because it is impractical if not impossible to get an accurate control
group, (i.e., children with thymic enlargement at birth
not treated with X-rays), children irradiated for otherreasons must be studied.
266. Conti et al:m,m studied in 1948 1,564 children
treated with X-rays in Pittsburgh-96 per cent had thy147

leukaemia in United States radiologists and the appearance of sporadic cases f?llow.ing long:term exposure
from diverse sources. 428 Smee mformabon on dose andother data are poorly documented, this evidence is not as
good as that for short-term radiation. Data are inadequate to allow even a guess as to relationship between
dose and induction of leukaemia after long-term exposure. Experiments in animals indicate that the leukaernogenic effects of cumulative doses are less in longterm than in short-term exposure. 269 Whatever the dose
rate in long-term radiation, it is likely that the cumulative
dose exceeds ,...,, 100 rad in those cases where leukaemia
is believed to have been induced by radiation.
Leukaemia in radiologists
274. Among United States physicians the ratio of leukaemia deaths to total deaths between radiologists andnon~radiologists was 10.3 :1, 1929-1943,416 6.7 :1, 1944 to1948 417 and 3.6:1, 1952-1955.418 The downward trend
probably reflects better precautions by radiologists andpossibly an increase of leukaemia among non-radiologists. From 1938 to 1952, there were seventeen leukaemic
deaths in United States radiologists ( 35-74 years of age)-an average annual rate, after correction for age distribution, of 610/10 5 compared with the population average, 121/106 •410 The ratios vary, depending upon timeand corrections for age distribution.
275. Braestrup' 53 estimates that radiologists working
with old-type X-ray equipment and few protective measures received as much as 100 rad per year ; that exposure
before 1930 was considerably higher; and that at present
it averages considerably less than 5 rad per ye'!-r. ~isestimates of accumulated total exposure of a rad1olog1st
using old-type X-ray machines was about 2,000 rad during forty years of practice. Lewis09 assumes the average
exposure of all radiologists to be 30 rad per year or
1,200 rad in forty years. However, these estimates andassumptions of dose must be treated with great reservein view of the uncertainty involved in their derivation,and it also has to be recognized that the distribution ofradiation dose throughout the body was far from
uniform.
276. In contrast, British radiologists who began practice after 1921 have had no increase in leukaemia; theonly two known cases were among those in practice
before this time,m probably for reasons previously discussed in the differences in life-shortening.
Pelvic irradiation and leukaemia in children (table VII)
277. In an extensive retrospective survey, Stewart.
Webb and Hewitt430 interviewed mothers of : (a) 677 of
792 children under ten certified as having died of leukaemia in England and Wales, 1953 to 1955; and (b)739 of 902 children under ten certified as dying in thesame period from other cancer. They also interviewed acontrol group of mothers whose children were still alive
and who were matched with the study children for age,
se.x, and locality. They found a higher frequency ( 13.7
per cent) of diagnostic X-ray pelvimetry in mothers ofchildren dying from cancer than in mothers of control
children (7.2 per cent). There was some correlation
between size of the ratio between numbers exposed toabdominal irradiation and number of X-ray films reported to have been taken. The ratio was highest formothers exposed during the first few months of pregnancy.
278. Four similar retrospective studies were made indifferent parts of the United States. Ford et al.' 31 corn-pared seventy-eight leukaemic children and seventy-fourchildren having other malignancies with 306 dead controls matched for colour, age and place of death in New
Orleans. Their findings are in line with observations of
Stewart et al. 430 26.9 and 28.4 per cent of the children
with leukaemia and other forms of malignancy were
irradiated in utero, compared with only 18.3 per cent ofcontrol children.
279. The three other studies, using other methods forselecting controls, do not show the same excess of foetal
irradiation in leukaemic children. Polhemus and Koch' 33
found no significant difference in the history of pre-natal
irradiation in 251 diagnosed leukaemic cases in theChildren's Hospital of Los Angeles, compared with thesame number of matched control children with nonorthopaedic diseases on the surgical service of the same
hospital. In a current study of childhood leukaemia in
California, Kaplan and Moses 432 found that the numberof children with leukaemia having a history of pre-natal
irradiation exceeded that of the group of siblings used
as controls; such an excess was not seen, however, when
the leukaemic children were compared with healthy playmates. Murray et al. 434 found no significant differencein the history of pre-natal exposure of sixty-five children
with leukaemia, sb::ty-five matched dead controls, andthe 175 living siblings of both groups.
280. In these retrospective studies, the choice of thecontrol group is crucial. The studies as presented do notdifferentiate clearly behveen the association of leukaemia
and (a) the effect of the medical condition which
prompted the diagnostic e...xarnination, or ( b) the effectof X-rays.
281. In an extensive prospective study on the incidence of leukaemia after exposure to diagnostic radiation in utero, Court Brown, Doll and Bradford Hill " 8 ·" 36
followed up 39,166 live-born children whose mothers had
been subjected to abdominal or pelvic radiation during
pregnancy, 1945to1956. Among their children nine were
found to have died of leukaemia before the end of 1958,
instead of the normally e...xpected number, 10.5.
282. It is clear, therefore, that existing data on sequels
to irradiation in utero have led to conflicting conclusions.
Stewart's data are very important for evaluating somaticeffects in man as they are the only data pointing to low
doses of radiation being carcinogenic. Because of theirserious implications, the circumstances surrounding
these data must be understood. If these data are not misleading for reasons yet unknown, one would have expected double the incidence of leukaemia in the Court
Brown, Doll, Bradford Hill study just cited. i.e., twenty
cases instead of the nine actually found. The data of
Court Brown et al. thus put into doubt the conclusions of
Stewart et al. On the other hand, if the ratio from
Stewart et al.'s 429 earlier report is used, 1.7 :1 instead of
2 :1, the difference between the expected figure of 17-+- 4
and 9 -+- 3 is not such that a definite conclusion can be
drawn.
283. The conclusion of Stewart et al.4 30 also implies
that foetal haematopoietic tissue is much more susceptible to the leukaemogenic effect of irradiation than adulttissue. As previously stated. it is not known whether
short-term exposure to doses less than ,_, 100 rad to theentire body or a portion is leukaemogenic. Neverthelessto answer the question raised by the data about the incidence of leukaemia among children exposed to diagnostic
pelvimetry in utero certain theoretical estimates can be
made. Such estimates for the adult suggest that 1 rad tobone-marrow produces one case of leukaemia per million
148

closed sample, are subject to the factors of selection thatmight enter into the admission of cases to this series.
With this important reservation the incidence increased
in inverse proportion to hypocentre distance. If the background incidence of all malignant neoplasms. i.e., 280
per 100,000 among the non-irradiated population is subtracted from the incidence of malignant neoplasms thecurve is linear and parallels the incidence of leukaemia(figure 7). The incidence correlated to site was higher
in all age groups (figure 8). Table VIII shows a significant difference between observed and expected cases ofcancer of stomach and lung at the 1 per cent confidence
level, while differences in cancer of the cervix and ovary
are significant at the 5 per cent level. though the numbers
are still small. These preliminary observations need extension in numbers and time so that the increased incidence of carcinoma developing only after many years oflatency after irradiation can be correlated with dose andtemporal occurrence.
288. Despite the numerical weakness of the data, 455 thedegree of initial leucocyte count depression in the first
fourteen weeks after e..xposure correlated with the occurrence of late effects. The data indicate that the more
severe the initial exposure as indicated by clinical signs
and early laboratory work, the oftener late effects appear(figure 9).

persons per year for perhaps ten years of risk. Since thenormal annual incidence of leukaemia in England and\:Vales under age ten is ,...., 37 per million and the amountof radiation received by the foetus from irradiation of
the mother's abdomen is estimated to be ,...., 1 rad, it follows that if this dose were to double the incidence of leukaemia in children it would have to be ,...., 40 times moreleukaemogenic than the same dose in the adult.
284. Although foetal tissue appears more radiosensitive than adult tissue, e.g., foetal nervous and thyroid tissues are more radio-sensitive than their corresponding adult tissues, there is no evidence that thisholds for haematopoietic tissue. In fact, adult haematopoietic tissue appears to be the one adult tissue that is as
radio-sensitive as embryonic tissue. From their study ofpatients irradiated for ankylosing spondylitis, Court
Brown and Doll412 estimated the dose to marrow that
doubles the expected incidence of leukaemia to be
30-50 r. Assuming that the leukaemogenic effect of radiation is the same in foetus and adult and that 40 r is the
doubling dose, and that radiation to the foetus in utero
is as high as 4 r, one would not expect to find more than a
10 per cent increase in leukaemia in children irradiatedin utero, i.e., in the Court Brown, Doll and Bradford
Hill study the increase to be expected over the estimated
10.5 would be one case.
285. Doubts about the controls in Stewart et al.'s
study have been discussed.rn A probable bias is underreporting of radiation exposures by the control mothers
since it is reasonable to suppose that mothers of deadchildren would recall the events of pregnancy more completely than mothers of children who are alive and well.
In the light of the study of Court Brown et al. 435 thequestion of the effect on the foetus remains open. Clearlya further study of this problem is needed.
286. It has not been established whether internal emitters selectively deposited in bone (bone-seekers) but notdelivering a uniform dose to the marrow are leukaemogenic in man. The apparent increase in leukaemia among
patients with polycythemia vera treated with P 32 is suggestive but not conclusive in the absence of an adequate
control population. Leukaemia has followed giving !1 31
in high and repeated doses in patients treated for carcinoma of the thyroid. Leukaemia has also been reported
after treatment of hyperthyroidism with relatively small
doses of !131 • In the latter instance, since the number ofcases is small and there are metabolic and other complicating factors in these patients, it is not possible to decide
whether or x;ot. radiation alone at this ~osage level isleuka_emog~mc m ~1.1· ~ recent ~xtens1ve survey byPochm• 55 gives no mdicat1on that this treatment induces
leukaemia. Mouse leukaemia has been induced with boneseekers ;456 however, it is questionable whether this disease, or the conditions or irradiation and tissues irradiated, are comparable to those for man. An estimate of
the probable incidence of leukaemia from deposition of?r90 has be~n computed. 419 No confidence can be placedm such estimates because of lack of meaningful estimates of dosage to the marrow. Data obtained from e..--.;ternal exposure studies• 2 ~ 2 e,._.o, 4H are not directly applicable in the case of non-uniformly deposited isotopes.

LoC.\L EFFECTS

Radiation cataract
289. Exposure of the optic lens to X-rays, y-rays,,8-particles and neutrons causes cataracts in man.

2000

1000

roo
400
0
0
0

200

CJ~

... 1000......

"'c.

u
"'
c:

u"'

60
40

~~\

',

~,

',

'O

= 20
10

\.

~Total Ieukaemias

6
4

\.

2

Distance from hypocentre in metresI I
I I I IMALIGNANT NEOPLASMS IN THE JAPANESE SURVIVORS OFATOMIC BOMB

1000

100 50 10 5

Air close {rad), without consideration for individual shielding

287. Harada and Ishida•~r have recently reported on
the incidence of neoplasms among survivors at Hiroshima during May 1957-December 1958. These aretumour registry figures and the data, not based on a

Figure 7. All malignant neoplasms (including leukaemia) among
atom bomb survivors, May 1957-December 1958, and total
leukaemias, 1950-1957, by distance from hypocentre per 100,000
population per year. Modified from Harada and Ishida •57

149

small granules and vacuoles develop as it enlarges. The
central opacity develops a relatively clear centre, giving
it a doughnut appearance by the time the opacity is
3-4 mm in diameter. At this time, granular opacities andvacuoles may develop in the anterior sub-capsular regionof the lens, usually in the pupillary area. The opacity
may remain stationary at any stage. Often it shows aslow progression for a long time to the point described
before it remains stationary. If the opacity progresses,
it takes on a non-specific appearance and cannot be differentiated from cataracts from other causes.

J.coo

:.ou

C>
C>
C>

g

.

c.

i.:c
-3

]

291. X- or y-radiation have caused,_, 200 cases of radiation cataracts in man. 459 • 467 :Most had latent periods
but in many these were not related to radiation variables
such as quality, dose, or duration of treatment. The doseand factors that might permit its calculation were notreported in many cases.
292. The problems of minimal cataractogenic doseeffect of dose and mode of exposure on incidence of stationary or progressive cataracts, influence of dose fractionation and dose or duration of exposure on the latent
period, effect of radiation quality, and age on lens sensitivity-are still unsolved for man.
293. From animal studies, radiation cataract resultsfrom radiation destruction of the anterior epithelium,
which supplies cells that differentiate into fibres of thelens. Young animals exposed pre- or early post-natally
have greater lenticular radiation-sensitivity than older
animals.

...•••...
d"--J;l Exposed between S00· 1499 m

••
"
"

Ii.~

Excluding l11<1koemios
ond lymphonua0-·~ Nan-posed (beyon.! 10,000 m)

••

••

:o

.

"

AG• In y..;,.s"Figure 8. Malignant neoplasms (excluding lymphoma and leukaemia) per 100,000 per year by age and exposure status, May
1957-December 1958. Modified from Harada and Ishida 4 57

294. Merriam and Focht464 studied in man 100 casesof radiation cataract and seventy-three cases of irradiation to the head without subsequent cataract. Duplicating
the radiation factors, they measured X- or y-ray dose to
the lens in a phantom. Any clinically recognizable characteristic opacity was regarded as a radiation cataract
regardless of whether vision was affected. Numerous
uncontrollable variables in this study made it impossible
to determine the threshold dose.
295. The minimal effective doses were the least radiation producing some lenticular opacity. It was impossible
to classify cases by dose and degree of lens opacity ;they were classified by whether opacities were stationaryor progressive and this was then related to dose.

2400

woo
0

1600
0

1200

0

800
0

296. Ninety-seven of the radiation cataract cases andseventy without radiation cataract were classified bytiming of treatment: single, fractionation over three
weeks, to three months, and fractionation > 3 months.
The minimal doses for production of lenticular opacity
in cases for each group were 200 r, 400 r, and 500 r
respectively. These figures suggest that the thresholddose increases with duration of treatment.

0

400

0
0

0

0....._-<>---'-~-f-~,._-.-t----'~-+~-'-~+---'>1000080006000400020000·
8999
6999
4999
2999
999
9000·
70005000300010009999
7999
5999
3999
1999
LOWEST WBC IN
14 WK POST- BOMB PERIOD

297. Of thirty-seven cases irradiated in a single treatment (with radium plaques), all twenty with doses from
200-L150 r developed lenticular opacities. The otherseventeen received doses from 40-175 r to the lens without developing lens changes. There were only two casesof stationary lens opacities of minimal degree at an
estimated dose of 200 r, first seen nineteen and twentytwo years after treatment. Because of the small numberof cases (four) with doses from 200-350 r, the fact that
there were none without cataracts does not prove thatthe lens cannot tolerate higher single doses. Further information on the effects at these dose levels is necessary
to determine the upper limits of tolerance. The maximal
non-cataractogenic dose in this treatment group was
175 r in a patient followed for 8}'2 years.

Figure 9. Incidence of late effects among Hiroshima atom bomb
survivors, plotted against the lowest leukocyte count in thefirst 14 weeks after exposure•ss

Although changes in the optic lens have been detectedaiter doses as low as 200 r, the minimal effective X-ray
dose (200 kv) for the production of clinically significant
cataract is 600-1,000 rad; this dose may be lower for
infants or children and is highly dose-rate dependent.
Neutrons are 5-10 X more effective in causing cataracts
than X-rays.
290. The characteristics of radiation cataract in earlystates of development are: an initial dot-like opacity,usually at the posterior pole of the lens, around which150298. Of eighty-seven cases given multiple treatments
for three weeks to three months, forty-nine developed
lenticular opacities with X- or y-ray doses of 400-6,100 r
to the lens. Lens opacity after 400 r (one case) was firstseen 20 years after treatment and was stationary. The
maximal non-cataractogenic dose in this group was

1,000 r with a treatment time of 20 months and a followup period of 13 0 years. The following table gives theincidences and types of lenticular opacities in patients
after irradiation in various dose ranges for a three-week-three-month over-all time.
Cataract lype

Dose range (r)CaJartut incicknce

40-350 ............................ 0 of 18 patients
351-550 ............................ 4 of 9 patients
551-750 .•..•....................... 6 of 10 patients
751-950 ......................••.... 16 of 26 patients
951-1,150 .......................... 2 of 3 patients
1,151-1,399 .......................... No cases
1,40D-6,100 ...............•...•.•.... 21 of 21 patients299. Of forty-three cases irradiated over a period
longer than three months. twenty-eight developed lenticular opacities after X- or y-ray doses of 550-6,900 r
to the lens. There were two cases of cataract after 550 r,
one progressive and one stationary, first seen forty-fourmonths and four years after treatment respectively. The
maximal non-cataractogenic dose in this group was
1,100 r, with a treatment time of 10 years and a followup period of twenty-two years.
300. The 100 per cent incidence level of lenticularopacities occurred at the lowest-dose level for the single
treatment group (200 r) and at any greater dose. In themultiple treatment cases, the longer the duration of treatment, the lower the incidence at a given dose range below
1,150 r; the higher the dose for a given treatment, theshorter the time of appearance of the lens changes andthe higher the incidence of progressive opacities withresulting decrease of vision. In general, fractionation ofdose delays the time of onset of cataracts and decreases
the incidence of severe opacities.
301. The lenses of children under one year of age
seem to be more sensitive to radiation than those of older
children and adults.
302. Cataract production by fast neutrons comparedwith X-rays increases significantly with protracted e.xposure; i.e., the RBE is about 2-4 for high-intensity and
9 or greater for low-intensity radiation, only because thedose of the "standard" radiation changes, not that forneutrons.
303. By December 1948, at least ten nuclear physicistsof mean age thirty-one had incipient cataracts after
cyclotron exposure. 468 Three cases were severe with definitely impaired vision. Four were moderately severe, andthree were minimal. It was estimated that over periodsof 10 to 250 weeks, these men had received total doses offast neutrons to the lens of 10 n-135 n with a mediandose of 50.* At the time the cataractogenic exposures
were received, periodic blood counts done on mostshowed no change in blood picture warning of overexposure to radiation.

Stationary

Progressite

Intkterminale

3
5
7
1

0
1
6
1

1
0

2

18

3
0

not reported, but it is inferred that they were generally
mild.
305. In 1955, Sinskey 41 z reported an intensi:re in':'estigation of 3,700 exposed and non-e.xpo~ed Hiroshima
Japanese from May 1951-December 19::>3: there. were154 survivors with posterior sub-capsular plaques m thelens large enough to be visible with the opthalmoscope.
Opacities not so visible in the greater percentage of survivors were not considered because they did not decrease
visual acuity in standard tests. Because '?f the relatively
negligible effect of the atom bomb on visual loss sevenyears after the bom~ing, the t~rm cataract, ass?ciat~dwith severe loss of vision or blmdness, was avoided mthis survey.
306. Sinskey found that of 425 survivors in Nagasaki
between 400-1,800 metres from ground, 47 per cent hadlens changes detected by slit-lamp examination, with orwithout history of epilation and shielding. Although most
opacities were so insignificant as to be invisible with theopthalmoscope, statistically significant lens changes were
present in survivors with no other known early or lateevidences of radiation damage.
307. Among,....., 8,000 e.xposed survivors of Hiroshima
and Nakasald e.xamined by 1956 (eleven years after theatomic bomb explosions), ten cases of severe cataract
were found. The relationship between these cases andradiation alone is not clear.
Radiation effects on fertility

308. The late pathological effects in gonads are chiefly
a hastening in involutional changes associated with advancing age. In animals, there is little evidence of radiation-induced testicular tumours, but ovarian tumours are
increased by radiation.
309. Histological sterility is complete absence ofgametes and even gametogenic elements. It is difficult topredict its permanency by biopsy ?r froi;n necro:p~y sections. Permanent and complete histological stenlity requires large doses to the gonads; such doses would be
lethal given in a short time to the whole body or a substantial part.

