REPORT OF THE
UNITED NATIONSSCIENTIFIC COMMITTEE
ON THE
EFFECTS OF ATO~IIC RADIATIONGENERAL ASSEMBLY

OFFICIAL RECORDS : TWENTY-FIRST SESSIONSUPPLEMENT No. 14 (A/ 6314)

UNITED NATIONSGENERAL ASSIEMBLY

OFFICIAL RECORDS : TWENTY-FIRST SESSIONSUPPLEMENT No. 14 (A/6314)....,...,, ..,,..
'II:;>• ..
t·•'<I/ 7 7
UNITED NATIONSNew York, 1966

Annex C

THE GENETIC RISKS OF IONIZING RADIATIONCONTENTSParagraphsl.

INTRODUCTION ......••••.•.•••..•....•••.•..

Paragraphs

1-2

Silkworm (B omby.r 111ori) ......•......•..
The chalcid wasp (Dahlbo111in11.s) ....•.••
Conclusions ............. ·................ .
Effects of low doses ..................... .
The effect of dose fractionation on the induction of point mutations ............. .
Conclusions ............................ .
The effect of the interval between irradiationand conception .......................... .
Conclusions ............................. .
The relative biological effectiveness (RBE)of radiations of different qualities ....... .
The mouse ............................. .
Pre-meiotic male germ cells ........... .
Post-meiotic male germ cells ......... .
Female germ cells ..................... .
Drosophila . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Silkworm .............................. .
Dahlbominus and M or111011iella ........... .
Conclusions ............................. .
Repair of pre-mutational damage ........... .
Para111eci"111 ............•..••..•.........
Bacteria ................................ .
Metazoan germ cells ..................... .
Quantitative traits ......................... .
Miscellaneous genetic effects ............... .
Space-flight results ..................... .
Effects of internally deposited radio-active
isotopes ............................. · ·IL PREVi'.LDICE OF NATURALLY-OCCURRJNG HEREDI·TARY DEFECTS AND DISEASES ..•...•..

Major disabilities due to single gene traits
maintained by recurrent mutation ....... .
Over-all rate of spontaneous mutation ..... .
Constitutional chromosome anomalies ....... .
Introduction ............................ .
Prevalence of constitutional chromosomal
anomalies ............................ .
Autosomal anomalies .................. .
Se..x-chromosome anomalies ............ .
Conclusions ........................... .
Chromosome anomalies
inmiscarriedfoetuses .............................. .
Factors affecting the prevalence of chromosome anomalies in human populations ... .
Modes of transmission ................. .
Mech:misms of induction ............. .
Possible aetiologic factors . . . . . ....... .

Ill.

EXPERIMENTAL DATA ON RADIO-SENSITI\'ITY OF
GERM CELLS in vivo . . . . . . . . . . . . . . . . . . . . .

Changes in the number of chromosomes ... .
Changes of ploidy . . . . . . . . . . ........ .
Loss or addition of individual chromosomes
Dominant lethals .......................... .
Introduction ............................ .
Male germ cells ........................ .
Female germ cells ....................... .
Summary and conclusions ............... .
Translocations ............................ .
Male germ cells ......................... .
Female germ cells ....................... .
Point mutations ........................... .
Specific locus mutations ......... .
Over-all rates of mutation ............... .
Recessive lethal mutations ............. .
Recessive visible mutations ............. .
Dominant visible mutations ........... .
Dose-rate effect on specific locus and recessive
lethal mutations ......................... .
Mice ................................... .
Drosophila ............................. .

6-15
16-36
37-70
37-41
42-51
42-46
47-50
51

52-53
54-70
54-58
59-62
63-70
71-2-13
il-S7
71-72
73-87
88-113
88-92
93-106107-110lll-113114-129
114-126
127-129130-155
130-135
136-155
136-146147
148-155

IV. R.tsx ESTIYAtts••••••••.•••••.•••.••••••..

Point mutations ........................... .
Total risk of induction ................. .
Risk of induction of dominant mutations .. .
Effects of cell stage and type of irradiation
Chromosome anomalies .................... .
Changes in chromosome numbers ......... .
Translocations .......................... .
Deletions ............................... .
V.

156-169
156-169
160-164

CONCLUSIONS . . . . ....•.............

165
166

167-169
170-173
174-180180
181-185185
186-203187-196187-192
193-195
196
197-199200
201-202203

204-223205-208

209-216217-223224-235236-243236-239240-243244-295249-272249-260261-265266-272273-295278-280
281-288289-295296-302
Pant

TABLES • . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
REFERENCES ...............•....•.........

I. Introduction

127
134

reviewed here, since they are not considered to be
directly relevant to the question of risk estimates.

1. The 19581 and 1962 2 reports of the Committee
surveyed in some detail the subject of the genetic effectsof ionizing radiation. The present paper updates thoseparts of the earlier revie"·s that require significant
revision in the light of recent progress, with particularregard to those results that more or less directly bearon the estimates of risk from radiation for humanpopulations.

TI. Tlie prevalence of naturally-occurring hereditary defects and diseases
3. The suITeys of naturally-occurring hereditarydefects and diseases made bv the Committee in its
1958 and 1962 reports are stili in large part valid. The
present annex will therefore refrain from discussing
again the hereditary factors involved in the generalmorbidity of the population or in the occurrence ofcongenital malformations, since too little has been
recently added t<:J our knowledge both with regard ~othe extent of their genetic component and to the mechanisms through which that component acts.

2. The present annex is not self-contained and should
be read in the context of the earlier reviews made bv
the Committee. particularly of that contained in its
1962 repo::t 1-.Ianv problems that were earlier considered in some detail by the Committee will not be

98

4. Likewise, no detailed discussion will be madeof those unfavourable traits that are maintained inhuman populations by mechanisms which, though reasonably well known, are not predominantly mmational.
Exposure of a population to radiation is likely only
slightly to affect the prevalence of these traits by comparison with those primarily maintained in the population by recurrent mutations. For the purpose of estimating risks.. the relevance of a discussion of these
traits is therefore, at most accessory.
5. Finally, the distribution of quantitative traits inhuman populations also will not be discussed in thepresent review. Their importance from the point of Yiewof risk estimates cannot be doubted, but our h"Tiowledge
has not sufficiently progressed to warrant a revisionof the rather detailed discussion contained in the 1958
report of the Committee.

at most. one order of magnitude. If this were so, thenumber, of loci involved would be correspondingly
higher.
10. Other limitations may result from the possible
inclusion of phenocopies and of recessives mimicking
dominant phenotypes. Again, however, the cumulative
frequency of traits here considered is unlikely to be
more than slightly over-estimated by ignoring thesecomplications.
11. Finally, the frequency of sporadic cases among
all cases of the traits considered here, though justified
by the need to obtain an over-all mutation rate, may be
misleading in as much as it may suggest that the traits
involved confer a rather small reduction in fitness. It
must be realized, however, that the traits on which theestimate rests span the whole range of severity, from
epiloia where the mean fitness is very low, to ichthyosis
and alopecia areata in which it is almost unimpaired,even though the latter two diseases may be a cause forserious physical or social hardship to some affectedindividuals.
12. Se.-r-linked traits. The category of traits that canbe confidently attributed to mutations at loci lying on
the X chromosome includes, according to a recent
survey of the literature. 4 some sbcty different disabilities. Another study5 indicates that the number of clearlys~x-linked harmful traits that are maintained in the
population by recurrent mutation is forty-nine, mostof them with very severe effects.
13. A tentative analysis of the distribution of frequencies of these forty-nine traits suggests that thecorresponding over-all mutation frequency is approximately 1.3 X 10-4 mutations per gamete per generation.
Assuming ·that each trait is determined at a single
locus, the rate per locus per generation is ·therefore
2.7 X 10-6 , in reasonable agreement with the upper
limit of the estimate obtained independently in paragraph 9 for autosomal dominants.
14. It is important to note, however, that only sixteen of ·the forty-nine sex-linked traits occur at a rate
higher than 10-6 • While it is likely that our inventoryof relatively common traits maintained by high spontaneous mutation rates is almost complete. it is to be
expected tlmt we shall continue to recognize an increasingly large number of very rare traits caused by Xlinked mutations. It follo\vs, therefore, that. as in thecase of autosomal dominants. the average rate per locus
here obtained applies only to those loci that have beensampled so far. and that it would be misleading toassume that they are representative of the spontaneous
rates per locus over the rest of the genome.
15. Aittosomal recessive traits. Recessive traits in
man are usually much more severe in their effects(homozygous ~xpressions) than those due to dominant
genes where. in general, only the heterozygous e.xpressions are observed. Special methods are now available
by means of which it is possible to recognize with ahigh degree of probability individuals heterozygous forrecessive genes. at least when the corresponding genefrequencies in the population are sufficiently high. Many
recessive gene traits, probably t.lie great majority. are
so uncommon that they are verv seldom seen or theirgenesis recognized. Finally, although recessive detrimental traits are less common, the corresponding genefrequencies, on the average, must be very much higher
than those of genes whose expression is easily recognizable in heterozygotes.

MAJOR DISABILITIES DUE TO SINGLE GENE TRAITS MAINTAINED BY RECURRENT MUTATION

6. In earlier reports, the Committee considered as
an individual category those hannful traits whosemechanism of inheritance was understood and whose
prevalence in the population was mainly determinedby recurrent mutations, excluding those traits that were
due to a cytologically detectable chromosome anomaly.
This category, apparently due to gene mutations, included autosomal dominant. autosomal recessive andsex-linked traits.
·
7. In its 1958 report, the Committee accepted afigure of about 1 per cent as the proportion of all liveborn infants falling into this category. Subsequent information suggests that this figure is slightly low. Of
this 1 per cent, about 70 per cent are believed to beaccounted for by approximately fifty dominant traits
determined by autosomal genes. The terms "dominant"and "recessive" as used here are conventional in human
genetics. Thus the term "dominant" includes traits
usually recognized by the heterozygous expression of
the mutation. although in the great majo·rity of examples the condition of individuals homozygous for suchgenes has never been observed.
8. Dominant autosomal traits. The relative frequencyof the fifty dominant autosomal traits referred to in theprevious paragraph is now estimated to be approximately
80 per cent. An analysis of the proportion of sporadic
cases at birth (i.e., cases having no affected relatives)among all living cases suffering from these disabilities
indicates that about 4 per cent of the cases are due
to new mutations arising in parental gametes.3 The
frequency of live-born children carrying new dominant
mutations responsible for major disabilities appears
therefore to lie around 3 X 104 ( 0.01 X 0.80 X 0.04).
9. This frequency corresponds to a rate of 1.5 X 10-4
mutations per generation per gamete. The average
mutation frequency of the individual loci responsible
for those traits is not knO\vn, estimates at individualloci being available only for a few of them which arerather more mutable and not likely to be representativeof the rest. It is a safe assumption. however. that the
fifty traits referred to in paragraph 7 are determinedat fifty loci at least. and, for the purpose of the present
discussion. this will be assumed to be true. ·with fiftyloci the average mutation rate per locus per generation
would be around 3 X 10-0 • This rate is an upper limit
to the average mutation rate at all loci at which
dominant visible mutations occur, but it seems unlikelythat the average mutation rate can be lower than by,99

20. Although it is not possible even with this method

OVER-ALL RATE OF SPO~TANEOUS MUTATION

16. The estimation of the rate of spontaneous mutation over the whole genome in man can be approachedin several independent ways. Most of them make use of
information obtained from studies of the sex-ratio andare based on the hypothesis that differences in the valuesof the ratio at birth and during various stages of intrauterine life may result from the elimination of various
stages of development of males hemizygous for recessive
lethals on the X chromosome. The assumption is obviously very crude, as it ignores the physiological factors
involved in the differential survival of foetuses of either
sex, and the complications due to non-disjunction, toloss or to structural rearrangements of sex ch:-omosomes which are now well documented in man. The
sex-ratio might also be affected to some extent by
sex-limited autosomal mutations. Accepting the assumption that the se..x-ratio is largely controlled by theoccurrence of se..x-linked recessive mutations and using
data on the sex-ratio of dead foetuses. the rate of
mutation over the whole X chromosome has been
estimated to be 6.8 X 10-s per generation for mutations
expressed between the twenty-eighth week of pregnancy
and birth. 6 The same method applied to different data
yields similar estimates.7• 8

17. Other data were analysed by a more refined
method 9 based on the assumption that lethal recessive
mutations on the X chromosome accumulate with theage of the mother. A negative correlation between the
sex-ratio of live-born children and maternal age istherefore expected and makes it possible to estimate
the rate of accumulation of mutants with time. This
study also presents several limitations, because theeffect of birth order and paternal age cannot in thesedata be separated from that of the age of mothers, andbecause maternal age may be correlated with maternal
factors differentially affecting foetuses of either sex.
The method also fails to remove the bias due to thepossible correlation between maternal age and the occurrence of chromosome losses that might alter the
sex-ratio at birth. Besides, very large samples areneeded to achieve a sufficient resolving power. because
the rate of accumulation of mutations in oocytes is expected to be low if at least part of the mutations that
occur spontaneously are due to copying errors. whose
frequency of occurrence is more dependent on the rateof cell multiplication than on time alone.
18. The study yielded an estimate of (2-+- 0.75)
X IQ-3 mutations per generation per X chromosome infemale gametes. Neglecting the theoretical limitations
t~at were outlined above, the estimate applies to recessive lethals acting between conception and birth.
19. Some of the limitations that weaken the validityof t~e pr~vious methods are removed by studying therelationship between the se..x-ratio and the age of thematernal grandfather at the birth of the mother.10 The
relationship is believed to be determined by the accumulation :vith age of recessive lethals that arise during
the contmued multiplication of spermatogonia. X
chromosomes carrying mutations will be transmitted todaughters, and. irom them. to 50 per cent of the maleoffspring that will thus be eliminated. The age of ther:iaternal grandfatl~er is therefore expected to be positively correlated with male mortality in 11tero and therefore with the sex-ratio of aborted foetuses and stillborn. and negatively correlated with the sex-ratio oflive-born children.

100

to allow for the occurrence of mutations with se..ic-

lirnited expression and for structural rearrangements ofthe sex-chromosomes, the three-generation approachhas the advantage that the correlation between time andsex-ratio is unlikely to be obscured by maternal
physiological factors or by the occurrence of chromosome losses.
21. The method has been applied to a sample oflive-born children with inconclusive results. 11• 12 \Vhenapplied to a sample of some 7,000 dead foehtses. 13 themethod showed a significant positive correlation of
grandpaternal age with the sex-ratio, once the confounding effects of other concomitant variables, suchas the age of the parents, age of the maternal grandmother, birth order and so on were eliminated. It ·wasthus possible to estimate a rate per generation in malegametes of (3.6 -+- 0.9) X lQ-3 sex-linked recessive
lethals acting between twenty weeks after conception
ai.1d birth. An earlier survey of the same size based on
still-born gave an estimate of 2.5 X 10-3 , in good
agreement with the previous one.
22. The rate thus obtained is probably an underestimate of the total rate of mutation, since, judging
from Drosophila clata, 14•16 sex-linked lethals, as opposed
to autosomal lethals, are strongly selected against in
spermatogonia, most studies indicating a reduction ofaround 50 per cent. If the same severe selection holds
in man, the rate of sex-linked recessive lethals per~eneration in the viable male gametes is only half thatm the genome before meiosis.
23. A certain number of sex-linked mutants mustalso be acting later in life. Their rate of induction must
be lower, however, since the excess male mortality
attributable to genetic causes is certainly very small.
If. on the other hand. the rate of spontaneous mutation?n ~.e X chromoso?1e is higher in spermatogonia thanm oocytes, the estimate of the spontaneous mutation
rate over the whole genome will over-estimate the overall rate representative of both sexes, but not by a factor
of more than two. Although not all the reservations that
may be advanced have been reviewed here, as a first
approximation the estimate just given. corrected for
germinal selection. may be taken as the total rate ofinduction of sex-linked recessive lethals. Assuming that
the X chromosome comprises about 5 per cent of the?uman genome and that its mutability per unit length
1s the same as that of the rest of the genome, the total
rate of. recessive mutations over the ""'hole genome isapproximately 14 per cent per gamete per generation.
24. The total rate of mutation as estimated above,d~vided by the rate of mutation per locus per generation,
gives an estimate of the size of the genome in terms
of. number of loci at which detectable mutations may
anse. The average rate of recessive mutations per locus
per generation is not known but is likely to lie between
2 X I0- 5 and 0.2 X 10-5 • indicating- that the genome
may contain anywhere between 7,000 and 70.000 loci.
A figure that has frequentlv been used-10.000 lociwa~ derived from Drosophila data by considering theratio between the over-all rate of induction of sexlinked lethals by radiation and the averaae rate per"' figure ofl ocus. i~• F or purposes of computation. the20.000 loci in man will be used in the rest of this review.
25. The significance of an over-all mutation rate interms of individual or collective hardship is verv difficult to assess. \i\Thile sex-linked recessive lethaf genes
are promptly eliminated in the hemizygous state inin the offspring is directly related to the number of
detrimental genes carried by the parents on the one
hand, and on the degree of consanguinity on the other.
As discussed in earlier reports of the Committee, therelationship between detriment and degree of consanguinity, when established on an adequate sample ofconsanguineous marriages, makes it possible to estimate
the number of genes, or rather of lethal equivalents. in
the population which. in the homozygous state, giverise to the type of detriment that i5 being studied. The
estimates vary from one sample to another. A recent
review25 of the available data sets three as a likely
upper limit to the mean number of lethal equivalents
per gamete acting after birth.
32. The estimate based on the three-g-eneration
approach refers to the whole of the newly arisen mutational detriment. The estimate derived from consanguinity studies, on the other hand, is a measure of the
detriment carried by the population, as expressed inhomozygotes after birth. Estimates of the corresponding
damage expressed before birth have so far been soerratic25 • 26 as to preclude conclusions regarding thein1portance of its contribution to the total detriment,
although there is reason to believe from results ofanimal experiments that it may be far from negligible.
Considering that, as discussed in the previous paragraph, the damage estimated on the basis of consanguinity data and the damage quite independently
assessed through sex-linked lethals are not entirely
the same, and taking into account the errors involved
in either estimate. the two approaches appear to leadto reasonably consistent results. Too much weightshould not be attached to their closeness, however,
because the estimates in both cases are dependent, indifferent ways. on a large number of assumptions.
33. It must also be mentioned that the damage
estimated through consanguinity studies may only inpart be due to balance between recurrent mutation andselective elimination through heterozygotes. Even if,
as was mentioned in paragraph 28, mutations conferring
selective advantage to heterozygotes were much rarer
in the population than the others, they could contribute
more to the detriment expressed in the homozygous
state. 27
34. The method of assessment of genetic detrimentthrough consanguinity studies was originally expected
to yield quantitative information on the respective roleof either mechanism in maintaining the detriment in
human populations. So far, however, the results ofhuman surveys have been inconsistent. Besides, theapproach through which the role of the alternative
mechanism can be assessed has recently been challenged
on the ground that some of the assumptions on which
it rests are unjustified.!) 8 The estimate based on thethree-generation approach can only be regarded asapplying to mutational damage. Comparison with thatobtained from consanguinity studies suggests that thelatter may include a large mutational component.
35. Even consanguinity studies do not provide information about the manner in which genes are eliminated at the levels of inbreeding commonly prevailingin human populations. The damage revealed by these?tudies is, by definition. due to detrimental genes acting
111 the homozygous state. There is no way at present toguess at what period of life this damage is being
expressed, although it seems unlikely that :t can be
expressed earlier than in homozygotes.

utero, fully recessive mutations ansmg on autosomes
are eliminated mainly in homozygotes and these, becauseof the low leYels of inbreeding prevailing in most humanpopulations, are rarely observed. As was mentioned inan earlier section, strictly recessive mutations that occur
spontaneously in man have usually a .-ery severe effectin the homozygote.
26. Evidence from Drosophila, 18- 21 however, suggests that newly arising mutations on the average are
not completely recessive but find a varying measureof phenotypic e..xpression in heterozygotes as well and,in fact. range from fully dominant to completely recessive. Their phenotype is usually harmful, and themutatiom are thus eliminated at a rate behveen 1 and
7 per cent per generation. No such figures are available for any other species. and the Drosophila estimate
can only be applied to man with the greatest caution.
27. The manner in which mutants are eliminatedthrough heterozygotes in man is also unknown. A number of mechanisms 22 can be thought of. such as lossof embryos and foetuses in utero, premature deaths
and reduction of fecundity due to physical or mental
defects of all shades of severity, and that ill-defined
but significant entity known as the genetic componentof morbidity. At present, it is not possible to determine
to what extent any of these mechanisms contributes tothe elimination; in particular, it is unknown what fraction of the elimination takes place through losses assessable in socially meaningful terms.
28. On the other hand, the very concept of unconditional harmfulness entailed by the assumption thatmutant genes are eliminated in the heterozygous state
has been questioned23 because a number of genes, bothin man and in experimental animals, are known to beadvantageous in the heterozygous state, at least in someenvironments, even though they are detrimental or
lethal in homozygotes. The existence of such genes isa matter of experimental observation, but it seems
unlikely that they represent more than a small fractionof the newly arisen mutants.
29. Since the phenotypic expression of any genedepends on the expression of the other components ofthe genome, it could also be argued that, with such alarge nun1ber of mutants as arise spontaneously in eachgeneration, their interactions with the rest of the
genome should be taken into account before reachingconclusions regarding how and when they are eliminated. This cannot at present be done with the available e.."i'.perimental data. Until evidence to the contrary
accumulates, however, it is reasonable to assume thatthe net effect can be neglected, as positive and negativeinteractions presumably tend to cancel each other.
30. If the rate of elimination observed in Drosophilais accepted as valid for man-and there is no denying
the tentativeness of such an assumption-and if, as afirst approximation, the rate of elimination of new
mutations is assumed to be between 1 and 7 per centper generation, the total number of detrimental genes
carried. on the average, by human gametes can be
estimated to be between two and fourteen (0.14/0.07
2; 0.14/0.01 = 14).
31. Some indirect support for this estimate comesfrom the study of the offspring of consanguineous marriages in man. 24 Consanguinity of the parents increases
the likelihood of their offspring being homozygous fora fraction of the genome. including lethal and detrimental ge.11es. The amount of detriment thus observed=

10136. This section has shown that estimates of theover-all spontaneous mutation frequency in man may
be derived mainly from human sources, but the degreeof confidence in these is still limited by deficiencies
both of theory and of the empirical data. However,there is merit in making as much use of human information as possible, and the methods themselves are potentially capable of improvement. It may be noted that the
only figure obtained in this section which is usedin estimating risks is the estimate of the total numberof mutable gene loci in the human genome. Although
this figure is based on human data alone. the uncertaintyof the assumptions that are used in obtaining it must
be clearly borne in mind.

