REPORT OF THE

UNITED-NAXI-ONS .

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

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

New York, 1962

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

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ANNEX C

THE flEREDITARY EFFECTS OF RADIATIONCONTENTSParagraph.,
The dose-rate effect... ...• ........ .••... ..•.. 84-87"Repair" of pre-mutational damage. ••.. .•.• •• . 88-92
Locus specificity •..•••..•..•...., .•.•.••.•• , ,93
Sex and stage of gametogenesis•..•••.•••••••, 94-100
Species specificity •••.••••••••••.•.•••••••••,• 101
Induced chromosome aberrations................ 102-117
Observations on experimental organisms ....... 103-115
Observations on human cells.................. 116-117
Comparability of radiation-induced and naturallyoccurring mutations ..................,...... 118-120

ParagraJ,hs
1-10

J. b,"TRODUCIION

I!. THE PREVALENCE OF NATURALLY-OCCURRING HEREDITARY DEFECTS AND DISEASES......................
Survey of hereditary disabilities.................
Category la ,,••.,••,••.••••• •• ••••• .••.••.••
Category lb •.•• ••••...•••• •••• ••. . . ..•. .•.••
Category II • •• ••••••••.••• •••• ...•••••••••• •Category III •.•..•••...,•••.••• ••. •• .•• .•..•
Category IV ..• ...•.•...•.•..•. ... ••• •••••• .•Role of heredity in premature death..............
Lethal and detrimental equivalents...............
Ill. THE ROLE OF MUTATION IN SUPPORTING THE PREVA­LENCE OF HEREDITARY DIS."'1IILITIES,,, ••••••••••,•,
Relative genetic fitness••••...•••••••...•....••••Natural mutation rates at individual loci in man••
Autosomal dominant traits•••••.••.•.•..•.•.••
Sex-linked traits ....•...•.••..••.•..••..•,•.•
Autosomal recessive traits ••.•.....••.••..•,•..
Natural mutation rates at individual loci in experimental animals ..........., ..................
Naturally-occurring chromosome aberrations in
man .••.•..•...•••.•..••.•••.•••••.•.....•••Natural_Iy-occurring !=11romosome aberrations in
expenmental organisms .•••••••••••.••••••.••
Factors affecting the frequency of natural mutation

11-41
13-37
14-17
18-29
30-32
33-35
36-37
38
39-41

V. EFFECTS OBSERVED IY DESCEND-"..',TS OF IRRADIATED
POPULATIONS •••••••••••••,•,,•••••••••••,•, •, •• 121-135
Induced mutations in the immediate progeny ofirradiated humans ........................... 121-125
Induced mutations in the immediate progeny of irradiated mammals •.•••••••.•.•.••••.•..••••• 126-130
Polygenic traits ................................ 131-135

42-80
44-52
53-64
58-59
60-62
63-64

VI. INTERPRETATION ........,•••...... ••..•••••• •••• 136-157
Direct approach ... .•..••.• .•.. ..•••••. •. ...••• 137
Indirect approaches ............................ 138-157
The prevalence of hereditary diseases and defects 139-140
The role of spontaneous mutation in maintaining
the frequency of hereditary disabilities•••.••• 141-143
Dose-mutation relationship ..••....•.••••••..• 144-145
The doubling-dose concept in indirect assessments ................, .................... 146-152
Conclusions ................................. 153-157

65-66
67-70
71-72
73-80

IV. THE INDUCTION OF MUTATION BY RADIATION••• , ••• 81-120
Factors affecting the frequency of radiationinduced mutation ••••••••.•.••••..••.••••••.. 82-101
Linearity of the dose-effect relationship andabsence of a threshold...................... 83

TABLESREFERENCES

I. Introduction

4. Developments such as these have been of great
help in understanding the basic problems of radiation
genetics. At the same time they have re-emphasized its
complexities. The present annex gives particular atten­
tion to the effect which these recent advances have hadon our ability to estimate the extent of hereditary damage
which may be induced in populations by ionizing radia­
tion. In stressing current problems, the report does notenumerate but is nevertheless based on a vast amount of
information which has been accumulated over many
years in the field of radiation genetics. For an accountof earlier data and well-established genetic concepts,
reference should be made to the previous report. How­ever, to make this annex self-contained, this older
information is summarized at relevant places.
5. All organisms are subject to hereditary diseases
and defects. In man, estimates of the size of this burdenof undesirable traits are based on the frequencies of:(a) Abortions, still births and neonatal deaths;(b) Infertility;( c) Hereditary diseases and defects;(d) Detrimental deviations from normal in continu­
ously varying traits such as intelligence, life-span andresistance to disease.