304. After the finding of radiation cataracts in thephysicists, Cogan et al. 469 • 410 found 10 heavily irradiatedJapanese atom bomb survivors with radiation cataracts.
In studies by Kimura in 1949, described by Fillmore.471
98 cases of lenticular opacity were reported, 85 among
the 922 survivors in the high-dose region 1,000 metres orless from the hypocentre. The severity of the lesions was

310. Functional sterility can be induced by sma~lerdoses; this may be temporary or permanent depending
upon size and intensity of dose. In the male, the rate ofsperm production need. only be reduced to \yhere th~reare insufficient sperm m semen to be effective. An mcrease in abnormal sperm after irradiation also reduces
the number of effective sperm. Since the number of nor-

* 1 n is equal to ,....., 2 rad.
151

mal sperms per ejaculate necessary for reproduction islarge sub-fertility may be associated with considerable
but s~bnormal spermatogenesis. These conditions can be
induced by doses to the gonads sub-lethal if given as TBR.
Sterility doses for men and women

311. The long-term pathological effects of radiation
on gonads have had little study with accurate dose estimates. From fragmentary data certain estimates areattempted.
312. Gonadal doses affecting fertility are probably
similar for men and women: a single dose of ,._, 150 rad
to gonads may induce brief, temporary sub-fertility inmany men and wome_n; a single dose of ,._, 250 rad may
induce temporary sterility for 1-2 years, and 500-600
rad permanent sterility in many, especially in people
with borderline fertility, with temporary sterility inothers for several years ; single doses of 800 rad or more
would probably cause permanent sterility in all but a
few most resistant men and women.
313. Gonadal doses causing only temporary alterations in fertility in fertile people are sub-lethal if given
as TBR. Gonadal doses that permanently sterilize mostfertile people are likely to equal the TBR lethal dose.
314. Limited experience with the Marshallese, exposed Japanese, and certain accident cases suggest that
substantial fractions of the mid-lethal dose for man( 400-600 rad) do not have a serious, permanent effect on
fertility, but gonadal doses are not known with certainty;
few people have been studied for this purpose for a longtime after exposure.
315. Men may be sterilized permanently withoutprominent changes in interstitial sex cells, hormone balance or libido. Women sterilized by radiation undergo
greater physiological changes since ovarian production ofsex hormones is intimately related to development anddischarge of ova. Radiation termination of productionof ovarian follicles induces an artificial menopause in
women similar to natural menopause, with amenorrhea,"hot flushes", diminished libido, and occasionally psychic
depression. From experimental data, long-term radiation
may seriously impair fertility in animals such as man
with relatively poor gonadal regenerative ability.
Degenerative diseases and histopathological changes

316. Injuries of the skin, atrophy, dermatitis, epilation, and epidermal neoplasia were among the first recognized late radiation effects. In human skin, 500-700 rad
may induce permanent epilation. Smaller doses cause
temporary epilation, may decrease pigmentation or graythe new growth of hair in irradiated areas. This effect has
not been reported in Japanese. Doses in the erythemarange or higher may also increase pigmentation of skin,epidermal atrophy, and decrease sebaceous and sweat
glands in irradiated regions. Hyperkeratotic areas inskin, and vascular sclerosis are also late effects of skinradiation. Surface doses of ,._, 1,600 rad may cause considerable permanent dilation of capillaries (telangiectasia) in irradiated areas. In the past late changes wereseen more commonly than today in the skin of hands
and faces of persons occupationally exposed to radiation ;radiation dermatitis and ulcers were often followed by
epidermoid carcinomas.

hypertension may be induced in man within months or a
few years by single localized X-ray doses of ,..., 3,0005,000 rad or by fractionated doses of lesser size (e.g.,a total dose of 2,300 rad to both kidneys in 35 daily
doses).4 73 These conditions have been induced in experimental animals in a short time by local radition of thekidneys with large doses. More recently, nephrosclerosis
with renal hypertension and associated generalized arteriosclerosis were induced in rats and mice as late effects
of TBR with much lower doses (sub~lethal or LD 5orange). Although the pathogenesis·of nephrosclerosis asa late effect is not clear, histopathological data indicatethat changes in fine vasculature are important in earlyand late initiation and development.
318. Nephrosclerosis and related hypertension may
appear as a late radiation effect in animals in which it
has rarely or never been seen within the average lifespan(later periods are not well studied) or its onset may be
advanced in animals in which the disease has appeared
spontaneously. Renal hypertension, once established andprogressive, increases vascular sclerosis throughout thebody; progressive arteriosclerotic changes often induce
progressive atrophy of parenchymatous organs. Consequently, when irradiation has induced or advanced
nephrosclerosis with related hypertension in animals orman, the incidence of death from related causes (e.g.,
renal and cardiac failure, and cerebral haemorrhage):increases with corresponding reduction in death fromother unrelated causes or from diseases having longer
induction times. Irradiation of human brain or spinal
cord with several thousand rad, given singly or in large
fractions over a few weeks, may injure blood vessels,cause ischemic damage of tissues, and progressive sclerosis of blood vessels, with subsequent secondary degeneration of brain or spinal cord. Blood vessels may rupture one to several years after exposure.
319. Atrophic and fibrotic changes, often with arteriosclerosis, have been seen in human haemopoietic organs
long after local radiation. Secondary anaemia has been
associated with myelofibrosis after long-term radiationof bone marrow and also as a late complication of radiation therapy. Radiation osteitis is a late degenerative
effect of intensive irradiation (a few thousand rad) of
bone. The degenerative and destructive processes develop
slowly, and after many years lead to necrosis, pathologic
fracture, and osteogenic sarcoma.
320. The gastro-intestinal tract has shown some permanent and late effects after fractionated doses of several
thousand rad; atrophic and fibrotic changes and sometimes late ulceration in mucosa, and permanently reduced
secretion of acid and pepsin by the stomach.
321. Intensive irradiation of the lungs in radiation
therapy causes slowly developing progressive fibrosis,
with vascular damage and arteriosclerotic changes. Radiation fibrosis 474 usually develops slowly, but there havebeen fatalities eight weeks after therapy. Lungs show
fibrosis with thickening of alveolar walls and vascularsystem. The alveolar walls may be lined by cuboidal
epithelium and the remaining alveolar sacs may be filledwith cells. Cough and dyspnea are the principal symptoms. Roentgenographs are similar to those of pulmonary fibrosis from other causes. There is considerable
unexplained individual variation in post-irradiation
fibrosis but in general the incidence depends on dose.
The degree of disability depends also on the amount oflung tissue irradiated; thus. treatment of intrathoracic
neoplasms where a large part of pulmonary tissue is317. Nephrosclerosis is long knO\vn as a complicationof over-exposure of the kidneys in radio-therapy. Renal152

exposed is apt to be more serious than treatment ofcarcinoma of the breast, where usually only part of one
lung is ex:posed. 415 Malignant neoplasms of the lung havebeen seen in miners who inhaled radio-active substances,and have been induced in animals by intra-tracheal injection and implantation of radio-active substances.
322. Substantial doses of radiation to actively proliferating mammalian tissues reduce their regenerative
capacity. Failure of such tissues to regenerate parenchymal cells to normal numbers is often associated withincreased connective tissue and vascular changes. In general, incomplete regeneration varies directly with size ofthe single dose or with dose rate in long-term radiation;
in some tissues such as testis, fractionation may increase
dose efficiency in damaging regenerative capacity. It is
not clear to what e..xtent the permanence of this effect isdue to the direct effect of radiation on stem cells, or todamage of supporting tissue. Nor is it clear to what e..xtent in each tissue incomplete regeneration is due to: (a)decreased reproductive capacity of existing stem cells,( b) decreased stem cells surviving, ( c) asynchrony inregeneration of histological elements with increase inconnective tissue, or ( d) damage of fine vasculature,
although any or all factors may be implicated depending
upon dose. Little is known quantitatively about the reproductive capacity of individual stem cells or the numbers of primitive stem cells surviving in the post-recovery
period after irradiation. Fibrosis of small blood vessels
with general reduction in vascularity is often associatedwith subsequent reduction in number of parenchymatous
cells and increase in connective tissue.
323. Changes in vascular and lymphatic systems, withdestruction of radiation-sensitive parenchymatous cells,
are important in the pathogenesis of many late radiation
effects. :Many late effects may come from metabolic andnutritional disturbances due to impaired blood supply
that reduce function and reparative capacity, and increase susceptibility to traumatic damage, infection anddisease in general.
Effects on growth and development

324. The regenerative processes of the body are fairly
sensitive to radiation; their inhibition may be prolonged
especially if vascular integrity .is impaired. More quantitative study is needed after local and TBR.
325. Some quantitative studies in rats indicate that
repeated TBR at 24 rad/wk inhibits growth. A significant decrease in growth can be caused by repeated TBR
without decrease in haemoglobin or absolute neutrophils
levels.
326. Localized· irradiation of the epiphysis inhibitsbone growth and shortens bones in man and animals, theeffects being greatest in youngest animals. Localized
irradiation of the jaws decreases tooth growth.
327. Studies in Japanese children after the atomic
bomb indicate a statistically significant if slight retardation of growth and maturation. However, the effect of
non-radiation factors has not yet been adequately evaluated. Extensive measurements on 4,800 children at 6, 7
and 8 years after e.xposure in Hiroshima showed generally that growth was retarded and maturation delayed.476• 411 In another study of several hundred children
in Hiroshima and Nagasaki. in years 2, 4 and 5 after
irradiation, physical growth and development wereaffected adversely, and retardation of height, weight,
and skeletal development was still evident at the end of1950. 478 The investigators believed that factors otherthan radiation-e.g. malnutrition-may have contributed
to these effects.

VI. Special features of internal andexternal contamination
PHYSICAL CONSIDERATION 479

328. The hazards of exposure to radio-nuclides depend greatly on their physical and chemical properties ;these determine their entry into the body and retention
in various organs. The duration of radiation depends also
on physical half-Ii fe and in some instances on complicateddecay chains causing a shift of the emitter from one place
to another as the isotope undergoes transmutation.
329. The nature of the emitted radiations may determine the range of exposure and hence the pattern of
injury e.g., an energetic a-ray will penetrate no further
than 0.07 mm. in tissue; /3-rays deposit their energy
largely locally; y-ray energy will be absorbed in larger
volumes or an appreciable portion of the energy will
escape the body altogether.
330. The degree of damage depends to some e..~tenton the concentration of ions along the path of ionization.
For an equal energy, this is greatest with the shortest
range emissions i.e., a-rays. For most types of response
the effects are greater where ionization is dense.
331. In recent years, attention has centred on thelong-term hazards of radio-nuclides of long half-life,e.g., Sr 90 and Csm. But, intermediate and short-lived
isotopes may be important, depending on circumstances.
Possible accidental discharge of radio-active materiaJ
from reactors, as nuclear detonations, may contaminate
local areas with various fission and activation products.
Even in global fall-out from the thermo-nuclear tests,
fission products of intermediate half-life are a source ofy-radiation which, for a few months after detonation athigh altitudes, has exceeded that from Cs 137 • 480 Amongthe short-lived isotopes the most interesting, especiallyin nuclear accidents is !1 31 •332. The important isotopes of intermediate halflife include Ba 140 , Ru 103, Ru 106 , Co 60 , Ce 1 n, Ce 144,
Y 91 , Zr 95 , and Sr 89• Some are so poorly absorbed that forpractical purposes they may be considered as external
y-ray sources; Ba 140 and Sr 89 are absorbed and must be
considered with Sr 90 as contributing dose to the skeleton.4B1
333. In past weapon tests, studies of fall-out patterns
have shown that the geographical distribution of isotopes
depends on many factors, including the altitude of e..xplosion and the nature and amount of surrounding material. Particle size and their solubility vary with distanceas with other factors. 482 Any nuclear accident is likely to
produce a unique pattern of variables, e.g., due to thefeatures of the accidental discharge from the Windscale
reactor in Great Britain the contaminating fission mixture had a lower content of radio-strontium relative toradio-iodine than might have been anticipated.
SPECIAL PROBLEMS ASSOCIATED
WITH INTERNAL EMITTERS

Localization of radiation
334. Theoretical and experimental considerati<:>nssuggest that the effects in tissues from uniformly appl~ed
radiation may differ from the effects of radio-active

153

particles aggregated into a "point source". 483 In the latter,dose-rates close to the point source differ from those near
the end of the range of the particles. Dose-rate near theorigin is extremely high; these high rates may be important, if the relationship between injury and dose-rate
is non-linear. Dose-rates are unimportant if the effectsof radiation are related to dose in a linear non-thresholdway. Then, the effect may reflect a single-event so that
only total dose is important; dose-rate and spatial distribution are inconsequential. When the radio-element
is diffusely deposited, the probability of the distributionof injury is the same for all cells in the tissue, whereas
in discrete deposition, the probability of injury of cells
close to the aggregate is increased but that of injury to
the cells far away is reduced.
335. If the relation between dose and degree or probability of injury is not linear then spatial distribution
is important. Also, different biological effects may show
different relationships with dose. Present data are notadequate to define differences in hazard between focal
and diffuse radiation.
Concept of REE

336. Even with uniform irradiation the concept of
RBE is by no means simple, as is discussed in otherparts of the report, since the relative effectiveness ofradiations of different quality may depened on manyfactors other than LET, including dose, dose-rate, biological end-point, and other factors. With many internal
emitters and particularly with the bone-seeking isotopes,
there is the additional problem of a very non-uniform
distribution of radiation dose, which introduces further
severe problems into the use of RBE factors, which have
not yet been solved.
337. Because of the many difficulties, the concept of
RBE can be applied only in a very general way, especially to internal emitters, and care must be taken whenusing it to establish standards of radiation safety forvarious types of ionizing radiations. In particular, it
must be emphasized that an RBE established for one
biological effect is not necessarily valid for another.
Modes of entry of radio-isotopes into animals and man

338. Among the :fission products only few are of significance with regard to internal contamination. The uptake and metabolism in the organism depends on thenature of the materials and their chemical and physicalproperties. The routes of environmental contamination
into the body are ingestion, inhalation, and skin absorption.
Ingestion

339. Gastro-intestinal absorption is the most important route of uptake of Sr90 and Cs137 from nuclear
weapons tests. The levels of these isotopes in animals andman correlate with their levels in the diet; they arereadily absorbed.

to fall-out levels except where rainwater is used for
drinking and cooking because of the relatively long times
in the ecological pathway.
341. Another factor is whether the isotope is a radionuclide of an element required by the body or of one
chemically similar to a required element. The actinide
and lanthanide rare earth series of elements have no
chemically similar counterparts among required body
constituents and are usually poorly absorbed by plants
and animals. For these radio-nuclides, inhalation may
be relatively more important than ingestion.
,
342. Although some generalizations are possible fromthe similarities of elements with families of the periodic table and from similarities to required body constituents, each radio-nuclide has its own metabolic properties. There is a continuing need, therefore, for data on
gastro-intestinal absorption of all radio-nuclides that arepotential contaminants of the environment.
Inhalation
343. In industry, inhalation has been found to be themost important route of entry of potentially hazardous
materials. Inhalation of radio-active isotopes creates
three potential hazards: absorption into the systemic
circulation and subsequent deposition in a critical tissueor organ; irradiation of the lungs themselves from materials deposited on respiratory surfaces and picked up by
bronchial lymph nodes ; ingestion. Inhalation is generally
the most important route of entry of short-lived radionuclides and of insoluble radio-active materials.

(a) Size of inhaled particles484344. The relationship between size of radio-active
particles and their deposition in the respiratory tract iscomplex, since retention and movement vary with particle size. In general, very small particles may be deposited throughout, freely entering the lower portionsof the lung. As particle size increases, deposition
throughout the respiratory tract decreases, and reaches aminimum at a particle size of ...... 0.4 µ.. With further increasing particle size, up to ,_, 10 µ., the fraction deposited in the total respiratory tract increases. Particles> 10 µ.will not penetrate the passages to the alveoli, andare deposited mainly in the upper respiratory tract,
where there is rapid clearance. As particle size increases
further, the point of deposition is further up the respiratory tract, until the probability of inhalation of large
particles becomes low because of the filtering action in
the nostrils.
(b) Radio-activity of inhaled particles
345. Suspended radio-active materials may be very
heterogeneous in particle size and in other physical andchemical properties. Compounds of several radioelements can be attached to a particle of inert material,or a single radio-active compound can be the entire
particle. Usually radio-nuclides become associated withinert materials during information or after subsequent
agglomeration.
( c) S olttbility of inhaled particles
346. Once a radio-active substance is deposited in thebody, its fate-translocation and excretion-is partly determined by its solubility in body fluids. Solubility depends principally on chemical composition, but physicalproperties such as size, shape, and surface area are also
important, especially of heterogenous particles in whichradio-active substances are adsorbed on the surfaces ofinert nuclei.

340. Ingestion is an important mode of entry only forsoluble isotopes. The solubility of interest is solubility
in body fluids rather than solubility in water. Many soluble compounds may be converted to relatively insolublehydroxides at the pH of body fluids. Also, relatively
insoluble compounds may be converted to soluble compounds in body fluids. Only those having intermediateor long half-lives can be absorbed by man in proportion154

Effects of internal emitters on the lung, including cancerof the lung352. In 1939, Rajewsky reported a technician in aradium plant who died with pulmonary fibrosis similar
clinically and anatomically to that after e..""ttemal irradiation.500 The technician was twenty-four years old andhad worked three years in the plant. At death, his lungs
contained ,..., 6.2 X 10-2 µ.c of radium which would
give a mean dose rate of ,..., 0.2 rad per week. Most radium previously deposited had almost certainly beencleared from the lung at the time of death; therefore
earlier dose rates must have been much higher. The lungcancers in the miners of Joachimsthal and Schneeberg,in Czechoslovakia. are familiar. The mines were first
opened in 1410 for copper and iron; in 1470 silver andarsenic were discovered and mined, and later bismuth,
nickel and uranium. Other metals found were tin, zinc,cobalt, manganese, magnesium and lead. At the beginning of the twentieth century, uranium was the principal
element mined for the dye industry. Three surveys weremade to establish the incidence and determine the causeof cancer of the lung among the miners. 50 1-5°3 The concentration of radon in the air of the mines 50'· m varied
considerably in different shafts (0.36 X 1()-6 -47 X
lQ-6) and averaged 2.9 X 1()-6 µ.c/cc.
353. Although the exact role of radium in the etiologyof the lung cancers is unknown, there seems little doubtthat their incidence among the Schneeberg and Joachimsthal miners is at least 50 per cent higher than that in thegeneral population. The cancers of the lung are morphologically similar to those in other groups of the population, with the possible exception of the absence ofadenocarcinoma. The average latent period for the induction of lung cancer in these miners was ,..., 17 years,
and calculations have suggested that assuming uniform
distribution the dose to the lung would have been,..., 1,000 r during this time. 606

Skin absorption
347. Absorption of radio-isotopes through the skinhas not been sufficiently studied. The skin is not usuallyconsidered an actively absorbing organ, especially for
inorganic substances. Animal experiments have been
limited because anatomical and physiological dissimilarities between human skin and that of the more common
laboratory animals lead to problems of interpretation.
The skin does not appear to be an important route ofentry of nuclides contaminating the general environment. However, skin absorption of radio-active materials
should not be ignored, especially when large quantities
may come in contact with the skin surface in industrial accidents. A specific example is tritium as tritium
water ( H 3 20). The amount of atmospheric tritium waterthat exchanges with moisture on the skin surface andenters the circulation is about equal to that entering via
inhalation of the same tritum-containing atmosphere.485• m Absorption of a few other radio-nuclides
through human skin has been studied. 487 When the skinis broken, e.g. in wounds, absorption of radio-nuclides
is greatly accelerated and increased.
EFFECTS OF RADIO-ISOTOPES AFTER ABSORPTION

348. The effects of radiation from materials within
the body are similar to those of external radiation.
Important differences arise because (a) radio-isotopes
are not distributed uniformly within the body; and(b) they serve as more or less continuous sources ofradiation.
EARLY EFFECTS

349. In animal experiments, haematopoietic symptomsof acute radiation disease appear 7-10 days after lethal
amounts of radio-isotopes given intravenously or parenterally488• 496 Sub-acute effects, frequently seen 1-5
months later, may include haematopoietic symptoms aswell as malfunction of those organs within which theradio-isotope is deposited most heavily, e.g., polonium
leads to kidney damage, plutonium and the rare earths
to liver damage, radio-iodine to thyroid damage, andradio-strontium to bone damage. 489 • 492 A recent paper on
the accidental e..xposure of 103 luminous-dial painters
to Sr00 gives data on its urinary excretion in man andgives some information on possible early haematologicaleffects. m A more complete account on urinary excretionof Sr90 in man is given in a report on a case of accidental
inhalation. •94

Long-term effects of internal emitters in animals
354. In animals, effects are generally measured interms of tumour induction and life shortening. Tumours
may appear in those tissues in which the isotope islocated and also in adjacent tissues within the range ofthe radiation. Thus radio-strontium, which localizes inbone, induces in mice osteosarcomas and rarely epidermoid carcinomas of the oral and nasal mucosa. 491 In man
radium has caused, in addition to the usual sequela ofbone malignancy, epithelial tumours arising in the mastoid cavity and the accessory nasal sinuses!99 Other instances in which tumourgenesis is associated with thedirect action of ionizing radiation on tissues include tumours of the liver, gastro-intestinal tract, lungs and skin.
In the case of thorium, for example, hepatic carcinomas
and hemangio-endotheliosarcomas have been noted abnormally often in patients given thorotrast intravenously
for angiography. 507 The incidence of these tumours increases with the quantity of incorporated radio-isotope,
the dose up to a given point and may also depend on thedose-rate within the critical organ. 3 ~350. It is unlikely that many human cases of acute or
sub-acute poisoning due to internal emitters will everoccur. In nuclear war or a reactor accident, the chance ofserious damage from e..xternal radiation greatly overshadows that from radio-nuclides which might enter the
body. On the other hand, the long-term effects of small
amounts might become a serious problem.

Late effects
351. Experience with the long-term effects of internal
emitters in man is essentially limited to radium, usedtherapeutically and in the dial-painting industry, tothorium used as a contrast medium for roentgenographic
diagnosis, and to elements in the decay chains of radium
and uranium to which miners have been exposed. Cancer
has appeared in these groups.• 9 ~ 99 More recently, radiophosphorus, radio-iodine, and other new nuclides havebeen used in treatment and diagnosis; scanty reports oftumour induction require verification.