39. In addition to these four common anomalies.
the occurrence of other types of autosomal alterations
has been described ;so-u(a) An e.xtra chromosome (e.g. 21) from which a
portion is deleted, so that a completely trisomic state
is not present.
(b) Deletions, particularly involving the short armor the long am1 of chromosome 18.
( c) Isochromosomes.
( d) Ring chromosomes.
( e) Translocations of two general types:(i) Those in which essentially all of one chromosome is exchanged to another, with noidentifiable reciprocal product. This produces a chromosome number of 45 in theindividual, without phenotypic change. This
type of translocation always involves one
acrocentric chromosome (groups D and G).
(ii) Translocations in which parts of two chromosomes are reciprocally translocated. This
does not produce phenotypic changes in thebalanced state, but results in severe damage
in the unbalanced condition.
(f) Mosaicism-a mD..1:ure of two cell lines in thesame individual. These may include various combinations of monosomic, disomic and trisomic cells (e.g.
involving chromosome 21) ; a mixture of diploid andtriploid cells; or a mixture involving any of the typesof abnormalities described above.
40. Among sex-chromosome anomalies, 30 •32•3 :;..a1
three types are particularly frequent, the XO (Turner's
syndromec), the XXY (Klinefelter's syndromed) andthe XXXe complements. The other complements thathave been described-XXYY, XYY, XXXY,XXXXY, XXXX, XXXXX-are much rarer. Structural anomalies are also known: ring X (XR), isochromosome X involving the long or the short armof the X chromosomes, deletion of the short (Xns)or of the Jong arm (XnL) of the X chromosome.
41. Several different types of mosaics, associating,for instance. an XO with an XX line or an XY withan XXY li~e. have been described. Sometimes structural anomalies of the X chromosome are involved,
such as XO/XXR. XO/X 1soX. etc. (table I). Each
type of mosaic determines different phenotypes depending on which line is preponderant. In true hermaphroditism . karyotypes vary from one case to another; both
XX and mosaics are knmm, the latter of the types
XX/XXY. XX/)...'Y and XO/XY.

CONSTIT"CTIO:>;AL CHROMOSOME ANOMALIESIntroduction

37. Despite the considerable advances that havebeen made in recent years in the field of human cytogenetics and that require a revision of the points discussed by the Committee in its 1962 report. it is still
too early to achieve a balanced inventory of thechromosomal anomalies prevailing in the human species.
This is not only due to the fact that it is often impossible to establish a close correlation between aclinical pattern and the chromosome anomaly that isobserYed. but also to the fact that it is difficult to identify certain pairs of chromosomes• and that still
relatively few subjects have been studied. Nevertheless,several specific syndromes can now be characterized by
the chromosome anomalies associated with them.
38. It is customary to consider separately autosomal
and sex-chromosome anomalies and, within each ofthese, changes in the number of chromosomes andstructural rearrangements. Among the autosomal
anomalies. four syndromes are especially frequent.
These are trisomy 21 (i.e., Down's syndrome associated with trisomy of one of the two pairs of chromosomes of the G group which is conventionally called
No. 21): trisomy 18 (i.e., of a No. 18 chromosome
in the E group) and trisomy 13 (i.e., of one of the
13-15 or D group chromosomes. Conventionally thee>..1:ra chromosome is assumed to be a No. 13). The
fourth syndrome is due to deletion of part of the short
ann of chromosome 5 (cri dit chat syndrome).b" The international conferences held at Denver and London!?9
defined the characteristics of the normal human karyotype ancl
the relevant terminology. At the London conference it wasagreed that chromosomes could be classified according to twosystems, alphabetical and numerical, as follows :1-3 (A), 4-5 (B), 6-12 and X (C), 13-15 (D), 16-18 (E). 19-20(F), 21-22 and Y (G).
b The syndromes due to these autosomal anomalies consist ofserious mental retardation associated with a constellation of malformations that makes possible the clinical diagnosis oi each
syndrome. The most frequent malformations are, schematically:
Trisomy 21: Peculiar facial features with palpebral fissure~slanted upwards and outwards, epicanthus, short nose withbroad base, thick lips, small and malformed ears, small andspherical skull, hands and feet short and broad, muscularhypotonism.
Trisomy 13: ~ficrocephaly, microphthalmia, harelip, ear andheart malformations. polydactyly, characteristic foot deformity,arrhinencephaly.
Trisomy 18: Ear and sJ...-ull malformations, abnormal position ofhands and fingers, cardiac malformations.
Cri d11 chat syndrome: roundish face, hypoplasia of the lower
jaw, hypertelorism and highly characteristic cry, particularlyin the first years of life.

Prez·alence of constitutio11al chromosomal anomalies
A utosomal anomalies
42. Trisomy 21. Most autosomal anomalies havebeen too recently known to make it possible to estimate
accurately their individual rates of occurrence. Several
investigations, ho·wever, have dealt with trisomy 21. theearliest among the anomalies to be defined as a syndrome. The frequency of trisomy 21 seems to be of
the same order of magnitude in all areas where it has
been estimated. 38 • 39 approximately 1.5 per 1.000 livec Turner's syndrome: gonadal agenesis, absence of secondary
sex-characters, small stature and various malformations inphenotypic females with amoenorrhea.
d Klinefelter's syndrome: phenotypic males with high stature,gynecomastia. gonadal hypoplasia and sterility.
e The XXX syndrome is a chromosomal rather than a clinicalentity that has been -observed both in seemingly normal and infeeble-minded women without serious genital disorders.
102births. Not all cases of trisomy 21 are regular but thefrequency of translocated trisomies 21 is difficult toassess because the samples that have been studied indifferent laboratories (table II) are usually biased,since karyotype analyses are carried out in most casesin children from mothers under thirty years of age when
the chances of detecting a translocation are highest.
Based on these selected cases, the frequency of D ,...., G
and G - G translocations is 7-12 per cent, 30 • 40 • 41 but
the most reliable estimates cluster around 2 per centof all trisomies 21Y• 43 • H These translocations areusually of the type D ,..., G and G ,..., G, other types
being e.."<ceptional. It should be noted that only in onethird of the families where two or more sibs areaffected is trisomy 21 accompanied by a detectabletranslocation. 45 Translocations involving chromosome
21 have recently been estimated to arise at an approximate rate between 2.1 X 1CT5 and 2.7 X 1CT5 per
chromosome 21 per gamete per generation. The e.."<pected frequency of translocated chromosome 21 among
live-born children would then be approximately
5.4
lQ--S.46
43. Among these translocations, only a minority isinherited from parents carrying the translocations
themselves. Only one in four ( 3/12) is found whendata from several authors 41 are pooled. According toa recent survey,46 49 per cent of D ,...., 21 translocations
and 5.6 per cent only of G ,...., 21 translocations are
inherited from parents. It can be estimated on the basisof current knowledge that de 11ovo translocations intrisomy 21 represent from one-half to three-quartersof all these translocations. The frequency of mosaicsof which one cellular line at least is trisomic 21 is low,
probably less than 1 per cent. 47 and partial trisomy
with deletion of part of a chromosome 21 is exceptional."8
44. Trisomies 18 and 13. Few statistical data on
autosomal trisomies 18 and 13 are available. The firstestimates for trisomy 18 give frequencies ranging from
0.2 to 1.6 per 1,000 births.30• • 9•51 For still unknown
reasons, a clear predominance of females is apparentforty-five females as against thirteen males according
to a recent survey. 52 Out of sixty-five cases of trisomy
18, sixty regular trisomies have been observed, twotranslocation trisomies and three mosaics, 52 but therelative proportions of the different chromosomal complements are probably not representative of the actual
population frequencies, inasmuch as a bias occurs inthe selection of published observations. The same istrue for trisomy 13 53 where. out of forty-eight cases,
two mosaics, three partial trisomies and three translocation trisomies have been observed. The frequencyof trisomy 13 at birth appears to be lower than thatof trisomy 18.51
45. Cri du chat syndrome. No data are yet available
on the frequency of this anomaly of which some fifty
cases are now known and which consists of deletion ofpart of the short arm of chromosome 5. Seven cases(including two sibs) have been observed in a population of 1.562 feeble-minded subjects.5 -1 The frequencyof the syndrome is probably higher than that ot
trisomy 13. The association of the anomaly with atranslocation has been described in one case. 55
46. Translocations. It is also difficult to assess thefrequency of translocations in the general population,
since balanced translocations are phenotypically undetectable and are usually identified through anomalies
occurring among the descendants of carrier individuals.

x

103

Thus, only systematic surveys can give an idea of thefrequencies involved. A recent investigation on 438
adults 56• ~· yielded a frequency of five per 1,000 forreciprocal translocations and possibly pericentric inversions, which represent major karyotypic anomalies.
Minor variations affecting the size of the short armof group D and G chromosomes or the location of thecentromere of a chromosome 16 are probably fairly
frequent (2-3 per cent). It is not proved, however, thatthose anomalies are associated with any detectable malformation.

Sex-chromosome anomalies
47. The frequencies of sex-chromosome anomalies
are better known than those involving autosomes since
the number of special stainable bodies (Barr bodies
or sex-chromatin) in interphase nuclei makes it possible to know how many X chromosomes are present
in a cell. In general, as many bodies are observed in
the interphase nucleus as there are X chromosomes
less one. Normal male individuals have no se..'C-chromatin and their cells are called sex-chromatin negative.
Cells of normal females have one Barr body which isvisible only in a certain percentage (from 20 per centupwards) of cells called sex-chroma:tin positive. Cells
with three X chromosomes have two Barr bodies andare called double-positive.
48. Sex-chromatin tests therefore make it possible
to recognize anomalies involving the number of X
chromosomes (XXX, x_x:y, etc.) and certain mosaics
in which normal cells are in sufficient proportion to
be detected in a relatively small sample of cells. If theabnormal cell population is a small minority, the mosaic
situation will be detected by this means only with great
difficulty.
49. In samples from certain selected populations
the frequency of sex-chromosome anomalies is higher
than in the general population. This is the case withfeeble-minded subjects, 36• 56 with sterile subjects,:> 8
with criminals59 • 60 and with fem ales with stature
below normal 61 (table III).
SO. A number of surveys have dealt with the frequencies of sex-chromosome anomalies among Iiveborn children. By pooling the data from five of thesesurveys 62 •66 involving altogether over 25,000 children,the following frequencies of subjects with abnormal
se..'C-chromatin are observed: 1.5 per 1,000 females, ofwhom three-fourths, or 1.2 per 1,000, were doublepositive (XXX), 0.3 per 1,000 negative, and 1.7 per
LOOO chromatin-positive males. In eighteen of the
10,725 males who underwent a chromosome examination, twelve were XXY. one was XXXY and five weremosaics XX/XXY. 64 In twelve girls among 10.000 thatwere investigated, nine proved to be XXX. two were
XO. and one was a mosaic XO/XnLX (deletion ofpart of the long arm). Those figures show the highfrequency of mosaics among individuals with sexchromosome anomalies. a frequency which has been
estimated to be about 18 per cent of these anomalies. 36
Finally, Y-chromosome polymorphism is known inman 62 as it is in other organisms, but its significanceis not clear.
C011clttsions

51. Although more information is needed. it isgenerally agreed that chromosome anomalies are observed in about ten per 1.000 lh-e new-born infants.
Autosomal trisomies and sex-chromosome anomaliesaccount for about 3.5 per 1,000 each, the rest being
accounted for by translocations (table IV). It must beborne in mind, however, that only relatively majoranomalies of the karyotype are detectable throughpresent techniques. A sizable number of chromosome
anomalies escape cytological diagnosis. On the other
hand, attention has recently been drawn67 to the existence in man of complex structural change!, forexample inset'tions, which can produce genetic imbalance in the children of carriers (duplications, deficiencies). These events do not seem always to be accompanied by detectable morphological differences between
the chromosomes of children and those of their parents.
Their frequency cannot at present be assessed.
Chromosome anomalies in miscarried foetuses

52. A certain number of spontaneous abortions areassociated with chromosome anomalies. Sometimes itis the abnormal chromosome constitution of one of theparents that is responsible 68 -71-mosaics or structural
rearrangements, particularly translocations. ~fore frequently, the anomaly concerns the foetus alone-monosomies and trisomies, triploidies-with no apparent anomaly detected in the parents. 72-1° The proportion of chromosome anomalies observed in a numberof studies of spontaneous abortions is large : thirty cases
out of eighty-two. 76-S-O The largest homogeneous survey
includes 200 cases. 81 •82 Chromosome anomalies wereobtained forty-four times: 11 XO. 9 triploids. 7 Etrisomics, 6 D-triSQmics. 5 G-trisomics, 2 C-trisomics,
2 tetraploids. 1 B-trisomic and 1 A-trisomic.
53. About one-fourth of all spontaneous abortions
therefore appear to be associated with chromosome
anomalies, particularly anomalies of the number ofchromosomes. The high pre-natal lethality of XO individuals probably explains why the proportion of XO
new-born children is much lower than that of XXX
or XXY new-born children. Assuming that 15 percent of all pregnancies result in spontaneous abortions, 83
chromosome anomalies would be responsible for theinterruption of about 4 per cent of the pregnancies. The
over-all burden of chromosome anomalies would therefore be 5 per cent per generation.
Factors affecting the prevalence of chromosome
anomalies in human pop11latio11s~~. Diplo-triplo-21 mosaics have also been observedin six families among the parents of children who wereregular trisomics 21. The risk of recurrence of trisomy
21 is all the more difficult to assess in these cases as
the respective proportions of the different cell lines
are not necessarily the same in the germ line cells asin the somatic cells where they are detected.
56. Another problem regards the transmission oftranslocations to the descendants of the carriers. The
most accurately studied cases are those concerning
D ,_, 21 translocations. According to certain authors,when the mother carries the anomaly, on the average
one-third of her children are normal, one-third carry
the balanced translocation and one-third are trisomics
21.39 Other authors believe that the latter proportionis between one-third and one-tenth.42 The inconsistency
may be due to the different statistical methods employed. When the father is the carrier, on the other
hand, the frequency of trisomics 21 among the offspringis much lower, certainly Jess than 5 per cent, 39 thereason for such a difference in transmission with thesex of the carrier being unknown.
57. In the case of G - 21 translocations, the sexof the transmitting parent does not seem to play arole. Therefore 21 ,_, 22 translocations will give rise
to one-third, one-third, one-third proportions, whereas
the offspring of 21 ,_, 21 translocations will be trisomics
21 since the lethality of haplo-21 zygotes is probably
very high.
58. The frequency of transmission of other typesof translocations is less known. A familial observationof a D ,.._, D translocation showed a 1 :1 segregation of
the anomaly in the course of three generations. 89 It is
not unlikely that the size of the chromosomes involvedin the translocation may influence the frequencies ofabnormal 90 segregation, but the available data are stillinsufficient. Interchromosomal effects91 are an additionalcause of aneuploidy among the descendants : thepresenc.e of an anomaly, e.g. a translocation, may increase the likelihood of an anomaly of a different typein the offspring ; several observations of regulartrisomies 21 have been reported in children born ofparents carrying translocations of the D ,_, D type andsex-chromosome anomalies in children of a parent
carrying an autosomal translocation have also been
observed.

Modes of transmission

Mechanisms of induction

54. Many individuals with constitutional chromosome anomalies have no descendants owing to sterility
related to a sex-chromosome anomaly or to somedebility associated with an autosomal anomaly. The
viability of trisomic subjects, particularly with regard
to chromosomes 18 and 13, is severely reduced, so thatit must be assumed that the frequency of these anomalies
is maintained in the population almost exclusively
through recurrent chromosome mutation. Nevertheless,
XXX females have been reported to have children;thus, eleven women have had thirty-one children. about
half of whom were examined and in whom no anomaly
was detected. 80 Recently. 64 two children with Klinefelter's syndrome (XXY) were observed, who wereborn respectively of an XXX and of an XX/XXX
mother, and an xx;xxx girl born of a mother also
XX/XXX. 8 ~ This confirms the possibility that sexchromosome anomalies can be transmitted as has beenshown in other organisms. including mice. Among the
few children of XXY/XY mosaics, no anomaly related
to the parental mosaicism has been observed. 86 • 87

59. Still relatively little is known on the mechanisms
of induction of chromosome anomalies in man. Anomalies involving the number of chromosomes may be due
to non-disjunction or to loss of a chromosome duringmeiosis. But both loss and non-disjunction may also
take place in the zygote.
60. \\-'hen abnormal segregation or losses of chromosomes occur at the blastomeric stage, they give rise
to mosaics consisting of two or more cell lines. The
e.iclstence of monozygotic twins \vith different karyotypes argues in favour of such a mechanism.:io If oneof the cells resulting from non-disjunction is unviable(e.g. YO). the complementary cell (XXY) only will
give rise to an anomalous homogeneous line.
61. Abnormal gametes may arise at meiosis intranslocation carriers. Certain structural anomalies may
also take place during meiosis (production of X isochromosomes) but not necessarily so. Other mechanisms
have been suggested to account for certain aneuploidies:asynchronous duplication of a single chromosome, 112104

polyspenny or double fertilization, of which several
examples have been recently described in the case of
XY/XX mosaics. 03 -95 The frequency of those accidents,
however, is still wholly unknown.
62. In certain cases it is possible to identify thestage at which the accident has occurred. Thus. an
Xll XP Y complementt is due to a non-disjunction during the first meiotic division in the male, whereasx~ 1 XP xr and XYY are belieYed to result from nondisjunction at the second division. 3 ;; By means of themarkers located on the X chromosome (colour blindness, glucose-6-phosphate-dehydrogenase deficiency, Xg
blood group), it is occasionally possible to determine the paternal or maternal origin of an X chromosome. Thus, among the XO subjects studied in one
series, the maternal origin of the X chromosome has
been ascertained twenty times and its paternal origin
once, 96 but because of the difficulty of the techniquethis cannot be taken as a reliable estimate. Likewise,
XXY subjects are known to have arisen as a consequence of non-disjunction occurring during gametogenesis in either parent.30 • 35 • 97 • 98 Finally, an XXYY
subject has been reported to originate from two successive non-disjunctions. 99

Possible aetiologic factors
63. A certain number of factors are known to induce chromosome anomalies, but their actual effectin man can only be indirectly inferred, since few
cytogenetic data on human gametogenesis and the earlystages of development of the human embryo areavailable.
64. Maternal age is positively correlated with theoccurrence of aneuploids. This is clearly proved in
the case of trisomy 21. 38 • 39 and is observed also withtrisomies 13 and 18 though to a lesser degree. 30 andperhaps in the case of Klinefelter's syndrome(XXY) 100 as well. but apparently not with Turner's
syndrome (X0). 101
65. Certain viruses may be responsible for chromosome or chromatid breaks. both in vivo and in vitro,and also for cases of aneuploidy, sometimes preferentially involving certain chromosome pairs.102 Attention
has been drawn to time fluctuations of certain constitutional chromosome anomalies and to their accumulationin certain limited areas. 38• 103 • 104 A correlation has
been suggested between an increased frequency of
X-chromosome anomalies and of trisomy 21 on the
one hand. and an epidemic of rubella in the preceding
months on the other, as well as between an increased
frequency of trisomy 21 and an outbreak of infectious
hepatitis. 105 • 106
66. Ionizing radiations, particularly x rays, havebeen suspected of inducing aneuploidy in man. It does
not seem, however, that exposure to radiation is actually
recalled more frequently among mothers of trisomics
21 than among mothers of normal children,107 , l08 as
had earlier been held,109 although the results of a
recent survey110 reopen the problem once more. The
possible role of parental radiation before conception
has again been suggested recently with regard to one
case of trisomy 13 111 and in several cases of trisomy

18.112

67. Very few cases of chromosome anomalies inhuman somatic cells have so far been observed aftert XM and XP indicate X chromosomes of maternal and paternal
origin, respectively.

105

pre-natal irradiation. In a recent observation the anomaly consisted of a mosaic of minute chromosomes,
with no apparent structural rearrangements, in a child
who had been e.""<posed to radiation in the first weeks
of intra-uterine life.11 3 Additional studies have also
been made in recent years on the effects of both x rays
and internally-deposited radio-active isotopes (I1 31 ,P 32 ) on chromosomes of human somatic cells. The
studies \Vere carried out on blood. skin or aponeurotic
cells drawn from subjects exposed to radiation accidentally1H·ll• or occupationally, 1H· 11 s-1 ~ 3 or exposed
for therapeutic or diagnostic reasons. 113 • lH. 121 • J2~H9
68. These in vivo studies have yielded informationon the types of anomalies observed and on their persistence in the organism. Both aneuploidies and polyploidies, frequently due to endo-reduplications, and also
structural anomalies have been observed: chromatid
and chromosome breaks, acentric fragments, minutechromosomes, di- and polycentric chromosomes, andring chromosomes. Some of these changes persist for
years. Observations have been reported in which theirradiation had taken place more than twenty or thirty
years prior to the observation.
69. In other studies, human somatic cells were e..xposed to radiation in vitro. 150-160 In vitro irradiation
makes it possible to select the quality of the radiation,
to estimate more accurately the doses and dose rates
received by cultured cells, and to evaluate the numberof various types of chromosome rearrangements as afunction of the dose. The frequency of deletions has
thus been shown to be linearlv related to the dose ofboth x rays and neutrons. 153•157 The frequency of twohit events ( dicentric and ring chromosomes) bears aquadratic relationship with the x-ray dose and alinear relationship with the dose of neutrons (table
V).153, 101, 162

70. Concl11si011. The respective role of each of thesefactors cannot at present be assessed, especially as stillother factors. that are not mutagenic stricto sensu may
also play a role. The association of several different
chromosome anomalies in certain families or in certain
subjects suggests the existence of factors predisposing tothese anomalies. An interchromosome effect (paragraph58) may enter into play in certain cases, while others
have been attributed by some authors to the effect ofa gene similar to those already known to be responsible
for non-disjunction in Drosophila. The role of a gene
responsible for familial mosaicisms has also been suggested.ss. 163
III. Experimental data on radio-sensitivity ofgerm cells in vivo
CHANGES I::-i" THE NUMBER OF CHROMOSOMES

Changes of ploidy
71. Several attempts have been made to inducechanges of entire sets of chromosomes in mammals.
Where radiation was used as the inducing agent theattempts have not been successful. Experiments not
involving radiation showed that triploid embryos cansurvive. They \Vere observed at nine and one-half andtwelve days gestation in mice and rats. respectively,
and at five months of age in human foetuses. 30 • 164 In
experimental animals. embryos of higher ploidy are
eliminated before implantation. If the same phenomenon

obtained in man, these embryos would be eliminatedduring the first week after conception.g
72. In contrast to what has been obsen•ed in mammalian species, viable triploid animals have been described in Drosophila. the parasitic wasp H abrobracon, rn5 the land isopod Trichoniscus and the salamander!riturn~ viridescens. 166 Polyploidy has been observedm the silkworm Bomb·yx mori and the butterfly Solenobia triquetiella.1c1-112
Loss or addition of individual chromosomes

73. Animals monosomic for one of the autosomes
have rarely been observed. The best known example
is that of the fruit fly which can survive the loss of oneof the fourth chromosomes, representing a few percent of the total genome. Mammals monosomic forone of the autosomes have never been observed andseveral lines of evidence suggest that monosomi~s arealways lethal before birth, although mosaics may
survive. 173
74. Instances of trisomy have been studied extensively in plants for a quarter of a century.17 4 They
are known for the fourth chromosome of Drosophila
and have recently been reported in the mouse by Griffen
and Bunker 175 who described three different autosomal
trisomics by analysing the male offspring of males, thespermatogonia of which had been irradiated with 350
and 700 R of x rays. Two of the trisomics were sterile
and the third semi-sterile. In each case, the extra
chromosome was a member of the smaller chromosome
classes, and none of the males showed external deviations from the normal phenotype. A phenotypicallynormal but sterile male trisomic for one of the smallest
chromosomes has also been found by Cattanach.176
75. Anomalies involving sex-chromosomes are muchbetter known than those involving autosomes. Information on the spontaneous occurrence of the sexchromosome anomalies in mammals has been reviewed
extensively by Russell. 173 The spontaneous occurrenceof these anomalies in mice and in Drosophila wasdiscussed in the 1962 report (annex C, paragraphs 71
and 72).
76. In experimental animals, the most commonly
observed anomalies are of the XO and XXY type.
irrespective of whether male or female germ cell stages
have been irradiated. XO individuals are observed
more frequently than XXY individuals, the reverse
being true in man (paragraph 53). because, in addition
to non-disjunction. XO individuals can arise throughloss of the paternal X or Y chromosome or the maternal X chromosome during genn cell formation as
well as during or before the first cleavage of the zygote.
By contrast, it is likely that the majority of XXY
individuals arise from non-disjunction.
77. Experiments with mice have demonstrated thata considerable increase above the spontaneous frequency
of XO and XXY individuals can be obtained byirradiating various germ cell stages as well as earlyzygotes. 177 • 178· 179 Table VI summarizes the data.
78. \\Tith regard to the induction of se.."<-chromosome
losses (XO individuals) in mice, the sensitivity ishighest in the early zygotes, namely. shortly after
sperm entry (completion of second meiotic division)
Major
Prc·1'mp/antati01i oraa1:oqtncsi.r
period ir. d<l)'S Period :r: days

Mouse ........... .
Man .............. .