1. In its consideration of the hereditary effects ofionizing radiation upon man this report, as did that of1958,1 centres its attention on the possible consequencesof the increases in the level of radiation to which humanpopulations are currently exposed.
2. The Committee's 1958 report presented a compre­
hensive outline of the genetic hazard of ionizing radia­
tion; the available evidence in man and other organisms
was reviewed thoroughly and a variety of approaches wasused to elucidate the problem. At the same time itwas emphasized that current knowledge was insufficient
to complete this task with more than partial success.
3. Since that time several significant developments
have been made in radiation genetics and in related
disciplines. In particular, progress has been very rapid
in the area of human cyto-genetics; considerable atten­
tion is now being focused on the induction of grosschromosome aberrations as a serious genetic hazard. In
addition, remarkable advances have been made throughinvestigations with mice. These have indicated theexistence of previously undetected intricacies in the dose­mutation relationship.
84

fects that are slight but nevertheless of importance tohumans are not easily recognized in other species. As aconsequence, generalizations based on the results ofinvestigations with experimental organisms entail many
uncertainties.

6. Deleterious genetic traits are a direct consequenceof the presence of specific basic faults in the genetic
constitution of affected individuals. These faults may beeither undesirable alleles or chromosome aberrations.
However, the prevalence of deleterious hereditary traits
in a population does not, in itself, provide a complete
picture of the amount of genetic damage present. In
some instances the fault is partially or completely
masked in the heterozygote. In other instances, its phenotypic e."--pression is so different in the homozygous andheterozygous states that it is impossible to express thetotal detriment to populations in simple terms. Furthermore, environment, in the form either of the remainderof the genotype or of external conditions, frequently
has a great influence on the manner in which the fault is
expressed.

II. The prevalence of naturally-occurring
hereditary clefeets and diseases

7. There is no doubt that any increase in the frequencyof radiation-induced mutation contributes to the burdenof undesirable traits. It is equally evident that the evaluation of this contribution must rely upon an understandingof the genetic structure of a population and the environmental forces to which it is exposed. Moreover, the effectof an increase in the amount of genetic damage, from
whatever source, must be considered in terms of a timeinterval; once inflicted on a population the damage may
persist through future generations and may be expressed
only intermittently and with varying degrees of severity.

11. It is generally accepted that there is a genetic component in much, if not all, illness. This component isfrequently too small to be detected ; in other instances theevidence for its presence is unequivocal. Nevertheless,the role of genetic factors in the health of human populations has not in the past been considered seriously invital and health statistics. As a consequence, data on theprevalence of hereditary diseases and defects are now
largely restricted to that collected by geneticists for special purposes in limited populations from a small numberof countries.
12. An assessment of the hereditary defects anddiseases with which a population is affiicted does notnecessarily provide a measure of the imposed burden of
suffering and hardship on the individual, the family,or society. Such evaluations require, among other things,
consideration of the development of medical services
and of the cultural values in communities. 2

8. There are a number of complementary approaches
to the problem of estimating the detrimental hereditaryeffects of an increase in rate of mutation in human populations. Estimates of genetic hazard can be obtained
empirically by the observation of irradiated populations.
However, information obtained in this way is meagre,
and estimates are more often calculated from what is
known about the induction of genetic damage by radiation and from a knowledge of the way in which thisdamage will be expressed. These more indirect ap•
proaches require information on:(a) The magnitude of natural genetic damage within
a population as ascertained from a knowledge of therole of heredity in morbidity, mortality, and infertility;( b) The role of recurrent natural mutation in maintaining the prevalence of this genetic damage;( c) The qualitative and quantitative relation between
a given dose of irradiation and the corresponding increase in mutation rate.

13. In the 1958 report, a detailed examination of data
accumulated in Northern Ireland over many years led
to a figure of about 4 per cent as the incidence of more
readily detected hereditary diseases and defects. That
survey has been the most comprehensive undertaken todate, and although limited to a single geographical region,it has provided a useful base on which to formulate overall estimates. New information now permits a ·revisionand reclassification of these. For instance, it is now possible to estimate the frequency of chromosome aberrations
and to transfer some conditions, such as Down's syndrome (mongolism), to a different category. The estimate of the incidence of congenital malformations has
also been increased. The revised values are summarized
below. Disabilities are placed in any of four categories.
They are classified according to the role which mutation
is believed to play in maintaining their frequency. Thissubject will be discussed in more detail in section III.