355. In other instances, however, irradiation by radioisotopes may lead to abscopal (other than local) effects.
Neoplasia of endocrine glands and of sex organs (typified by the hypophysis and ovaries) are induced by various radio-isotopes irrespective of their organ distribution. Their incidence is not clearly related to dose or
dose-rate, and may depend strongly upon such factors as strain and se.x. Hormonal dysfunction inducedby radiation plays an important role in their etiology. 304
155

bronchial epithelium, or 12,000 rad to epithelium one cm.
from the source. They were unable to produce carcinoma
in mice at doses > 70.000 rad to bronchial epithelium.
For Sr 90 the dose given bronchial epithelium to withinfiye mm from the source was 13,000 rad after 200 days.
Not all mice developed epidermoid carcinoma.
362. Other e..xperiments with relatively insoluble particles retained in the lung for long times have shown an
increase in malignant tumour incidence. Intratracheal
Pu 239 0 2 , 0.06 to 0.16 microcurie, caused fibrosis, sterile
pneumonitis, and benign papillary cystadenomas in 60-80
per cent of mice within 100 days. 519 Similar results wereseen after intra-tracheal Ru 106 0 2 • Malignant lung tumours were seen in these mice. For various tumours adose has been calculated assuming uniform distributionof radio-isotope in lung tissue and exponential loss fromlung. 520 The authors original estimate of dose to lungwas used where reported (table IX).m The smallest
lung doses mean values associated with malignant tumours were 115 rad after 0.003 µ.c Pu 239 0 2 and 300
rad after 0.15 µ.c Ru 106 0 2 •521 However, the etiology ofthese tumours is uncertain because autoradiograms failed
to show radio-activity in the area of the tumour.
363. In other studies, at least 2,000 rad was the estimated dose to lungs that developed tumours. The estimated dose is questionable in many cases because of the
non-uniformity of the distributed radio-active materials.
Autoradiograms showed that inhaled particulates werelocalized in discrete areas of the lung. 519 In these cases,
dose to microvolumes of tissue could be considerably
greater than that estimated by assuming uniform distribution. Therefore, from the dose estimates given intable IX one should not conclude that the dose required
to induce lung cancer is necessarily as low as 2,000 rad ;it may, indeed, be much greater. Lung carcinogenesis
after inhalation of radio-active particles has not beenvery common; only a few studies have been completed.
Lisco 522 has described epidermoid carcinoma, adenocarcinoma, and hemangio-endothelioma in 50-100 per centof rats inhaling about 0.2 to 1 µ.c Pu02 smoke. Recently,
Temple et al., 523 in preliminary work, found a bronchiolar carcinoma in a mouse killed SOO days after depositionof 0.01 /LC of Pu 239 0 2 by inhalation. In most reportssummarized in table IX, the authors also found significant metaplastic changes, some at doses lower than thosegiven in the table. Other effects causing death of mice
were seen after inhalation of Pu2390 2 •524 Ninety per centmortality occurred within ten months after depositionof 0.34µ.c. No increased mortality occurred after deposition of smaller quantities, although some lung pathology was present. Cember reported no increase in nonspecific mortality after implantation of sufficient Sr9°in glass beads to produce bronchogenic carcinoma. 514
364. Although radio-isotopes accumulate in pulmonary or tracheobronchial lymph nodes, little is known of
their effects. A tracheobronchial lymph node from a dog
two years after 20 µ.c of intratracheal Pu 239 0 2 showedcharacteristic radiation damage . The architecture of thenode was destroyed and there was only limited regeneration of lymphatic tissue. In other dogs, possible histologic changes were seen within a year after inhalationof 2 µ.c Pu23902.s2s

An intermediate position is occupied by mammary tumours and lymphomas, where the incidence is dependenton dose, but which are unaffected by the pattern of isotope distribution ..In mice, lJII?phocytic neoplasms n:ay
arise where the pnmary target is bone, perhaps resultmg
from the TBR occurring while the isotope is circulating.491
Effects of internal emitters on the lung in animals
356. More striking effects were seen after depositionof radio-active gases and particles in the lungs. e.g. highincidence of pulmonary tumours in mice inhaling radon. 508 They were exposed continuously to air containing
radon at 1.2 X lQ-11 µ.c/cc, and lived 161-453 days. Tenor twelve animals had lung adenomas, and one an adenocarcinoma arising in a small bronchus. There was one
adenoma in the controls. Tracheal administration of 50
mg of quartz and three-hour e...xposure to air containing
8 X 10--G curies radon per litre retarded weight increase
and changed the peripheral blood composition . 509 Radon
affected the silicotic process significantly inducing metaplasia of bronchial and alveolar epithelia, and in somecases, malignant tumours and bone tissue in the lungparenchyma and in blood vessel walls. Proliferation of
bronchial epithelial cells along with atrophy and proliferation of the tubular epithelium of the kidney were seenin mice five months after an eighteen-hour e..xposure to
2.4 X 1Q-1 curie of radon per litre of air. ~ 10 The carcinogenic action of radon is due to its distintegration products. 511• 512 Pneumoconiosis does not play a decisive partin the pathogenesis of lung tumours due to the effect ofradon. 513
357. Changes in pulmonary histology have been seen
after various a- and ft-emitting elements, Ru106 , Rh106,
Sr90 , Ce1+1, Pu 239 , Po 210 and Co60 , were given to rodents,
mostly by intratracheal injection.
358. Strontium-90 was given by transthoracic injection of glass beads 514 and in one study Ru'1° 6 was plated
on a platinum cylinder introduced into a bronchus. 515
In most studies, squamous metaplasia of the bronchial
epithelium was seen in many of the animals; fibrosis andpneumonitis were common. Because of the high frequency of lung pathology in rodents, it is unsafe toascribe all changes to the radio-active elements. The
tumours thought to be bronchogenic were unencapsulated and invasive. In studies with implants many of thetumours surrounded the implants.
359. Cember intra-tracheally injected up to 4 . 5 millicuries of S 35 as BaS0 4 , in rats, and found no effects definitely attributable to the radio-active particles. m In another study after 375 microcuries of BaS 35 04 given
intra-tracheally to twenty-four rats once a week for ten
weeks, two of sixteen rats surviving showed severe squamous metaplasia in the lung. and two had bronchogenic
squamous cell carcinomas. The estimated average doseto the lung during ten weeks was 12,000-20,000 rad. 517
360. Cember also reported bronchogenic squamouscell carcinoma after pulmonary implantation of Sr90
glass beads. 514 Four squamous cell carcinomas, twolymphosarcomas, and one lymphoma were seen in rats
carrying the Sr90 beads. Six tumours were intimately
associated with the beads. The total dose given the lungranged from 5 X 1()4 rad to > 2 X 105 rad.
361. vVarren and Gates 518 induced epidermoid carcinoma of the bronchus in mice with Sr90 glass beads andwith Co 60 implants. For Co 60 the radiation doses werehigh, up to 400,000 rad in 200 days, to the nearest viable

Effects of internal emitters on bone 526(a) Histological damage in bone365. Whatever the source of radiation, external orfrom internally deposited isotopes. the general patternsof histological change are remarkably similar in different

156species. Histological damage includes: (i) empty lacunae (ii) vessel injury, (iii) irregular abnormal new
bon'e, and (iv) varying degrees of fibrosis_; in '!-ddition,
in rats and mice where endochondral ossification continues in adult animals and in young rabbits there maybe (v). unresor?ed cartilage, (vi) ab!:ormaliti.es of cartilage m the ep1physeal plate, and ( vn) severmg of old
and abnormal resorption of new spongiosa.
366. Bone damage takes two forms. First, bone may
be injured probably by indirect destruction through vascular injury and by direct action on the osteocytes. The
presence of osteotropic isotopes especially Sr90 during achronic phase of injury (after 180-200 days and later)induces a sharp deterioration in the blood supply, as aresult of the emptying of considerable sections of thevascular bed of blood forming and bone tissues with thedisruption of vascular innervation.m,m The damage toosteocytes and vessels can be seen within a few days inanimals given a large short-term radiation; but it is best
seen as a late change in bones of patients with radium
poisoning, as well as in experimental animals. Secondly,
radiation having damaged osteoblasts and osteoclasts,
can initiate abnormal activity in osteogenic connective
tissue. Short-range a-emitters, radium, mesothorium,
radio-thorium and plutonium affect the osteogenic connective tissue lining endosteal surfaces and resorption
cavities of bone trabeculae, inducing marked terminal
fibrosis, especially when the dose injected is high. The
longer-range ,8-emitters, Sr9° and P 32 , and external irradiation affect loose connective tissue in the bone marrow
spaces between bony trabeculae as well as on the surfaceof the trabeculae. They induce variable degrees of active
cellular fibrosis often characterized by proliferation ofpleomorphic spindle cells with conspicuous numbers ofmitotic figures and abnormal giant cells.
367. At higher dose levels most changes are seen indifferent species. Their severity decreases considerablywith time, especially with an isotope of relatively shorthalf-life, e.g., P 32, where irradiation is short comparedwith that of longer-lived isotopes. With decrease in doseor end of radiation, these changes become less severe,and at sufficiently low doses, the initial damage is repaired so that no histological evidence of damage remains ; bone has a considerable capacity for repair.

(b) Histogenesis of bone tum,mrs
368. Gross damage causing dead bone and repair may
occur without malignant change. Tumours do not necessarily arise at the site of maximum damage. In fact, it ispossible that, in very heavily irradiated bone, the tumour
incidence decreases, since the capacity of the tissue toproliferate will be greatly influenced. There is no obvious
correlation between incidence of sarcoma and degree ofradiation damage. Thus external irradiation of the knee
joint and adjacent ends of the femur and tibia of rats
damages and induces tumours in the epiphysis and metaphysis of both long bones; but not in the patella, whereenergy absorption is lower. In the long bones of rats
given P 32 and of rabbits given Sr00 , the earliest microscopic tumours appear as small foci of proliferating cells
amongst spindle cells of osteogenic connective tissue
that show fibrosis in rats. In rabbits fibrosis is Jess evident. This does not mean that the tumour arises from
cells responsible for fibrosis-only that it arises in thesame region of bone. To have a reasonable chance ofseeing microscopic tumours when animals are killed, onemust use a radiation dose large enough to give hightumour incidence. The types of cells giving rise to tu-

mours cannot be defined morphologically because of theextremely abnormal environment in damaged tissue. The
histological characteristics of tumours seen in various
species show that the cells at risk are the "osteogenic"
connective tissue cells. There is no precise evidence as towhether all these cells are equally susceptible to irradiation, though it appears unlikely that the osteocyte is.
The cell may be an undifferentiated "reticulum cell";
if so, it is surprising that there is no evidence of myeloid
leukaemia unless there are at least two different types ofundifferentiated "reticulum cell". The increased leukaemia in mice after Sr90 was always lymphatic.
369. The sequence of bone tissue changes in rats fromthe moment of introduction of the radio-isotope ( Sr90 ,Sr89 , Cew) to the appearance of the primary tumour
nodule, postulated by Kraevsky and Litvinov3 21 is:( i) lst to 20th day: initial unspecific response of thebone in the form of development of endosteal tissue andintensified remodelling of bone ;(ii) 20th to 80th day: inhibition of bone modelling.
Slowing down of osteogenesis. Abrupt dystrophic
changes in the osteogenic tissue. Reduction in the number of osteoblasts and vessels. Coarsening of the basic
material. Onset of atypical bone formation-the background for subsequent tissue malignancy;(iii) 80th to 120th day (first pre-tumour phase): onset of redundant and degenerate bone formation.
Intensified formation of pathological bone structure ina radically changed environment;(iv) 120th to 150th day (second pre-tumour phase):
growth of polymorphous osteogenic tissue among pathological bone structures. Appearance of accumulation of
atypical, free, intensively-dividing, osteogenic cells;(v) 150th to 180th day (third pre-tumour phase):proliferation of atypical osteogenic and immature bone
tissue;( vi) 180th day and later: tumour-appearance of primary tumour nodules and their subsequent growth.
370. Whether antecedent histological bone damage isalways found in a bone having a radiation-induced
tumour must be left undecided at present.

( c) Relationship betwem the pattern of radiationdose in space and time, histological bone damage,and bone tumour induction
371. The radiation dose, i.e., the absorbed energy e.xpressed in rad, is important in relation to histologicaldamage. Some investigators have considered only thedose given or retained in µ.c without attempting to calculate rad, since there are many difficulties in calculatinga meaningful dose in rad. Calculations in rad should be
encouraged since it is only in this way that a quantitative
relationship between radiation and biological effect canbe obtained. The relationship between dose, dose-rate
and the formation of bone tumours has been studied ine."rperiments with Sr 9o, Ce•u, Pu22a, PmH1 yin, ao•,629, Gao
Within certain limits the incidence of osteosarcomas increases with dose and dose-rate.
372. l\fost difficulty in interpreting the response ofbone to bone-seeking isotope arises from the considerable
spatial and temporal non-uniformity of dose, and fromthe changing spatial relationship between cells and radiation source, especially in young growing animals. The
difficulty is knowing which of the many variables predominates in inducing histological changes. Two variables are: (i) accumulated dose and (ii) dose-rate to thesite. The incidence of osteosarcomas increases with dose
1157

nificant incidence of tumours, a more detailed histological search or a new indicator might reveal persistingdamage. Pre-tumour proliferations of immature osteogenic tissue can be resorbed if the dose-rate (Sr89 , Y 90 ),is reduced, thus demonstrating that repair of "carcinogenic" injuries is possible.mand dose-rate. Accumulated dose and dose-rate are interrelated: a great problem with accumulated dose is thetime over which it should be integrated. The dose accumulated up to the time of tumour induction is useful,
but a proportion of radiation given in the later stages
may be "wasted" for tumour induction. Attempts havebeen made to relate accumulated dose and dose-rate todamage and tumour production in studies in space andtime with Sr90 and P32 in rats and rabbits. Information
on dose and bone damage with other isotopes is far lessdetailed.
( d) Accumulated radiation dose to the site373. With isotopes that emit long-range /3-rays, e.g.,
Srv 0 , Y90 and P 32 , maximum dose-rates in different partsof the skeleton of rats and rabbits varies considerablyfrom one bone to another, mainly because of variation inbone size. In a small bone, contribution to dose-rate fromcross-fire in neighbouring deposits is less than in a larger
bone. This causes variation in the maximum accumulated
dose in different bones. When maximum accumulated
dose is compared with distribution of osteogenic sarcomas in the skeleton with Sti 0, sites of maximum accumulated dose correlate with sites of osteogenic sarcomas.
However, other factors must also be important: sites ofmaximum accumulated dose (usually the ends of thelong bones in young animals) are also the areas of maximum growth and therefore of actively proliferating
tissues ; they are also the largest volume of irradiatedbone.
374. Where damage was compared with dose-rate intime and accumulated dose in the upper half of the tibiaof young rabbits, given Sr90 (i) as a single intravenous
injection or (ii) as daily pellets by mouth, the bone volume given maximum dose-rate and accumulated dosecorrelated with the sites of tumour origin. In animals
given a single injection, maximum dose-rate and accumulated dose and site of tumour origin were confined toa small length, - 5 or 6 mm., of bone. In fed animals,
maximum dose-rate and accumulated dose were along a
3-cm length of bone along which abnormal bone tissue
appearing to be the tumour origin was wide-spread.
375. The injection of P 32 at different time intervals(fractionated doses) shows that the rate at which tumours appear can be altered for a given total injected
dose. The maximum accumulated dose was approximately the same in groups of rats injected at different
intervals; this indicates that factors other than maximum
accumulated dose also influence the induction of bonetumours.
376. From a comparison of the dosages in mice given
Ca°' 5 and Sr1'0 causing the same incidence Of bone tumours, the conclusion was that cells on the surface ofthe bone and bone trabecules ( osteoblasts and connective
tissue cells) were the cells at risk and not osteocytes,
This conclusion is not necessarily unique. In this comparison, two difficulties are: (i) at the dose levels compared there were fewer tumours in long bones with Ca• 6
than with Sr90 ; and (ii) dosimetry of Ca45 is subject toerror. These data suggest that after Ca' 5 and Ra 226 "hotspots" might soon become buried in bone and hence
unimportant in giving significant radiation to bone surfaces. The "diffuse component" with these isotopes, may
be the more important in giving the effective dose.
377. Several workers have reported complete histological recovery in bones of young animals of all species
with maximum accumulated dose (to time of sacrifice)2,000 rad. However, since this dose still induces a sig·( e) Radiation dose-rate to the site378. A range of dose-rates from 50 rad/min. for
X-rays, 0.2 rad/min. for P 32 and 0.05 rad/min. for Sr00
induced similar tumour incidence, i.e., 30-60 per cent for
maximum accumulated doses of 3,000-8,000 rad. In asmall group of rabbits a maximum dose of - 20,000
rad over 6-8 months gave 100 per cent tumour incidence.
Over this relatively high range, the dose-rate may not be
important in carcinogenesis.
379. At the relatively high radiation dose levels maximum accumulated radiation dose correlates with bonedamage and tumour incidence with Sr00 in rabbits; thisrelationship is less clear with P32 in rats. Data are not
yet available from which to plot the relationship of radiation dose to damage with short-range ,B-emitters or
a-emitters.
380. Many other variables, such as volume and oxygen
supply of tissue, proliferative activity, and irradiatedmovement of cells at risk must be important in determining the effect of dose-rate and accumulated dose; theirrelative importance is unknown.
Dose and dose-rate in carcinogenesis by internal emittl!1's

381. The relationship between tumour induction andabsorbed dose of radiation is obscured by a series ofproblems. The basic difficulty is that internal irradiation,
unlike external irradiation, continues indefinitely, but at
an ever-changing intensity. Consequently, questions suchas the relative importance of dose-rate and total dose intime and space are difficult to attack experimentally.
382. Several lines of evidence indicate that dose-rate
is a major factor in the induction of osteosarcomas bybone-localizing isotopes. In mice, tumour incidence has
increased as the second or third power of the dose expressed in terms of amount of radio-activity given, andtumour incidence has varied with the time pattern ofadministration.
Internal emitters and leukaemia
383. An increased incidence of leukaemia after in-

ternal emitters have been seen in mice but it is overshadowed by far greater induction of bone tumours. 581
An increased incidence of leukaemia induced by incorporated isotopes was obtained in rats with Sr90 , Cerium144, Niobium-95, Caesium-137 and other isotopes andin dogs with Sr90 .582• 538 The disease has been reported
in radium patients, but only in those exposed occupationally also to much external y-irradiation. 5 a. In studiesof tumour induction by radium in dogs, no leukaemiasor allied conditions have been seen under conditions thatinduce a high incidence of bone sarcoma. 585
Internal emitters and life-shortening

384. Reduction in life expectancy is an important consequence of radiation from internal emitters: this response has been seen in mice irradiated at low levels thatfailed to show an increased incidence of neoplasms.
At such levels of radiation it has not been possible toattribute reduction in life span to any specific degenerative or infectious disease. The animals die with the same
pathological conditions seen in control populations.
158

METABOLIC CHARACTERISTICS OF PARTICULAR
ISOTOPES' 79

Alkaline earlh.s (calcium, strontiiem, barium, radium)385. These nuclides are metabolized qualitatively like
calcium: they are rapidly and almost exclusively deposited in the skeleton, where they are retained verytenaciously. Unless the physical half-life of the isotope
is short, the significant residence time of these boneseeking radio-elements may cover the life span of man.
Like calcium, they are readily absorbed from the intestine, provided they are in soluble form.
Radium-226
386. Radium-226 is of special significance since its
toxicity in man is well established. It has, therefore,
been used for estimating the potential toxicity of otherbone-seeking radio-elements. The value for maximum
permissible burden was established without reference tothe time of exposure. The symptoms of radium poisoning and body burdens alluded to earlier were found inpeople ,.., 20-30 years after their exposure to radium.
During the early part of the post-exposure period, theamount of radium in the body was certainly considerably
higher than that finally measured. The best estimates arethat an individual retaining 0.1 µ.g Ra 226 30 years after asingle exposure must have initially absorbed about

391. Recent work with Sr8 5 retention in normal adults
shows results similar to those in animals. 538 The retention of the alkaline earths, including Sr9°, can be described by a power function of the form
Rt= At-b
where Rt is retention at time t, in days after injection,
A is equal to Rt at one day, and b is the slope of the loglog line. The slope, b, for strontium in man is about halfthat estimated for Ra 226 in man, i.e., the rate of excretion of Sr110 at time t is considerably less than that rateof excretion of Ra 226 at the same time after e.."'Cposure.
However, experiments with rats and dogs indicatedqualitatively the opposite; this further complicates directcomparisons between Ram and Sr9°.
Lanthanide and actinide rare earlhs (including yttrium)
392. The lanthanide rare earths are produced in highyields in fission reactions : the parent materials in suchreactions are members of the actinide rare earth series.
These elements behave similarly in their chemical andbiochemical reactions. However, differences in chemical
behaviour within these groups (particularly the lanthanides) are reflected in changes in their biologicalbehaviour.m
393. Members of both classes are distributed over theearth from nuclear devices; they have not as yet been
identified in appreciable quantity in mammals and man.
This is undoubtedly because of their e..xtremely low solubility and correspondingly low absorption from the intestine. In animals, less than 0.01 per cent of an ingested
dose is absorbed. Very young animals may be exceptional
since suckling mice absorbed 2-3 per cent of plutonium
given orally in milk or as citrate. m Distribution studies
suggest concentration of plutonium in bone, liver andovary. In the latter organ, auto-radiography has shown aselective uptake in certain follicles. 541

lQ µg.53S

387. Many dial painters, who provided much of theinformation on Ra 226 toxicity, were also exposed to otheremitting elements, specifically Ra228 and Th 228 • Thus
they received a much greater radiation dose than is estimated from Ra 220 burdens alone. Such a single exposure,or exposures of reasonably short duration, produce heterogeneous deposition patterns in bone. Continued exposure, as shown for Sr9°, causes a much more uniform
pattern. This further complicates definition of the effective dose. There has been no work showing how theeffects of Ra 226 in the adult may differ in children.