0-5

0-8

6-13
9-56

Foctalperiodin days

14-20
57-270106

and also in the early pronucleus stage. Sensitivity thenbecomes relatively low in the mid-pronucleus stage(probably post-DNA synthesis). Male and female
germ cells at all stages are much less sensitive than areearl~ _zygote stages ..Spermatids appear to be the mostsens1t1ve germ cells m males.
?9. In Jemales, the early prophase stages of the
primary oocyte, which are only present in the ovaries
of foetuses and new-born children, are about as sensitive
as e3;rlY . sper:n<l;tocytes .. From the point of view of~enettc ~1sks, lt JS the dtctyate stage of the oocyte that
IS most important. Dictyate oocytes in various developmental phases are present in the ovaries from shortly
a_fter birth until about eight hours before each ovulation. In man, cells at that stage therefore absorb morenatural and man-made radiation by several orders ofmagnitude than any other female cell stage.
80. ~oc~es in the early phases of the dictyate stage
are easily killed by exposures as low as 8 R. 180 Genetic
effects have therefore not yet been studied for thisearly stage. Preliminary results on later phases ofthe dictyate stage (table VI) have shown that thesensitivity of these cells with regard to se..x-chromosome losses is on the average of the same order as thatof the male germ cell stages.
81. Studies on the induction of sex-chromosome loss
in the metaphase of the first meiotic division of theoocyte are in progress. In view of the results of theinduction of dominant lethals (paragraph 108), it is
to be expected that radiation-induced se..x-chromosome
loss in this stage will be high compared to other female
germ cell stages.
82. In adult Drnsophila males, several independent
attempts have been made to determine the rate of induction of XO animals. 181 -186 The absolute frequencies.
however, are dependent upon the age of the males at
the time of irradiation and the type of X chromosome
carried by the irradiated males. In decreasing orderof sensitivity, male germ cells rank as follows: spermatocytes > spermatids > spermatozoa > spermatogonia.
~elow l .~00 ~· the results for sperrnatocytes are consistent with a lmear dose-effect relationship and suggestthat the induced rate of XO animals per R is about
2.3 X 10-~. This figure is remarkablv close to thatobtained for spermatocytes in mice (tible VI).
83. Information on the induction of sex-chromosome loss in spermatogonia of Drosophila is scanty. The
induced frequencies observed are close to those of thecontrols. Sensitivity would therefore seem to be much
lower than for other stages.
84. With regard to the induction of non-disjunction
by irradiation, the peak sensitivity for XO and XXY
animals is found in the same stage ( s) of spermatogenesis.181, 186, 187

85. Experiments with oi:icytes in different developmental stages have clearly shown that XO and XXY
a~imals ~an result from the irradiation of Drosophila
oocytes m the prophase of the first meiotic divisi~n.188· 189 The most recent study provides goodevidence that the frequency of XO animals increases
f,.aste: than linearly with dose in the exposure range:iOO-:l,000 R. The dose-effect relationship for the
production of XXY animals is more complicated anddifficult to interpret.
86. The induced frequency of occurrence of X!>!
(maternal X) loss in Drosoplzila is 0.58 X I0-5 perroentgen (calculated by taking account of the factthat YO is lethal) at an e:-..--posure of 500 R.

87. The evidence presented in the preceding paragraphs demonstrates that loss of sex-chromosomes (andmost probably of other chromosomes as well) and nondisjunc:ion of these chromosomes can be induced byionizing radiation in experimental animals. There are
no reasons to doubt that chromosome changes of thistype can also be induced by radiation in the germ cellsof man. In fact, there is already some evidence that
this is the case.U 0 It is perhaps not coincidental that asimilar frequency of induction of sex-chromosome loss
is observed in the spermatocytes of Drosophila and of
the mouse. Results for dictyate oocytes of the mouse areof the same order of magnitude. Information on the
induction of sex-chromosome loss and non-disjunction
in dictyate stage oocytes and spermatogonia is still far
from complete. In view of the results obtained with
Drosophila, one can surmise that the rate of inductionof sex-chromosome losses in the spermatogonia of miceand man may also be much lower than the corresponding frequencies obtaining at other stages of spermatogenesis. Special emphasis needs to be given to thefact that the early zygote stages in mice have proved
to be extremely sensitive to the induction of chromosome loss by irradiation.

The first method measures changes in litter-size ofirradiated animals. The second method takes into account the components of pre-natal mortality as observed by dissecting pregnant females about twelve
to eighteen days after mating. and counting the numberof corpora lu tea and of dead and living implanted embryos, thus making it possible to estimate the proportionof pre-natal deaths that occur before or after implantation. Not all pre-implantation losses can be attributed
to zygotic deaths. They can also be due to (a) lackof fertilization: ( b) lack of fertility of the egg. Similarly.
not all zygotic deaths result from dominant lethal
action. They may also be due to maternal factors, suchas failure of the uterus to respond to the appropriate
endocrine stimulus, thus precluding implantation offertilized eggs.
92. Both methods have been in use since 1932.
Litter-size, however, has proved to be an extremely
variable character. so that more reliance is now placedon estimates based on pre-natal death data. Litter-size
can be affected by many factors, such as the numberof implanted embryos in the uterus and the lactation
stimulus which in turn is also dependent on the numberof sibs in a litter. In e.xperiments with highly inbred
animals. litter-size data can be misleading. because
the death of an embryo may increase the chances ofsurvival of the remaining embryos by reducing intrauterine competition.

DOMINANT LETHALSIntroduction
88. For the purpose of this section "dominantlethals" are defined as those genetic changes, irrespectiveof their e.xact nature, that cause embryonic death andearly post-natal death in heterozygotes. However, theterm has more specifically come to be applied to thoseembryonic deaths that result from point mutations or
chromosome breaks in parental germ cells. All inducedchanges that affect the germ cells themselves or render
the gametes incapable of participating in fertilization
are excluded from the dominant lethal category. 164
89. There should be a clear distinction between
dominant lethals arising in mature gametes as comparedto those in immature germ cells. In post-meiotic malegerm cells. the frequency of dominant lethals rises
linearly with dose at low x-ray doses. The damage
primarily results from chromosome losses due to single
chromosome breaks. Ii the broken ends of chromosomes
remain unrestituted and form acentric fragments anddicentric chromosomes during the development of thezygote, they cause death. At higher doses of irradiation, two-break events lead to structural chromosome
anomalies which may also result in zygotic death.
However, the main contribution to zygotic mortality
is probably from single chromosome breaks.
90. In pre-meiotic male germ cells. most, if notall, of the chromosome breaks which yield acentric anddicentric chromosome combinations will be expected
to lead to death of the descendant cells and therefore
to be selectively eliminated prior to becoming mature
germ cells. On the other hand, most dominant lethals
induced by treatment of pre-meiotic cells are the consequence of multiple (two or more) chromosome breaks
leading to simple translocations, inversions. etc. In
their original form. such changes frequently do notkill either the germ cells carrying them or the resultant
zygotes. However, as a result of events at meiosis, they
may give rise to genetically unbalanced gametes still
capable oi fertilization but eventually leading to unviablezygotes.
91. In the mouse, two methods are available toestimate the dominant lethality induced by radiation.

Male germ cells
93. Spermatogonia. As early as 1956, it was foundthat the irradiation of mouse spermatogonia led to asignificant decrease in mean litter-size as measured
three weeks after birth. 190• 191 These reductions wereobserved following acute exposures of 600 and 1,000
R. Even after a single exposure of 300 R. a reduction
in litter-size of about 3-4 per cent was found.
94. In more recent years, most data have been obtained through the pre-natal death method. There is,however. no common opinion as to how the measurements of pre-natal death should be used to estimate
dominant lethal damage. Therefore in this review,comparing results obtained by different authors 192•197
made it necessary to recalculate their data. as the figures
given in their tables were such that comparisons could
othenvise only be made for post-implantation deaths.
Table VII gives the results of the recalculations andshows that the total rate of induction of dominantlethals increases significantly when spermatogonia areirradiated with acute x-ray exposures of 300 R andhigher.
95. The data obtained by the various authors areconflicting with respect to the question whether prenatal death occurs predominantly before or after implantation.
96. There is evidence that the induction of dominantlethals is dose-rate dependent. 194 • 198 Results presented
in table VII show that irradiation at 600 R
600 R
acute x rays increases the frequency of dominant lethals
significantly. 198 whereas a single dose of chronic radiation does not. 194
97. With regard to the question of the persistenceof irradiation-induced dominant lethal damage inspermatogonia. the results obtained by Sheridan196 areof particular importance. His data showed that thefrequency of dominant lethals. as measured by the
proportion of dead implants among total implants,
remained constant over a period of at least twenty-fourweeks. These results indicate that dominant lethals+

107once induced in primary spermatogonia may be indefinitely transmitted to the more mature germ cells
that originate from these spermatogonia.
98. It is not unlikely that the dominant lethality
which is observed over the twenty-four-week period
can at least partly be accounted for by translocations
induced in primary spermatogonia. Translocations will
be dealt with in the section on translocations (paragraphs 114-129).
99. Other germ cell stages. The most recent information on sensitivity with regard to the inductionof dominant lethals in the male germ cells of mice atother stages is presented in table VIII. Older data
have recently been reviewed. 164 In interpreting the data
in tables VII and VIII, it must be borne in mind thatpart of the spermatocytes and spermatogonia could havebeen killed almost instantaneously by the x-ray dosesthat were employed, thus leading to sperm depletion.
As a consequence, an unknown fraction of the nonimplanted eggs may be accounted for by lack of fertilization rather than by the induction of dominant lethals. 11H
It is therefore more appropriate to base estimates ofdominant lethal damage on post-implantation data.
100. The post-implantation data in table VIII showthat spermatids are the most sensitive cells. Spermatozoa in the vas deferens and in the epididymis are
more sensitive than those in the testis tubules, whereas
part of the spermatocytes are probably as sensitive
as spermatozoa, others being less sensitive. Finally,
spermatogonia appear to be somewhat less sensitive
than spermatocytes.
101. The changes in sensitivity in maturing malegerm cells of Drosophila are very similar to thoseobserved in mice. 199•20 G Dominant lethal induction ishighest in spermatids and spermatocytes. Spermatozoa
are roughly half as sensitive as spermatids, and. finally,
spermatogonia are about half as sensitive as spermatozoa. The pattern of response of male germ cells of
the sil1."'worm to the induction of dominant lethals.
although less well known. follows essentially the same
pattern as observed with Drosoplzila. 206 Studies on
various species of insects have provided a powerful toolin programmes to control insect pests by means ofradiation-induced sterilization. 201
102. Induction of dominant lethals in post-meiotic
cells has not only been studied in the mouse, but also
in guinea pigs, rats and rabbits. The data, summarizedin table IX. indicate the variability in sensitivity bet\veen mature spermatozoa of different species. It wascalculated that the LD 50 's due to induced dominantlethals in these species are 730, 430, 380 and 305 R,
respectively. 208• 209 However, general conclusions on
the relative sensitivity of these species cannot be madesince it varies with dose.
103. Dominant lethal induction has also beenstudied in swine. 210•214 Since in these experin1ents only
the effects on spermatogonia have been studied, thesedata cannot be compared with those of the species
mentioned in the preceding paragraphs.
104. The objective of the studies with swine wasto measure the effects of paternal irradiation ( 300 R xrays) on the first generation offspring. Changes inlitter-size at birth. mortality between birth and weaning.
and increase of weight within the first 152 days of life
were some of the criteria which ·were used to detect
the genetic effects. In these e.;;:periments, two different
breeds of pigs were used-Duroc and Hampshire. Thus
far. 2,315 litters have been examined. In the Duroc
108

breed, radiation caused a slightly significant increase( 4.2 per cent) in the litter-size at birth and a rise in
the se.x-ratio. On the other hand, irradiated Hampshire
males sired smaller litters than their unexposed brothers
though the difference was not significant. At present
the discrepancy between the two breeds cannot beadequately explained.
105. The mortality of new-born pigs was analvsed
during three periods ( 0-1 day; 2-6 days : 7-42 days)
between birth and weaning. In each of these periods
the mortality rate in Duroc pigs was higher in theirradiated than in the non-irradiated series. The irradiated group of the Hampshire breed showed higher
mortality only in the first period. In the Duroc breed,
total mortality at forty-two days was significantly higher(P < 0.05) in the irradiated than in the non-irradiatedseries. The total mortality rate in the control andirradiated series of the Hampshire breed was not
significantly different.
106. In general, mortality was greater in large
litters than in small ones. Furthermore, male pigs had
higher mortality rates than females, the relationshipbetween sex and mortality being more pronounced in
the Duroc than in the Hampshire breed. All data taken
together indicate that t11e results obtained with the
Duroc breed are inconsistent with those obtained with!he Hampshire breed and make it premature to generalize on the consequences of irradiation of sires in swine.
Female germ cells
107. Information on dominant lethal induction in
the different stages of oogenesis in mice and otherspecies is not as extensive as that for spermatogenesis.
The earlier data on various mammalian species havebeen extensively reviewed164 and show that stages
which possibly correspond to the diakinesis stage orto the metaphase stage of the first meiotic division aremuch more sensitive than those between the early
dictyate and the diakinesis stages. In more recent
years, the relative sensitivity of mouse oocytes at differ~nt stages has been studied by using the techniqueof mduced ovulation, by means of which it is possible
to irradiate oocytes at different stages throughout the
meiotic divisions. 2 1s
108. The results of these studies are summarizedin table X and show that the total rate of induction of~omi~ant le~ls reaches its largest values in oocytes
ir.r~d!ated durmg the metaphase of the first meiotic
d1vis1on. Anaphase I and metaphase II are less sensitive
than metaphase I oocytes, but still considerably moresensitive than the dictyate and pro-nucleus stages. The
same pattern of sensitivity can be demonstrated for~nduced post-implantation death. For induced pre1mplantat10n death, as defined in table VII. no clear
sensitivity pattern can be obser.-ed. In practically all
stages, .pre-natal death occurs predominantly after implantation; in particular. this is evident in the series
in which the females had been e.xposed to 200 R.
109. The data obtained with oocytes lend themselves
to a comparison with those obtained in male germ cells.
The best possible comparison is that between the dataof Bateman195 (table VIII) and those of Edwards andSearle 215 (table X), since both e.xperiments •vere
performed at the same e.xposure of 200 R. Although
it is realized that these e.xperiments were carried out
by different authors. and that the total rates of induction of dominant lethals can varv because of differences in experimental technique. it seems justified
to conclude that metaphase I oocytes seem decidedly

I
....J

more sensitive than spermatids. From a comparison
between oocytes in the dictyate stage and spermatogonia,
it may be presumed that oocytes in the dictyate stage are
more sensitive than spermatogonia by a factor of ten
to twenty. However, this has only been observed at
200 R. At other doses this factor may be completely
different, since sensitivity to cell killing and to the
induction of genetic damage can vary widely amongcells of the spermatogonial population and among cells
in the dictyate stage.
110. In insect species, as in mice, it has repeatedly
been observed that oocytes in metaphase I are much
more sensitive to dominant lethal induction than during prophase stages (Drosophila, 216 •218 Habrobracon,'-219
Cochliomyia homi1livora 220 ). Similarly, studies withthe silkworm ( Bomby.1: mori) have shown that thefrequency of dominant lethals observed after irradiationof oocytes immediately before metaphase is twenty times
higher than the frequency observed after irradiationof oogonia when only lethals which act in the embryonicstage are taken into account. Most lethals induced in
the oocytes were found to be eliminated during e.rnbryonic and larval stages, whereas death caused bylethals induced in oogonia was evenly spread over all
developmental stages.221

Male germ cells
114. In mice, the presence of translocations is usuallyascertained by analysing the F 1 progeny of treated andcontrol animals for heritable semi-sterility. In practice,semi-sterile animals are recognized as those animals of
the F l progeny which have considerably less than thenormal number of F 2 offspring. In addition to thecriterion of semi-sterility. most authors confirm thepresen~e _of translo_ca~ions by e.xamining cytologically
pre-me10t1c and me10t1c germ cells of presumed translocation carriers. Table XI surveys the data presently
available on translocation induction in spermatoaonia"of mice.
115. It is highly probable that translocation induction in spermatogonia is an important cause of
dominant lethality in zygotes descended from thosecells, since in the mouse each spermatocyte (division
product of spermatogonia) heterozygous for a translocation will produce one gamete carrying the translocation. one gamete with the normal chromosome
complement and two unbalanced gametes carrying
duplications and deficiencies. Unbalanced gametes,
upon fertilization, give rise to zygotes which usually
die at about the time of implantation. However, somezygotes die between implantation and birth, while a
few apparently survive to maturity.:: 22116. Experiment 1 in the table shows that irradiation of spermatogonia with two acute exposures of
600 R each results in a significant increase in thepercentage of translocations in both female and maleFi progeny. The pooled data from experiment 1 showthat about 4 per cent of mature offspring of theirradiated males carry induced reciprocal translocations.
From this percentage it was calculated that the frequency of translocation heterozygotes among spermatogonia was 14.8 per cent.:!!?3 Since radiation was given
in two fractions to prevent substantial killing of spermatogonia. the translocation frequency might have beendifferent if the total had been given in one single
exposure instead of two.
117. The e.xperiment mentioned above was not only
performed to obtain an estimate of the rate of inductionof translocations but also to provide information on
the total rate of induction of dominant lethals. By
studying data both on translocation induction and on
dominant lethal induction. it is possible to estimate thatabout 67 per cent of the total amount of dominantlethality (total amount of pre-natal death) in the 1,200
R experiment can be attributed to translocation.s,
whereas the remaining dominant lethality is thought
to be caused by "primary dominant lethal mutations".1 9 s
The situation is different when the haploid post-meiotic
germ cells are irradiated. In that case, the contributionof translocations to dominant lethality is much smaller,
because in these cells translocations of the aneucentric1
type will cause death of the zygotes. whereas eucentric
translocations will be tolerated.
118. Experiments 1 and 2 in table XI are the only
ones that provide information on the effect of dose rateon translocation induction in spermatogonia of mice.
As expected, the dose-rate effect is very pronounced194· 198 (see also paragraph 124).
119. Experiment 3 provides information on translocation induction in spermatogonia following irradiation with an acute exposure of 700 R. 224 The frequencyof translocations in this e.'{periment is significantly
lower than the frequency in experiment 1. even when
the difference in dose is taken into account. Differencesin the e.xperimental procedure and in the strains used
are mentioned as the possible factors which might
account for the observed discrepancy.

h Monotocous and polytocous mammals produce respectively
one and many young at a birth.

1 Aneucentric translocations involve the centromen: so that
there results an acentric and a dicentric chromosome.

Summary and conclasi<ms
11 L With regard to dominant lethal induction, it
is clear that the sensitivity pattern for the various
stages of gametogenesis is strikingly similar in widelydifferent species. In all species studied, the highest
frequencies of dominant lethals are observed in spermatids and the lowest frequencies in spermatogonia.
Among female germ cell stages, the highest frequencies
are found in metaphase oocytes in the first meiotic
division, whereas the lowest frequencies are encounteredin dictyate stage oocytes of mammals and in oogonia
of insects. Induced frequencies of dominant lethals inspermatogonia vary widely among species, even within
mammals.
112. Experiments with mice, rats and guinea pigs
have shown that death due to dominant lethality occurs
mainly at about the time of implantation or shortly
thereafter. In rabbits, however, dominant lethals act
predominantly before implantation of the embryo.
Predictions concerning the time of action of dominantlethals in man are difficult to make on the basis ofresults obtained with other mammals. This is so
because man is monotocous. whereas the other mammals are polytocous.h Furthermore, there e.xist differences in nidation and placentation between man andprimates on the one hand, and other mammalian specieson the other.
113. Results of studies with mice indicated that
dominant lethals induced in primary (predefinitive)
spermatogonia of the mouse can be transmitted to theimmediate offspring of the carriers of these spermatogonia for over a period of at least twenty weeks andpossibly much longer.
TRANSLOCATIONS

109

120. Results obtained from experiment 6 do notprovide evidence in favour of or against the validityof the estimates derived from experiments 1 and 3.
The percentages of semi-sterility obtained at the threedifferent doses in experiment 6 do not differ significantly; neither do they differ significantly from thepercentage of semi-sterility ( 4.14) observed in experiment 1. The data of experiment 6, however, must
be interpreted with some care, because only an unknown
percentage of the semi-sterile F 1 individuals has been
analysed cytologically. Since it can be deduced fromexperiment 6 that not all semi-sterile F 1 animals had
cytologically detectable translocations, it might wellbe that the frequencies obtained from this e.xperimentlead to over-estimates of the rate of induction of translocations by a factor which is unknown and thatprobably varies with dose.
121. Experiments 4, 5 and 7 in table XI were notprimarily designed to detect translocations. 196• 191• 225
The results of these experiments seem to be consistent
with those of experiment 1, but accurate estimates of
the rate of induction of translocations cannot be obtained from them because of the fairly small numberof animals involved and because cytological analyses
were not performed.
122. The experiments summarized in the previous
paragraphs have shown conclusively that translocations can be induced in pre-meiotic male germ cells.
The rate of induction being low. as had already been
noted in the 1962 report on the basis of much more
limited information, translocations have been recovered
only at high doses and dose rates. It must be pointed
out that the rates of induction thus obtained refer tothose translocations alone that are recoverable throughsemi-sterility. This procedure may lead to an underestimate of the total rate of induction of translocations.
123. Older data on translocation induction in otherstages of spermatogenesis have been reviewed by L. B.
Russell. 164 These data. together with the more recent
data of Griffen.226 show that post-meiotic cells are much
more sensitive than pre-meiotic cells, and that among
the post-meiotic stages the spermatid stage is the mostsensitive one. Pooling the data reviewed by Russell andthose of Griffen indicates that approximately 25 percent of the offspring are semi-sterile when post-meiotic
cells are irradiated with a dose of about 700 R. It thus
seems that post-meiotic cells are about six times assensitive to the induction of translocation as spermatogonia.223 On the basis of theoretical considerations,
Auerbach and Slizynska227 conclude that post-meiotic
cells are twelve times more sensitive than spermatogonia.
124. Besides genetic studies, cytological studies also
have been performed on the induction of translocations.
Arsenieva and Bochkara228 discovered that, when
primary spermatocytes are irradiated with 50 R or
less. both balanced and unbalanced translocations occur
twice as frequently in monkeys ( }.1acaca 11111/atta) as inmice. Other cytological studies provided informationon the effect of dose rate on translocation induction in
spermatogonia of mice which were exposed to 600 R ofx or gamma rays. 292 Frequencies of multivalent configurations (indicath·e of heterozygosity for reciprocaltranslocations) in spermatocytes at dose rates of 913.
89 and 9.7 R per minute did not differ significantly. allbeing 12-13 per cent. At lower dose rates. however.
frequencies were much lower. being about 5 per cent at.
0.86 R per minute, and falling to only 1.5 per cent at
0.02 R per minute. It therefore seems that. with regard
to translocation induction in type A spermatogonia at
110

the dose level of 600 R high dose-rate irradiation isabout eight times as effective as low dose-rateirradiation.
125. The application of the cytological technique
has also revealed a marked discrepancy between thetranslocation frequency in spermatogonia as found in
the genetic experiment (600 R
600 R. paragraph116). and that observed cytologically in spermatocytes.220• 290·292 The observed frequency of translocations in the genetic experiment is about half thatobserved cytologically. It is thought that the observed
discrepancy does not result from a failure of translocation heterozygotes to show semi-sterility. but rather
from a selective process between meiotic metaphaseand fertilization.
126. As far as the genetic experiments are concerned, it is remarkable that the sensitivity pattern
for translocation induction in the different stages ofspermatogenesis in mice is very similar to that observedin Drosophila. Information on the latter species is,however, much more detailed.205 · 230 ·233 Drosophila
spermatogonia appear to be less sensitive to translocation induction than mice. For the F 1 male progeny,
the frequency of induction of autosomal translocations
is around 0.5 per cent (3,280 tested gametes). 231 No
translocations were found in an experiment by Oster(2.000 R, 813 tested garnetes) 230 and only one in theexperiment of McCarthy and Nafei (400 R, 901 tested
gametes) .282+

Female germ cells
127. Information on translocation induction in
oocytes of the mouse is very scanty. Irradiation of lateoocytes with 400 R acute x rays, resulted in a frequency
of induced heritable partial sterility of about 2 per
cent. 16• This figure is not far removed from the figureof 4 per cent semi-sterility which has been obtained forspermatogonia irradiated with 600 R
600 R (paragraph 116).
128. The observations on the induction of translocations in female germ cells of mice confirm the findings
in Drosophila, where it has also been found that thefrequency of radiation-induced reciprocal translocations
in female germ cells is very low.234-236
129. The preceding paragraphs on the induction oftranslocations in germ cells of e>..-perimental animals
have shown that these anomalies are induced in bothmale and female germ cells. The studies indicate thatthe frequency of radiation-induced translocations ishigher in spermatogonia than in dictyate oOcytes. At
present, only results obtained with spermatogonial
irradiation can be used to estimate the rate of inductionof translocations in man.

+

POINT MUTATIONSSpecific locus mutations
130. In its 1%2 report, the Conm1ittee reviewed
extensive data on the induction of recessive mutationsat seven specific loci in the mouse. Since then. moredata have become available. Both old and new data
are listed in table XII. They only refer to specific locus
mutations induced in spermatogonia and oocytes. Ignoring variability between loci. the spontaneous mutation
rate at the seven specific loci in male germ cells lies
benveen 0.46 X 10-5 and 1.0 X 10-6 mutations per locus
per generation (95 per cent confidence limits).
131. In spermatogonia the rate of induction of specific locus mutations rises linearly with acute exposuresup to 600 R. At higher doses, the yield of mutations
falls off. Th'.s has been attributed to "selective elimination at high doses of the more mutationally sensitive
cells in the spermatogonial population'·.~ 37 In spermatogonia, the rate of induction is about 2.2 X l0- 1
mutations per locus per roentgen. Owing to the sampling
variability of the data and to variations in mutability
between loci. the rate of induction may lie anywhere
between 0.75 X 10-7 and S.5 X 10-7 (95 per cent confidence limits). These data were obtained from themutation rates observed after exposure of spermatogonia
to 600 R of acute x rays.
132. Recently. results have been published of a study
on muration rates at a set of six specific loci in themouse. 238 Only one locus in the new set is common
to both sets. So far, only three mutations have been
recovered in the new stock, yielding a rate of inductionof about 0.5 X 10-7 mutations per locus per roentgen.
Because of the small numbers involved, this estimate
is affected by a large error. As it stands, the estimate
lies below the mean of 2.2 X 10-7 obtained with theseven specific loci stock, but two of those loci had evenlower rates.
133. A joint estimate is difficult to obtain, but thedata taken together suggest that it may be around1 X 10-7 mutations per locus per roentgen, with presumable confidence limits (P0.9S) one order ofmagnitude apart. .
134. The spontaneous mutation rate in female germ
cells is not well known. With one mutation observedin 98,828 offspring, the confidence limits are very wide.
Data on the induction of mutations at seven specificloci are also much scantier in mouse oocytes than in
spermatogonia. The data from high doses of acute
x rays lead to an estimate of 4.8 X 10-7 mutations per
locus per roentgen with 9S per cent confidence limits
2.S X 10- 7 and 7.7 X 10-7 , suggesting that acute irradiation of oocytes might yield more mutations than
irradiation of spermatogonia. Oocyte data have not yet
been obtained for the new set of six specific loci.
135. The results of experiments on the induction ofrecessive mutations at specific loci in the mouse andin other species are summarized in table XIII. It isapparent that Drosophila stands out as the species leastsusceptible to mutation induction by radiation, eventhough the comparison of species can be based only onvery small samples of loci.

=O'i/er-all rates of nmtc#:ion
Recessive lethal mittations
136. Drosophila. Abrahamson exposed spermatogonia of Drosophila males to 8,500 R gamma rays froma caesium source and analysed the induction of secondand X-chromosome lethals in these cells. 16 The rate ofinduction of recessive lethals in the second chromosome
turned out to be 12.01 per cent, whereas in the X chromosome it was 2.17 per cent. Since the number of mutations in the very small fourth chromosome is negligible
and the third chromosome contains as much genetic
material as the second chromosome. it can be estimatedthat the over-all rate of induction of recessive lethals
in the •vhole genome is equal to 26.19 per cent at an
exposure of 8.550 R. From this it follows that the overall rate of recessive lethals per gamete per roentgen is
3.1 x 10-5 •137. In Abrahamson's data, the ratio of second
chromosome lethals to X-chromosome lethals is S.S.
The second chromosome contains about twice as muchIllgenetic material as the X chromosome ; therefore it
would be expected that the ratio between second andX-chromosome lethals would be roughly 2 instead of
S.S. That the ratio is 5.5 and not about 2 is explainedby germinal selection, whereby about half the leihalcarrying spermatogonia are killed by the action of theselethals on the cell's own metabolism. Germinal selection
does not occur in post-meiotic cells, because in thesecells the ratio of second to X-chromosome lethals is inaccordance with what one would e.xpect on the basisof the length of the respective chromosomes.14·16. 2a 9138. In experiments of i\ticSheehy, 240 spermatogoniaof larvae or adult males received gamma ray doses in
the range 200-800 rads. The dose-effect curve for second chromosome lethals proved to be linear. Taking
into account germinal selection and the relative lengthof the chromosomes, it is possible to derive fromMcSheehy's data an estimate of the over-all rate ofinduction of recessive lethals per gamete per rad thatis equal to 2.9 X 10-5 • This value is close to that obtained by Abrahamson. The induction of second chromosome lethals in spermatogonia has also been studied
by Ytterborn. 241 The over-all frequency of recessive
lethals in his experiment is 3.4 X 10-5 per gamete perroentgen. Because of the absence of data for nonirradiated controls. it is not possible to estimate theover-all rate of induction of recessive lethals. The overall rates obtained by Abrahamson and McSheehy are
consistent with the rate of induction of recessive visible
mutation at specific loci in the same species.
139. The 111011se. In 1959. a first attempt was madeto calculate the rate of induction of autosomal recessive
lethals in mouse spermatogonia by following a method
proposed by Haldane.~ 42 It was found that the efficiencyof the method was rather disappointing. 243 The same
method has also been used by other authors. 244• 245 The
results. however, were inconclusive. In 1961, anothermethod was used to estimate the frequency of recessive
lethals per gamete. 198 This attempt was also unsuccessful because, among other things, the presence ofinbreeding depression made a proper evaluation of theamount of induced recessive lethals impossible.
140. In an experiment by Lyon et al. 198 inbreeding
was avoided, and, furthermore, the scale of the experiment as well as the doses were increased. Hybrid F 1
males were given two exposures of 600 R high intensity
x rays eight weeks apart. Twelve weeks after the application of the second dose. the males were outcrossed
to females from a different stock. F 1 males free oftranslocations and of other factors likely to interferewith tests for recessive lethality were mated to females
derived from a stock different from that used for F 1
females. F 2 females were then backcrossed to F1 males.
The offspring from father-daughter matings was used
to analyse the presence of recessive lethals (and visibles)
which had originally been induced in the spermatogonia
of P 1 males. A control experiment was also carriedout in which the males were not irradiated.
141. Evidence on the rate of induction of recessive
lethals was obtained from three different sets of data:(a) embryonic lethality at fomteen days gestation in
first litters of F 2 daughters backcrossed to their sires;( b) litter-size at birth and weaning of litters from F 2
daughters allowed to produce three litters: ( c) fourth
litter dissection data of daughters having already produced three litters.
142. The final estimate of the radiation-induced recessive lethality \Vas derived exclusively from the firstand third sets of data. These data showed that embryonic survival in the irradiated series was 96.8 percent of that in the controls. From this figure, it could
be estimated that the rate of induction of recessive
lethal mutations was about 29.5 X 10-2 per gamete, or
2.46 X IQ-4 per gamete per roentgen. The estimate hasa large standard error and only makes it possible toestablish an upper 95 per cent confidence limit of
4.3 X lQ-4 mutations per gamete per roentgen.
143. A different experimental procedure to estimate
the rate of induction of recessive lethals per genome
was followed by Liining. 246 Liining exposed males ofa mouse population to 276 R acute x rays in each ofseven consecutive generations and prevented inbreedingby starting every generation with a sufficient numberof different pairs. A similar experiment was performed
in which the males were not irradiated. The presenceof recessive lethals in the third and following generations was analysed by making sib matings in eachgeneration. Any induced recessive lethal was thus expected to become manifest in the offspring of thosematings. The analysis was similar to that made by
Lyon et al. 198 on the progeny of father-daughter matings,
information being obtained on embryonic death and on
litter-size at birth and at weaning.
144. As in Lyon's experiments, data on embryonic
deaths were regarded to be the most reliable. They
were obtained from the offspring of the fourth to eighth
generation of sib matings. The data were then pooled,making allowance for the different doses of radiationthat individual generations had received. To evaluate
what percentage of deaths among the offspring of sib
matings between control and irradiated individuals could
be attributed to dominant mutations, Liining performed
an additional experiment using non-sib crosses in theirradiated and control series. The ratio of embryonic
death among the offspring of irradiated sibs andirradiated non-sib crosses. once corrected for the rateof spontaneous recessive letha.ls, indicated that theembryonic survival in the irradiated population was 98.9
per cent of that in a standard population. Such asurvival ratio leads to an estimate of the rate of induction of 0.8-2.0 X 10-4 per roentgen per gamete, afigure rernar:kably close to that obtained by Lyon et al.
Here also the error is large, but the upper limit to therate is 6.4 X 10-4 mutations per gamete per roentgen.
145. Despite their large error, the obsen•ed rates
of induction of recessive lethals per gamete are, at firstsight, apparently lower than might be e.'{pected fromthe estimated average rate of induction at the sevenspecific loci most extensively studied, if it is assumed
that the number of mutable loci in the mouse is thesame as information in man and Drosophila leads us to
expect. However. allowance must be made for only
75 per cent of the mutations induced at the seven locibeing lethal. Furthermore, it must be noted that radiation-induced lethality was scored in utero in the studies
of over-all induction, whereas in the investigation at
the seven loci the scoring included lethals acting perinatally and post-natally. Allowing for these two factors
alone narrows the gap between the two sets of estimatesto the extent that, rather than being inconsistent. they
may support each other.
146. If the recent data on five additional loci aretaken into account as was done in paragraph 133, wherean estimate per locus per roentgen of 1 X 10-7 mutations was suggested, the apparent discrepancy between
over-all rates and rates per locus is reduced even further.
112

Recessive visible mutations
147. The over-all spontaneous rate of mutation torecessive visibles in mice has been estimated to be
7.04 X 10-s per generation. The confidence limits ofthis figure are very wide since only one mutation has
been observed in 142 tested gametes.198 The over-all
rate of induction of recessive visibles in the same experiment was estimated to be 1.8 X 10-5 mutations
per gamete per roentgen. At first sight, such an estimate
seems inconsistent with the rates observed at specificloci and with the presumable size of the mouse genome,
even when account is taken of the fact that only about
25 per cent of the induced mutations at specific lociare viable. It must be observed, however, that the results of comparisons of the over-all frequency of visible
mutations with the frequency of mutations at specificloci are difficult to assess, since ascertainment is practically complete in the case of specific loci and incomplete to an unknown extent in the other.
Dominant visible mutations
148. The over-all spontaneous rate of mutation todominant visibles in mice appears to be 1.7 X 10-5 per
generation with 95 per cent confidence limits of 2 X 1~
and 6 X I0-5 •247 The estimate is lower than the spontaneous rate observed in man, but it would be unwise
to draw conclusions regarding the mutability of thetwo species with respect to dominant visibles, as too
many traits that would require intensive investigationin the mouse are easily detected in man.
149. The over-all rate of induction of dominantvisibles by acute radiation can be estimated on thebasis of one experiment to be 4.6 X 10-7 mutations per
gamete per roentgen. 198 The over-all rate of inductionof recessive visibles as estimated by the same observers( 1.8 X lQ-G) appears to be considerably higher, theratio between the two rates being about 40. Such aratio is based on few mutations only, but it is highly
significant, with approximately 95 per cent confidence
limits of 7 and 250.
150. Two extreme hypotheses may be advanced toaccount for that ratio. According to one hypothesis,
the ratio would indicate that the genome is made up
of two groups of loci, a smaller one where only dominant
mutations arise and a larger one where only recessive
mutations arise. and that the average rates of induction
per locus are the same in the two groups. Alternatively,
one could assume that most or all of the loci can mutate
both to dominants and to recessives though at different
rates. the rates of induction of dominants being forty
times lower than those for recessives. The true explanation probably lies somewhere between these two
extreme hypotheses, but both theory and empirical data
are inadequate to provide a satisfactory interpretationof the results. The ratio between induced recessive
and dominant mutations in Drosophila is known to beabout 5, 248 a value significantly lower than in the mouse.
A larger proportion of the induced mutations appears
therefore to be recessive in the mouse than is known
in Drosophila. The reason for the difference between
the two species is not known.

151. In the past few years. Ehling:? 49 ·:?~2 has shownthat irradiation of pre- and post-meiotic male germ
cells of mice can lead to the induction of mutations
that give rise to skeletal abnormalities. Since thesemutations become manifest in the first generation offspring of the irradiated male parents. it is thought thatthey represent a type of dominant visible mutation.

( c) At. t~1e rate ?f 9 R per minute ( x rays) the
respon_se is mtermed1ate between the responses at 90 R
per mmute (x rays) and 0.8 R per minute (gammarays).
. ( d) A reduction of the rate from 0.009 R permmute (gamma rays~ to 0.001 R per minute (gammar.ays) does not result ma further lowering of the mutat10n frequency.
157. Oocytes. Data on dose-rate effects in oi:icytes
c.re fewer than those obtained in spermatoaonia because
the early follicle stages of the oi:icyte de:elopment areeasil? destroyed at t~ose doses that are necessary toobtam adequate mutation frequencies. The data collectedthus far lead to the following conclusions:. (a)_ The ~ose-rate effect in oi:icytes is in the same
direction as m spermatogonia but considerably larger.
At comparable e.xposures, the mutation frequency for
99 R per minute x irradiation in oi:icytes is substantiallyhigher than for spermatogonia irradiated at the samer~te. At a rate C?f 0.909 R per minute gamma irradiation .~he opp?s1te is true, the mutation frequency
for oocytes bemg lower than for spermatogonia.
( b) The mu!a~on freq1;1ency at 0.8 R per minute(gamma rays) 1s mtermed1ate between the frequencies
at ~.009 (grum_na rays) and 90 R per minute (x rays).
Tl11s finding differs from the results for spermatoaonia
0
w~ere mutation frequencies at rates of 0.8 R per~mute and 0.009 R per minute are not significantly
drfferent.
158. In the course of studies on dose-rate effects
in oi:icytes, 253 it was shown that the genetic responseof old females to irradiation ( si.'C to nine months old)
was different from that of young females (two to fourmonths old), the mutation frequency after e."'<posure of
400 R (0.8 R per minute) in second litters of old~emales bei?g considerably higher than the frequency
m second litters of young females. No such difference
has been found for first litters. No satisfactory e.xplanation for this age effect in females (which has also
been observed at a rate of 0.009 R per minute) has
yet been given.
. 159. Sii:ice t~e publication of the 1962 report, the1:it~rpre~t1on ot the dose-rate effect has not changed.
~t is believed that the dose-rate response is a direct~ntracellular effect on the mutation process, although
1t n;ay be influenced to some extent, and particularly
a.t high doses, by secondary processes such as cell selection or change in cell stage during irradiation. Accept~ng the evidence that the dose effect operates at themtracellular level, it can be e..'Cplained in terms of repairof pre-mutational damage. Russell suggests two alternative ways in which the dose rate might affect repairof pre-mutational damage. Firstly, there is more damage
to the repair system at high than at low dose-rate irradiation. Secondly, the repair system is saturated by~ig~ ~ose irradiation, because its capacity for repair
15 111mted and it has only a limited time in which it
can act. Whatever the correct interpretation of the doserate effect may be. it seems evident that there is a
threshold dose rate below which the repair system is
not affected. This threshold is somewhat higher in
spennatogonia than in oi:icytes.

152. A rather large number of skeletal malformations were observed, and _it was considered quite likelythat only a small proportion of the abnormalities were
due to freshly induced mutations. To distinruish between the possible causes of abnormality. the ~alforma­tions were divided according to whether they occurredonl~ once in particular experiments (class 1 abnormahty) or more frequently (class 2 abnormality). Mostof the class 1 abnormalities were considered to be due
to dominant point mutation_s. In view of what is genera_ll:y: known about mutation frequencies at specificloci, it was thought that under the conditions of thesee..'\.periments a specific dominant mutation would havebeen likely to occur at most once in the testing of
3,000 to 4,000 gametes.
153. In e..xperiments in which pre- and post-meiotic
gerz:is cells were irra~ia~ed with 600 R acute exposure,
Ebling observed a s1gmficant increase of class 1 abnormalities (scored at four weeks of age). The excess
over control of class 1 abnormalities per gamete perroentgen _was 3.5 X ~0-:5 for post-meiotic stages and
2.3 X 10-" for pre-me1ot1c stages.
154. Excluding the portion of class 1 abnormalities
that m~y not be _mutationa~ in origin, the frequencyof dommant mutations affectmg the skeleton after single
exposure with 600 R is 2.9 X 10-5 mutations per aamete
per roentgen for post-meiotic germ cells and 1.1
IO-G
mutations per gamete per roentgen for pre-meiotic germ
cells. Additional data were obtained from two experiments in which spermatogonial cells had been irradiatedwith a split dose. A total of twenty-three dominant
mutations was observed in 1,968 offspring derived from
irradiated males. and one mutation was observed in
1,739 offspring derived from unirradiated control males.
155. The ratio between dominant skeletal mutations
induced in spermatogonial and post-spermatogonialstages is similar to that found in the specific locuse."'Cperiments. This observation indirectly supports thenotion that a sizable proportion of the skeletal abnormalities may result from point mutations. If they had
been predominantly chromosomal aberrations. one
would have expected a larger difference between thefrequencies in spermatogonial and post-spermatogonialstages. The question \vhether these dominant mutations
are transmissible to the second and later generations
after irradiation is still open but under investigation.

X

DosE-RATE EFFECT ON SPECIFIC LOCUS AND RECESSIVELETHAL MUTATIONS

Mice156. Spermatogonia. Table XII shows that most of
the information on dose-rate effects in the spermatogonia of mice was reviewed by the Committee in its
1962 report. The final results of experiments which
had not been fully completed when the 1962 report
was adopted do not significantly alter the results available at that time and largely confirm the following conclusions arrived at by the Committee :(a) \Vhen spermatogonia are given exposures of
300 to 600 R gamma radiation at a rate of 0.009 R per
minute (90 R per week). the frequency of induced
specific locus mutations is lower by a factor of about
three than when the same doses of x rays are deliveredat a rate of 90 R per minute.
( b) At 0.8 R per minute (gamma rays) most of thedose-rate effect has already occurred, and the yield
does not differ significantly from that observed at
0.009 R per minute (gamma rays).

Drosophila
160. S pernzatogonia. In a series of e.xperiments wit11
Drosophila. Purdom et a[. 2 5 4-256 investigated the dose-

rate effect in spermatogonia. The data indicate thepresence of an effect at very low dose rates in a single
113

e.xperiment, but not in others, and the investigators do
not interpret their data as providing conclusive evidence
for such an effect at the dose levels studied.
161. Although different dose rates were used in experiments of Oftedal,257 -259 there is no clear evidenceof a dose-rate effect for mutation induction. There is,however, strong evidence of a total dose~ effe~t at highdoses similar to that reported by Russell- 37 with x rays
and neutrons and by Batchelor et al.260 with neutrons.
In experiments with Drosophila (table XIV) Oftedal
reported a linear increase in mutation frequency at
low doses, while the frequency of mutations decreased
at higher doses. These results suggest that spermatogonial mutation rates in Drosophila may be severely
biased by the irradiation technique us~d.. Ofte~al, !nfact, suggests that acute doses of radiation will killmore of the sensitive cells (that is, the more mutablecomponent) of a heterogeneous spermatogonial population, thus allowing sampling of a less sensitive cell type.
The data of Abrahamson et al.261 and McSheehy, 240
measuring recessive lethal induction at doses higher
than those used by Oftedal, showed a linear increasein mutation frequency as a function of dose. These
results indicate that the less sensitive spermatogonial
cells were sampled.
162. Oogo11ia.. In adult Drosophila females, theoogonial stage is the only one that is maintained fora time long enough to permit the application of chronic
radiation doses that extend over several weeks. Resultsof a pilot study of dose-rate effects in oi:igonial cells262
were mentioned in the 1962 report, where it was indicated that 4.000 R Co 60 gamma rays given at therate of 7,333 R per minute were significantly moremutagenic by a factor of 2.5 than the same dose appliedat the rate of 0.2 R per minute.
163. In subsequent large scale experiments,263 summarized in table XV, it was found that the results
obtained were different depending on ( 1) the experimental conditions under which the acute or chronic
radiation was given and (2) whether the radiation doses
were measured physically or biologically. On the basisof more recent results 264 • 265 which have not yet been
published, Muller favours the view that in Drosophila
there is no significant difference in the mutagenic
effectiveness of gamma rays over the approximate sixtyfold range of rates (0.016 to I R per minute)used. It was observed, however, that at high dose
rates there was a reduction of effectiveness of about
SO per cent as compared to that at low dose rates.
164. Oocytes. The effect of changes in dose rate on
the induction of sex-linked lethals in stage sevenoocytes of Drosophila is now being studied byHimoe. 402 Preliminary results show that the yield of
mutations is the same whether the oocytes are irradiatedat 330 R/min or 9.4 R/min.