394. These materials, put directly into the bloodstream, behave like colloids and are rapidly taken up in
the reticulo-endothelial system and in the more superficial parts of the skeleton. In the skeleton retention isvery tenacious, but movement from the reticulo-endothelial system is appreciable over a few months."2

Strontium-90
388. The general qualitative similarities in the distribution and metabolism of the alkaline earths have beenshown from single-dose studies after strontium, radiumand calcium in several species, although their rates oftransfer are not identical. Thus knowledge of the metabolism of the other alkaline earths assists in understanding
the fate of Sr90 in the human body. This information,
combined with tracer experiments with strontium andstudies of stable strontium, enables reliable estimates tobe made of the body burden after a given intake of Sr'°,but some uncertainties remain in estimates made on newborn and young children.

395. Locally injected solutions of the uncomple..xed
ions tend to remain at the site of injection. The complexed ions are removed from the site fairly rapidly andfollow the pattern of the intravenously injected material.
396. Attempts to damage the intestinal mucosa by repeated high doses of the rare earths Cr.ttrium and plutonium) have shown that the susceptibility of rats tosuch an exposure is low. Considerable energy is absorbed
within the contents of the large intestine, while passage
through the small intestine is quite rapid.

389. Sr 90 is found universally in the biosphere, and its
primary source in man is from calcium-rich foods, especially milk. It follows calcium qualitatively in the biosphere and its absorption into plants varies somewhat
with availability of calcium. This may be partly true also
in animal uptake of Sr9°; however, there is evidence thatthe absorption of Sr9° from the intestine proceeds independently of calcium to some extent. Growing animals
retain Sr90 more efficiently than adults, reflecting themore active calcium deposition in young animals. 537

397. Caesium-137 is present in the biosphere. Early
spectrographic studies failed to detect radio-caesium inany animal. More recently, it has been found in mammalian and other vertebrate species. In man, the concentration of stable caesium is about 1 X 10-10 g/g wet tissue.
Cs 137 from nuclear debris has now been measured infood and man. 6 • 3390. The metabolic patterns of the alkaline earths differ quantitatively, e.g., preferential absorption of calcium over strontium from the gastro-intestinal tract andgreater renal excretion of strontium.

398. The amount of Cs131 in the bodv reflects thequantity of isotope in the diet in turn affected by the degree of radio-active contamination. As a result of therelatively short residence time of Cs131 in man (the bio-

Caesium-137

159

logical half-time is about 140 days)5H attention is being
focused on this isotope as a means of studying fall-out
rates and mechanisms.
399. The major portion of the Cs137 burden of theUnited States population is probably derived from milk,
and meat products are the second most importantsource.m The 1959 mean Cs13 ' burden of a United States
resident is estimated at 0.01 µ.c. 546 This burden contributes a dose of ,....., 1 mr/yr., i.e., ,....., 2 per cent of naturalradiation background.

to the carcinogenic effect of large doses of !1 31 • In thechild's thyroid weighing ,....., 5 gm, 1 µ.c of I 131 per grammeof thyroid was estimated to yield an integrated dose ofabout 130 rad. After the Windscale incident, milk samples from nearby farms contained more than 1 µ.c/litre.
To limit radiation to the thyroids of children to 20 rad,it was necessary to prohibit consumption of milk containing more than 0.1 µ.c of !131/l of milk. This meantdiscarding much milk for six weeks.

400. Because of the chemical similarity of caesium,
potassium and rubidium, their metabolism is similar.
Caesium, like potassium, occurs chiefly intracellularly,
with low concentrations in body fluids and bone. Tissue
distribution studies have shown that muscle mass contains the largest part (perhaps 60 per cent) of body
caesium, with visceral organs, brain, blood, bones andteeth following in that order. 547 Radio-autographic
studies in mice have confirmed the high accumulation inmuscles and also indicated a rapid and high uptake of
Cs 137 in cartilage. 5 • 5401. Caesium salts are quite soluble, and are quickly
and completely absorbed, more or less independently ofroute of administration. The ion is excreted through thekidney, except in ruminants where a considerable portion is excreted by way of the gut. Tracer studies in the
cow show that about 13 per cent of a single dose willfind its way into the milk within 30 days.kll
Jodine-131

402. !1 31 is produced abundantly in fission and being
volatile is readily liberated. Therefore, under special
conditions, !1 31 may constitute a problem. Wheneversuch a situation arises, the concentration of iodine in thesmall volume of the thyroid gland is the primary hazard.
403. The Windscale reactor incident in England in1957 550 is an example of this. An accident during reactor
operation released fission products from the reactor
stack. The fission products escaping through the filters
were predominantly !131 • Significant downwind contamination covered an area of 518 square kilometres. The
only major vector for human intake of !131 was milk.
The adult thyroid tolerates at least 4,000 rad with nodemonstrable ill effects. However, evidence from young
children given 200 r of X-rays to the neck suggests that
this dose may produce carcinoma of the thyroid in ,....., 3
per cent.H9 This comparison of the carcinogenic effects
at high levels (thousands of rad) of irradiation with !1 31
in the adult thyroid and effects of lower levels (hundredsof rad) of external' radiation with X-rays should not betaken to mean that the child thyroid is more susceptible
than the adult to the carcinogenic effect of radiation.
Evidence of a carcinogenic effect of external X-irradiation on the adult thyroid is still most scanty, but very
limited data suggest that irradiation of the neck of young
adults treated for tuberculous adenitis has induced thyroid cancer, 551 Moreover, the very low incidence of
thyroid carcinoma in patients with hyperthyroidism mand the well-documented experimental evidence thatcarcinogenic dose response curves eventually reach amaximum and decline at high levels with many types ofneoplasm, and particularly in the induction of thyroid
tumours by P 31 in rats, (figure 10), 553 presumably due tocomplete thyroid destruction at higher dose levels, casts
considerable doubt on the significance of the apparent
resistance of the adult, and usually hyperthyroid thyroid,

1131 Doss !µcl

Figure 10. Incidence of thyroid tumours in male Long-Evans rats
given injections of various doses of pa1 ns, 1so
o Follicular adenoma
D Alveolar carcinomab,. Papillary and follicular carcinoma

404. Two problems in radio-isotope metabolism are of
special concern: (a.) estimation of body content fromexcretion data ; ( b) acceleration of e.""<:cretion of a deposited radio-isotope by therapeutic measures. Where
total body counting methods are inapplicable, due to theradiation characteristics of the isotope, measurement ofradio-isotope levels in excreta offers the only method for
estimating body content. The relationship between bodycontent and excreta levels as a function of time after
exposure and route of exposure is therefore an important
study in large animals and in man after exposures giving
rise to detectable radio-isotope excretion. Efforts to promote the excretion of deposited radio-isotopes are discussed in paragraph 525 below.

VII. Dose.effect relationships
EARLY EFFECTS

Immediate405. At very high doses, usually > 10,000 r, mammals
die in minutes or hours probably due to brain injury.
Typical central nervous symptoms develop soon after
irradiation (acute ataxic phase), similar to irradiationof the head only. 62 An experimental exponential relationship has been established for mice6 • between dose andsurvival time: log (median survival time, hrs) =a - bdose (figure 11).
Early death406. Between 1,200-10,000 r, the survival time ofanimals is ,_, 2-6 days. Death is caused by "intestinal
syndrome". No dependence of survival time on dose
within this range was found (according to Cronkite375
the range is even broader. up to 30,000 r), but this may
be fortuitous: injury to intestines might be decreasing
160

100

tissues. Damaged metabolism and lowered food intake
contribute to weight loss.

e 250 1cvp X-rays
0 F1ss!on neutro!lll

80· 409. Voluntary food and water intake by an irradiatedanimal can be used for plotting dose-effect curves · no
doubt other indices would serve also.
'

X Thermal column radlatlon

§

g 60

410. Unfortunately assessment of atrophy has usually
been limited to weighing the organ. Some componentsof tissues decline rapidly after radiation; biochemical
descriptions are lacking. In mouse spleen after TBR
concomitant atrophy of some elements and hyperplasi~of others result in a comple..'{ dose relationship. 55•

•

~
t::
.:l

~

§

C1l

~
E

?<
40

External irradiation~

411. Smith and Tyree 555 irradiated rats with 250 kvp
X-rays and showed that three responses to radiation
increase with dose-weight loss, time required to regain
pre-irradiation weight and limitation of food and water
intake. The linear relationship was obtained (24 hours
after radiation) for percentage of weight lost or percentage of food intake against log of dose over 25-1,000 r.m(figure 12). Weight loss of rats increased linearly withdose over 100-1,200 rad. 556 When weight loss of irradiated rats was compared with that of starved and dehydrated rats, no linear relationship was found within
50-1,400 rad for X-rays and thermal column radiation. 111

30

0

5

10

15

20

:15

30

Dose, 103 r or rep

Figure 11. Relationship between high dose and survival time inirradiated mices•with decreasing dose, and the effects of the "bonemarrow" or other injury might become more pronounced.
Autopsies of animals always show changes in manyorgans.

Internally-deposited radio-isotopes

407. From 1,000 r down to SO per cent of the LDGodose survival time is increased. Death after weeks is due
to bone marrow injury accompanied by secondary infection. Survival vs. dose follows the familiar sigmoid
curve, often seen with delayed toxicity. From such
curves, conveniently after probit transformation, themean lethal dose can be calculated. The mean lethal dose,
LD 50 for mammals, is,....., 200-900 rad (table I).

412. Pregnant rats were injected with P 32 and embryos weighed days 6-10 after fertilization to measureweight loss due to internally-deposited radio-isotopes.
Weight loss of 6-day-old embryos correlated linearlywith dose but was curvilinear for older embryos. 557

Intestinal atrophy

Body weight loss and organ atrophy413. The weight of intestines decreases sharply after
irradiation; correlation between dose and effect is linear.

408. Irradiated animals lose body weight ; this loss
is dose dependent, and represents atrophy of different
organs and a general deterioration of nutrition of many

414. The weight of intestines ( e..'{pressed as percentage of control) of rats given 250 kvp X-rays andthermal column irradiation depended linearly on dose
100

10
9

I

I

90

decrease in food uptake

80

8

i

i

i
...

•

7

70

l<>
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60

6

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.(()

a.

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30

t
f

2

20

l

10

$l

&

25

50

100

250

500

800

Dose,rFigure 12. Relationship between body weight lost or decrease in food intake in rats plotted against dose 117161gover 100-400 rad. 556 The equation of the regression line
was: intestinal weight (per cent of control) = 102.1 0.075 dose (rad).
415. The method, although simple and rapid, is notconvenient for studying dose-effect relationships because
the change is small: even at high dose (about 400 rad)no more than 30 per cent weight reduction of intestines
was found. This is because the radio-sensitive componentof intestines, the epithelium, forms only a part of thetotal weight, the rest being radio-resistant muscle.
416. DNA content as an index for measuring radiation atrophy of intestines was recently suggested by Mole
and Temple 558 but detailed studies have not yet been
published.
The atrophy of spleen and thymus

differences. 5j) 2 The dose-effect curve in mice indicated atleast two components ; in hamsters and rats only one.
The first component was highly radio-sensitive: after
75 r, testes weight was ,...,, 75 per cent of control. The
over-all equation of the dose-effect curve, over 0-1,500 r,
was:
W = Ae-kaD
Be-kbDin which W = weight, D = dose.

+

423. In mice irradiated with 250-kvp X-rays, Co 80
y-rays, thermal-column neutron, and a-particles together
with Li 7 recoil nuclei dose dependence was entirely different. The relationship was exponential, over 50-300
rad with 20 per cent weight loss at the lowest dose and55 per cent at the highest. The computed equation was:W = a-b log D. This discrepancy cannot be resolved atpresent.

417. Thymus and spleen weight decrease in irradiatedanimals. This effect has been used to correlate dose andeffect, and to estimate the RBE of various radiations.

424. The exponential equation of Kohn and Kallman562 suggests that a single event inactivates one biological unit in testes; the effect appears independent of
dose-rate.

External irradiation
418. 'Weight loss of spleen and thymus in mice exposed to various radiations was related linearly to thelog of dose. With 250 h."Vp X-rays, organ weight decreased 10 per cent after 50 rad; no experiments withother radiations have been done at doses < 100-150
rad, at which a 20-30 per cent weight loss was foundwith ColHl ,.-radiation, 4MeV ,.-radiation, thermal, 14
Me V, and fission neutrons. 558

425. However, this interpretation is questionable in
the testis containing various cells, ranging from diploidto haploid, with numerous intermediates. One type of
spermatogonia is extremely radio-sensitive; their number is significantly reduced after 20 r. Testes atrophy is
due to loss of mature cellular components, along with
inhibition of differentiation of earlier stages.

Internally deposited radio-isotopes
419. The dependence of organ atrophy on dose frominternal sources of radiation suffers from uncertainties
in dose estimation and chemical toxicity. In mice given
tritium-water the rapid equilibration of water enables
dose to be calculated on the assumption of an even distribution of tritium. The percentage reduction in spleen
and thymus weight was linear with log of dose over
150-600 rad; the corresponding weight loss was 30-70
per cent.

426. Recently in rabbits given 35 r-1,000 r with 220
kvp X-rays sensitivity of lymphatic tissue was measured
by the volume of the appendix in vivo and in vitro. 583
The appendix volume decreased 55-75 per cent. The
percentage decrease of appendix vs. dose has two components; from 35-100 r linear and > 100 r exponential(figure 13) .

Lymphatic tissue

80420. Correlation between organ atrophy and radiationfrom internally deposited fission products (plutonium
plus products of neutron irradiation of plutonium deposited in tissues) showed a linear relationship between
reduction of spleen weight and log of the concentrationof radio-active isotopes in tissue. The dose-range was,...,, 400-1,600 rad. The thymus did not incorporate any
isotope and could not be used as an index.
421. Thymus is useful for correlating dose andatrophy because of its relatively simple cellular composition. However, there are two competing processes inthymus atrophy: (a) decrease of mass, predominatingin the lower-dose range, and (b) weight gain predominating at higher doses especially > 1,000 r. 559 Perhaps .
measurement of ribonucleic acid (RNA) would be amore useful index of radiation injury to thymus. ConcenFig1tre 13. Decrease in volume of appendix irradiated in vivo intration of RNA 560 (per wet weight of tissue) correlated
rabbits plotted against dose ss3
linearly with dose; RNA decreased 10-80 per cent within
lQ0-.600 r. Activity of nucleodepolimerases in thymus
was also dose-dependent, varying from 40-60 per centDepression of mitotic activity·
with 40-160 r.m
427. Suppression of mitotic activity is a prominent
effect of ionizing radiation.
Testicular atrophy422. Testes weight (expressed as log of percentage
control) of mice, rats and hamsters irradiated with 250kvp X-rays varied with dose, but with important species

428. With isolated single cells, e.g. grasshopper
neuroblast, mitosis and the influence of radiation may befollowed directly. Radiation given in late prophase162

shortly before dissolution of the nuclear membrane ismore efficient in inhibiting mitosis (in grasshopper
neuroblast) than if given later.Wf
429. The numerous mitoses in irradiated animal
tissues make quantitative evaluation more difficult;results depend not only upon irradiation but also upon
the stage of mitosis at the time of irradiation. The
general picture from many studies is that irradiation
decreases the number of prometaphases, metaphases,
anaphases and telophases. This is probably because
cells irradiated in one of these phases complete
mitosis regularly while cells in interphase are prevented from entering mitosis. The decrease in prometaphase-through-telophase cells correlates with dose.
If the dose is sufficient to reduce mitotic cells to zero,
the time of their reappearance also directly relates todose. 565 (figure 14).

fibroblasts: ,...., 30 r reduced the mitotic index ,...., 70 per
cent, and doses of 180 r decreased the mitotic index tozero. Grasshopper neuroblast was still more sensitive ·the dose-effect curve was similar (figure 1S).
'
432. Doses as low as S r of X-rays depressed by SO
per cent the mitotic activity of the adrenal glands.
jejunum, lymph node and epidermis of mice (figure16). 568 Log of dose vs. percentage reduction of mitosis
was approximately linear. Some curves showed athreshold effect ; others did not.

.,..

•

90 .mu. all8r osposme

H

120 m1ll. after exposure

TS

I

180

•

)(

j

GO

il

1
l

25

Dose, rFigure 16. Relationship between dose and mitotic activity of theadrenal glands, jejunum, lymph node and epidermis ofmice 5"I

1•433. Probably a more useful method of following
dose-effect relations is by measuring the time for the
mitotic inde."< to return to normal. This method used to
study the mitotic inde.."< of mouse ear epidermis cells
irradiated with thermal neutron or X-rays over 5-55 radshowed a linear relationship between log of duration ofdepression of mitotic activity and dose. 585•.

.Tlmll allR lmldllllal

Figure 14. Relationship of dose to time of reappearance of
mitosis &65

430. The effect of radiation upon mitotic activity ofanimal somatic cells has been studied quantitatively onchick fibroblasts, rat retina cells, grasshopper neuroblastand epidermal and lymphatic cells of mice.

Depression of iron uptake by erythrocytes anderythocyte-forming tissues
434. The functional state of erythrocyte-forming
tissue is usually gauged from incorporation of Fe59 • Moreextensive studies usually measure Fe 59 in erythrocytes
simultaneously with isotope content in isolated bonemarrow cells and various other tissue compartments,
e.g., spleen, liver and plasma. Irradiation depresses ironincorporation. 569

431. The doses of X-rays in chicken fibroblasts were80-450 r; the smallest depression of mitotic inde.."< was,_, 60 per cent.588 The relationship between dose andpercentage of normal mitotic index was curvilinear, butlack of data at lower doses precludes extrapolation of
the curve. A similar curve was obtained with rat retina
cells ;561 their radio-sensitivity was higher than chicken100...._.....

Qimntitative studies
435. Iron incorporation by bone-marrow of animals(mice) irradiated with X-rays (250 kvp), y-rays(4 MeV Co60 ), neutrons (14 MeV fission and thermalcolumn), and tritium f3 particles over 40-300 rad m wasdepressed 10-80 per cent. Correlation between dose andeffect followed the exponential equation; effect = a - b
log dose.

,Clllckmircbluta>c >e cenao1c!OTo1Dp1agrcN111&-e--e- ~·~blut

I

•

200

soO

•

)(

100

400

·-

436. A different dose-effect was found in rats irradiated with Co 60 gamma-rays and with thermal neutron(with REE equal about 1) over 40-500 rad (figure17) :610 iron-uptake decreased steeply with increasing
dosage ; it was significantly lowered at 60 rad and reachedabout 30 per cent of control value at 150 rad; further
increase in dose had less effect on iron uptake. The two-

IOO

Figure 15. Relationship between dose and percentage of normal
mitosis in chicken fibroblasts,568 cells of developing rat
retina,567 and grasshopper's neuroblast

163

~

20
0

eo60

ra19

x Flaalml nouh'on wUh gamma-ray oOl1tamllWfOD
16

~
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IJ

g
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Ij

....,, 9
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40

30

5

4

SL-~-L~~-1-~~..J.-~~~~""'-:~~-:~-

O

100

200

300

400

500

600

Dose, rads

Figure 17. Depression of Fes9-uptake in bone-marrow of rats
irradiated with eoso Y-rays and thermal neutrons5rocomponent character of the curve corresponds probably
to two main systems of iron incorporation in blood
marrow (a) in dividing and differentiating cells of
normoblast series, ( b) in surviving, less sensitive cells(e.g. reticulocytes), and perhaps the iron-protein storage
complexes in bone-marrow.
437. A plot of log percentage iron uptake vs. dose over
40-150 rad gave a straight line. The graph shows that
doses below about 40 rad have very little if any influenceon iron uptake by bone-marrow. The equation derived islog-effect = a - b dose (figure 18).
438. Results obtained by various authors disagree,
possibly due to differences in experimental methods.
Storer's and Rambach's studies show a threshold dose
for iron incorporation at 30-40 rad while others found
an impairment of bone-marrow erythropoietic function
at 5 rad. A still more pronounced difference is apparent
between dose-effect function of the two groups of investigators: in Storer's results effect varies proportionately to log-dose; in Rambach's data, log of effect variedwith dose. Experimental differences were considerable; the incorporation time for iron in one groupwas 6 hours, in the other, 72 hours; the amount of radioactive iron given controls was five times larger in
Rambach's work than in Starer's.