Silkworm (Bombyx mori)165. Two types of dose-rate effects have been discovered in the silkworm, one being the reverse of theother.206 • 266 In one type (type 1) which occurs in theprimordial germ cel1s ( spermatogonia and oogonia) in
the gonads of newly hatched larvae. the yield after
chronic irradi<>.tion ( 0.1 R per minute) is lower tha:lthat after acute irradiation (100 to 300 R per minute).
In the other type (type 2). where the effect is foundin larvae about eight days old in "·hich the gonial cells
are in later developmental stages, the mutagenic effectiveness is hig-her for chronic irradiation than for acuteirradiation. After extensive cytological studies and dose-

fractionation investigations (paragraph 176) and neutron studies (paragraph 200), the authors proposed
the following hypothesis for the interpretation of thecomplicated features of the dose-rate effects in the silkworm. At least two mechanisms are involved:(a) A certain part of the radiation-induced premutational damage is subject to repair, and the extent
to which this damage will be repaired is primarily
dose-rate dependent. This results in the production ofhigher mutation frequencies following acute irradiation.
( b) Because the gonial cell population is changing
with time from exclusively primordial germ cells toa mixture of primordial and primary spermatogonial
cells, and because the metabolic cycle of many cells in
the population is blocked by radiation at a sensitive
stage, chronic irradiation can give rise to higher mutation frequencies than acute irradiation. Presumably.
the degree and extent of the occurrence of either phenomenon depend largely upon the metabolic activityof the irradiated cells.
The clwlcid wasp (Dahlbominus)
166. In contrast to what was mentioned in the 1962
report, more recent information indicates that a small
dose-rate effect is detected in oogonia of Dahlbominus. 261
Significantly more eye colour mutations are inducedwith 1,000 R acute irradiation ( 1,000 R per minuteof 2 MVp or 300 kV x rays) than with chronic
irradiation (0.08 to 0.17 R per minute gamma rays).
The mutational yield following acute irradiation isabout one and one-half times that obtained after chronic
irradiation. Although these results could be explained
as a dose-rate effect, other explanations are possible,
for example, differences in radiation quality (paragraph 199).
Conclusions
167. Dose-rate effects have been and are being
studied in widely different organisms and in various
stages of germ cell development. The above survey
is not comprehensive, because it has dealt only with
the induced genetic damage that most probably finds
its origin in one-hit events (specific locus and recessive
lethal mutations) and with the germ cell stages thatare most important in the consideration of genetic
radiation hazards.
168. Among the several species studied. the mouseis the most closely related to man. In this species, we
now have exhaustive and indisputable evidence ofa dose-rate effect in spermatogorua and oocytes. The
dose-rate effect is more pronounced in oocytes thanin spermatogonia (see table XII).
169. Dose-rate effects have been reported also in
Bomby,t: mori. Drosophila. and Dahlbominus. These
effects are not only less pronounced than those obtainedin the mouse but also conflicting in nature, and morework is necessary to clarify the situation.
EFFECTS OF LOW DOSES

170. As early as 1958, on the basis of the dose-rate
effect observed in mouse spermatogonia and oi:icytes.
it was suggested that repair of pre-mutatio!1al damage
might be affected not only by the dose rate at which
the radiation \\'as giYen but also by the dose itself. it
being argued that acute high doses might hamper the
repair of pre-mutational damage to a larger exi.ent
than 'vould acute low doses. Preliminary results 268 • 269
now indicate that in oocytes the mutation yield after114

SO R acute x rays (table XII) is significantly lower
than would be expected from the results of irradiation
at 400 R if the dose-effect curve on \Vhich the frequency
at 400 R lay was a straight line through the origin.
This finding is supported by the results of new fractionation experiments in which the total e.xposure is partitioned into small acute exposures of 50 R separated byintervals of time presumably long enough for the
repair process to recover (paragraph 175). These experiments now in progress yield mutation frequencies
below those obtained with single. unfractionated exposures.
171. These results from small doses and small dose
fractions indicate that the saturation of the repair
system or the damage to that system is dose-dependent.
It appears that the repair of pre-mutational damage
that takes place at low dose rates can also occur to an
appreciable extent with acute exposures as high asthan would be predicted on the basis of results atlarge doses (paragraph 170), it was anticipated thata reduced mutation frequency might be obtained whenlarg~ doses were f~actionate~ into small doses separated
by intervals of time suffic1ently long for the repair
process to recover. There is already so:ne evidence
that this is occurring in mice. 269
176. Fractionation effects similar to those observedin the mouse were reported for spermatogonia andoogonia of the silkworm. 266 • 2 • 5- 277 'When a total e."posure of 1.000 R was delivered in two or threefractions separated by twelve- or twenty-four-hourintervals. a striking increase in the induced frequencyof specific locus mutations was observed in comparison
with the unfractionated exposure. The mutation frequencies in the fractionated series were about two times
or four to eight times as high as in the unfractionatedseries, depending on whether the spermatogonia andoogonia were sampled immediately after the hatchingof the larvae or seven to nine days later. As in thefractionation experiments with mice, other fractionation procedures increased the mutation frequencies toa lesser extent. The results of the most recent experiments indicate that the depression of repair isdue to post-radiation blod..;ng of the cell cycle at theG2 and/or Gi phases, in which the amount of repairof the pre-mutational damage is assumed to be small.
177. In Drosophila, the effect of dose fractionation'.ms been studied for pre- and post-meiotic male germ
cells. Purdom's results of a study on the effect of dose
fractionation in spermatogonia were inconclusive. 256
178. Alexander and Bergendahl278 reported a fractionation effect for sex-linked recessive lethals inspermatids when irradiation was carried out in theabsence of oxygen. Glembodsky et al. 279 investigatedthe effect of acute and fractionated doses of radiationon the induction of sex-linked recessive lethals inspermatids, and no differences were observed. Tates.2sohowever. has reported a significant decrease in thefrequency of se.,-linked recessive lethal mutations ingerm cell stages that probably correspond to young
spermatids and late spermatocytes when the dose isdelivered in five equal fractions, each separated by twohour intervals, instead of being acute unfractionated.
179. A number of investigators 281- 2 sa have reported
that the sex-linked recessive lethal mutation frequency
induced in mature sperm of Drosophila is the same
whether the dose is given in a single exposure or in
fractions separated by intervals of days or weeks.

so R.

172. Additional evidence on the effects of small
doses on repair mechanisms is provided by the experiments with primary cultures of human and monkey(Macaca mulatta) cells in tissue culture.270- 212 Althoughthese data concern chromosome damage rather thanpoint mutations, and somatic cells rather than germ
cells, they may be pertinent. Dubinin found that chemicals like cysteamine were able to protect the cells
against chromosome damage (most probablv due to
two or more hit events) resulting from e.xposures to
2S and 50 R x rays or SO and 100 R gamma rays. The
same chemicals had no protective effect at 12.5 R xrays or at 2S R gamma rays. More evidence that theeffectiveness of the repair system is dose-dependent
has recently been obtained for the early spermatidsof Drosophila (paragraph 219).
173. There is now evidence to support what had
already been anticipated as soon as the dose-rate
effect was discovered, namely that, when acute irradiation is delivered in very small doses, the induced mutation frequency may be as low as that occurring withlow dose-rate irradiation. The finding that a substantial
repair effect of this kind is occurring in the mouse withacute exposures as high as SO R indicates that the
principle may apply to most of the range of doses usuallyencountered in human genetic hazards.
THE EFFECT OF DOSE FRACTIONATION ON THE
INDUCTION OF POINT MUTATIONS

174. Several lines of evidence indicate that fractionation of the radiation dose sometimes results in a rateof mutation induction that is different from thatobserved after a single dose. In experiments with
spermatogonia of mice, it was observed that the moststriking effect of fractionation was found when a total
dose of 1.000 R x rays (90 R per minute) was given
in two 500 R fractions separated by twenty-four hours(table XVI). 273 • 274 Under these circumstances, themutation frequency in the fractionated series proved
to be approximately five times as large as that obtained
from the unfractionated series. Some of the other fractionation procedures listed in table XVI also resulted insome increase of the mutation frequency.
175. This effect is presently e.xplained partly interms of cell-stage synchronization and partly by cellselection. On the other hand, an effect of dose fractionation working in the opposite direction was expectedunder certain conditions. Thus. since small doses ofradiation are now known to produce fewer mutations

C011cl11sio11s
180. The increased· mutation frequency observed asa result of dose fractionation occurred only in experiments in which the dose in each fraction was quite
high. Therefore. these results would probably apply
only to very rare conditions in the e.xposure of man
to ionizing radiation. However. the preliminary evidence on the reduced mutation frequency obtained whena dose is delivered in small fractions mav well have
many applications in estimating the genetic effects ofradiation in man. Quantitative information is needed
before these estimates can be made.
THE EFFECT OF THE INTERVAL BETWEE::\ IRRADIATIONAND CONCEPTION

181. In the male mouse. extensive data on spermatogonia have shown no evidence of any significant
change in mutation frequency with time after irradiation.

llS

This holds true even to the end of the animal's reproductive life. 237
182. In contrast to these findings in the male, recently published results from irradiation of female micewith fission neutrons clearly show that the interval
behveen irradiation and conception has a very pronounced effect on the mutation frequency observedin the offspring. 284 In the first seven weeks after
irradiation, a period in which two litters are usuallyconceived, the mutation frequency is high. \Vith adose of approximately 63 rads, a total of 59 specificlocus mutations was observed in 89,301 offspring
conceived in that period. After that, no mutations·were found in a total of 120,483 offspring. Of all theother biological factors affecting mutation frequency
that have been studied. none has produced such a
striking effect. There is preliminary evidence (table
XII) that the same effect occurs with x rays.
183. The low mutation frequency in the later period
comes from oocytes that were irradiated in immature
follicle stages. It is not yet known whether the marked
difference in mutation frequencies in the two timeintervals is due to a low mutational sensitivity ofoocytes in early follicle stages, to an efficient repair
mecllanism in these stages, or to cell selection.
184. The extreme lowness of the mutation frequency
in the later period is worth emphasizing. In the neutron
experiment, the dose was high enough to be highly
mutagenic in the early interval after irradiation. Yetin the later period the observed value of the mutation
frequency was zero, and even the upper 99 per centconfidence limit of this zero figure was below the
spontaneous mutation rate in male mice. (A reliablevalue for the spontaneous rate in females is not available,
although it appears to be lower than that in males).

C011clusions
185. The mutation frequency in female mice ismarkedly dependent on the interval between irradiationand conception. The frequency is high in the first few
weeks after irradiation but then plunges rapidly to
an extremely low value. Caution should be used in applying the results to the human female, because theoi)cyte stages involved in the two species may not becomparable in their responses. However, there is certainly a possibility of a similar effect and, therefore, anindication that the genetic hazard from the exposure ofwomen may, on the average, be much Jess than that
calculated on the basis of female mouse mutation rates
observed after irradiation.
THE RELATIVE BIOLOGICAL EFFECTIVENESS (RBE)
OF RADIATIONS OF DIFFERENT QUALITIES

186. In 1963, the RBE Committee set up by theInternational Commission on Radiological Protection
and the International Commission on Radiation Units
and Measurements 2s5 reviewed the information available
at that time on the relative biological effectiveness ofdifferent types of radiation with regard to the inductionof genetic damage. In general terms, the conclusionsof the RBE Committee were that neutrons of various
energies were about 2.3 to 7.3 times more effective thanx or gamma rays in inducing dominant lethal mutationsin spermatozoa of Drosophila and the mouse. The
actual values depended on the doses and dose rates
at which they 'vere determined. RBE values for the
induction of sex-linked recessive lethal mutations wereof the order of 1.1 to 1.6. The following paragraphs
116

update these conclusions, but the main emphasis ison the recent results obtained with mice. since they
have a more direct bearing on the problem of estimationof human risks.

The mouse
Pre-meiotic male germ cells
187. Studies of Russell 237 showed that the rateof induction of specific locus mutations increases withdose when spermatogonia are irradiated with highdose-rate (79 rads per minute) fission neutrons. At
doses higher than approximately 100 rads, the mutation frequency is lower than the actual value at 100
rads (table XII). The mutagenic effect of high doserate neutrons was compared with that of low dose-rate(0.17 and 0.79 rads per minute) fission neutrons. It
was found that there was no dose-rate effect at about
60 rads. However, above 100 rads. high dose-rateirradiation was mutagenically less effective than low
dose-rate irradiation. Such a reverse type of dose-rate
effect can be explained by assuming that there is adifference in the degree of cell selection under highand low dose-rate irradiation.
188. Comparison of the results of 60 rad neutron
irradiation with x irradiation at 90 R per minute indicated an RBE of 5.8 for specific locus mutations.
Since the mutagenic effect of 300 R high dose-rate xrays is about 3.3 times larger than the effect of 300
R low dose-rate gamma rays (0.009 R per minute),
it follows that an RBE of 19.1 is obtained when the
mutagenic effectiveness of neutron irradiation is compared with that of low dose-rate gamma irradiation.
Russell arrived at a closely similar RBE value ( 18.1)
on the basis of results of another experiment in which
he compared the mutagenic effects of 100 rads of low
dose-rate neutron irradiation (0.14 rads per minute),
with that of 600 R low dose-rate gamma irradiation(0.13 R per minute).
189. Searle and Phillips reached essentially thesame conclusions as Russell with respect to a reversed
dose-rate effect at doses above 100 rads (table
XII).2ao, 280, 288
190. An analysis of the dose-mutation relationshipfor very low dose-rate neutron irradiation revealed
that it was linear behveen 0 and 307 rads. The relationship applies to both specific locus mutations anddominant visible mutations. Comparison of the mutagenic effectiveness of 307 rads very low dose-rate
neutron radiation with that of 608 rads very low doserate gamma radiation led to an estimated RBE of
about twenty-three for specific locus mutations andto a figure of twenty for dominant visible mutations. 288
191. There is little information on the inductionin spermatogonia of mutations resulting in dominantlethality. Comparison of litter-size at birth after 307
rads of chronic neutrons compared to 608 rads ofchronic gamma rays showed a significantly smaller
litter-size in the former. 2 88
192. Recent cytological studies have shown thatabout 21 per cent of the spermatocytes derived from
irradiated A type spermatogonia showed multivalentconfigurations (indicative of translocation heterozygosity) when the spermatogonia were irradiated with307 rads of low dose-rate neutrons. A percentage of
3.5 was obtained when similar cells were irradiatedwith 207 rads of higher dose-rate neutrons. 289 • 290 If
the data obtained for low dose-rate neutron irradiation
are compared with those for low dose-rate gamma

irradiation (paragraph 124), and if it is, furthermore,assumed that the dose-mutation relationship for low
dose-rate neutron and gamma induction of translocations is linear. then fast neutrons may be as much as
forty times as effective as gamma rays from this pointof view.
Post-meiotic male germ cells
193. Recently Searle et al.~ 86 obtained some information on the induction of dominant lethal mutations in spermatozoa which had been e.xposed to 0.7:MeV neutrons at 0.01 rads per minute. The biologicaleffectiveness of these neutrons was calculated by comparing them with x rays on the basis of induced
dominant lethality as estimated through live embryos/
corpora lutea ratios in the control and in the irradiatedseries. At about 50 per cent induced dominant lethality( 100 rads for neutrons, 600 R for x rays), neutrons
turned out to be 5.8 times more effective than x rays.
Searle's results confirm the results of Russell's studies 293
on the relative effectiveness of neutrons from a nuclear
detonation and from a cvclotron. Both Searle andRussell observed that neutron irradiation induced moremutations in spermatids than in spermatozoa. This had
been found in earlier studies with x irradiation.
194. The REE values obtained by Searle and Russell are fairly close to those published by Pomerantseva.294· 295 The post-meiotic germ cells in her e..xperiments were irradiated with fast neutron (1 MeV)
doses from 17 to 228 rads ( 4.3 to 11.6 rads per minute).
Using pre- and post-implantation death as criteria fordominant lethal induction, Pomerantseva estimated thatfast neutrons were five to six times more effective than
Co60 gamma irradiation and four times more so than
x rays.
195. Pomerantseva also studied the RBE of 660
MeV protons and observed that this type of radiation
was about half as effective as x rays and 0.65 times
as effective as Co60 gamma irradiation. As a resultof studies with rats, Plotnikova et al. 296 found that the
REE of 500 MeV protons for dominant lethals inspermatozoa was 0.6 to 0.7 when compared to 180
KeV x rays.

review of the RBE Committee. The same applies to theresults of Abeleva and Lapkin's studies on the induction by neutrons of sex-linked recessive lethals mspermatozoa and spermatids. For this cateaorv ofgenetic effects, the RBE for neutrons comp';.red to
gamma rays is 1 to 1.5.
198. The finding that the RBE value for spermatids
is lower than for spermatozoa is presumably due tothe fact that spermatids have a higher sensitivity thanspermatozoa to the induction of genetic damage by
x rays in the presence of oxygen.:?oo Dattch et a1.aoo
observed that, for spermatozoa sampled on the second
day after irradiation, the RBE for fast neutrons. asmeasured by the induction of both recessive lethals
and translocations, was considerably higher than in
sperm sampled during the first day after radiation e..xposure. This difference can be ascribed to a differencein oxygen tension between the two stages, because
Sobels 301 was able to show that the higher sensitivity
to x irradiation of fully mature spermatozoa comparedto that of almost mature sperm cells is a consequenceof a higher degree of o>..)'genation in fully mature
spermatozoa.
199. With 660 MeV protons, Rappaport et a/.30 2
obtained a linear yield of sex-linked recessive lethals
in spermatozoa at doses between SOO and 12.000 rads
and a rate of induction of 2 X 10-5 mutations per rad.
The data suggest that the RBE of 660 MeV protons
compared with gamma rays is approximately one. The
early studies of Edington303 and Edington and Randolph304 on the induction of se.x-linked recessive lethals
in spermatozoa had shown that the RBE of x rays
compared to gamma rays was approximately 1.1 or 1.4
depending on the dose level at which it was estimated.
The fact th:i.t high dose-rate x rays are mutagenicallymore effective than high dose-rate gamma rays has more
recently been confirmed by Seeley et. al. 305 for se.x-linked
recessive lethals in spermatozoa and by Purdom and
McSheehf?55 for Ilnd chromosome lethals in spermatozoa and spermatogonia.

Silkworm
200. The relative biological effectiveness of 14 MeV
neutrons, fission neutrons and gamma rays was determined for specific locus mutations induced in early(type 1 dose-rate effect) and late gonia (type 2 doserate effect) .306-369 Since mutation frequencies were
found to increase faster than linearly with dose regardless of the type of radiation applied, it is impossible todescribe the difference in mutagenicity of these typesof radiation by one single RBE value over the wholedose range. Therefore the authors estimated the RBE
values at a fixed mutation frequency. The RBE valuesof 14 MeV neutrons in comparison to gamma rays are
the following: early spermatogonia (0.8 pe-locus: 1.0
re-locus) : late spermatogonia ( 3.2; 2.1) : early oogonia(1.2; 1.2) and late oogonia (1.i; 2.8). For 1.5 MeV
fission neutrons, these values are: early spermatogonia( 1.7; 1.9) ; late spermatogonia ( 4.2; 3.5) : earlyoogonia (2.1; 2.4) and late oogonia (3.8: 3.0). These
RBE values make it possible to rank the three typesof radiation according to their relative efficiency ofmutation induction as follows: gamma rays, 14 :r..IeV
neutrons and fission neutrons.

Female germ cells
196. Comparison of the effects of high and low doserate neutron irradiation of oocytes with a dose of
approximately 60 rads showed that high dose-rateirradiation is significantly more mutagenic than low
dose-rate irradiation. 284 However, the dose-rate effectfor neutrons is smaller than that for gamma rays.
At high dose rates. the published data on mutation
frequency in oocytes indicate an RBE similar to thatobtained for spermatogonia. 2 84

Drosophila
197. Abeleva and Lapldn 297 • 298 irradiated spermatozoa and spermatids of Drosophila with doses of600, 1.200 and 2,400 rads fast neutrons ( 55 rads per
minute), on the one hand. and 1.200 and 2.400 rads
acute x rays on the other. The relative biologicaleffectiveness of neutrons. compared to x rays, asmeasured by the induction of dominant lethals. was
2.4 to 2.8 for spermatozoa and 1.3 to 1.5 for spermatids.
If one takes into account the fact that REE values varywith dose, dose rate and energy spectrum of the neutrons. the RBE values obtained by Abeleva and Lapkin
are in good agreement with those mentioned in the

Dahlbominus and Mormoniella201. In experiments on the induction of specifi.c
locus mutations in early and late oocytes of Dahlboimntts by 750 rads of 14 MeV neutrons and 750 rads117

of gamma rays, Baldwin310 observed that high doserate neutrons were mutagenically more effective thanhigh dose-rate gamma rays, but not significantly so. The
relative mutagenic effect of neutrons and gamma rays
in early and late oocytes was the same.
202. The induction of specific locus mutations inoocytes of M ormoniella has been studied by Kayhartsu
who compared the relative mutagenic effectiveness ofthermal neutrons, fast neutrons and x rays. The RBE
for thermal neutrons could not be estimated, but theRBE for fast neutrons was seventeen to twenty-one in
the low dose range ( 45 to 70 rads) and two to fourat higher dose levels (240 to 1,400 rads).

Conclusions
203. All evidence confirms that neutron irradiation

is mutagenically more effective than x or gamma irradiation. There are indications that the relative mutagenic
effectiveness of neutrons increases with their linear
energy transfer. Results of studies with such widelydifferent species as the mouse and the silkworm indicate that RBE values for neutrons are almost always
in the range of one to six. An RBE value for themouse of about twenty was obtained when the mutagenic
effects of low dose-rate neutrons or of low doses (60rads) of high dose-rate neutrons were compared withlow dose-rate gamma radiation. It has been establishedthat RBE values can change with doses and dose rates,
and it is also known that the RBE values may bedifferent for germ cell stages and types of genetic
damage.
REPAIR OF PRE-MUTATIONAL DAMAGE

204. Since dose-rate effects and some fractionation
effects are usually interpreted on the basis of repairof mutational damage, it seems appropriate to review
some of the recent advances in this field.