·50

100

200

SOO

Total dose, radFigure 18. Effect of dose on Fe59-uptake in bone-marrow of rats
after 40-150 rad s10

useful in evaluating the effects of radiation on erythrocyte-formfug cells. Unfortunately no satisfactory experiments have been done. In some reported so far, long-term
irradiation has been given as repeated single irradiationand this, obviously, might permit recovery between
irradiations; also, the time between the last irradiationand the assay of the iron uptake was in some experiments
10-11 days-ample to make injury negligible by repair.
Some injury persists as shown by experiments of Baumand Alpen m who computed the exponential correlation
between number of exposures and decrease of Fe incorporation into erythrocytes. In long-term exposure,
this irreversible or very slowly reversible injury might
accumulate and become a noticeable injury.
Sitppressi01i of immunological mechanism
440. TBR damages the immune response of the body:
production of antibodies is suppressed, susceptibility toinfection increased and transplanted heterologous tissues
survive in the host for a long time. Neither antibody
production nor susceptibility to infection is a convenientindex of the effect of radiation. However, the incidenceof successful tissue transplants has been used to study
the dose-effect relationships.
Leukaemia transplantation

439. The high sensitivity of erythropoietic tissue andthe ease and precision with which its functional status
can be followed make it one of the most suitable for workon the sensitivity of mammalian cells. It is doubtful
whether single dose experiments will solve the problem,
as fast division leading to numerous cell types at each
moment in bone marrow implies a mixed population ofpresumably different radio-sensitivities. Long-term irradiation, preferably at very low levels, might be more

441. The incidence of successful transplants of mouse
leukaemia into another strain increases with dose over
100-500 r. A straight line can be plotted of probit of percentage of leukaemia vs. log of dose.
442. In mice irradiated with X-rays or neutrons 100600 r or rep-log of dose was linearly related to percentage
of successful leukaemia transplants (after probit transformation) .m Different strains of mice showed marked

164differences. The mean dose producing 50 per cent leukaemia deaths ranged from 327-+- 20 r-470-+- 41 r for
X-rays, and from 258-363 rep for thermal column
irradiation. The slope of the probit percentage incidence
vs. log dose line varied 5-10 for various strains.

one out of three patients given 600 r of 200-kvp X-rays
developed a cataract; with increased exposures the time
for appearance of opacity was shortened. A survey of
100 cases of radiation cataract and 73 cases of patients
given radiation to the head was made by Merriam a;id
Focht:164

LATE EFFECTS

451. The patients were grouped according to thetime-schedule of irradiation. For the cases given a single
dose, the minimum cataractogenic dose was 200 r, forthe cases given doses spread over 3-12 weeks the cataractogenic dose was 400 r, while for those whose treatment spread over more than three months the dose was
550 r. The greater the dose the less the time for the appearance of cataract. In figure 19, incidence of cataract
is shown as a function of dose among patients irradiatedwith doses given over more than three weeks.

Induction of lms opacity

443. Cataract formation is not understood; but
opacity of the lens is due to radiation damage of lensepithelium that has a relatively high mitotic activity. The
mitotic index decreases to ,..., 0 after ,..., 1,500 r, followed
after a time (dose-dependent) by recovery with atypical overshoot in mitotic index. Abnormal cells areformed: some showing increased size, decreased transparency and multiple nuclei. Similar abnormal cells canalso be seen in many other tissues of high mitotic activity,
but they cannot be shed from the lens as they can frombone-marrow. They remain inside the lens structure(probably because of the restricting tough capsule surrounding the lens) and form centres of opacity. Recent
data indicate that slight recovery of the lens is possible. 573

----

100

so f.

444. Cellular homogeneity along with inability toslough the injured cells make the lens useful for studies
on dose-effect correlation, only limited by the methods
for assaying the injury and by difficulties in estimating
the dose.

0'"

Methods
445. The degree of injury (i.e. the degree of opacity)
is estimated by an ophthalmoscope or slit lamp; thisnecessarily subjective method has a rather high thresholdof resolution. Comparison of the effect of radiation invarious animals is more difficult because of variation insusceptibility among species and dependence on age.
Lastly, estimation of the dose to the lens has a large
margin of uncertainty; especially with neutron-irradiation.

zo

'"
100

300

500

700

~00

1100

1300

Dose at lens, 1'

Figure 19. Relationship of cataract incidence to dose given overmore than three weeks• 0 •Experimental studies

446. Reduced glutathione decreases in an irradiatedlens, as does the activity of the enzymes of glutathione
metabolism. m Irradiation also decreases the weight andRNA content of the lens, even when no opacity is seen. 575

452. A number of experimental studies permit roughestimation of the lowest dose for cataract formation.
Storer 576 found that any doses of 250-kvp X-rays, 12.5 r
and up increased the incidence of cataract in mice (lower
doses were not tested); this agrees well with the increased incidence of lens opacities after 15 r of
X-rays.174 •m The lowest dose for rabbits for hard
X-rays ( 1,200 kvp) was ,..., 250 r.

Human studies
447. The lowest dose for lens opacities formation has
been estimated from experimental as well as humanaccident studies. The slow formation of cataract makes
the outcome difficult to interpret.

REE

448. Notwithstanding these reservations, a number of
estimations of the critical dose for cataract formation
have been made. Among Japanese survivors up to 1950,
100 people with radiation cataract have been found~mong those who received an estimated dose of 5-15 rep
m neutrons and about 600 r of y-rays.

453. Neutrons have a higher efficiency in inducing
cataract: their RBE for purposes of human protection
has generally been taken as 10 by ICRP (A). Someearlier studies on neutron-induced cataracts employed
cyclotron-produced beams, i.e. neutrons together withhardy-rays: Evans 578 found that 80 rep of fast neutrons
produced lens opacity in 100 per cent of mice. Storer576
found the REE of neutrons was 15 relative to 250 kvp
X-rays; 2.9 rep of fast neutrons produced lens opacities
in 50 per cent of exposed mice.

449. In 10 cases of nuclear accidents, August 1945September 1946, cataract formation was seen in only
one person who received whole body dose of 15 rep
neutrons and 26 r of y-rays ; the calculated dose to theeye was 45 rep. The critical dose for cataract formation
apears to be ,..., 20-45 rep.

454. During Operation Greenhouse, mice receiving
1-10 rep of fast neutrons (together with about 1 r of
hard gamma-rays) all showed cataracts. In rabbits,
Cogan et al.1'119 estimated the threshold dose of 14 MeV
neutron for cataract induction to be ,..., 10 rep (RBE ofneutrons ,..., 220).

450. The data on radiation-induced cataract in man
are hard to analyse quantitatively. Dosage is often very
uncertain and the follow-up time of patients not longenough. A report of Cogan and Dreisler"60 shows that165

~erefore, to short-lived animals. Exclusion of multiple
mterc!'lrrent fa~tors, e.g. infections which in long-term
expenments might affect any group is essential. Moreover, for adequate study of the cause of death, large~umbers .of ~mmals are needed, especially when the maininterest lies ma rare effect, e.g., as in studying the incidence of tumours. Strains with higher incidence of thiseffect may be selected but this may restrict the validityof the results. Usable results are therefore still rather
meagre.
. 4?7. .The life of animals exposed to continuous irrad~atton.is us~lly shortened. Survival plotted against time
gives s1gmo1d curves ; the median survival time is shortened with exposure. Different strains of mice differ ins:nsitivity. to radiation as i;neasured by LD~ 0 's 28 and in~ifferent hfe-span shortemngs linearly related to theirlife expectancy. m .
458. If shortening of life-span is plotted against doserates, the relationship is linear for y-rays and fast neu-

Dose-effect correlation
455. Cataract formation is dose and dose-rate dependent: the RBE of different radiations is perhaps morediverse than with other radiation injuries and does not
permit setting up an equation for dose vs. effect. The
dose dependence of cataract formation for neutronsM 0
and for y-rays114 shows a clear correlation between dose,energy of neutrons, and degree of opacity (figures
20-21). Constants cannot be derived.
Shortening of life-span

456. Continuous exposure to low doses of radiation
does not cause the dramatic effects seen at high doses.
The symptoms are not specific to radiation. The effects oflong-term exposure necessitate study of life-span andcomparison of ~uses of death between exposed and nonexposed populations. Observations have to continue until
the death of irradiated subjects. Experiments are limited,+
01-.----------~20~0-----------4~0~0-----------.J60~0-----------J80~0--Dose (rep)Figure 20. Relationship between dose and degree of opacitym

"100

81!0

~00

fOO

l)ose (rep)Figure 21. Relationship between dose and degree of opacltysso

166

llOO

trons within the range of dose rates shown in figure22.681459. When irradiated animals are given a second
course of irradiation, the LD 1m depends on the time between the first and seconQ. e.xposure, and increases
asymptotically with time. 582

.•

100
80

••

•
•• •
•
•
•

60
40

i=

0

., Lorenzc.
"'"' 100~'O• Upton fil.fil.

"' c

80

i=

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i:;
·:::>

~

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• Henshaw~ Henshaw et al.

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•

20
#

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o Upton .fil.il.
A Henshawu

""0

c

40

0

20

0

D

0.1

a

0

~

1.0

10

100

Dtlse rat~ <rad/day!
Figure 22. Reduction of mean or median survival time in mice
exposed daily for the duration of life (solid symbols, X- and'Y-rays; open symbols, fast neutrons). Redrawn from Upton663

460. From these data, Blair formulated a theory on
the shortening of life-span by irradiation :257(a) The total injury caused by radiation is proportional to the dose;( b) The injury is partly reparable;(c) Recovery from reparable injury is exponential;( d) Irreparable injury accumulates in proportion tototal dose;( e) Reparable and irreparable injury are additive anddeath occurs when their sum reaches a level inversely
related to the age of exposed animals.
461. Blair's theory has stimulated design of e.xperiments and many results fit its predictions.48 Blair's postulates have been challenged. Radiation damage is made upof many individual injuries,683 mostly unidentified, andthe pattern varies from strain to strain. 224 Accordingly
any simple recovery mechanism is over-simplification.
Recovery also differs according to kind and manner ofirradiation.66 That the lethal threshold is inversely related to life expectancy is doubtful, since the LD 50 varies
with age but less simply than as proposed by Blair.m-m

observed statistically is not aging but mortality-something related to it and which measures it. The analogy is
supported by the pathology of irradiated animals showing histological damage resembling lesions of sen~scence.
464. Sacher2 31 • 256 has stated that the physiologicalstate of an individual fluctuates around some central
value and any individual leaves the population when his
state reaches a limit called the lethal boundary. It is
assumed that such a limit is a fixed one, common to allindividuals of the population. The physiological state of
the individual decays with time, approaching asymptotically the lethal boundary. From mathematical argument
Sacher asserted that log rate of mortality follows linearly the mean physiological state of a homogeneous
population. If it is assumed that the physiological state
decays linearly with age, as seems the case for many
physiological characters, the force of mortality will also
be linearly related to age. This is indeed observed formost animal populations. A corollary of Sacher's theoryis that impairment of the physiological state brings it
closer to the lethal boundary, so that the probability oftransgressing it through random fluctuations increases.
Irradiation would shift the physiological state so that theforce-of-mortality curve of the e.xposed population
would coincide with the curve for some later age.
465. Sacher's brinkmanship theory is closely related
to the information approach to lethality and radiation
damage. Although cloaked in different language andusing different mathematical conventions, this theory as
expounded by Quastler2 52 and by Y ockey687 leads to aparallel with Gompertz' law.
466. In their present state these theories are so allinclusive that they are not concerned with the natureof the radiation injuries or with the recovery processes;
physiological state (or degree of orderliness according toYockey) is largely undefined, as is the death to which
the theories refer. Accidental deaths are not consideredby them; it is less clear whether the only relevant deaths
are not those ascribable to senility-the observed causesof death are dependent on diagnostic accuracy. Radiation
studies have been confined mostly to recording the overall mortality, thus lumping specific and "senile" causesof death; but as the experiments are expanding, consideration of the causes of death becomes unavoidable.
467. Differences among strains disappear for males
when deaths from leukaemia are e.xcluded. On the other
hand, when animals dying from leukaemia or females
carrying ovarian tumours are e.-.ccluded, even differences
between sexes disappear. 224 Larger numbers of animals
might well have brought out further differences ascribable to the differential incidence of other conditions.
Something of the kind is seen in human populations
where Gompertz' law holds, but only approximately andover a limited age range. However, on plotting the forceof mortality for individual causes against age, linearityof most of the resulting graphs is striklingly improvedand can be carried down to a much earlier age.

462. Demographers have long known that the log ofage-specific death rate of a population ("the force ofmortality") plotted against age at death, is roughly
linear beyond early childhood. This relationship, Gompertz' law, applies to irradiated populations. Force-ofmortality curves for exposed animals parallel control
curves at a distance directly related to dose for single
exposure, whereas for constant long-term irradiation,
the slope of the curve increases by a factor depending on
dose rate. 235

468. Although nothing is known about the lesions
shortening life-span in multi-cellular organisms, knowledge that irradiation is powerfully mutagenic has incited
speculation about the role of somatic mutation.
469. Somatic mutation has been invoked by Szilard588
as the cause of aging. He thinks a cell dies when both
homologous genes of a pair responsible for an essential
cell function are impaired by mutation. Mutation can be
inherited, when it is called a fault, or be spontaneous, and463. These observations have encouraged analogies
between chronic irradiation injury and aging. Aging,while familiar to everyone, is difficult to define. What is167called an aging hit. The number of faults carried by anindividual is fixed at birth, whereas the aging hits accumulate randomly with time, so that at any moment the
number of surviving cells carried by an individual depends on his hereditary load and on his age. Death occurs
when the number of sun-iving cells carried by the individual approaches a critical limit. Szilard calculated theaverage number of faults carried by the individual in
human populations, and predicted the shortening of lifespan by radiation in man. His results cannot be checkedin our present state of ignorance about the life-shortening effect of radiation in our species. The theory in its
present state does not predict the expected parentoffspring correlation in life-span; if it did it would
prompt a not too difficult test on human populations.
470. Besides Szilard, Faillam also interpreted aging
as a mutational effect, and showed that Gompertz' law
can be derived by assuming that the change in mortality
rates with time is a one-hit process. It is none the lesspremature to attribute such a comple..-x: phenomenon as
aging to somatic mutation which in vertebrates has beenstudied mainly in cell cultures. There is littleimowledge
about possible repair and recovery mechanisms of mutational effects. Even in unicellular organisms, radiation
damage is not confined to the genome and it would be
surprising if this were not true for the cells of higherorganisms. Attempts to shorten life-span by giving
chemical mutagens were unsuccessful, 5 S11 but more recent
work in two laboratories has confirmed the radiomimetic
effects of chemical mutagens for life-shortening. 219 • 500
Induction of timiours

476. Change in susceptibility with age of animals is
still another complication in studies on tumour-induction. 696 This and the long latent period for tumourinduction make correlation of injury with accumulated
dose difficult in animals exposed to long-term low-level
irradiation.
Quantitative studies
477. The rate of tumour development and amount ofstrontium-89 injected into mice were related linearly,
after a latent period which increased with diminishingdose. 597 However, the plot of the number of tumours at
any time after treatment becomes curvilinear and appears as a higher power of the dose. 286
478. Dose-response curves for mouse lymphomas,2 97
ovarian tumours and myeloid leukaemia were nonlinear.303 Bone tumour induction in mice by strontium-90
is not proportional to incorporated radio-isotope and may
be described as proportional to the square or cube of thedose. 698

479. Data on the influence of dose-rate in the induction of neoplasm by ionizing radiations are as yet fragmentary. In most instances a given dose is substantiallyless carcinogenic absorbed over a long period at low doserates than it is absorbed in a single short exposure. 559 • 599
Blum, 600 from skin-cancer induction in mice by ultraviolet light, suggests that the time for the appearance oftumours is inversely proportional to the square root of
the dose-rate; the dose-effect curve would have a rising
inflection with increasing dose-rate, and a threshold, if
any below limits of observability.

471. In man the induction of leukaemia at present provides a basis for inferences about the dependence ofincidence on dose, and data being accumulated as to the
induction of bone tumours by radium is adding valuable
information to this. 691 Animal data prove that ionizing
radiation induce benign and malignant tumours. If tumour incidence increases with dose, taking into accountthe statements made later on threshold, studies on doseeffect relationships are by their nature inconclusive
about ·what the mechanism is.

Radiation-induced leukaemia in man
480. Radiation-leukaemia surveys may examine a
population of exposed and non-exposed people and observe directly the incidence of leukaemia in the twogroups. In retrospective studies, groups of leukaemic
and non-leukaemic populations are selected, the frequency of irradiated and non-irradiated individuals calculated, and the risk of leukaemia estimated.

481. Retrospective studies, beginning with people selected without prior knowledge of their radiation history,
are likely, in the present state of radiation records, tomisestimate exposure ; the reliability of information
about past radiations depends largely on memory.

472. Knowledge on tumour growth is limited and experimental difficulties abound. The long latent period in
the appearance of tumours impedes work at higher doses,
since other radiation-induced pathological disturbances
may cause death before tumours appear. At low level ofirradiation animals have to be kept a very long time;intervening infections often vitiate experiments. Moreover, the incidence of tumours is low; low-level irradition studies require unwieldy numbers of animals.

482. Three major prospective studies are the Hiroshima and Nagasaki atom bomb survivors, 420426 children treated with X-rays for thymus enlargement,438 · 40
and adults treated with X-rays for anl-ylosing spondylitis:m, oo

473. _/\s a further complication, radiation is not necessarily the direct cause of tumours: lymphoma in miceand mouse ovarian and pituitary tumours are an indirect effect of irradiation.

The Hiroshima and Nagasaki .rurveysuo-m

483. The Hiroshima and Nagasaki explosions offer aunique and most important opportunity to study theradiation-leukaemia problem. They should answer thequestion about the long-term effects in child and adult.
The irradiation dose was large and the population exposed substantial : ,_, 1,000 survivors received an LD:;odose, and 10,000 a dose over the greater part of the bodyof ,_, 100 rad or more. Important effects could hardly be
missed. Overlooked effects could only be those produced
from prolonged exposure to smaller doses or those requiring intense radiation to a restricted part of the body.
Such effects would be observed most readily amongpeople occupationally exposed and among patients given
large doses of therapeutic radiation.

474. The role of co-carcinogens is almost completely
unknown in radiation carcinogenesis. In chemical carcinogenesis, \•.;ith a co-carcinogen. the amount of carcinogenic agent was related linearly to tumour incidence ;carcinogen alone has a threshold. 592 Croton oil after radiation increased the incidence of benign tumours inskin. 593
475. Combined radiation and methylcholanthrene
were synergistic in inducing leukaemia, P 32 and methylcholanthrene5~ in inducing skin tumours, and mechanical irritation and X-rays in inducing sarcomas. 395
168

484. Data from the Hiroshima and Nagasaki populations will be less clear about dose-effect relationships.
The irradiation was instantaneous ; the results cannot
tell what is likely to happen where the dose is spread out
in time or intermittent. Great efforts are being expended
to make exposure history as accurate as possible; nevertheless, how people were shielded is, in many instances,
uncertain and hence there will always be some uncertainty about the exact irradiation received. Therefore,
information about dose-effect relationships must also be
sought elsewhere. Here data from hospital patients or
persons occupationally exposed should prove useful. The
dose-effect relationship is discussed in paragraphs248-253.

Children irradiated for thymus mlargementi 38 • 438 · " 5
485. The data are too scanty to warrant conclusions
about the relationship between dose and incidence of leukaemia or thyroid cancer among children given radiation
to the thymus (see paras. 263-272).
X-ray treated ankylosing spondylitism, « 0486. An extensive survey on irradiated ankylosing
spondylitis in England by Court Brown and Doll gave
special attention to dosage e.'Cpressed as maximal bonemarrow dose, mean bone-marrow dose, and whole-body
integral dose for every leukaemic, and for every patient
belonging to a random sample of the whole exposed population. The results are familiar. As there were only two
leukaemic female patients, the quantitative study was
limited to males. Age distribution ranged from fourteen
years onwards.
487. The clinical treatment of ankylosing spondylitis
consists usually in irradiating the affected bones with adose of ,_, 1,000 r. If the symptoms recur, re-treatment
is often given. This is the e.'Cplanation in this study ofthe positive correlation between cumulative mean bonemarrow dose, and the time between the first treatment
and death of the patient. One possible explanation of thefindings not excluded by the data could be that patientswith ankylosing spondylitis, irrespective of the methodof irradiation, are more likely to develop leukaemia thanhealthy people.
488. "With these limitations in mind, the incidence ofleukaemias was plotted against maximal bone-marrow
dose, mean bone-marrow dose, mean bone-marrow doseamong patients whose spine and sacroiliac regions only
were e.'Cposed, and whole body integral dose. The incidence in all depends on dose and the dose-response curve
bends upward. This suggests a non-linear relationshipbetween exposure and incidence.
489. Owing to the fewness of cases on which it isbased, the ankylosing spondylitis survey only proves that
there is a dependency of incidence on dose but gives little
information as to quantitative relationship. Further
details on the dose-effect relationship are given in paragraphs 254-262.

Concept of threshold
490. Thresholds have been observed for many somaticeffects, but it is a question whether radiation and leukaemia incidence are related below a certain dose. \Vbatever the dose-response curve, a critical e.xposure level
might be required before irradiation brings about thecellular derangements responsible for inducing leukaemia and other tumours. Experimental and clinical dataon tumours and leukaemia considered as demonstrating
the linear character of the dose-effect curve are all oh-tained in the higher dose-range, 100 rad and above. The
nature of this relationship has not been studied for lower
d?se levels. Kan;b and Pauling 801 have e.xpressed theview that the existence of a very low threshold or its
absence cannot be feasibly determined by studies inanimals. A. V. Le~edinsh."Y's 802 conception may prove to
be correct : he believe~ that for initial changes in any
structures of an orgamsm at the molecular leyel there isno threshold dose at which the various types of ionizing
radiation begin to have an effect, whereas a thresholddoes e.'Cist at the level of the cell, the tissue, the organs
and the organism due to compensatory responses andregenerative processes. The ankylosing spondylitis andthe Hiroshima surveys hint that at the lowest doses nodifference can be shown between the observed incidenceof leukaemia and the incidence e.xpected in the general
population. In such circumstances a search for a threshold is futile. It cannot be taken as a...xiomatic that if atmoderate or large doses an effect is proportional to dose
it is justifiable to extrapolate the same relationship tolower doses. Recent evidence neither proves nor disproves the existence of a threshold for radiation effects
in inducing tumours in man. To avoid the danger ofunder-estimating the probability of radiation-induced
leukaemia and other malignancies, it seems reasonable
to assume that the observed cases of malignancy will not
exceed the number predicted, if the relationship between
incidence of malignancy and dose were considered linear(no threshold) for all doses.

VIII. Protection and modification ofradiation injury
INTRODUCTION

491. This chapter discusses the physiological, biochemical and biological methods that have been developed
to protect against and modify the injury of living organisms by radiation. Although to date work on radiation
protection and recovery has found few practical applications to the survival of higher organisms, this is a rapidly
developing field and more recent ways of promoting
recovery by transplanting blood-forming cells may develop practical significance.
PROTECTIVE AGENTS

Anoxia492. That anoxia reduces radiation mortality was firstshown by Lacassagne603 in newborn mice. Also, rats
e.'Cposed to 800 r in S per cent 0 2 + 95 per cent N 2 werealive 30 days after exposure; all controls died. 6 G4 At
1,200-1,400 r, 50 per cent of treated animals survived 30
days. Results with mice in 7 per cent 0 2 + 93 per centN 2 were less impressive; ,...., 80 per cent of the treatedanimals survived 800 r, lethal to all controls. Similar
results were obtained in chicks, 605 rats, 60 6-60 7 andmice. 608 • 609 Some symptoms, e.g., desquamation, can bealleviated by hypoxia.610 Lamson et a/.m.s 12 studied
long-term effects, such as life-shortening, tumour incidence, hypertension, and nephrosclerosis, in rats surviving 1,000 r of hypoxic TBR. Carbon monoxide also
reduced the radio-sensitivity of mice. 613 • 814 guinea pigs,
rabbits, and rats.615 C02 was ineffective.616 Correlationof anoxia with various responses has been reviewed 617
and the mechanism discussed. 618- 62° Cyanide-induced
anoxia was particularly effective in mice ;821 otherworkers have had difficulty in getting similar re-169

suits. 95 • 96 • 622 • m Nitrate also reduced radiation mortality
somewhat. 624 • 625 P-aminopropiophenene, a methaemoglobinaemia-producer, gave 72 per cent survival in mice
given an LD 10o radiation exposure. 6260627 Another wayof lowering 02 tension, hypothermia, increases survival
rate in newborn mice 628 as confirmed in mice andrats. 629 • 530 On the whole, this approach, while illuminating the mechanism of protection, offers few practicalpossibilities.
493. Radiation response may be modified in two ways:(a) preventing injury to vital parts of the organisms;( b) aiding recovery of the affected system. Injury can beprevented by supplying cells with chemicals interferingwith or limi~ing formation of free radicalS or making
the cell constituent less susceptible to interaction with theradical; the protective chemical might even reverse
actual damage, e.g., oxidized thiol groups. A pharmacological drawback of preventive chemicals is that theymust be given immediately before irradiation so as to
be at the target site during irradiation. Biological entities-cells or tissues-introduced after radiation canreplace affected cells and tissues and thus permit recovery. Modifying factors in irradiated organisms may betransient or permanent.

501. Differences in activity of closely related compounds might reflect inability of some to enter the cell.
Protection against the direct action of radiation might
be explained by assuming that thiol compounds restore
enzymes to the -SH condition needed for their function-an hypothesis suggested by Pihl and Eldjarn. 634 Proteins form mixed disulfides ea!ily, e.g., insulin fragments.
502. Compounds containing the labile - SH groupprotect molecular structures against direct and free
radical-mediated-action of radiation. Undoubtedly, an
additional action is lowering intraceIIular 0 2 tension andreducing number of free radicals ;m thiols share thelatter property with several other chemicals e.g. choline
derivatives.u 2 Several thiols protect animals against 0 2
poisoning; this supports the belief that lowering of 0 2
tension is important in the action of protective chemicals.643
503. These theories of the action of protective chemicals cannot account for the protection given by certain
pharmacologicaJiy active substances, e.g., reserpine6 "which can protect rats if given as early as 24 hours before
irradiation; its action correlates with obvious changes intissue metabolism. Similarly, the effects of parathyroid
hormone and EDTA could be related to the effects ofcalcium on cell permeability that prevent the loss of intracellular constituents due to the radiation-induced increasein permeability.6'~• 646

Protective chemicals
494. Serious study of protective chemicals began
after Barron's demonstration that sulfhydryl compounds
protect many enzyme systems in vitro. 681 Patt 632 firstused a sulfhydryl compound for protection of animals,
and was soon followed by others. oss

Modifying treatments

504. Death of an animal exposed to the lower rangeof lethal doses is mainly due to bone-marrow injury.
This suggested treatment with viable bone-marrow cells
that might permanently or temporarily take on the function of the destroyed cells. The feasibilty of repairingradiation-induced damage by biological means was suggested from the prevention of thrombopenia in X-irradiated guinea pigs by shielding of bones in the early experiments of Fabricius-Moller 647 and by the shielding
experiments of Jacobson et al.us The success of bonemarrow therapy depended on genetic similarity between
irradiated host and donor animals. Isologous marrowgave many more survivors than homologous marrow,and heterologous grafts were even less effective.M9 - 651
Proof of cellular colonization was given by Lindsley,
Odell and Tausch in 19SS,m using as index antigenic
differences between ceIIs of host and donor. Ford et al.,1°
distinguished host and donor cells by means of marker
chromosomes.

495. Table X m lists many varied compounds tested
for protective effects.
496. The way in which protective compounds work is
controversial. Table X shows how widely different chemical entities offer varying degrees of protection. Presumably, no single theory encompasses all substances.
497. Protective chemicals may act in the following
ways:(a) Inactivation of radiation-induced free radicals;( b) Minimizing free radicals formed by inductionof hypoxia;( c) Induction of metabolic changes;( d) Reversion of injury in the primary target.
498. Inactivation of free radicals formed in water byradiation is the most widely accepted theory of chemical
protection.

SOS. The survival of transplanted bone-marrow isdetermined by the compatibility of its antigenic patternwith that of the recipient. As a rule, only bone-marrowfrom a uni ovular twin or from another individual of thesame highly inbred strain (isograft), persists; transplants from another individual from the same outbred
species (homograft) or from another species (heterograft) are rejected. If the immunological mechanism of
the host is suppressed, the graft may take. One way of
suppressing the immunological mechanism is irradiation ;this is why animals exposed to much radiation accept
marrow transplants. However, if the suppression of immunological mechanisms in the recipient is transient. as
may happen if the dose of radiation is not high enough,the graft will eventually be rejected. If the dose is highenough, the graft will take, but owing to the immunological competence of the transplanted marrow, a reverse
immunological reaction will take place, i.e. reaction of499. Thiol compounds are known to react rapidly withfree radicals 6 3.5 thereby scavenging intra-cellular free
radicals. Some sulfur-containing compounds are protective in vivo through the formation of a thiol, e.g.,alkyliso-thioureas rearrange into mercaptoalkylguanidines. u6, 63<

SOO. The radical-scavenging hypothesis does not account for several facts in radiation protection. Marked
differences in protection are given by structurally closely
related compounds (e.g., N -diethylcysteamine andN-methylphenylcysteamine) ;638 reaction products ofthiols with free radicals in irradiated serum are a minutefraction of the total free radicals formed ;639 also, it does
not explain protection against the direct action of ionizing radiation which is probably responsible for mostdamage. iHo170the grafted tissue against the host. This reaction, called"secondary disease", is a wasting syndrome characterized by atrophy of the host's lymphatic tissues, which
frequently results in death.
506. The antigenic pattern of tissues is determinedby isoantigens. Two broad groups of isoantigens are
distinguished: (a) the so-called H-antigens evoke production of humoral antibodies ; ( b) the other type,T-antigens, produces tissue immunity by accelerated rejection of grafts, but does not elicit the appearance ofantibodies in blood plasma and body fluids.
507. The chemistry of H-antigens is understood,
mainly from studies by Morgan and Kabat. 653 H-antigens are polysaccharides in which an amino-acid or
lipide moiety is firmly bound but does not contribute to
immunological specificity. Immunological specificity isdetermined by a small segment of the polysaccharide
molecule. Several more-or-less distinct molecules of thesame immunological specificity may be found in the same
individual: blood-group substances in erythrocytes arelipopolysaccharides, while blood-group substances intissue fluids are polysaccharide-amino-acid complexes;
the latter show broad polydispersity.

specific agglutination. 563-665 Identification of donor's
granulocytes was carried out by demonstrating alkaline
phosphatase in the circulating cells, alkaline phosphatasebeing present only in the rat's (donor) granulocytes andnot in the mouse's (recipient) granulocytes. aeH1a1 The
repopulation by rat's lymphoid cells in irradiated micehas been shown by finding rat's chromosome number
and structure in dividing lymph node cells of the recipient 78 and by employing cytotoxic sera with cell-culture
technique. 688
511. When animals, irradiated with doses sufficient tocause acute death due to bone-marrow syndrome, areinjected with living erythropoietic cells, they survive.
The 30 days' median lethal dose is roughly doubled ifbone-marrow transplantation is used to protect mice ;with other types of irradiation the results are less consistent, but at certain dose levels of y-rays and 14-MeV
neutrons marked protection has been shown." 9512. Many authors confirmed the protective action ofbone-marrow transplantation in acute radiation syndrome in various species. Homologous bone-marrowprotected rats, 670 hamsters, 8 n rabbits, 812 dogs, 813 andguinea pigs.en
513. The feasibility of bone-marrow transplantationin man has been studied to a limited extent. An exchangeof bone-marrow cells can occur between non-identicaltwins before birth.m-e 75 The phenomenon can be explained as acquired immunological tolerance, due totransplantation of immunologically immature cells, asseen by Owen. 671
514. In studies on man, suppression of immunologicaldefence of the host has been achieved by "acquired
tolerance". Attempts at homo-transplantation of bonemarrow into donors whose immunological mechanism
has been suppressed by radiation or by radiomimetic
drugs have met with little success, and indeed contraindications seem clearer. The studies may be divided into
two groups : (a) patients accidentally exposed to highdoses of radiation ; ( b) patients deliberately irradiatedto replace diseased with normal marrow. Thomas
et al. 618 have shown that transplanted marrow functioned
temporarily in leukaemic patients given TBR: the donor
cells in some cases persisted for two months in the recipient though they disappeared completely after ,_, 3months. In another study,879 9 patients with acute leukaemia irradiated with 300-500 r were given marrow(obtained from excised human bones) containing about
5 X 109 viable cells without evidence of a successfultransplant. Bone-marrow given to patients with bonemarrow aplasia, without irradiation, gave similar results.
There is evidence of a temporary acceptance of bonemarrow in irradiated leukaemic patients.080- 682 In moststudies, the percentage of donor's type blood cells in therecipient's circulation was low at the beginning andsteadily decreased; a notable exception is a patient withbone-marrow failure due to chemotherapy of Hodgkin's
disease 882 given bone-marrow taken from her sister. The
difference in blood groups between donor and recipient
was marked, and skin grafts were rejected. Nevertheless, bone-marrow transplantation was successful, thedonor's blood cells, low at first, began to increase in therecipient's circulation at about the sixth month after
transplantation and were still present after nine months.
The success in this case is probably due not only to pretreatment with radio-mimetic drugs but also to Hodgkin's disease: a patient with Hodgkin's disease 683 may
tolerate a skin graft for a prolonged period. Hodgkin's
disease is accompanied by a production of abnormal

508. The chemistry of T-antigens is largely unknown.
The relatively insensitive and imprecise tests available
for assessing their activity, along with the inherent difficulty in isolating them from living mammalian cells,
made it appear that "T-antigenicity" is the property ofliving cells only. However, R. B. Billingham, L. Brent
and P. B. Medawarm isolated an antigenically active
substance in a DNA-containing fraction of disintegrated
lymphoid cells. Activity was destroyed by DNA-ase
treatment, by periodate oxidation, and by digestion with
crude enzyme preparation known to be mucolytic andcapable of destroying the activity of blood-group substances. Current information shows that T-antigen may
again be mucopolysaccharide,865 and therefore not unlike
H-antigens.
509. Even though repeated skin-grafts do not cause
the appearance of precipitating or cytotoxic antibodies
in the blood of recipient animals,6 511 several studies indicate an association between tissue transplantation and theappearance of cytotoxic, haemaglutinating or otherantibodies ;851-m H-antigens and T-antigens may bedifferent complex molecules but with the same haptenicgroups in their structure.680 The antigenic potency as well
as chemical stability depend on molecular components
not directly determining immunological specificity.
Morgan 661 has shown that purified somatic hapten of
Sh. shigae may acquire full antigenic potency if coupledwith protein derived from the same or other bacterial
species ; human blood-group substance A from erythrocytes (lipopolysaccharide) is resistant to hot alkali,
while blood-group A substance from body fluids (anamino-acid-polysaccharide) is easily hydrolyzed by thesame treatment. 662 If the T-antigens were lipopolysaccharide, ·then their lesser potency compared with Hantigens in eliciting the production of humoral antibodies,and their liability to lyophilization and other procedures,
would be explicable. The T-antigens and the H-antigens
might well be a diverse group of substances upon which
the histo-incompatibility genes have imprinted specificantigenic configuration, probably in their polysaccharide
components.
510. The ability of transplanted bone-marrow cells
to persist in irradiated animals has been variously demonstrated. Erythrocytes and platelets were identified by171

y-globulins and a marked decrease of immunologicalreactivity; proliferation of abnormal and immunologically incompetent cells may be taking place at the expenseof normal lymphoid cells.
515. Bone-marrow was given five men accidently irradiated in Yugoslavia on 15 October 1958. Of six
exposed, the five who received the higher doses were
given marrow. The man in most serious condition was
injected at first with foetal bone-marrow ( 4 X 109 cells),
and then with adult bone-marrow. There was no evidence of improvement after foetal marrow; after adultmarrow the number of blood cells, mainly platelets andgranulocytes, increased sharply. Neverthless, the patient
eventually died with symptoms of delayed intestinal
damage and haemorrhages from the respiratory tract.
The remaining four patients were given bone-marrow amonth after the accident from donors of a similar bloodgroup pattern; about 1010 marrow cells were injected.
Soon after transplantation of marrow, the number ofcirculating blood cells increased. However the initial
number of donor's cells, ,..., 20 per cent of the total,
dropped to negligible values in 3-4 months. 394 It appears
that for a short time the transplanted bone-marrow assumed normal haemopoietic activity, although the evidence supporting this has been challenged by Fliedner 785
and it was certainly ultimately rejected. The relatively
low percentage of the donor's type blood cells, and theirrapid disappearance demonstrates that the recipient's
bone-marrow maintained its activity although diminishedthroughout the period of acute radiation sickness.
Furthermore, as discussed earlier in paragraphs 217-220,
the haematological recovery patterns were similar to
those of patients recovering spontaneously from lesser
amounts of radiation.
516. The transplantation of foreign bone-marrow inexperimental animals prevents acute death; the same ispresumably true for man. Survivors usually die later,
the mortality beginning usually in the fifth week postirradiation, but sometimes earlier. Death of animals is
preceded by diarrhoea, loss of weight and dermatitis;
at autopsy a generalized atrophy of lymphoid tissue isvisible. The syndrome is usually called secondary
disease, but sometimes also homologous disease or foreign bone-marrow disease. The main cause of secondary
disease is reaction of grafted tissue against the host, thelatter having been rendered immunologically incompetent by irradiation. Minor factors influencing both timeof onset of secondary disease and its final outcome include late radiation effects in the host and decreased
resistance to infection.-0 84
517. Evidence for the immunological pathogenesis ofsecondary disease is based mainly on genetical studies,F 1 -hybrids do not usually react against grafted tissues of
either parental strain but may in certain circumstances
react immunologically against inbred parental strain
tissue. However, when irradiated hybrids received parental tissue, fatal secondary disease ensued. In thereverse case, i.e. irradiated parental strain grafted withhybrid tissues, the survival was almost complete. In thefirst case, parental tissue encounters foreign antigens in
the host, derived from the other parent and produces
antibodies to histo-incompatibility antigens ; in the othercase, the specificity of transplanted tissue is broader thanthat of the host and no antibody production is possible.6es,ess

519. These two lines of evidence indicate that theimmunological reaction of grafted tissues against thehost form the basic pathogenetical factor in secondary
disease; several other factors enter. Delayed radiation
effects in the host is one881 • 658 and the delayed reactionof the hosts' recovering immunological system against
grafted tissue is another. 684 Transient decrease in resistance to infection, at a time when the host lymphoidsystem has not yet recovered and the grafted bonernarrow is not potent enough, contributes considerably tothe mortality due to secondary disease.
520. The indications for transplantation of bonemarrow in cases of radiation damage are limited. It may
be useful when the patient's bone-marrow remains viable
even though seriously affected : the implanted tissue
may in this case help the organism through the mostdangerous period of haemopoietic failure; eventually theforeign tissue will be rejected and the danger of fatal
secondary disease will disappear. In serious cases, grafting bone-marrow, substituting for the patient's haemopoietic cells, may eventually cause death by secondary
disease. 689 The dangers in bone-marrow treatment of
acute radiation disease influenced the decision not to use
it in the Y-12 accident in June 1958.588
521. There are at least three possibilities of increasing
the usefulness of bone-marrow treatment: (a) pretreatment of the recipient with "enhancing antibody";( b) use of foetal marrow; and ( c) antigenic adaptationof transplanted marrow to the hosts' antigenic pattern.
522. Enhancement might be useful when the host's
immunological reaction is not completely abolished andis sufficient to cause speedy rejection of the graft before
it might exert supportive action. Enhancement supports
the growth of transplanted tissues by inducing the immunity status in the host, before transplantation. It canbe effected by injection of the lyophilized tissue to be
implanted~ 90 or by passive immunization with a serum
containing anti-implant tissue antibodies. 688 The latterbut not the former method might be useful clinically.
523. The persistence of grafted bone-marrow could
be improved if its antigenic pattern was made compatible
with the antigenic pattern of the host. Very little work
has been done in this direction. From the studies on thetransplantation of neoplastic tissues, it is known thattumours after passage through F 1 -hybrids (strains oftumour origin and some others) have more takes whentested in backcrosses with the same two strains. 691 Thisfinding is open to more than one interpretation: Klein 59 z
showed that the increased frequency of takes in backcrosses is due to antigenic adaptation of tumour tissues
and not to selection of more resistant cellular clones
during the passage. The phenomenon resembles thechanges by pararnecia of their antigenic pattern to suitunfavourable environments containing specific antibodies, in which the newly-acquired character is inherited
cytoplasmically.698 • 494 In tissue transplantation, somepreliminary experiments aimed at inducing antigenic
compatibility have been carried out :695 parathyroid
embryonic tissue was cultured in media containing increasing concentration of recipient sera before implantation. The evidence for the successful grafting was clinicalimprovement. No analogous experiments have been doneon marrow cells, but with modern techniques of marrowcultivation, it should be possible to assess the probabilityof increasing takes and survival time in donors.

518. Secondary disease can be potentiated if transplantation of bone marrow is accompanied by even asmall amount of the donor's lymph-node cells. 654

524. On the basis of the immune tolerance theory,
foetal marrow, theoretically, might lead to the creation
172

of a permanent chimera where there has been total destruction of lymphoid tissues. The grafted marrow cells
would not be rejected and in time should acquire tolerance to the host's antigens. If foetal cells are used, as has
been shown, immunological interaction between donor
and recipient is reduced. 696 - 698 Similar e..xperiments in
man are limited and very preliminary. Mathe et al. injected foetal marrow in one of the victims of the Yugoslav reactor accident but found no evidence of haemopoietic activity of implanted tissue: the patient, however,
was apparently in the preterminal stage with intestinal
symptoms. 394 In toxic bone-marrow failure, injection of
foetal liver cell suspensions produced circulating blood
cells characteristic of the donor's for about three
weeks. 6119

logical effects of small dose irradiation should now bebased primarily on an analysis of functional changes andnot only on morphological changes as in the past.
529. ·while the mechanisms of radio-sensitivity have
not yet been clarified, the radio-sensitivities of cells
tissues, and organs can be arranged in order, and show ~remarkable similarity in all mammalian species.
530. The clinical course of the acute radiation syndrome in man is well known through observation on
Japanese and Marshallese e..xposures, criticality accidents, and radio-therapeutic experience. Howeverlargely because of uncertainties as to the physical factors'
the e.xact relation between dose and effect is not wellunderstood. The best estimate of the median lethal dose
for man is 300-500 rad, short-time TBR.