Paramecium
205. Kimball's extensive studies312•314 with Para11tecimn showed (a) that various post-irradiation treatments can reduce the amount of x-ray induced mutation
but only when applied before the first chromosome
duplication that follows irradiation, thus demonstrating the existence of reparable pre-mutational damage;( b) that the mutation yield is inversely related to thelength of the interval between irradiation and chromcsome duplication. By sufficiently prolonging the timeinten·al between irradiation and DNA synthesis, up
to 60 per cent of the maximum mutation yield can beeliminated. Irradiation damage produced during postduplication (G:? phase) and early prophase is subject
to most effective repair, and probably almost all of
the initial lesions produced during these phases arepotentially reparable: (c) that the reduction in mutation yield. and therefore the amount of repair. depends
on gro"·th conditions and on the presence of metabolic
inhibitors. suggesting that an enzymatic process is responsible for the observed reduction.
206. The hypothesis that enzymes are involved inrepair of pre-mutational damage in Paramecium ismade probable by the observation that the mutation
vield is increased when the time between irradiation
and DNA svnthesis is decreased. If there is little time
between irr~diation and DNA synthesis, there is less
opportunity for repair to occur. and. as a consequence,
most of the pre-mutational damage will be irreversibly
fixed at the time of chromosome duplication.

118

207. Kimball's investigations into the nature of theinitial radiation damage led him to conclude that there
were at least two different kinds of pre-mutational
damage, one producing permanent alterations (i.e.,mutations) through misrepair, the other through misreplication. The results obtained with Paramecium
suggest that misrepair is less efficient than misreplication.313 since the longer the time between irradiation
and replication, the lower the yield of mutations. Thus,
potential mutagenic lesions tend to disappear without
producing mutations prior to replication but tend to beconverted to mutation at replication. Studies of the
pre-mutational lesions that cause mutations bv misreplication revealed that these lesions usually affectedboth conserved strands of the DNA and therefore allprogeny of such cells.sis, am
208. Repair processes have also been observed formutations induced by 2,537A ultra-violet radiation. byalpha particles. 316 • 317 by nitrogen mustard, and by
tri-ethylene melamine (TEM). 318 At least with TEM
mutations, however. the pre-mutational damage thatis repaired differs from that due to x rays, since most
TEM-induced mutations, unlike those induced by xrays. affect only a half or a quarter of the progeny of
the cell in which a mutation has been induced. Fromobservations on the repair of x-ray and TEM-induced
mutations. it appears that Paramecium aurelia iscapable of repairing more than one kind of pre-mutational damage. The two mutagens. furthermore, differ
in that the x-ray damage incurred in the G:! phase isalmost completely repaired, 319 whereas a comparatively
high yield of mutations is still obtained after TEM
treatment of G2 cells. 318
Bacteria
209. Studies of repair in bacteria deal mainly withdamage affecting the survival or the growth of thetreated cells and, therefore, would not seem to bestrictly relevant to the problem of repair of premutational damage. The reason for mentioning someof these studies in this report is that they have thrownconsiderable light on the molecular and enzymaticmechanisms of repair of ultra-violet or chemicallyinduced damage in the DNA. Since no comparable
information is available with regard to ionizing radiation, these results may help us to understand thephenomena resulting from x irradiation.
210. Part of the damage affecting the survival ofultra-violet-irradiated bacteria (or bacteriophages) consists in the formation of thymine dimers and can be
repaired through the intervention of two groups of
enzymes. The photo-reactivating enzymes have beenslrown320• 321 to split the ultra-violet-induced thymine
dimers in the DNA into the original separate thymine
residues in the presence of light with wave-lengths
ranging from about 320 to 450 mµ. Dark-repair
enzvmes. on the other hand. excise the ultra-violetindi1ced thymine dimers. 322•325 The excision of dimers
is followed by 1·estit11tio ad intt'grum of the original
DNA molecule through a process of reparative replication that fills the gaps with new material. Unlike thephoto-reactivating enzymes, the dark-repair enzymes
do not require visible light.
211. Both enzymatic systems are genetically controlled and manv radio-sensitive mutants. lacking
either the photo-reactivating or the dark-reactivatingenzvmes. have been isolated. On one occasion. anenz}'!l1e capable of initiating dark-repair in 'Vitro has
been isolated from M icrococcus lysodeikticus. 3 26 •328

212. Investigations into the action of the difunctional
alkylating agent mustard gas on the growth and survival of E. coli strains, with and without dark-reactivating enzymes, have provided evidence that chemicallyinduced lesions in the DNA can also be repaired. 3 ~ 9
The strain carrying the dark-reactivating enzymes wasable to excise (i.e. repair) the inter-strand cross-links
between guanine moieties that are induced by mustardgas. The strain which did not have the dark-reactivating enzymes could not remove these inter-strand crosslinks in the DNA.
213. Less is known with regard to repair of premutational damage. 'Witkin et al. 330 studied mutationinduction in three different strains of bacteria. The
first strain ( H/r) was used to study the induction of
mutations to streptomycin resistance. The second strain(H/r30) was an arginine requiring substrain of thefirst and was used to study mutations to prototrophy.
Neither of these strains carried the photo-reactivating
enzyme. 'vhereas the third strain (B/r) did. The mutations studied in the B/r str~in were mutations to streptomycin resistance. Mutation induction by ultra-violet
in all strains was studied in the absence or presenceof post-treatment with photo-reactivating light (wavelength 320 to 450 mµ).
214. It was found that the H/r strain was notcapable of repairing potential mutations to streptomycin resistance in the presence of photo-reactivating
light. The H/r30 strain, on the other hand, was able
to repair potential mutations to prototrophy in thepresence of photo-reactivating light. The B/r strain
which has the photo-reactivating enzyme was capableof repairing potential mutations to streptomycin
resistance in the presence of photo-reactivating light.
From these results, it was concluded that ultra-violet
light induces two kinds of pre-mutational damage.
Repair of the first kind of damage (i.e.. potential
mutations to streptomycin resistance) can only takeplace in the presence of the photo-reactivating enzyme
and photo-reactivating light. The second type of damage(i.e., potential mutation to phototrophy) requires only
photo-reactivating light for its repair.
215. The mechanism of repair of pre-mutational
damage in bacterial strains which have or lack thephoto-reactivating enzyme is not yet well understood.
This applies even more to our knowledge concerning
the process of repair of ultra-violet-induced mutations
in bacterial strains having or lacking the dark-reactivating enzymes.
216. The examples given above have shown striking
parallelism between the error-correcting mechanisms forsuch different lesions in the genetic material as thoseinduced by ultra-violet and mustard gas. There is nosuch detailed evidence for the mechanism of the repair
processes in bacteria exposed to ionizing radiation.
However. it has been demonstrated that bacterial
strains show a difference in sensitivity to ionizing
radiation depending on whether they are equipped withrepair enzymes or not. These results seem to suggestthat damage from ionizing radiation may be repaired
in a way similar to that observed with ultra-violet or
chemirally treated bacteria.
kl etazoan germ cells
217. In the sections on dose-rate and dose-fractionation effects, it was shown that results of dose rate anddose fractionation on mutation induction could be
explained by assuming that the mutation process in119metazoan germ cells was subject to repair. The possibility of interfering with repair processes in metazoan
germ cells by means of pre- or post-irradiation treatments with metabolic inhibitors has been amply demonst~ated in the past decade. The details of the evidence
are comprehensively analysed in recent reYiews. 314 • :m
The main conclusions only will therefore be outlinedin this report.
218. Evidence for the operation of repair processes
in early spermatids and mature spermatozoa of Drosophila has been obtained in studies on the effects ofdifferent post-treatments by Sobels et al. 2 ~ 9 • 3o1, aa1-3:i1
It is remarkable that early spermatids and spermatozoa
give an opposite response to the same treatments. Thissuggests that the metabolic pathways involved in themutational event are essentially different in these twodifferent stages of sperm development.
219. For early spermatids, post-treat.inent withcyanide or nitrogen following radiation exposure in air
leads to an increase of the frequency of recessive se.xlinked lethals in a ring X chromosome.331 •335 Since theformation of peroxides could be ruled out in the cyanide
experiments335 it was concluded that inhibition of
respiratory enzymes enhanced the mutation frequency
by inhibiting a repair process. Further evidence forthe oxygen-dependence of the repair system in earlyspermatids was provided by the observation that. after
inhibition of the repair process by anox.ia before andduring irradiation, the mutation frequency was markedly lowered by post-treatment with 02, as comparedto that observed with N 2 •299 By applying the same treatments (pre-treatment with N 2 • followed by post-treatment with either N 2 or 0 2 ) at three dose levels ( L250,
2,500 and 3,750 R), Watson 338 observed that theabsolute reduction of the mutation frequencies in the
02 post-treated series was the same at all three doses.
These results suggest that the repair system can only
cape with a limited amount of damage, because at the
low dose level repair is considerably more effective thanat the high dose level where the system apparently
becomes saturated. The repair process in early Drosophila spermatids therefore shows a remarkable similarity to that postulated by Russell to e.xplain the effect ofdose (paragraph 171) and dose rate (paragraph 159)
in the mouse.
220. In contrast to the findings in early spermatids,
post-treatment with 0 2 of mature spermatozoa irradiated under anox.ia, increases the frequency of mutations
as compared to that observed after post-treatment with
N 2 •299 • 336 Post-radiation interaction of radicals with
0 2 cannot explain this effect.301 As in spermatids. thepost-radiation reduction of the genetic damage in spermatozoa by N 2 is thought to be mediated by an enzymatic repair process which derives its energy fromglycolysis. The modification by 0 2 versus that by N 2shows a remarkable similarity to glycolysis. which isalso adversely affected by oxygen, but favoured byanoxic conditions. This idea is supported by the findingthat pre-treatment with two specific inhibitors of theglycolytic pathway. i.e. sodium fluoride and iodoacetamide. leads to a considerable increase of the radiation-induced mutation frequency in spermatozoa. 301• 339
221. A contrasting response of early spermatids andspermatozoa has also been observed after inhibition ofprotein and/or RNA synthesis. since pre-treatmentswith chloramphenicol. ribonuclease or actinomycin-D
all result in an increase of the radiation-induced mutation frequency in sperm, but in a decrease in earlyspermatids. 301 • 331 • 337 It is clear therefore that protein

observed a decline in maze-performing ability in theirradiated series. In the same series, they noticed a
70 per cent increase in "dull" animals (animals witherror scores that exceeded the mean by more than one
standard deviation) and a 30 per cent decrease in"bright" animals (animals with scores lower than themean by more than one standard deviation). Contrary
to expectations, analysis of the variability of errorscores revealed a decreased variability in the irradiatedseries. By analogy with the author's findings withregard to radiation-induced changes in body-weight,
it is assumed that radiation-induced reduction in mazelearning ability could also be explained as being due
to hereditary changes and not to differences in littersize between control and irradiated series. At present,
it is difficult to evaluate to ·what extent maze-performing ability in rats can be equated to a clearly definedcomponent of human intelligence.
228. Life span. As early as 1957, Russell349 obtained
evidence of a reduction in life span in the offspring ofmale mice that had been e:>..i>osed to 30 to 80 rads ofdetonation neutrons. Since then, several other workers
became interested in this subject, because radiationinduced life-shortening represented a genetic hazard
for the human population that had been hitherto unforeseen. Spalding3 50 irradiated male mice with 30 to 180
rads acute fission neutrons in one experiment and with60 to 300 rads gamma rays in another. His results did
not indicate any reduction in life span in the offspringfrom irradiated sires or grandsires. On the contrary,
the average life span of all control females was shorter
than that of the female offspring from irradiated siresor grandsires. The effect was even more pronounced
in the male progeny. The results for neutrons andgamma rays were the same.
229. Frolen3 G1 observed no shortening of the life
span in the first generation offspring of male mice exposed to 500 R acute x rays. The results were thesame when the irradiated males received a pre-treatment with cysteamine. The life span of the female offspring of irradiated males was not analysed.
230. Studies were also made concerning the life
span of descendants of mice populations which had received irradiation during five or more generations.
Spalding and Strang352 failed to demonstrate any
reduction of life span attributable to ancestral irradiation in male and female mice from sires exposed for
five, ten and fifteen generations, to 200 R acllte x rays
per generation. Gowen and Stadler 353 e_xposed mice togamma irradiation from mating to death. Each following generation was maintained in the irradiation fieldfrom conception to death. Extensive analyses of thelife span were made when the strains oi mice hadcompleted lives through the sixth generation. The average ancestral radiation doses for each generation were,in order of generation, 370, 680, 820, 980, 1.180 and
1.290 R. The results of these experiments indicatedthat ancestral irradiations over six generations had
little effect.

and/or RNA synthesis also play a part in the mutation
process in Drosophila. It is not yet possible, however,to state more precisely which specific steps are involved
from the induction of premutational damage to mutation fixation.
222. Several lines of evidence indicate that theobserved post-radiation modifications in early spermatids and mature spermatozoa cannot be explained by:(a) Shifts in the sampling of germ cells with different radio-sensitivities among groups of flies(or pupae) having received different post-treatments, ao1, 336, aas nor by( b) Selective elimination of cells with recessive
lethal mutations or with translocations. 301 • 339
223. Exi>eriments of Tazima et al. 340 with silkworm
showed that it was possible to increase the yield ofspecific locus mutations in spermatogonia and oogonia
by subjecting these cells to post-irradiation treatmentswith cyanide, chloramphenicol, nitrogen gas and low
temperature.
QUANTITATIVE TRAITS

224. The general problems associated with radiationinduced changes in quantitative traits were discussed
in great detail by the Committee in its 1958 report. In
particular, the Committee analysed the implications of
induced changes of the variance and the mean of such
traits as birth-weight, intelligence, life span and fertility.
The discussion was largely based on data collected in
Drosophila and in plant material. Further experimental
results were reviewed more briefly in the 1962 report.
225. Although more data on Drosophila have beenobtained in recent years, 341 · 345 in this report attention
will only be given to recent results obtained withvertebrates, on which almost no data were available forinclusion in earlier reports. While the information
available on the induced changes in quantitative traits
in vertebrates is much less complete than in Drosophila
and plants, the results reviewed here may have a far
greater relevance to the situations likely to obtain inman.
226. Body-weight. Touch berry and V erley346 obtained evidence that body-weight at thirty-two days
was increased and growth rate speeded up in theoffspring of mice whose ancestors had been irradiatedduring six generations with doses from 10 to 240 R.
Newcombe and McGregor347 studied radiation-inducedchanges in body-weight in the offspring of rats whose
male ancestors had 'received gonadal exposures of 600
R of x rays over thirteen successive generations. It
was found that rats in the irradiated series tended tobe heavier than their controls. The relative incidenceof "heavy" as compared with "light" animals (definedas those in the upper and lower halves of the weight
distribution for irradiated and control groups combined) was significantly higher in the irradiated thanin the control group bv factors of 3.4 for males and
2.2 for females. It could be demonstrated that theradiation-induced changes in body-weight were primarily associated with induced hereditary changes andnot merely a secondary effect of the radiation-induced
reductions in litter-size.
227. Maze-performing ability was studied in rats
which descended from a population in which males(in one experiment both males and females had been
irradiated) had been e_xposed to 400 to LOOO R acute
x rays during twelve consecutive generations. Newcombe and !\IcGregor,348 who performed these studies,231. All studies listed above, with the exception ofthat of Russell. have shown that irradiation has little
or no effect on life span in offspring from mice irradiated during one or more generations. Russell's
experiment was the only one in which fission neutrons
were used to irradiate the mo5t sensitive oi the postmeiotic male germ cell stages, these conditions being
chosen as likely to increase the probability of obtaining
an effect.

120232. Reproductive life and its modification by irradiation have been studied by Spalding et al. 352 Theyobserved that the average period of fertility was longer
in the offspring of mice that had been irradiated with
200 R per generation during twenty successive generations than in controls.
233. Skeletal abnormalities. Searle354 studied continuous and quasi-continuous skeletal variation indescendants of sublines of an inbred strain of mice
which had been kept in a radiation field for about nine
generations. receiving 1 R per night and about 80 R
per generation. The study has not yet produced a clear
picture. and further studies are indicated.
234. The only other vertebrate species in which theeffect of irradiation on a quantitative trait has beenstudied is the chicken. In these e.xperiments. 355 cocks
were irradiated to induce genetic variability in stocks
which would othenvise no longer respond to selection
for high egg numbers. Irradiation of cocks with 1,000
to 1,500 R acute x rays per generation over a periodof seven generations, followed by selection for highegg numbers during six generations, led to a negative
result; namely, the response to selection was no different, or perhaps slightly less, in the irradiated lines thanin controls.
235. In conclusion. studies on radiation-inducedchanges of quantitative traits in vertebrates have yielded
results that must be considered as still fragmentary.
The information available does not make it possible
to evaluate how the means and variances of these
traits are changed by radiation. It must, however. be
noted that the only experiment concerning an intellectual function reveals a decrease in the mean without
an increase in the variance. Estimates of risk of induced changes of quantitative traits in man must wait
until further results are obtained with vertehrates, particularly with mammals.
:MISCELLANEOUS GENETIC EFFECTS

Space-flight results
236. In the context of the present report, resultsof genetic experiments performed in orbiting spacecraft are not of immediate relevance to risk estimates,
since the doses received by man and experimental
animals have thus far been extremely low and mostlyof the order of tens of millirads. It seems, however,appropriate to mention this subject. because some results suggest that genetic damage is induced during
space flights even if the detectable amount of ambient
radiation in the spacecraft has been small. indicatingthat other space-flight parameters, such as vibration,weightlessness and acceleration. may induce genetic
effects either by themselves or in combination with theambient radiation. 356•367
237. Two lines of research have been followed instudying the influence of space-flight parameters. Firstly,
several attempts have and are being made to simulatethese parameters in ground tests. Thus far, these modele.xperiments on the ground have mainly focussed on
the action of vibration alone and in combination withacceleration or with irradiation. The results have beenfound to be dependent on the type of vibration, theduration of the treatment. the type of genetic damage
under study and on whether the vibration was applied
before or after the irradiation.ar,s.311
238. In the second line of research. the biologicalmaterial (human blood cells) was treated by irradiationfrom a man-made radiation source during the orbital

phase of the spaceship mission. 372 · 373 The frequenciesof single and multiple-break aberrations induced in the
blood cells were compared with the frequencies in nonirradiated cells aboard the spaceship and with thefrequencies in irradiated and non-irradiated cells thatremained on the ground. The in-flight control gave thesame result as the control on the ground, indicatingthat the space flight by itself did not induce aberrations.
Comparison of in-flight irradiated cells with those
irradiated on the ground on the other hand revealed
that, while there was no significant difference withregard to yields of multiple-break aberrations. the frequency of single-break aberrations was significantly
higher in the samples irradiated in flight. Apparently,
synergism exists for the production of human chromosome aberration between radiation and some spaceflight parameters.
239. It is still too early to obtain a complete pictureof the interaction of irradiation with space-flight factors,
and, so far, there is no common opinion as to whether
space-flight factors by themselves are able to induce
some kinds of genetic damage. The current findings
are important, because they lead us to realize that themagnitude of the genetic and somatic risks encountered in space flights is not only determined by dose,
dose rate and quality of the radiation received in thosecircumstances but also by parameters that are peculiar
to space-flight situations.
Effects of internally-deposited radio-active isotopes
240. Increased rates of dominant lethals in malemice have been observed by Liining et al. after injection with Sr90• New and extensive data indicate thatthe increase of dominant lethals is not observed inmatings within the first three weeks after injection,but only from the fourth week onwards. This corresponds to effects on spermatocytes and spermatogonia.374-376
241. The genetic effects of CH incorporated into
Drosophila have been studied by Purdom. Preliminary
results suggest that the recessive lethals induced by CH
are largely due to the emitted beta radiation andprobably not, or to a much lesser extent. to transmutation.377
242. Tritiated thymidine and deoxycytidine havebeen studied for their capability to induce sex-linked
recessive lethals in Drosophila males. 378• 379 The
distribution of the lethals along the X chromosome wasdifferent for the two types of radio-active chemicals.
Two regional differences have been noted. one of highmutability after tritiated thymidine and one of highmutability after tritiated deoxycytidine.
243. Olivieri and Olivieri380 studied the mutagenic
effect of tritiated thymidine and uridine in Drosophilamales and found that tritiated uridine increased significantly the frequency of sex-linked recessive lethals
in spermatocytes. The mutagenic effect of tritiateduridine was even more pronounced when applied in
combination with actinomycin D.

IV. Risk estimates
244. Risk estimates express a probable quantitative
relationship between doses of radiation and frequenciesof certain effects. In this report. risks of genetic
effects will be expressed in terms of expected frequencies of genetic changes (point or chromosome
mutations) induced per unit dose or function (e.g.
121power) of dose. In earlier reviews of genetic effects by
the Committee, risks were expressed in terms of
doubling doses, these being the doses required to
produce a number of mutations equal to those occurring naturally in one generation. Doubling doses caneasily be computed when both the natural incidence
and the rate of induction of a certain category of mutations are known. When both figures are available, thedoubling dose is a compact way of summarizing theinformation regarding a given effect in given circumstances. The use of the doubling dose, however, is notnecessary in arriving at risk estimates. and for thatreason the more direct approach is employed in thisreport.
245. Risk estimates as defined in paragraph 244
have the advantage that they can be obtained in the
non-linear case in which a single doubling dose would
have little meaning. They are also absolute estimates
which give at once the risk in terms of effects. whereas
this type of information is Jess directly obtained fromthe doubling dose and involves unnecessary assumptions regarding the proportionality between spontaneous and induced rates. Finally, risk estimates as
expressed in tl)is report are consistent with the practice followed by the Committee with regard to therisk of induction of malignancies.
246. It may be pointed out that, while estimatesof risks of induction of malignancies in man can bederived from the results of irradiated human populations, this is not possible with regard to genetic risks.
As will be discussed below, in vivo human data areinadequate to provide estimates of genetic risks. These
must be based on results of experiments with animals-mainly mice-and with human somatic cells in vitro.
While there appears to be no alternative at present tothe use of such experimental material. its limitations
must be clearly borne in mind and will be stressed
throughout the following paragraphs. Because of unavoidable inferences from one species to another orfrom one type of cell to another, the estimates thus
obtained are Jess reliable than the data from which
they are derh·ed.
247. An additional difficulty with genetic risks is
encountered in expressing them in meaningful terms.
The eventual result of the great majority of genetic
changes is, sooner or later, the failure of cells carrying those changes to be transmitted to the following
generations. Only in a minority of cases-such as
certain dominant traits and certain chromosome anomalies that occur frequently in the population and thatare easily detected-can we make assumptions as tothe manner in which the damage will be expressed.
For most genetic changes even conjectures are notpermissible regarding the actual manifestation of thedamage throughout generations in tern1s of individual
or collective hardship.
248. The estimates reviewed in the following paragraphs were obtained for acute irradiation of spermatogonia by low LET radiation at high single doses.
The consequences of irradiation of oocytes, and thoseof exposure to radiation of different quality at different
doses and dose rates, will be considered separately.
POINT :>1UTATIONS

Total risk of indHction
249. ).foch as the total rate of spontaneous mutation
can be derived from an analysis of the excess of female
over male new-born children, so the total risk of122

induction could, in principle, be obtained from theshift of the sex-ratio to be expected in the offspringof irradiated mothers as a consequence of the inductionof sex-linked recessive lethal mutations. Such a shifthas, in fact, been observed and was used by the Committee in its 1958 report to obtain risk estimates.
Further observations were summarized and discussed
in the 1962 report, in which the Committee discarded estimates of risk of point mutations based on the
sex-ratio shift, because. while the shift undoubtedly
was largely due to genetic damage and might havereflected a point mutational component, it was notpossible to rule out or separate the possible confounding effect of induced chromosome anomalies, the highfrequency of which was not known in 1958.
250. Such a reservation is still valid now, despite
new data 381 • 362 on the offspring of irradiated mothers
which confirm earlier observations, and although noincrease in the frequency of sex-chromosome anomalies
was noted in a survey3 63 of the female offspring of
irradiated mothers. The size of the survey was too
limited. however. to exclude the possibility that induced
anomalies of the sex-chromosomes may account for atleast part of the effect on the sex-ratio.
251. A further reason why risk estimates basedon the sex-ratio shift are not being made in this reportlies in the limitation of the data themselves. The largest
and dosimetrically best known material is still thatcollected among the irradiated populations of Hiroshima
and Nagasaki.38 ~ Doses in the parental populations
were between 0 and 200 rads, however, and the observed shift was not significant.
252. Some effect on the sex-ra,tio may also be expected after paternal irradiation, primarily as a consequence of the induction of sex-linked dominant
Jethals. The expectation has not been conclusively borneout by observations in man, and experimental studies
have shown that in mice the results of paternal irradiation cannot be explained on the sole basis of the induction of sex-linked dominant lethals. 384 • 385
253. No other human data are yet available thatwould make it possible to obtain risk estimates for the
induction of point mutations. As in the 1962 report, it
will therefore be necessary to base risk estimates inman on ~ates of induction observed in the mouse.
However, it is no more possible now than it was in
1962 to assess how close the rates of induction in man
and in the mouse might be. For want of better data,
it will be assumed that rates of induction of mutations
are the same in man and in mice, but the arbitrary
nature of such an assumption needs to be underlined.
The possibility that rates of induction may be higher in
man than in mice should not be overlooked.
254. The average rate of induction of mutations at
twelve specific loci in mouse spermatogonia exposedin the range 300-600 R acute x rays is estimated to beabout 1 X 10-7 per locus per roentgen (paragraph 133).
The confidence limits. when this figure is used as an
estimate of the average rate for all loci in the mouse,
are presumed to be about one order of magnitude apart.
255. The size of the human genome in terms ofloci at which detectable mutations arise was estimatedin paragraph 24 to be between 7.000 and 70.000. As
mentioned earlier, the estimate, although Yery crnde,
is in agreement with similar but more precise estimatesvalid for Drosophila. It also agrees ·with a number ofother published estimates of the number of mutableloci in man.

256. Ii the rate of induction of specific locus mutations assumed to apply to man (paragraph 254), is
multiplied by the estimated size of the human genome,
the resulting estimate of total risk of point mutationin man is 2 X 10-3 mutations per gamete per roentgen.
Taking into account the variability of the data on which
it is based, it can be assumed that the approximate
confidence limits of the estimates are between one andtwo orders of magnitude apart. 'While this range reflects
the sampling variability of the estimate, the dubiousness of some of the underlying assumptions must also
be borne in mind.
257. It will be recalled that direct estimates of thetotal rates of induction of lethal recessives in mice havebeen obtained from two independent sets of experiments and are remarkably close (paragraphs 143, 144).
Allowing for the fact that these estimates measure only
a known part of the damage measured by experiments
at specific loci makes it passible to compare direct
estimates of the rate of induction over the wholegenome "';th those obtained indirectly. The direct
method gives a lower estimate (- 0.5 X lo-3) than
the indirect method. The upper confidence limit of thedirect estimate (1.6 X lo-3), however, is well within
the range of the indirect one. Such an agreement gives
strong support to the estimate discussed in paragraph
256, especially as the direct estimate is based on asmaller number of assumptions.
258. The nature of the damage measured by the
total rates of induction is as difficult to assess as isthat measured by the total rate of spontaneous mutation
which was discussed in paragraphs 25-27. The total
rate of induction includes all mutations of every degreeof dominance and harmfulness. They will all eventually
he eliminated from the population.
259. The mechanisms through which the spontaneous mutational damage could be eliminated werementioned in paragraph 27. These mechanisms also
apply to the induced damage, but the relative contribution of any mechanism to the process of elimination
cannot in the current state of our knowledge be assessed. It is therefore not possible to express damage,as measured by the total rate of induction, in termsof individual or collective hardship.
260. If observations made in Drosophila can be used
as a model for the situation obtaining in man, the induced damage will initially be eliminated at the rateof 4-7 per cent per generation. The rate will, after a
few generations, taper off into a rate between 1 and 2
per cent that will persist approximately at the samelevel until all the induced damage has been removed.
Genes will persist in the population for periods of timeinversely proportional to their rate of elimination andtherefore dependent upon the severity of their expression in heterozygotes. If a population was steadilye."'posed to a constant amount of radiation per generation
for a number of generations. the rate of elimination of
the damage would tend to become equal to the rate ofinduction.
Risk of induction of dominant mtttations
261. The difficulty of evaluating the total mutational
damage in socially meaningful terms justifies attempts
to obtain independent estimates of that part of thedamage that can be expected to find its expression in
an indisputably injurious way. Experimental data thatlead to high estimates of dominant skeletal damage inthe mouse were discussed in paragraphs 151-155. While
it is too early to evaluate from these data the effects

123

at lo\v doses, the Committee wishes to emphasize that
this type of observation may in the future offer a clue
to the estimation of risks of induction of dominant
mutations in man. In the meantime. domina.11t damaae
in man can only be estimated for that portion of the
genome that is responsible for a selected group of
dominant traits (paragraphs 8-11 ).
262. 'When the Committee reviewed genetic effects
in 1958 and 1962, it gave estimates of the expected
frequency that these traits would reach in the population at equilibrium under conditions of steady irradiation. It is. however. more informative and more consistent with the approach adopted for estimating theover-all mutation rate if the rates of induction after asingle e..xposure are obtained, and this approach will
be followed here.
263. For that purpose,· the rate of induction per
locus per roentgen ( 1 X 10-7 ) as observed at specificloci in the mouse will be used. The rate, however.
applies to recessive mutations. It will be recalled (para~graphs 149, 150) that limited mouse data show thatthe over-all rate of induction of dominant v1sibles is
considerably lower than that of recessive visibles. Theinterpretation of that phenomenon is difficult, but it
cannot be excluded that it may in part reflect a lower
average rate of induction of dominant mutations. The
rate of induction used therefore can only be considered
as an upper limit, for it probably over-estimates therate of induction of dominants, though by not morethan two orders of magnitude (paragraphs 149, 150).
264. As discussed in paragraph 9, the part of thehuman genome under discussion, namely that responsible for some fifty dominant traits most commonly
observed and easily detected, consists of at least fiftyloci and is unlikely to consist of as many as 500.
Multiplying the assumed number of loci by the rateof induction discussed in the previous paragraph gives
a total rate of induction ranging from 5 X 1()-li to
5 X 10-8 mutations per gamete per roentgen depending
upon the assumptions concerning the number of loci involved and the proportion of dominant mutations
induced.
265. Assuming full penetrance. the damage thus
estimated will become apparent in the offspring of
irradiated subjects and. because of the reduction of
fitness that it entails (paragraph 11), will, on the
average, persist in the population for some twenty-fivegenerations. The genes responsible for those traits
that more drastically impair fitness will be eliminatedin the first generation. whereas the mildest ones will
persist for a very Jong time. Under conditions of steady
irradiation for several generations, the frequency of
the induced traits in the population would build up toa value equal to the rate of induction.
Efject.s of cell stage and type of irradiation
266. As mentioned in paragraph 248, all mouse
data used for numerical estimates have been derived
from e.."<periments in which mouse spermatogonia were
irradiated with high, unfractionated doses of acute, low
LET radiation. However. it needs to be emphasizedthat the final yield of mutations bas proved to bedifferent when the germ cells of mice are irradiat1:dwith (a) lo\v doses, (b) fractionated doses, (c) chromeradiation, and ( d) high LET radiation.
267. As has been discussed in part III of ~sanne..x. experimental results in a number of species
show that matters may differ considerably when othergerm cells are irradiated. On the basis of results oh-tained at seven specific loci in the mouse, acute x-ray
irradiation of oocytes at high doses yields more mutations per unit dose than acute irradiation of spermatogonia. Although the rate of induction in oocytes
is known with little precision, data suggest that it may
be twice as high as in spermatogonia. When individualsof both sexes are irradiated, the total number of mutations induced will therefore be about SO per cent higher
than if oocytes had the same sensitivity to radiationas spermatogonia.
268. Preliminary results indicate that in oocytes theyield of specific locus mutations per unit dose after
50 R acute x rays (paragraph 170) is significantly
lower than would be expected from results of irradiation at higher doses. It seems therefore that low dosesof radiation are relatively less mutagenic than highdoses of radiation, at least in oocytes. Since humanpopulations are more commonly e..xposed to low thanto high radiation doses. it might well be that the estimates of genetic risks which are presently made will
eventually prove to be too high.
269. Experiments with spermatogonia and oocytes
have shown that chronic radiation is mutagenically lesseffective than acute radiation. Under conditions ofchronic irradiation of spermatogonia the yield of mutations per unit dose at rates of about 1 R per minuteor less is about one-fourth of that at 90 R per minute(paragraph 156). With oocytes, the reduction of themutation yield is even more pronounced (paragraph157). \Vhen both sexes are exposed to low dose-rate
x or gamma radiation, the over-all yield of mutations
can therefore be expected to be between one-eighth andone-fourth of that expected when the same population
is exposed to high dose-rate radiation. Preliminary
data indicate that a small dose-rate effect obtains withlow doses of neutrons in mice oocytes but not inspermatogonia (paragraphs 187, 196). More detailed
information is needed before this dose-rate phenomenon
with neutrons can be taken into account.
270. Results of new fractionation experiments (paragraph 17 5), in which the total radiation exposure ispartitioned into small acute exposures of SO R, indicatethat this type of fractionation procedure yields mutation
frequencies which are below those obtained with single.
unfractionated procedures. Although mutation frequencies in the fractionated and unfractionated series differ
by less than one order of magnitude, it is thought that
this effect may be of importance for the estimationof human genetic hazards, because the fractionation
procedures used are similar to those used in somemedical practices.
271. Results of investigations at seven specific lociin spermatogonia show that low doses (up to about
100 rads) of acute or chronic fast fission neutrons are
mutagenically more effective than x and gamma rays,suggesting an RBE of five for acute irradiation andof twenty for chronic irradiation (paragraph 188).
Since human populations are usually exposed to low
doses given at low dose rates. it seems that in spermatogonia the rate of induction of mutations per unit doseof neutrons may be some twenty times higher thanthe corresponding rate ior x or gamma rays.
272. The final yield of mutations is not only affectedby factors associated with radiation procedures but also
by biological factors. One of the latter factors has
recently been discovered and may have an important
bearini; on the estimation of genetic risks from irradiation of germ cells of females. Experiments w1th female
mice have shown that the interval between irradiation124

and conception has a very pronounced effect on themutation frequency observed in the offspring (paragraph 182). The frequency obtained after irradiationof females with low doses of neutrons is high in thefirst few weeks after irradiation, but, after that period,
drops to a very low value, in fact zero in the sample
size studied so far. Similar results have been obtainedwith x rays. There is a possibility of a similar effectin man and, therefore, an indication that the genetic
radiation hazard from the exposure of women may,on the average, be less than that calculated on the basisof female mouse mutation rates obtained in the earlytime interval after irradiation.
CHROMOSOME ANOMALIES

273. The estimation of risks of induction ofchromosome mutations can only be made on grounds
as tenuous as those on which the estimates of risks of
induced point mutations are based. \Vhile with regard
to the induction of point mutations detailed and reliable
quantitative information from Drosophila and from themouse can be used, no comparable amount of data isavailable concerning the induction of chromosome
anomalies. But the induction of point mutation is notborne out by direct observations in man, and thecorresponding quantitative relationships between doseand effect are unknown. To estimate risks of inductionof point mutations in man, a very major step is therefore
necessarily involved in extrapolating from the experimental animals to our own species.
274. With regard to the induction of chromosome
anomalies, on the other hand. there is clear evidence
that a number of them can be induced by radiationin human cells in vitro. Preliminary observations suggestthat some can be radiation-induced 1'.n vivo in germ
cells. However, information on rates of induction in vivo
in man is absent. and that obtained from humanperipheral blood cells irradiated in vitro must be supplemented with observations in experimental animals.
275. Inferences regarding the induction of chromosome anomalies in our species based on animal material
are especially open to criticism, inasmuch as the radiation sensitivity of chromosomes is k-nown to change
from one species to another. Thus, there is someevidence that human somatic cells might be moresensitive to the induction of chromosome anomalies byradiation than those of mice. Likewise, e..xtrapolations
from in vitro studies of human cells can also be quite
misleading because of the known dependency of chromosome sensitivity on a number of factors associatedwith the stage and metabolism of the irradiated cells.
276. It was shown in part II of the present review
that constitutional chromosome anomalies are responsible for a large part of the defects of genetic origin
carried by human populations. Most of the anomalies
are eliminated either pre- or post-natally in thegeneration immediately following the one in which
they have arisen, and are associated with very severe
hardship. Some. however. notably translocations, canbe transmitted for a number of generations and are also
the cause of serious harm to those who carry themin the unbalanced state.
277. Only for some types of chromosome anomalies
can tentative risk estimates be obtained. These will be
discussed in the following paragraphs. The estimates
apply to a minor fraction of the total spontaneouschromosome damage detectable in the population. No
estimate of the over-all risk of induction of chromosome

techniques would not make it possible to detect thosetranslocations that involved small quantities of chromosome material or fragments of equal size. Finally, invitro observations are available only on somatic cells,
and it does not necessarilv follow that, if the anomalies
that were observed in vitro occurred in pre-meiotic
cells in vi1:o. they would be transmitted to a viablegamete. as is indicated by the fact that haplo-21 zygotes
appear not to be viable, whereas haplo-21 somatic cells
are. 113285. Rather than determine the frequency of translocations in vitro. most authors have therefore assessed
the frequency o{ breaks, dicentrics and ring chromosomes. Breaks are events whose frequency rises linearlywith dose, whereas the frequency of dicentrics and ring
chromosomes, like that of translocations. at least wheninduced by x rays, is proportional to the square of thedose at low doses and to its l.Sth power at high doses.
At very low doses, the effect may be proportional to
the first power of the dose.
286. The number of dicentrics and of ring chromosomes obtained through irradiation of blood cells at
e..xposures between 50 and 200 R is 0.52 X 10-5 percell per roentgen squared of which 0.45 X 10-5 aredicentrics. 187 The rate of 0.27 X 10-5 dicentrics percell per roentgen squared was also obtained. 386 but itis perhaps less relevant because it is based on observations at exposures ranging between limits too far apart(25 to 1,200 R).
287. If it is assumed that translocations on one sideand rings and dicentrics on the other are induced at
the same rate, and that rates at high doses increase
with the l.Sth power rather than with the square of
the dose, the expected translocation rate after 1,200 R
based on in vitro data is approximatell 21 X 10-2translocations per cell (or 18 X 10- if only the
results on dicentrics are taken into account). Thisrate is fairly close to that deduced from semi-sterility
daita in mouse spermatogonia. Under the same reservations as were formulated for that case, the rate oftransmission of translocations through the gametes
would be four to six times less.
288. The rate of induction of translocations is known
to be highly dependent on the rate of delivery of radiation. The estimates of rates of induction discussed in
the previous paragraphs refer to acute irradiation. The
actual rates under chronic irradiation mav be considerably lower, as indicated by the mouse data discussed
in paragraphs 118 and 124.

anomalies can be obtained in the current stage of ourknowledge.
Changes in chromosome mmtbers
278. E.."'perimental results indicate that in Drosophila
the frequency of sex-chromosome loss rises linearly withdose below 1,000 R (paragraph 82). The rate of induced loss per pre-meiotic cell is very close to thatobtained from irradiation of mouse spermatocytes at
200 R-between one and four chromosomes per
100.000 cells per roentgen. A comparable figure fornon-disjunction cannot be obtained, because in that casethe dose-effect relationship as observed in Drosophila
is more complicated.
279. The possible importance of the induced sexchromosome loss in man becomes apparent when it isrecalled that XO karyotypes have been identified in
5 per cent of a sample of aborted foetuses and may
therefore be responsible for a sizable proportion of
spontaneous miscarriages. However. the possibility thatat least part of the observed losses may have occurred
after fertilization cannot be excluded.
280. No estimate of risk can, in the present stageof our knowledge. be obtained for the induction oi
losses or additions of autosomes. Some still inconclusive
evidence, indicating that they may be induced byradiation in man, was mentioned in paragraph 66.
Tra11slocatio11s
281. Translocations in experimental animals areassociated with. and frequently recognized through, theincidence of semi-sterility. In man, semi-sterility is ahardly applicable criterion, since the family-size usually
falls very short of the natural fecundity of the species.
The importance of translocations in human populations
lies, therefore, much more in the suffering that they
involve for those who receive them in the unbalanced
state than in the effect they may have on the fertilityof carriers of balanced translocations.
282. The estimation of risks of induction of translocations in man may be approached either from results
obtained in mice or from results obtained in humancells in ·vitro. As discussed in part III (paragraph 116),
from the incidence of semi-sterility in mice irradiatedwith 1.200 R of x rays, the number of induced translocations has been estimated to be approximately 14.8
X 10-2 per pre-meiotic cell. The estimate is based on
the assumption that translocations are not further transmitted unless they are balanced. that no selection takes
place between normal cells and cells carrying a balanced
translocation, and that non-disjunction does not bias
the observed frequencies of the translocations that arerecovered.
283. In this connexion. it must be borne in mind
that some of these assumptions may not strictly apply
to man. since in our species the association of translocations with trisomies 21 does occur with a frequency
of about 5 X 10-5 of all live-born children (paragraph42), and the viability of cells carrying balanced translocations may. in fact, be different in mice. since thespontaneous frequency of translocations seems to belower than in man.
284. The use of cell cultures to estimate the frequency of radiation-induced translocations is also far
from being free from objections. For example. it is
not possible to determine directly the rate of inductionof translocations by radiation. because. even if the
karyotype of each scored cell were established, present

Deletions289. Estimates of rates of induction of deletions inhuman germ cells are not available. but an idea of thepossible magnitude of the risk of induction of certain
clinically significant deletions can be obtained on thebasis of the rates of induction of deletions by radiationin human cells in vitro. Induced rates in vitro areprobably reliable, since they are consistent with scantierobservations on peripheral cells of subjects irradiatedaccidentally in vivo. 1G·t
290. It is not known whether one single break issufficient to bring about a stable "terminal" deletionor whether, in fact, an additional break is required
to make it possible for the telomere to attach itself
to the centric fragment. The linear rise of the frequency of terminal deletions in vitro (paragraph 69)
speaks in favour of the one-hit theory.
125291. To obtain estimates of the risk of induction of
given syndromes due to terminal deletions, it is necessary to know the size of the fragments whose loss
is responsible for each syndrome. As mentioned in paragraphs 39 and 40. the following terminal deletions are
known to be associated with clinical syndromes severely
detrimental but compatible with survival : deletion ofpart of the short arm of chromosome 5 ( cri du chatsyndrome), of the short arm and of the long arm of 18,
and of the short and of the long arm of the X chromosome. It is not known whether any other deletion, be it
terminal or interstitial, is compatible with survival nor
to what sort of detriment it may be associated.

297. Even taken together, the estimates given earlier
do not meet these requirements. The risk of inductionof dominant mutations (paragraphs 261-265) applies
to those major and easily recognizable traits that areclearly undesirable from the individual and social pointsof view. These traits are frequently observed in all
known populations. That damage would always be aminor fraction of the over-all damage due to point
mutations, though a particularly conspicuous one, bothbecause of its immediate manifestation and its persistence for a number of generations, and because of thenature of the detriment to which the risk estimate
applied.

292. In the cri du chat syndrome, the size of thetarget, i.e .. the length of the segment of chromosome 5
where a break must occur to produce the required deletion, amounts to over 50 per cent of the short arm of
this chromosome or to about 1 per cent of the lengthof the diploid chromosome complement. This has been
estimated387 by studying the variations in length of
the residual fragment of the short arm of chromosome 5in the known cases of cri du cha.t syndrome.

298. An approach to the estimation of damage frominduced dominant mutations could in the future result
from the application to man of the observed frequenciesof skeletal defects in first generation irradiated mice(paragraphs 151-155). However, it is not certain thatcomparable rates of induction apply at low doses.

293. Observations 1 fi 7 on blood cells irradiated invitro have shown that x rays induce 1.1 X 10-3 deletions per cell per roentgen. If a single break wereenough to bring about the cri du chat syndrome, thedeletion would be expected to occur with a frequency of
1.1 X 10-S X 10-2 = 1.1 X 10-5 per cell per roentgen.
If two breaks were required, the expected frequency
would be lower than the square of this (i.e., 1.2 X 10-10
per cell per roentgen squared).
294. Similar estimates can be obtained for the otherdeletions mentioned previously. Deletions of part of theshort and of the long arm of chromosome 18 compatible
with survival involve 0.25 and 1 per cent of the lengthof the diploid chromosome complement, respectively,
leading to estimates of 0.3 X 10-S and 1.1 X 10-11 deletions per cell per roentgen in the case of single events,and of 0.8 X 10-10 and 1.2 X 10-10 deletions if two
breaks are required. Likewise, deletions of the shortand of the long arm of the X chromosome, involving
3 and 4 per cent of the complement length, respectively,
would occur with probabilities of 3.3 X 10-6 and4.4 X 10-5 deletions per cell per roentgen if one break
was required, and 11.0 X 10-10 and 19.0 X 10-10 deletions per cell per roentgen squared otherwise.
295. Nothing is known about the selection that deletions arising in germ cells might undergo. It is conceivable that a fraction of those that radiation may
induce would be eliminated sometime before birth orperhaps before fertilization. Neither human nor e.xperimental data are available which would make it possible to assess the extent of the elimination.