INTERNAL DECONTAMINATION

531. At low doses, functional changes appreciably outweigh permanent somatic damage. Among the more sensitive of these are transient changes in gametogenesis,
neural function, and haematological responses, especially in the lymphocytes. However, evidence of permanent damage becomes apparent only with larger doses
approaching the lethal range.

525. Recent efforts to promote the excretion of deposited radio-isotopes, such as plutonium, thorium,
yttrium and the rare earths, have been encouraging. For
these elements, the chelating agent, diethylenetriaminepentaacetate (DTPA) has proved much superior to theearlier studied ethylenediaminetetraacetate (EDT A)
and should be a practically useful agent for the prompt
treatment of accidental e..xposure to these radioisotopes.100 Prolonged treatment with DTPA is effective
in removing substantial fractions of firmly deposited plutonium from bone. 701 The removal of strontium or radium appears less hopeful; no practically useful treatment can be recommended for radio-isotopes of theseelements. Increasing the level of dietary calcium deserves to be studied further as a possible means of delaying the uptake of strontium-90. However, the benefits tobe obtained therefrom must be large enough to justify
any risks entailed in greatly increasing the intake ofcalcium,

532. Life-shortening in animals has been well established as a consequence of long-term and of short-term
irradiation. Life-shortening in man is probable, however,results are still inconclusive.
533. The development of neoplasia may follow shortterm or long-term exposures of both animals and man.
Apparently, leukaemia is the earliest neoplastic changethat has been observed in man. Leukaemia induced in theJapanese and in other groups of e.xposed human beings
has usually been of the chronic myeloid type or of theacute type, and the incidence has increased roughly with
dose.

TREATMENT OF ACUTE RADIATION SYNDROME1o 2 , ;03534. There is some evidence of an increased incidenceof some malignant tumours other than leukaemia inJapanese survivors, but the evidence so far is inadequate
to permit reasonable inferences as to dose-effect relationships.

526. The management of radiation injury is governedby the same considerations that influence the management of any other clinical problems, namely the history,
clinical picture, laboratory data, and estimated magnitude of exposure to the injurious agent. In most instances, it is not possible to estimate dose accurately.
Even if it were possible, knowledge of the dose would
be of limited value in governing the management of thepatient since there is individual variation in the response
to a given dose as well as great uncertainty about thedose-effect relationship in man. Experience with theJapanese atom bomb casualties, the Marshallese exposed
to fall-out radiation, reactor and critical assembly accidents, and other accidental e..xposures to radiation, haveshown that some estimate of biological effects can bemade from careful clinical and haematological data. Suchcontinuing scrutiny should determine therapy.
527. The conservative medical management of theacute radiation syndrome is recommended,«, 399 , 7 o4 reserving for desperate situations those therapeutic measures that carry a high intrinsic risk to the patient.

535. There is no satisfactory evidence as to the concentration-effect relationships in man as regards carcinogenesis from internal emitters. No tumours have thus far
appeared with residual radium of less than 0.7 µ.g.
536. Consideration of possible mechanisms of radiation carcinogenesis, including a number involving thegenetic apparatus of somatic cells, indicates a wide divergence in possible dose-effect relationships as a consequence, and indicates further that the question of thesemechanisms may be amenable to experimental testing.
Further analysis of carcinogenic action of radiation will
require careful study of the dependence of such action
on the type of radiation {alpha, beta, etc.) and its
physical properties (quantities of energy, ionization
density, etc.) and, in particular, a study of the role ofdose-rate. These data will provide the key to an understanding of the relevant mechanisms. However, elucidation of this problem will require an equally careful studyof the processes of regeneration, particularly in relation
to dose rate and the temporary characteristics of irradiation. An analysis must be made of the types of mutation
which result in the formation of tumours, and theirprobable character. Lastly, there must be a stage-bystage analysis of data to establish a scale of effects related
to the conditions of irradiation.

Summary528. Biological effects depend not only on total dose(energy absorbed) but also on type of radiation; distribution of dose in time and space and on the physicalstate of the organism and species. Determination of bio173

537. The embryo, at least in certain stages, is more
susceptible to radiation than the adult.

except possibly in instances of localized therapeutic
irradiation.
539. Many investigations are under way to determine
the value of general supportive and specialized therapy
for the treatment of acute radiation injury in man andfor decontamination.

538. Radiation protection can be achieved in animals
by a variety oi chemical and physical procedures, noneof which has yet been established as of value in man

TABLE l.85 LD,. VALUES FOR MAMMALS•
LD..•ol:us~Rodiolion used

Riulioli<ni faaon

Air
d4u

Ab1orbtd(r)(r<Jd)

IU/. Ne.

521+ to
638+
55s+
666+

(70S)

"'u

rOkvpX-ray

O.S mm. Cu, 1 mm. Al HVL 1.6 mm. Cu

Mouse.. . . . • . . • • • • . 200 kvp X-ray
Bomb gamma

0.2S mm. Cu, 1 mm. Al HVL 0.8 mm. Cu
High energy and dose rate362+ to
443+
405
759

{200 kvp X-rayat· • · • • · · · · · • • · · · 200 kvp X-ray

0.4S mm. Cu, 1 mm. Al HVL 1 mm. Cu
0.5 mm. Cu, 1 mm. Al HVL 1.05 mm. Cu

665
640

sis+
796+

(708)
(709)

Ground squirrel. ••••. 2SO kvp X-ray

0.25 mm. Cu, 1 mm. Al HVL 0.9 mm. Cu

700

>700+

(710)

r,000 kvp X-ray
Hamster. . . . . . • • • . . 2SO kvp X-ray
200 kvp X-ray

HVL 5 mm. Pb
0.5 mm. Cu, 1 mm. Al HVL 1.6 mm. Cu
0.2S mm. Cu, O.S mm. Al HVL 1.5 mm. Cu

800
460+
700

>BOO+
586+
>700+

(711)
(712)
(671)

0.2S mm. Cu, 1.0 mm. Al HVL 0.8 mm. Cu
0.2S mm. Cu, 1.0 mm. Al HVL 0.8 mm. Cu(crossfire exposure)
Multiple sources
Dose rate 70 r/min (w exposure)

337
400

400+
380+

(42)
(649)

SOO

490+

(43)

0.5 mm. Cu, 1.0 mm. Al HVL 0.98 mm. Cu(bilateral exposure)
3.2S mm. Cu HVL 3.4 mm. Cu(multiport exposure)
Parabolic filter HVL 2.0 mm. Cu(crossfire exposure)

800

73s+

(24)

805

1s1+

(713)

100+

680+

(714)

1,094

911+

(715)

760+

S46+

(65)

550

s22+

(716)

R

roo

kvp X-ray
186 kvp
X-ray

Guineafpig. . • . . . • . . C "o gamma
1.10 Mev (S03)
1.33 Mev (S03)
200 kvp X-ray

2SO kvp X-ray
Rabbit ..•.•....... 2SO kvp X-ray
Co•o gamma
1.10 Mev (S03)
1.33 Mev (SO%)

Monkey ...........

r·

kvp X-ray
250 kvp X-ray

(706)
(707)

HVL 5.1 cm. Al
Dose rate 50 r/hr (multiple sources)
HVL 1.6 mm. Cu Dose rate 3 r/min.
(bilateral exposure)
O.S mm. Cu, 1.0 mm. Al HVL 1.0 mm. Cu(animals rotated}

174

TABLE I. 85

LD.. VALUES FOR Mli.MMANs* (continusd)
LD .. •ah«

Radialion wud

250 kvp X-ray
1,000 kvp X-ray
2,000 kvp X-ray
Dog ............••. Co" gamma
1.17 Mev (503)l.33 Mev (503)
250 kvp X-ray
Bomb gamma
1.000 kvp X-ray
2,000 kvp X-ray
2,000 kvp X-ray
Swine •....•....... Bomb gamma
Co" gamma

Air
doJe
(r)

Absorbed{rat!)

IU/.No.

281

244+

(717)

304
312
465+

250+
260+
303+

(38}
(37)
(718)

14.2 mm. Al Parabolic filter, 0.5 mm. Cu
HVL 2.15 mm. Cu (unilateral exposure)High energy and dose rate

450

322+

(38}

271

250+

(378)

HVL 2.0 mm. Pb (bilateral exposure)
HVL 4.3 mm. Pb (bilateral exposure)
HVL 4.3 mm. Pb (unilateral exposure)High energy and dose rate
HVL 5.1 cm. Al Dose rate 50 r/hr
(multiple sources)

510
388
500
225
618

247+
237+
305+
187+
242+

(38}
(719}
(719}
(720)
(721)

HVL 3.9 cm. Al Dose rate 20 r/hr
(multiple sources)

524

205+

(722)

0.5 mm. Cu, HVL 0.98 mm. Cu(bilateral exposure)

350

237+

(723)

HVL 5.1 cm. Al Dose rate 50 r/hr
(multiple sources)784

HVL 4.3 cm. Al Dose rate 20 r/hr
(multiple sources)651

HVL 3.9 cm. Al Dose rate 20 r /hr(multiple sources)

585

Dose rate variable (plane field)

350 (?)

Radiolio~ '""'""

0.5 mm. Cu, 1.0 mm. Al HVL 1.5 mm. Cu(bilateral exposure)
HVL 2.0 mm. Pb (bilateral exposure)
HVL 4.3 mm. Pb (bilateral exposure). HVL 5.1 cm. Al (bilateral exposure)dose

1.17 Mev (503)
1.33 Mev (503)!

Nb" and Zr"

Sheep ..••.•....... o./:~~~s(933)0.23 Mev (73)Goat ............... 200 kvp X-ray
Co'° gamma
1.17 Mev (503)
1.33 Mev (503)
Tam gamma
Burro ••••••..•.•.• 1.22 Mev (573)
1.13 Mev (373)
0.2 Mev (63}Nb•-Zr 115 gamma

(721)

256+

(724)

(722)

0.73 Mev (933)0.23 Mev (73}!

Fall-out gamma
1.5 Mev (19%)
Man.············· 0.75 Mev (573)
0.1 .Mev (24%)

300 (?)(53)

with Co60 gammas to approximately 45 per cent with 250 kvp~orlower energy X-rays.n• 121, TH Ellinger quotes the LD 60 /14-day
value for guinea pigs, which is not significantly different from his
LD10/30-day value. Depth-dose measurements under the unusual
geometrical conditions of the Oak Ridge multicurie .,..ray exposure
field were made by the present authors in collaboration with
Col. Bernard Trum. The large ratios, air dose-midline absorbed
dose, obtained for burros, sheep, and swine result principallyfrom geometrical factors. 31 In most positions, occupied by the
exposed large animals, over 50 per cent of the dose is received
from a target to skin distance of less than 1.5 m.; thus inverse
square fall off is appreciable. Large animals standing in the fieldreceive much of the dose at the midpoint in the animal from theanterior or posterior directions, as opposed to the transverse(shorter) a.'tis with bilateral irradiation in the laboratory (thiswould not apply to an upright man). All midline doses probably
are maximal for an acute LDu value, since if the data for theeffect of dose rate on LD 5o in the rat131 apply to the larger
species, the values should be further reduced by a factor of
approximately 0.8 to allow comparison with radiation deliveredin the course of minutes. The values should be also reduced further
for comparison with X-ray LDu values because of the apparently
reduced effectiveness of 'Y·radiation relative to X-radiation.i7
The LDn value for man can be considered only a rough approximation, since the dose is poorly known and there was no mortality
in the exposed group (see below).

•See text for additional explanatory material relating to thetable.
+Value not given in work cited. Calculated or estimated fromdata given.
All dose-rates used were of the order of 5 to 60 r/min., and all
exposures were unilateral unless otherwise noted. The LD1avalues in rad represent the absorbed dose in soft tissue at thecentre (midline) of the animal. The dose in rad was estimated asfollows: the tissue dose in r was first estimated, if not given, fromthe air dose by estimating all scattered radiations and taking into
account the geometry of the exposure conditibns used." Scattercan be approximated from standard depth-dose data.u• 101, 1:is, m
The present authors duplicated as nearly as possible many of theexperimental conditions and used the air/tissue dose ratio thus
obtained. The tissue dose obtained represents the dose a dosimeter would indicate if it were embedded in tissue (or phantom
material). The tissue dose in r was converted to absorb dose inrad, using the appropriate soft-tissue conversion factor.m. nt
The conversion from air to tissue dose is an approximation madein many cases from incomplete physical data, and the conversion
factors from tissue dose to rad are still open to question (seeabove). Additional details of the conversion used for any of thesituations will be furnished on request. Total scatter varied withessentially full scatter, from less than 5 per cent of the air dose

175

TABLE II.

DISEASES OF MAJOR FREQUENCY IN Y-IRRADIATE.D MICE (OPERATION GREENHOUSE)2so

Perunlate obsnwd i...:Uknu in mice reuil'i11t indualed .,..,.oy dcse
Co,.ITol

DiseaseZZJ rod

368 rad578 rod697 rod

Malu

FemausMaks Ftmolu

Maks

FemaksMaks

FemaksMaks

Females

None ....................................•
Pneumonia .............••.................
Nephrosclerosis, mild .......................
Nephrosclerosis, moderately severe .••........
Nephrosclerosis, severe .••..•........•.......

4.25
9.48
1.31
0.33
0

0.97
12.01
2.60
0.33
0.65

1.90
6.19
2.38
0
0.48

0.94

0
6.21

1.68
4.36
6.71
3.02
18.79

4.07
5.56
3.70

1.38
3.45

1.96
5.23
3.59
1.63
10.13

3.76

2.36
0.47
0.47

3.16
7.91
2.85
0.63
1.58

21.48

4.51
7.14
37.22

Nephrosclerosis, severity unspecified ..........
Enteritis and colitis .........•.......•.......
Dermatitis ••.•....•....•...........•..•....
Emaciation ..........•...................•.
Cyst, liver ........•..•..•..•...........•...

0.33
4.58
10.78
0.65
2.61

1.95
2.27
1.95
1.62
1.30

3.81
3.33
10.48
0
1.90

2.36
2.36
2.36
0
2.83

7..59
1.90
8.86
1.27
0.95

4.48
2.41
0.69
1.03
2.07

24.51 17.79
4.90 3.36
4.90
0.67
0.65
1.68
1.96 4.36

28.52
1.85
3.70
5.56
1.11

15.79
1.88
0.38
3.38
1.88

Cyst, kidney .....•..••.......•.............
Cyst, ovary ..............••................
Cyst, all sites ...............•. , ......•.....
Atrophy, bone marrow .•....................
Atrophy, testis ...•.............••..........

0.65

0
1.30
3.25
0.32

1.43

0
1.42
4.25
0.47

0.95

0
1.72
4.83
0.69

2.94

1.48

0.75
1.50
4.89
0.75

Atrophy, adrenal cortex .....................
Dental defects •............•.•.......•...•.
Volvulus ................................•.
Abscess, all sites .. , .........................
Hyperplasia, endometrium .......•...........

0.33
8.83
0.98
7.52

8.12
1.63
0.65
2.92
1.95

3.33

Hyperplasia, adrenal cortex ....•..........•..
Hyperplasia, Harderian gland ................
Hyperplasia (myeloid), bone marrow •........•
Hyperplasia (myeloid), spleen .•..............
Hyperplasia (lymphoid), spleen, lymph nodes ...

0
0.98
0.33
0.33
0

0.97
0
0
1.30
0.32

2.86
0.95
0
1.43
0

Haemorrhage, testis ...........•..•......•••
Haemorrhage, brain ..•.....................
Haematoma, testis ..........................
Haematoma, ovary ...........................
Haematoma, adrenal. ....•......•......•....

0
0
0.65

0

0
0
0.95

Thrombosis, auricle ....•..••..•.............
Infarct, all sites ........................•...
Angiitis, all sites .•.•.........••...........•
Hepatoma .........•.......................
Luteoma .....••.........•........•.........

0.65
0.65
0.65
7.84

3.6-0
0
0.65

0

13.31
0
1.62
0
0
3.25
1.30

3.33
0.48
1.90
1.43
7.15
8.10

0
1.90
1.43
0.95
7.62

0.32
0.32
0.32
19.16
0

Granulosa-cell tumour, ovary .......••.......
Tubular adenoma, ovary ••..................
Mixed tumour, ovary ••..•....•........•....
Supcapsular cyst, ovary ...•.•............•••
Cystadenoma, ovary ........•...............

3.77

2.53
0.32
0.95

3.79

4.90
0
0.95

1.01
1.34
9.06
1.68

3.33

2.96
1.48
1.11

2.63

8.96
1.42
0.47
1.42
1.89

1.27
8.86
0.63
3.48

7.93
2.07
1.03
1.72
1.38

1.63
6.86
0.65
1.31

8.72
1.68
0.34
1.34
0.67

2.96
1.48
1.11
1.11

10.53
1.13
1.50
0.75
0.38

3.77

2.12
2.85
1.27
1.90
1.27

3.45
2.07
0.34
4.48
1.03

3.92
1.31
4.58
6.21
1.63

3.36
1.01
2.35
6.38
1.01

5.18
0.74
4.44
7.41
2.59

6.01
0.75
3.01
15.41
2.26

0.63
0.63
0.95

0.34

2.29
0.33
1.31

1.68

1.11
1.85
1.85

1.13

13.42
2.01

0.37

0
0.94
3.37

0.47
0
10.38
0
0.47
0.47
0.47
10.38
16.51

0
2.85
1.58
1.03
11.71

3.30
5.19
10.85
2.36
2.83

12.76
0
2.41
0.69
2.98
14.83
19.66

0
1.96
2.94
6.71
8.82

2.35
2.01
5.04
8.05
17.11

0.37
1.48
7.04
4.44

Adenoma, pituitary ...•..•..................
Adenoma, lung ......•....•..•..............
Adenoma, kidney ........•.....•...••....••.
Adenoma, adrenal .•...•...........•........
Cytadenoma, lung .......•........•.........

0.98
9.48
1.96
0
2.29

3.57
9.42
0
0.97
3.25

1.43
9.05
1.43
2.86
3.33

4.25
8.49
0
0
1.89

0.95
11.08
1.90
2.22
4.75

7.59
7.59
1.72
3.10
4.48

1.96
7.19
1.63
3.27

Cystadenoma, Harderian gland ...............
Squamous-cell carcinoma, stomach ..•......•..
Squamous-cell carcinoma, skin •..............
Adenocarcinoma, lung ..•.........•..........
Adenocarcinoma, breast .....................

0
0.98
0.33
2.94
0

0.32
0.65
0
0.97
0.97

0.95
2.38
0
0.48
0

1.42
1.42
0.94
2.36

1.27
1.58
0.32
1.27
0.32

Adenocarcinoma, Harderian gland ............
Sarcoma, voluntary muscle .........•........
Sarcoma, breast ...........•................
Sarcoma, bone •.................•..........
Lymphoma, thymus ........................

0
0
0
0
1.64

0
0
6.82
0.65
3.24

0
0.48
0
0
2.86

Lymphoma, abdomen .......................
Lymphoma, other ......•...................
Myeloid leukemia, all sites ................••.

7.52
10.14
0.33

NumlJer of neoplasms per mouse
Neoplasms, all sites ••..........•..........

1.08

1.13
2.63
13.91
1.79
15.41
2.26
1.50
5.64
0.38
2.26

4.36
2.68
7.05
1.68
0.67

4.14
4.48
10.69
2.41
2.76

7.52
2.63

0.74
2.96
1.11
1.48
1.48

3.38
2.26

3.59

12.42
6.04
1.01
3.69
2.01

1.38
1.38
0
1.38
3.79

0.33
0.65
0.98
0
0

2.01
0.34
0.67
1.01
3.02

0.37
0
0
0.74
0

0
0
0.38
0
1.88

1.38
0.69
4.14
0
4.13

0.33

0.33
0.65
0.33
6.86

0.34
0.67
2.01
2.01
11.08

0.74
0.37
0
0
13.07

0
0

0
5.66

1.58
0.63
0
0
2.85

0.75
10.15

20.22
18.52
0.65

12.38 14.62
7.21 10.85
0.48
1.42

13.30
12.34
0.95

8.64
16.21
1.03

3.92
9.14
1.31

6.72
9.06
0.34

2.60
4.81
1.11

3.63
4.89
0.38

1.15

1.37

1.46

2.26

1.11

1.73

0.66

1.07

176

3.77

1.42
0.47
3.77

2.21

0.38

1.88
1.13

0.38

TABLE Jil. 732

MAJOR ABNORMALITIES INDUCED IN M.·UI~ALS BY FOET.-U. IRRADIATION

Brain

Exostosis on proximal tibia
Metaphysis
Amelogenesis•
Scleratomal necrosis

Anencephaly
Porencephalyl\Ucrocephaly*
Encephalocoele (brain hernia)
Mongolism•
Reduced medulla
Cerebral atrophy
Mental retardation•
Idiocy•Neuroblastoma
Deformities
Narrow aqueduct
Hydrocephalus"
Rosettes in neural tissue
Dilation of 3rd and lst ventricles
Spinal cord anomalies•
Reduction or absence of some cranial nerves

Eyes
Anophthalmial\Iicrophthalmia •Microcornia*
Coloboma•
Deformed iris
Absence of lens and/or retina
Open eyelids
Strabismus*
Nystagmus•
Retinoblastoma
Hypermetropia
Congenital glaucoma
Partial albinism
Cataract*
Blindness
Chorioretinitis*
Ankyloblepharon

Skeleton
General stunting
Reduced skull dimensions
Skull deformities•
Head ossification defects•
Vaulted cranium
Narrow head
Cranial blisters
Oeft palate•
Funnel chest
Congenital dislocation of hips
Spina bifida
Reduced and deformed tailOvergrown and deformed feet
Oub feet•
Digital reductions
Calcaneo valgus
Abnormal limbs"
Syndactyly*
Brachydactyly 0
Odontogenesis imperfecta•

Miscellaneous
Situs inversus
H ydronephrosis
Hydroureter
Hydrocoele
Absence of kidney
Degenerate gonad*
Abnormalities in skin pigmentation
Motorial disturbance of extremities
Increased probability of leukaemia
Congenital heart disease
Deformed ear*
Facial deformities
Pituitary disturbances
Dermatomal and myotomal necrosis• These anomalies have been found in humans exposed in ulero to radiation and are attributed to the action of radiation.