299. The over-all risk of induction of all point mutations, which are all assumed to have some degree ofdominance and to be eliminated predominantly in heterozygotes (paragraphs 253-260), includes the risk of
induction of dominant mutations discussed in paragraph 297. One major practical limitation of the overall risk estimate is due to the fact that the damage
that is thus assessed is expressed in terms of loss ofmutants through generations. This Joss has a clear
biological meaning, and has an undesirable characterfor the individual and for society. However, we do notknow how many of the harmful mutations induced byradiation will at some point be eliminated through, say,loss of a zygote before implantation-an event which
is not usually detectable in man-rather than throughdrastic reduction of fertility, miscarriages or serious
genetic defects. But the estimate does, at any rate,
provide the required upper limit to the damage due
to point mutations.
300. This is, however, only part of the induced
damage, since it does not include that due to chromosome anomalies. At present, we have no way of estimating the over-all risk of induction of chromosome
anomalies. Their high frequency in human populations
makes it likely that such a risk may not be negligible.
\Ve only have estimates of the induction of se."<chromosome loss (paragraphs 278-280), of translocations (paragraphs 281-288) and of those deletions thatare known to be associated with severe clinical syndromes (paragraphs 289-295). The total damage frominduced chromosome anomalies is likely to be higher,
but our present knowledge is inadequate even to guess
its possible magnitude, while such partial estimates as
we have discussed are based on assumptions that makeconclusions conjectural or, at best, very tentative indeed.
301. In considering the significance of radiation
damage to the genetic material, it may be of interest tocompare it with the rate of naturally-occurring genetic
changes. It was estimated in the report that. on the
average, a total of 140 point mutations arose spontaneously in I.OOO gametes in each generation and that
under conditions of acute irradiation at high doses one
rad induced a total of hvo mutations per 1,000 gametes.
Thus a dose of one rad per generation would add about
one-seventieth to the total number of mutations arisingspontaneously per generation. To this point mutational
damage must be added that due to chromosome anomalies which occur spontaneously in I per cent of liveborn children. It is not possible at present to estimate

V. Conclusions
296. The estimates given in the preceding paragraphs
must be e..'Camined in the light of the practical value they
have in assessing the detriment that will result fromexposure of human populations to any source of radiation. For that purpose. risk estimates must. ideally.
be comprehensiYe, therefore taking into account all
major genetic effects of social. rather than merely
biological, import. If this did not prove possible, itwould still be valuable to know the range in \vhich theover-all risk estimate lay or even an upper limit to theestimate.
126

comparative risks. This is possible only at low doses
and dose rates, in so far as linearity of the dose-effectrelationship can be accepted as a computational approximation even for those effects that take place as a consequence of more than one event. X o such approximation is allowed at high doses and dose rates, and evencomparative risks cannot be determined for them.

the over-all rate of induction of these anomalies byradiation, but the rate is expected to be very low at
low doses.
302. Since neither a comprehensive estimate of thegenetic risk. nor an upper limit to that estimate isavailable, the assessment of genetic damage from main
sources of radiation must still be made by means of
T,\BLE I.

MArn TYPE£ :JF SEX-CHR0~10so:.1E ~ros.-1.rcs or.s£R\'ED
IX

A.

TABLE

FREQUENCY OF TRANSLOCAT!ONS AMO?>G'l1USOMICS 21

Obser.;cd
ca.sesIVithoul structural a110111alies of the X chromosome

Heavily biased samples . .

(1) In Klinefelter's andrelated syndromes

XY/XXY
XX/XXYXXXY/XJCXXY

Less biased samples

XXXX/XXXXYXXY/XXXXY/XXXXXY
XO/XY/XXY(2) In Turner's and related
syndromes ........ .

Samples with little bias . .

XO/XX
XO/XXX
XO/XX/XXXTABLE

XO/XYY( 3) In the XXX syndrome(4) In other syndromes ...

XO/XY

TABLE IV.

Feeble-minded
Chromatin-positive males ..
Double-positive females ..
Chromatin-negative females
Criminals
Chromatin-positive males ..
XYY males ........... .
Sterile subjects
Chromatin-positive males ..
Females with sex-chromosome anomalies ...... .
Childless males with sexchromosome anomalies ..
Females with small statnre
Chromatin-positive females

C.

280

2

o2

58

i3

61

(8/130)

Trisomy 18

3/10,345

51
51> 0.2b

44/2JO

Frequency of structural changes
in an unselected adult population

220(165-284)5"95 per cent confidence limits.

b Higher than

127

8.77

2

0.2
(0.021-0.69) a
0.3(0.058-0.85)

1.7( 1.16-2.98)
1.2(0.62-2.1)
0.29(0.095-0.69)

Frcqiundcs
per 1,000 Ri!ferenccz

30

2/10,345

Over-all frequency of anomalies
in spontaneous abortions ..... .

388

60

Trisomy 13

5/16,920

4.7

59

2,39

Turner's syndrome . . . . . . . . ..

2
2.1

30
43
390
44

20

1.5

12/10.000

389

4
1.7

35

1,522/1,022,042

XXX syndrome ............ .

5(lj/760)(7/197)

Reftrnices

31/18,147

30
40
41

2
2
2
2

Freq11tncy
ptr 1,000

Cri d11 chat syndrome ....... .
Klinefelter's and relatec! svndromes ................. ~ ..

11.8
7.9
7

9.jl
4.46
0.37

cases

A. Individual anomalies among liveborn children
Trisomy 21 . . . . . . . . . . . . . . . . . .

Refen>1cu(29/3,306)(70/7.358)(12/2,689)(1/2,689)

FREQUENCY OF SOME CO:O.D!O:S- CHUOMOSO~!E ANOMALIESObJCt'!'td

Per cer.t

frequency

FREQliENCY OF ANOMALIES IN' SEX-CHRO~{OSCMENUMDER IN SE.l.ECTF.ll POPliLATIONSOburJtd
C4Jes

1-Vith stnictural sez-chromosome a110111olies

B.

Ill.

(13/1 to)(18/227)(3/41)(5/101)(2j/652)(1/58)(4/203)(2/96)(6/127)

XX/X.XX
XY;XXXY
XX/XXY /XXYYY
XX/XY

B.

II.

~!.\NSO-ll~, 3,;_3;

62-66
64

62-66
82

56,57
frequency oi trisomy 13.

TABLEV.

RATES OF INDUCTION OF CHROMOSOME AXO?.!ALIES BY ACUTE IRRADI..\TION
OF BLOOD CELLS

X rays
Chromatid breaks per cell per roentgen ........... .
Chromosome breaks per cell per roentgen ......... .

Deletions per cell per roentgen .................... .
Dicentrics per cell per roentgen squared ........... .
Dicentrics per cell per rad squared

TABLE VI.

0.26 x 10-2
0.24
10-2
0.39
lQ-!l
0.69 x 10-2
0.11 x 10-2 ± 0.012
0.45 x 10-5 ::!: 0.07
0.27
lQ-5 ± 0.014
0.09 x 10"~

154
154

x IQ-2 ± 0.022
x 10-2 ± 0.06

161

x
x

x

155
156
157
15i
386
156

14 MeV neutrons
Deletions per cell per rad ......................... .
Ring and diccntrics per cell per rad squared ....... .

0.23
0.81

25 MeV neutrons
Deletions per cell per rad ......................... .

0.26 x 10-2

162

Fission neutrons
Deletions per cell per rad ........................ .

0.45 x 10-2

162

161

FREQt:E.."'CY OF SPONTANEOUS AXD RADI..\TION·INDUCED SEX-CHROMOSOME AXOMAL!ES IN MALE AND FEMALE GERM CELL
STAGES IN THE MOUSE

lrradi4ted gnm cell stage

E:poJ11rt

Animalsclassified

150-250(weighted mean,
220.5)

2,402(R)

Adjustedb induced
freq,.,,ncy 1>er R per 1()II

Spontaneou.sfrequency(per unt)

Loss ofxPorY

XXY

Refertnus

1.51

0

179

3.34

0

Xl!U•

FEMALE GERM CELLS

Prophase primary oocyte (irradiatedfoetuses and newborn, 13;4-20~~ days
post-conception) .................. .

785

CONTROLS ••..•....•.•.••.••.....•.

Dictyate (irradiated adults ; ovulations
1-32 days post-irradiation) ....... .

0.0

100-400(weighted mean,
342.0)

331

200

1,508

1.6

0

20G

2,370

3.6

0.4

20t)

1,752
3,059

0.7

0

0.06

1,656
1,299

0.13

1,112
1,285

0.14

MALE GERM CEI.l.S
S~erm~to~es (mating 36-42 days post-

1rra<l1atlon) . . ................... .
Sp.erma.toc;ytes (mating 29-35 days po.::t1rrad1atlon) ........ _.. . ......... .
Spermatocytes (post-pachytcne, 22-28
days post-irradiation) . . . . . . . .....
CONTROLS...........•...•....••....

177

S~rm~ti~s(mating 15-21 days post1rrad1ation) ...................... .

CONTROLS . . . . . . . . . . • . . . . . . . . . . . . . . . .

Spermatozoa (vas and epididymis) ..

60(1CONTROLS . . . . . . . . . . . . . . . . . . . . . . . . . . .

5.7

177

2.0

177

PRONUCLEUS STAGES

Q anda early pronucleus

422
227
193
70
822
196

100

100
Q

and (; mid-pronuc!eus

100

200
Co~rnoLs" XlIQ was the only spontaneous sex-chromosome abnormality observed in controls. OXP and XXX occur
spontaneously with very low frequencies.li3

19.0
17.6
0
0
0.97
0.51

23.2
12.5
0
2.1

0
0
0

0

177
178
li8
li7
177
178

b Irradiated minus control frequency. In the case of Xlt
loss, frequency is calculated by taking account of the fact that
OY is levhal.
c Loss of entire chromosome as well as a iew cases of
deficiency.

128

J

T.~BLEVII. DO:l!IXAXT LETHALS IN SPER~rATOCOXIA OF :II!CE
Ra:e ofdelivtry(R/min)E.rposurr(R)

lttduced Pre·

Induced post·lo.ssesl.

lossesb

dominant /et/:a/s'

0.02

0.02

Total rate':/implan:atfr,n

imp/an:a:ion

indicction aRt•fert:nce

196

()

69

550
0
300
0
200
0
600 + 600
8 weeks

391. 392
100

0.06d

0

0.04d

100

0.01

0

0.01

217

U.01

(l.11

0.02

0.02

195
198

apart

194

0
1,200
0
275
55 5•

0.017

197
0.04

75

x

i5

implanted embryos/corpora lutea in irradiated series
implanted embryos/corpora lutca in control series
live embryos/total number of implants in irradiated series .
live embryos/total number of implants in control seriesb 1live embryos/corpora l:ttea in irradiated series •c 1 - live embryos/corpora lutea in control seriesd Significantly higher than controls.
e 5 R per day for fifty-five consecutive days.

" 1-

TABLE VIII. INDUCTION OF DO:IIINANT LETHALS IN GER:I! CELLS OF J\IALE MICE
E.4'jlosure(R)

Weeks after irradiation

300

Total rate of induction of dominant letha)sa ........... ·······
Post-implantation deathh ........
Total rate of induction of dominant lethals• ' ....... ... ' ...
Post-implantation deathb .........

300
200
200
a

..

z

3

0.21
0.19

0.15
0.01

027

0.23
0.20

0.13
0.12

0.42
0.32

1 _live embryos/corpora lutea in irradiated series .
live embryos/corpora lutea in control series

b

0.38

5

6

7

8

Rcfumces

0.28
0.08

0.28
0.05

0.24

0.05

O.o4

391, 392

0.30
0.13

0.40
0.21

0.55
0.09

0.44
0.13

0.01

195

1 _live embryos/total number of implants in irradiated series
live embryos/total number of implants in control series

TABLE IX. RATE OF INDUCTION OP DOMINANT LETHALS
I:s POST-!liEIOTIC CELLS OF VARIOUS MA~O.BLS

Mammal:Mousen

1fouseb

Rat8······ ..

...........

Guinea pigc
Guinea piga

Rabbitn

Rabbitc........
·······.

E.rPomre(RJ

Corporalute a

0
400
670
0
400
500
600
700
0
400
670
0
500
0
300
450
700
0
450
600
0
500

387

Per cent
ind,.eed pre·implantatW..
lossesPer cent
induced post- Total rate of
implantatW..
induction oflossesdominant let/uJ/s

References

208

248
178
1,244
1,029
1,052
1,120
1,165
758
419
403
59
95
69
47
46
40
203
214
195
32
105

13
28

40
51

4S
65.6

15
16.6
18
23

21
35
41
45

33
45
51
.58

13
29

49
61

55
72

2

43

44

13
28
50

10

25
45

65
63

18
17

71
69

49

16

Si

391,392

200
393
209

208
393

a Matings within 3 days after irradiation.
b Matings within 4 weeks after irradiation.
c Matings immediately after irradiation.

129

TABLE£;pos11rt
(R)

100
100
100
100
100
100
200
200
200
200
200
200

x. DOMINANT LET HALS IN OOCYTES OF MICE215

Oifryte stage

Corpora lutea

A

B

668
250
217
266
184
227

0.20
-0.07
0.43
0.37
0.29

0.02
-0.09
0.35
0.20
0.22

149
668
279
309
185
193
274

0.11

0.05

0.11
0.38
0.74
0.69
0.57

0.14
0.36
0.75
0.68
0.55

130

0.15

0.21

Control ......... ·········· .....
Dictyate .......................
Late prophase I .................
Metaphase I . ···--·· ...........
.i\naphase I .....................
Metaphase II ...................
Pronucleus stage before or during
DNA synthesis .... ···········
Control . ··········-············
Dictyate .......................
Late prophase I . ···-···· .......
Metaphase I ....................
Anaphase I ·····················
Metaphase II ··················
Pronucleus stage before or during
DNA synthesis ................

.

A-total rate of induction (see footnote n to table VIII).
B-induced post-implantation deaths (see faotnote b to table VIII).

TABLE

XI.

bposure(R)

Rate ofdelivery{R/min)F,
Males··········

0600+ 600

217

2 ..........

0
1,200

0.017

E.r:periment

3 ..........

4 ...........

5 ..........

6 ..........

i - ..... ....

n 95

0
700

TRANSLOCATIONS IN SPERMATOGC•N!A OF MICE
P~r 1.-.111

Per cent

427
427

0.2
3.5
(1.7-5)o.

109
104

216
214

0.0
0.9

Yes

?
1,010

?
0.5
(0.02-1.6)

Yes

69

80
80

0.0
0.0

1,092

Acute

110

2.7
(0.6-8.7)

scn:i-

sterile

Total
F,

0
6.7

536
531

25
25

0,0
0.0

Yes
198, 223

Ko

196
~o

225
1,037
452

iOO

Acute

444

1,000

Acute

238

i5

References

224

Acute

112
112
112

0.2
4.1
(2.4-5.8)

c:ylo·

logically

194

0
350

75

CheckedF,
Females

0
550

0
275
55 x 5h

Per cent
semi..
sterilesemi·
sterile

0.0
0.0
0.9

0.0
2.2
(1.1-4.0)
3.2(1.4-4.8)__ ;,Partly(0.9-5.4)

PartlyPartly226

Partly

?~

197

Xo

per cent confidence limits.
per day for fifty-five consecutive days.

b5 R

130

-------,
T ABU:. XII.

N.UURAL AND INDl.:CED MUT.-\TION RA!E5 AT SEVE!';

Total
SourctX rayc.rposure
(R)

300
600
1.000

X ray
X ray
X ray
(;-060 x ray ............. .
cs131

600
600
600
600

c51a•

300

Rott ofdelivery(R/min)SPECIFrC LOCI IN

Number ofoffspring testtd

80-90
80-90
60-70
24

119,326
31,815
10,761

111

23
11
33
23 (14)10 (10)

10.3
14.6
10.6
8.1 (7.1)
5.1 (5.1)

10
5
12

2.4

2.7
7.1

2
16

3.9

237
237
237
237
395
288

1.4
1.4 (1.5)

237

0.009
0.009
0.007-0.009

26,32524,281
10,763Fission neutronsn

37.5
86
300
600
307

0.005
0.0011-0.0078
0.001
0.001
0.001
0.002-0.003

58,79563,32259,810 (56,993)•
49,56;Jf
31,652!
41,875!

Fission neutrons

207

55-60

39,028!

Fission neutrons

104
101

0.001
0.13
0.17

39,083!
19,506!
18,194f
17.04Jf

Csl3i
Co CO

603
609

cono
Co60 and radium ....... .
cs1a1

Cs137

................. .

Cs137................ .

Fission neutrons
Fission neutrons
Fission neutrons
Fission neutrons

C-0NTROL

63
59
59/'Cr ¥t:mcte X 10'

8.7 (8.8)
13.3

28,059 (27,840)•
58,457516
861,.l[ ut:Ztions p~r locus

40 (25)9c51a1

Number ofmutationsobser.:ed

AND OOCYTES

65,548 (40,408)•

0.8
0.009

.............. .

SPER)!ATOf,(!NI.-\

80-90

44,35240,326 (28,339)PX ray

ADULT )IOUSE

0.79
79

.•••.•.••••••••

6
6 (6)

15
13
67
8

2.7

394
395
396
237

247

4.3
5.9
22.9

237

2.9

287,397
287,397
237
237

237
288

14.6
102
10.1

16.758f

27
20
13
12
10

8.5

237

531.500 (544,897)•

28 (32)0.8 (0.8)

237

15 (16)7 (13)

19.3 (17.8)
4.8 (5.2)

237

9.9

237

06CYTESX ray . . . . . .. . . . . . . .. . . .

c5 1s1 . . . . . . . . . . . . . . . . . .
Cooo . . . . . . . . . . . . . . . . . . . .
Cs137. . . ... . .. .. . . .. . ..

cs1s1

. . . .... .. . .. ... . ..

coao . . . . . . . . . . . . . . . . . . .
X ray . . . . . . . . . . . .. . . . . .
X ray . . . . .. . . . . . .. . . . . .
Fission neutrons
Fission neutrons
Fission neutrons
Fission neutrons
Fission neutrons

C-0NTROL
C-0NTROL

400
400
600
400
258
450
50
SO

63
63

63
63
104

90
0.8
0.05
0.009
0.009
0.004
81
81
79
79
0.17
0.17
0.001

11.124 (12,853) b, e
20,827 (36,083)•
10,11737,049f
27,174
11,225 1
127,391"• f
54,621d, f

2

1

0
10

0

43,000•· r
40,092d, f

37
046,301•· t
80,391d, t

22

0

12,0SSt

98,8280

13,402n Neutron doses in rads (gamma component is included).
b Includes data from an old experiment, which was later
excluded.
c Oocytes sampled up to first seven weeks aiter irradiation.

131

d O&ytes

1.4
0.8
0.5
0
1.1
0
12.2
0
6.8
0

237
401
237
237
397
268,269

268,269
284
284
284
284

1.2

397

0.14

396

0

397

sampled more than seven weeks after irradiation.
•Revised from the 1962 report.2
t New data.237

TABLE

Species

XIII.

SPECIFIC LOCUS

MUTATIONS IN EXPERIMENTAL ANIMALS

Spontaneous "'"tati<m rates at individuoJ lociPtr generation X 10' induced mutation rates
ptr Jo..--.u per gamete per R X ltJS

Number"/ lociteste

E.rposure(R)

Rate ofdelivery(R/mi'11)

7

0
400
600

90
60-90

22

0
600

88

0
5

0
900

85

1.5

Mouse ........

Mouse ........

6

Drosophila ....

8

Dahlbominus ..

4

Spern1atogo11ia Oooo11ia

752

238

M ormo11iella

..

5

552
30
45

100
100
100

400

65
8,900
65
23

0

0
1,136

267,39990Re-locus•

2

599
1,000

1,00Qb
1,000
1,000

1,000
1,000
0
1,000
1,000
1,000

144
48

0

1,000

Refere11us

398

1,000

Bomb}•.i" ······ Pe-locusa

Ooc:yles60-10060-10060-100

28
0
32
9
6

60-10060-10060-100

266

9.200
28
12
18
8,800
24

5
12
717

311

14

854

a Cells irradiated on the seventh, eighth or ninth day after hatching of the larvae.
older stages of oocyte development.

b Progressively

T •.\BLE XIV. SEX-LINKED RECESSITJ!: LETHALS IN
SPERMATOGONIA OF Drosophila LARVAE257, 25S

Total

1rponcre(R)

Rate ofdclivtr:1(R/mir.)Number of offsprinotestedJf utali'on f"f11llnCY
per cent

ACUTE RADIATWN

0 ................... .
56
109
163

25,65021,53821,154
20,860
8,405
8,330

25
25
25

0
307

?"
-~

0.30 (024-0.37) a
0.40 (0.33-0.49)
0.42 (0.34-0.52)
0.43 (0.53-0.36)
0.26 (0.18-0.39)
0.26 (0.18-0.39)

CHROXIC R.-\D!ATIOX

0144 ........... .
267
300
400
542

25,738
9.583
8,310
5,i05
5,793
7,641

0.30
0.55
0.60
0.83
1.13

a 95 per cent confidence limits.

132

0.31 (0.25-0.39)
0.50 (0.38-0.66)
0.66 (0.51-0.86)
0.75
0.40 (0.27-0.60)
0.38 (0.27-0.55)

T ADLE xv.

IXDUCTION OF SEX-LIXKED RECESSIYE L'ETHALS IX OOGOX!.\ OF
111ela11ogaste1· BY "4,000'' R

Drosophilu(Modified from M11ller et aJ.203)
Rat6 ofdelivery(R/min)Room af
irradiation

7,333
7,333
7.333
2: 1 .............................. .
1.7; 1 ............................ .
0.2 ............................... .
0.2 ............................... .
0.1-0.2 ............................ .
0.1-0.2 ............................ .
0.1; 0.05; 0.02 .................... .
0.05; 0.02 ........................ .

Hot
Hot
Hot
Hot
DilutionHot
Hot
Dilution
Dilution
Dilution
DilutionAB

1.6 ± 0.2
1.7 ± 0.15
2.0 ± 0.15
1.7 ± 0.17
1.0 ± 0.09
0.86 ± 0.11
1.0 ± 0.15
1.08 ± 0.11
1.4 ± 0.11
1.25 ± 0.15
1.5 ± 0.5

1.67 ± 0.23"
2.07 ± 0.16
2.21 ± 0.17
1.44 ± 0.18
1.23 ± 0.11
0.68 ± 0.09
0.9 ± 0.14
1.28 ± 0.13
1.5 ± 0.11
1.42 ± 0.17
1.7 ± 0.6

A - Percentage observed minus spontaneous lethals.
B - Percentage after correcting ior results of sperm irradiation in females.
a Spermatid instead of spermatozoan frcqt:ency was used for obtaining correction factor.

TABLE XVI. l-IUTATJON FREQUENCY IN THE MOUSE FROM SINGLE AND FRACTIONATED IRRADIATION

Cell stage

Spermatogonia

Oocytes

Total e.1Jos11re
(R

0
300
600
1,000
600
1,000
1,000
1,000
!,OOO
1,000

{

.E.xpos11re ;,. eachfraction (R)

100 and 500
600 and 400

500
500
200
200

interval
betweenfraeti<ms

200

x o•

24 hours>15 weeks
2 hours
24 hours
24 hours
1 week

531,500
65,548
119,32644.64924,811
4,904
14,879
11,164
8,588
10,968

26.6
20.9
8.5
39.1
28.4
10.8
49.2
25.9
18.8

274
274
274
274
274
274
253
274
253
274

24 hours

37,297
12,853
6,086

40.2
44.5
52.8

274
274
274

200
400
400

Mea11 nmnberof mutations
Number of p<r loc11s par Refer·offspring roentgen•
1~HCCS

a Mutation rate in oocytes is not adjusted for the control value. Spontaneous mutation
rate in females is not accurately known.

133

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