TABLE 1v.1s2

CORRELATIONS IN DEVELOPMENT: MOUSE A,.~D MAN DEVELOP:MENTAL
STAGE IN HUMAN: ORGAN PRIMORDL.\

Age in days
Embryo

mm

Mouse

Man

5

9

6
14
16
20.5
25.5

0.15
0.40
1.5
2.4

10.5

28.5

4.2

11.5

33.5

7.0

12.5

36.5

9.0

13.5

38.0

12.0

14.5

47.0

17.0

15.5

65.0

40.0

8

Implantation
Germ layers, extra emb. membranes
Primitive streak
Neural groove, blood islands, notochord
Cephalization, extensivevascularization, neural folds meet, primordia
of sense organs, th}Toid, limbs, muscles, pronephros, branch,arches, somites
Prim. brain w. vesicles, complete circulation, GI tract and derivatives,
mesometanephros, vertebrae, 31 somites, yolk haemopoiesis
Genital ridge, heart, liver, mesonephros protuberant, limb and lungbuds, 5 brain vesicles, all sense organs, cardiac septs and 38
somitesHeart chambered, nerves and ganglia differentiating thyroid anlageo.
bilobedSexless gonad primordia, liver haemopoiesis, brain flexures, limbs,
thymus, GI tract actively differentiating
Cerebral hemispheres, corpora striatum, thalamus, blood vessels all
actively differentiating, endocrine glands, peripheral and sympa·
thetic nerves, eyes well formed
Cerebral cortex, intest, villi, thyroid follicles, first ossifications, se.~differentiation with sex cords and germinal epithelium

177

TABLE V.T83

fun:crs OF IONIZING llADIATION ON MAN-SCHEMATIC SURVEY
A""4 radiation IYftbome, form

Cerebral

Gastro-i..u.rtinal

Determining organ...........

Central nervous system

Small intestine

Bone-marrow

Threshold dose, r. • • • . • • • • • . •

2,000

SOO

100

Latent period.. . • . • . • • . . • . . • .

31-3 hr.

3-S days

3 weeks

Characteristic signs andsymptoms

Lethargy, convulsions, ataxia

Diarrhoea, fever, disturbanceof electrolyte balance

Leukopenia, purpura, infection

Underlying pathology. • • • . . . •Inflammatory reactions in
Denudation of gastro-intestinal
central nervous system, brain
mucosaoedemaAtrophy of bone-marrow

Time of death (if occurring)...

Within 2 days·

Within 2 weeks

Within 2 months

Cause of death. . • • • • • • • . . • • •Respiratory arrest

Circulatory collapse

Haemorrhage, genera!U.ed
infection

Prognosis. • . . . . . . . • • . • • . . . • • Hopeless

Poor

Good

Source of information........

Animal experiments, bomb
casualties, nuclear accidents

Bomb casualties, nuclear
accidents, radio-therapy

Animal experiments

TABLE VI. EPIDEMIOLOGICAL STUDIES OF THYROID NEOPLASIA AND LEUKAEHIA IN CHil.DREN
TREATED m INFANCY ON THYMIC REGION: SUMMARY OF PUBLISHED DATA

Refernsu

Reason for
inadiatioa

Dose1'}1tl~'","f

Numberi"adiatechilbt11

Control''" ci rwma.

UuAIUfflia~iJ11uMh<:rThyroid

Conti et al. "'Pittsburgh

Prophylactic thymus
irradiation

7S-300

1,S64

2,923

0

0

3 cases of malignancy! leukaemia

Simpson-HempelmannFuller 4'li

Thymic enlargement(1) 200

2,393(80%
traced)

2,722

21

9

3.6 cases of malignancy(2) 20(}600

Simpson-Hempelmann m

1 leukaemia

Simpson " 7
Latourette and Hodges m

Thymic enlargement

Average200

861

Murray et al. "'Various benign
Averagediseases (45% chest)
400

6,473

Snegireff 451

Thymic enlargement

Cronkite-Moloney·
Bond •21

Thymic enlargement

Saenger <.1•

Chest-mainly forthymic enlargement

Stasek et al. m

Average400

148

1 lymphoma 0.1 carcinoma! leukaemia 1 lymphoma andleukaemia
8
162

12S

SC>1,200 r

1,644

Cervical lymphadenitis 10(}300 r

S2

178

3,777

0

0

2 (out of
7 neoplasias)

0

11

2 leukaemia

0.12 carcinoma

TABLE Vll.435 FREQUE.~CY OF ABDOMINAL IRRADIATION DUIUNG PREGNANCY OF J.!al'HERS OF
CANCEll. CHll.DREN AND MOTHERS OF CONTROL CHILDREN: SUMMAll.Y OF PUBLISHED DATA

Can&6 ehildn:11

CorrJrol diildre11

Praj>artw11 of rr.olhers"'/w reeei'Ped abdominal
irradwtion dsui111

Description of poup

P,tinancy

Propcrtkm of""'thers

ir/so rati'Ped obdomi"alirradialkm d11rin1

Descriptkm of poup#•g><ancy

Kjeldsberg no ••.•...•••••.•.••.•••.••

Children withleukaemia seen at
Riks-hospitalet,
Oslo, 1946-56

5/55 (9.13)

Healthy children

8/55 (14.5%)

Kaplan"' 3 ••••••••••••••••••••••••••••

Children dying ofacute leukaemia
in California,
1955-56

31 /150 (24.7%)
34/125 (27.2%)(a) Oosest Sib

24/150 (16.03)
21 /125 (21.6%)

Children withleukaemia seen at
the Children's
Hospital, Los
Angeles, 1950-57

72/251 (28.7%)

Children attending
the Children's
Hospital, Los
Angeles, 1950-57
with otherselected
conditions

Polhemus and Koch~ •..•••.•.•••••.•.

Ford el al."'' ........................ . Children dying ofleukaemia under
10 years of age
in Louisiana,
1951-55:(a) White(b) Coloured
MacMahon na ••••••••••••••••••••••••

20/70 (28.6%)
1/8
8/114 (7.33)

Children dying ofcancer under 10
years of age in
New York City,and born in a
specified maternity hospital,
1947-57(b) Moi;t habitual
playmate

58/251 (23.13)

Children dying ofcauses other thancancer under 10
years of age inLouisiana, 1951-55:(a) White(b) Coloured

1% sample ofchildren born in
one of 11 specified
maternity
hospitals,
1947-57, residents
of New York
City only

48/247 (19.43)
8/59
173/2,520 (7.33)

TABLE VIII.OT CoMPAJUSON OF OBSERVED AND EXPECTED INCIDENCE OF MALIGNANT NEOPLASMSIN SELECTED SITES AMONG SURVIVORS IN Hll!.OSHIMA EXPOSED WITHIN 1,5()() METRESFROM THE HYPOCENTRE, APRIL 1957-DF.CEMBEll 1958

Obs..wd

24
10

Cancer of stomach, sexes combined ....•...
Cancer of lung, sexes combined .......... .
Cancer of breast. .•.....................
Cancer of cervi:< uteri ...................•
Cancer of ovary •••....•................•

5
8
4

N.S. Not significant.
•Significant at the confidence level of 13.
••Significant at the confidence level of 53.

179

12.41
2.32
2.49
3.67
1.01

Rolw

T1ll rttall

1.93
4.31
2.00
2.18
3.96

•
N.S.
••
••

•

TABLE !X,H9

OBSERVED TUMOURS AND CALCULATED DOSE FROM RADIO-ACTIVE MATERIALS DEPOSITED IN THE LUNG

J{attri4J

end

}to.

redial ion•

Potto (alpha)

Rat

PutnO, (alpha)

Mice
:Mice
(inhalation)Rats(inhalation)

BaS"O, (beta)

Mice
Rat

Ru 1oeo, (beta)

Mice

Ru1oe
(metal cylinder)(beta)Sr" (glass beads)(beta)
Ce1UF I (gamma)

Rat

Co'° (gamma)

Mice

Rat
Rat

(wire)Squamous cell carcinoma
Fibrosarcoma•
Squamous cell carcinoma
Bronchiolar carcinoma

2/15
1/21
2/17
1

Calculattd
dose

Remuks(rod)b2,500

Refertncu

115
2,300
600

5 and 15 months after S µe/Kg
SOO days after 0.003 µe
400 days after 0.06 µc
SOO days after 0.1 µc

S10
521

522

517

Epidermoid carcinoma

Bronchiolar carcinoma

1/41

4,000

Between 50 and 100 per cent surviving 2SO days after depositionof 0.2 to 1 µc developed malignant tumours
100 days after 0.16 µC

Squamous cell carcinoma

2/16

12,000 to
20,000
300
4,000
9,000

300 days after 37S µc/week for 10
weeks
340 days after 0.15 µc
422 days after 2 µc
3SO days after 4.S µc

Lymphosarcoma•
1/23
Alveolar cell carcinoma
1/10
Non-differentiated tumo:ir 1/11
Bronchogenic carcinoma
5/26

Lymphosarcoma
Carcinoma
Carcinoma

4/23

2-9 x 101
S0,00070,000

1/27
1/23
7/28
4/15

2,200
5,500
8,900
15,000

Epidermoid carcinoma of
bronchus

12,000 to
400,000•All materials administered iritratracheally or otherwise as
indicated.
b Assuming uniform distribution and exponential loss unlessotherwise indicated.

TABLE X.7 3 7224 to 337 days after implantation of
2.1 to 14 µc (dose calculated at 100
microns from source)
131 to 375 days afterimplantation of
1.1 to 59 µc
127 days after 5 µe
48 days after 15 µc
93 days after 2S µc
83 days after 50 µc
200 days after implantation

523

523

521

515

514
736

518

• Classed as incidental by author because autoradiograms
showed no radio-activity in area of tumour.

CHEMICALS USED FOR PROTECTIVE EFFECTS

Thiols related to cysteine a11d C)'Steamine
CompoundAnimalDase mi/kt

Proltcli•eefft~

Refermcts

N-Alkyl and N-aryl derivatives of cysteine and cysteamine

Cysteine ........................................ .
Cysteine ....................•...................•
Cysteamine ......•...............................
Cystine ..........................•...............
Cystamine ...•...•.•...•.........................
Cystamine ...................................... .
N-Monomethylcysteamine ........................ .
N-Dimethylcysteamine ........................... .
N, N'-Tetramethylcystamine ...................... .
N-Diethylcysteamine ............................. .
N-Piperidylcysteamine ............................ .
N-Methylphenylcysteamine ...................... .
N-Phenylcysteamine ............................. .
S,2-Aminoethylisothiruonium bromide HBr (AET) ... .
S,2·Aminoethylisothiuronium bromide HBr .......... .
S,2-Aminoethylisothiuronium bromide HBr .......... .
S,2-Aminoethyl-N-methylisothiuronium chloride HCI..

Mice, rats
Rats
Mice, rats
Mice, rats
Mice
Mice, rats
Mice
Mice, rats
Rats
Mice
Mice
Mice
Rats
Mice
Mongrel dogs
Macaca mulatta
monkeysMice

950-1,200 i.p.
1,900 per OS
75-2SO i.p.
240-280 i.p.
150-300 i.p.
4~00 peros
60-120 i.p.
40-70 i.p.
60 i.p.
50-60 i.p.
2S i.p.
2SO i.p.
150 i.p.
240480 i.p.
100 i.p.
200-2SO i.p.

3
2
3
0
3
2
2
2
2
2
0
0
0
3
0
3

738, 739, 632
740
741, 738, 742, 363, 743
744, 74S
744, 746, 747, 363
748, 749, 750, 751
638
752, 638
638
752, 638
638
638
638
753, 636
754
755

150 i.p.

2637

Mice, rats
Rats
Mice, rats
Mice
1\Hce
Mice

800-1,000 i.p.
2,000 per OS
120-250 i.p.
240 i.p.
250-300 i.p.
350-550 i.p.
150 i.p.

3
0
2
0
1
0
0

744, 756, 7S7, 745
745
752, 638, 747
637
752, 738
746, 752, 738
638

N-Acyl derivatives of cysteine and cysteamine

Glutathione ..................................... .
Glutathione .................... , ................ .
N-Acetylcysteamine .............................. .
N-Acetoacetylcysteamine ..........•..........••...
Aletheine ....................................... .
Pantetheine ..................................... .
N-Acetylmethylcysteamine ........................ .

Mice

180

TABLE X. 737

CHEMICALS USED FOR PROTECTIVE EFFECTS

CompoundAnimal(co1itinued)

Dose mg/kg

Protectire

effect•&feren=Compounds with covered sulfur function

a-Homocysteine thiolactone........................
N ,S-Diacetylcysteamine. . . . . . . . . . . . . . . . . . . . . . . . . . .
S-Methylcystearnine................... . . . . . . . . . . . .
S-Benzylcysteamine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Methionine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
S,2-Dimethylaminoethylisothiuroniumchloride HCI. . . .
S,2-(1-Morpholyl) ethylisothiuronium bromide HBr...
Di(ethylaminoethyl)sulfide. . . . . . . . . . . . . . . . . . . . . . . . .

+Mice1\'lice
Mice
Mice
Mice
Mice
Mice
Mice

280-320 i.p.
850 i.p.
160 i.p.
500-1,500 i.p.
350 i.p.
150 i.p.
140 i.p.

0-1
0
0
0
0
0
0

Mice
Mice
l\tiice
Mice
Mice
Rats

90 i.p.
125-250 i.p.
450 i.p.
35 i.p.
40 i.p.
100 i.p.

3
3
2
0
0
0

752
637
738
638
638
638

Thioglycolic a;i? ... : ............................. .
Mercaptosuccrn1c acid ............................ .
2,3-Dithiopropanol (BAL) ......................... .

Mice
Mice
Mice, rats

0
0
0-1

744, 738
744
82, 752, 737

Dithiopentaerythrit .............................. .

Mice

180 i.p.
350 i.p.
150-200 i.p. ands.c.
75 i.p.

0759.r..Iice
.Mice
Mice
Mice
Mice

100 i.p.
420 i.p.
500 i.p.
270 i.p.
50 i.p.

0
0
0
0
0

637
759
744
759
759

Mice
Mice
!Vlice
Mice
Mice
Mice
Rats

500 i.p.
600 i.p.
2,500 i.p.
200 i.p.
150 i.p.
150 i.p.
5 i.v.

3
3
2
0
0
0
0

760
760, 761
762, 763, 738, 760, 764
744744, 759
750
745

220-350 i.p.
500 i.p.
75-95 i.p.
95 i.p.
25 i.v.
95 i.p.
80-275 i.p.
80 i.p.
50 i.p.
75-300 i.p.
3-5.5 i.p.
2.75 i.p.
0.7-1.4 i.p.
5 i.m.
1 i.p.
78 i.p.
6 i.p.
23-40 units/kp
i.p.
4 s.c.
5 i.p.
6.5 i.p.
15-30 i.p.
10 i.p.
10 s.c.
250 or.

2
0
3
3
3
2

744, 746
765
744, 746, 765
746
766
746
744, 746

758
339, 636, 752, 738
744
738
738
637

637
752

Compounds with branched or prolonged carbon chain

3-Mercaptopropylamine...........................
3-Mercaptopropylguanidine. . . . . . . . . . . . . . . . . . . . . . . .
Homocysteine . . . . . . . . . . . . . • . . . . . . . . . . . . . . . . . . . . . .
1-Mercapto-5-diethylamino pentane.................
1-Ivlercapto-7-arninoheptane. . . . . . . . . . . . . . . . . . . . . . . .
a-l\Iethylcysteine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Thiols with alcoholic or carboxylic acid groups

Thiophenols

2-Mercaptothiazoline..... . . . . . . . . . . . . . . . . . . . . . . . . .
1 (-)-2-Thiolhistidine.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Ergothioneine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4,6-Dirnethyl-2-mercapto pyrimidine. . . . . . . . . . . . . . . .
o-Aminothiophenol. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . • .
Miscellaneous sulfur-containing substances

Ammoniumdithiocarbonate.... . . . . . . . . . . . . . . . . . . . . .
Diethyldithiocarbamate.... . . . . . . . . . . . . . . . . . . . . . . . .
Thiourea. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Thiocyanide......................................
Thicacetamide.... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Sodium tetrathionate..... . . . . . . . . . . . . . . . . . . . . . . . . .
Sodium sulfide....................................

Compounds with pronounced pharmacological and toxicological activity

Histamine........................................

!VliceTryptamine ..................................... .
Serotonin ....................................... .

Mice
Mice

DOPA ......................................... .
TyTamine ....................................... .

Mice
Mice

Hydroxytyramine ................................ .

Mice

Arterenol ....................................... .

Mice

Epinephrine ..................................... .
Amphetan1ine ................................... .
Ephedrine .......................•................

Mice{Chickens
Mice
Mice

Oxytocine ....................................... .

Rats, mice

Reserpine ....................................... .
Sodium cyanide .................................. .
!Vlalononitrile .................................... .
p-Aminopropiophenone ........................... .
Apresoline ...................................... .

Mice
Mice
Mice
Rats
Mice

Amine oxides .................................... .

Mice

181

3

0
0

765

2
0
1
1
1
0
0
3

765
744, 746
746
765
767, 768
605
766
746
766
767, 769

3
2
3
3
2
2
2

644
744
744
7i0
771
771
772

3

TABLE X.737

CHEMICALS USED FOR PRorECrIVE EFFECTS (continued)

AnimalVarious metalJol~s and "inert" compounds
Fructose..................... . • . • • • . . . • • . • . . . . . • .

Mice

Glucose................. . . • • . . . • . . . . . . . . . . . . . . . • .

MicePropylene glycol. • . . . • . • • . • • • • . . . . . . . . • . . . . . . • . . . .
Glycerol. • . . . . . . . . • . . . . . . • . • • . . . . . • . . . . . . . . . . . . . .
Formic acid....... • • . • • • • . . . . . . . . . • . . . • . • • . . . . . . .
Pyruvic add. . • • • . • . . • • • • • . . . . . . . . . . . • • . . . • . . . . . .

Mice
Mice
Mice
Mice

Lactic add. . • . • • . • • • • • . . . . . • . . . . . . . . . . . . . . . . . . . . •MicetJ-Ketobutyric acid................................
Caprylic acid. . . . • . • • • • • • . . . . . . . . • . . . . • . . . • . . . • . . •Saliqil!c ac:!d. , • . • . . • . . . • . . • . . . • . • . • • . • . . • • . . . . . . .
Sucawc acid .•..• , . • . • . • . . . . . • . . • • • • . . • • . • . . . . • . .
a-Ketoglutaric acid................................
Ethylenediaminetetraacetic add. • • • • . . . . • • . . . . . . . . •

Mice
Mice
Mice
Mice
Mice
Mice

• Protective effect. The grading of the optimal protective effecthas been carried out according to the following arbitrary scale:
0 - no protective effect; 1 = slight or dubious protective effect(e.g., a-ketoglutaric acid); 2 - moderate protective effect (e.g.,

182

Dost rnr/'ft.i

13,500 i.p.
5,000 i.v.
13,500 i.p.
5,000 i.v.
3,000 i.p.
185 i.p.
92 i.p.
700 i.p.
250 i.v.
180 i.p.
250 i.v.
250 i.v.
290 i.p.
275 i.p.
950 i.p.
250 i.v.
580 i.p.

Prol«:liu
tfd

2
0
1
0
3

0
2
1
2
0
0
1
2
2

Re/ertneeS

744608, 773
744
773
744
744
744
744
608, 773
744
608, 773
773
744
744
744

1
1

773

2

744

formic acid); 3 = strong protective effect (e.g., cysteamine, AET).
i.p = intraperitoneally; i.v. = intravenously; i.m. = intramuscularly; s.c. "' sub-cutaneously; or. - orally.

REFEREKCES
1. National Academy of Sciences, National ResearchCouncil, Effects of ionizing radiation on the humanhemapoietic system, Report of the Subcommittee
on Hematological Effects, Committee on Pathologic Effects of Atomic Radiation. Puhl. No. 875(1961); v.e. United Nations document A./AC.82/
GjL.569.
2. International Commission on Radiological Protection, Recommendations of the International Commission on Radiological Protection, Pergamon
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3. National Committee on Radiation Protection andMeasurements, Permissible dose from externalsources of ionizing radiation. Recommendations of
the National Committee on Radiation Protection
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6. Powers, E. L., R. B. Webb, C. F. Ehret, An oxygen
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