SURVEY OF HEREDITARY DISABILITIES

9. Every approach has its own difficulties and limitations. The direct approach is impeded not only by ameagreness of data but also by the absence of proper
controls. Furthermore, in man it is quite impractical,
through direct observation, to ascertain the spread ofdamage over what may be many generations. On theother hand, more indirect approaches require a knowledge of the genetic structures of populations and ofgenetic mechanisms which we do not fully possess at
this time.

Category la
14. This includes harmful traits whose mechanism ofinheritance is understood and whose prevalence is determined mainly by the frequency of individual gene, orpoint, mutations.
15. Several hundred traits determined by single genesubstitutions have been identified. A majority of thetraits, perhaps 70 per cent, are determined by autosomal
dominant genes. Approximately 5 per cent are SC.'C-linked
recessive traits, and the remaining 25 per cent are
determined by the homozygous e.'{pression of autosomal
recessive genes.
16. The majority of dominant traits are sufficiently
mild in their effects to be transmitted through several
generations. In contrast, the detrimental recessive
traits now recognized in man are very severe in theireffects and, with few exceptions, are lethal in the genetic
sense. As a result, although about 70 per cent of wellestablished specific traits are determined by dominant

10. All approaches often make use of investigations
with other organisms because the mechanism by which
hereditary information is transmitted is basically thesame in all forms of life. Experimental observations ina wide variety of organisms can thus provide a working
model of the effects of ionizing radiation on man. However, there may be radical differences in genetic structure
between populations because this structure is undoubtedly
affected by the environmental conditions under which
a population exists. Furthermore, many hereditary de-85

genes, in perhaps 90 per cent of persons who showmonomeric traits, these defects are determined by dominant genes. In terms of gene frequency, however, genes
for recessive harmful traits must far outnumber thosefor dominant harmful traits in a given population.
Furthermore, many hundreds of traits are encounteredin man for each of which a recessive mode of inheritanceis suggested, but each is so uncommon that adequate
evidence for this is lacking. It seems likely that many ofthese traits are in fact the homozygous expressions ofrecessive genes and that they contribute in total morethan any other class to the frequency of detrimental traits
in populations.

individuals with Down's syndrome are known to havea forty-six chromosome complement in which part of an
extra chromosome 21 is translocated to another autosome.16-18 Other disabilities that have been associatedwith translocations or other types of aberration are listed
in table II.
24. Defective traits caused by chromosome aberrations are sometimes, as might be expected, inherited
through successive generations. A chromosome rearrangement which permits Down's syndrome to betransmitted by phenotypically normal females with atranslocation in the balanced state has been demonstrated
repeatedly.11- 20 Cases have also been reported of translocation-carrying phenotypically normal males whosechildren exhibit Down's syndrome. 20021 Other balanced
and unbalanced karyotypes have been noted in parental
and child generations (table II). There are indicationsof differential transmission of aberrant chromosomal
types in the two sexes. 22
25. Mental retardation is one of the common consequences of gross chromosomal aberration. Relevant
data have been obtained through the procedure of nuclear
sexing of buccal mucosa to detect sex-chromosome anomalies. This procedure reveals deeply staining chromatinbodies within nuclei. The number of these Barr bodies
per cell is, in general, one fewer than the number of X
chromosomes present; the cells of a normal male arechromatin negative, whereas those of a normal female
contain one Barr body. In five sunreys, the combined
frequency of chromatin-positive individuals among
males attending special schools for the mentally backward was 8.77/1,QOO (29/3,306).2 s-: 7 Five surveys ofmale inmates of institutions for mental defectives indicated a frequency of 9.51/1,000 (70/7,358) chromatinpositive cases. 2 s-s 2 Two surveys of female inmates of
institutions for mental defectives showed a combined
frequency of 4.46/1,000 (12/2,689) females with double
sex-chromatin bodies and one chromatin-negative
female. 31 These figures may be compared with thosefound in the general population (para. 28 below).

17. Traits listed in this category are at present estimated to affect about 1 per cent of all live-born.

Category lb
18. Harmful traits which are determined by cytologically demonstrable chromosome aberrations are includedin this category. Their frequency is maintained mainly
by recurrent mutation.
19. There is direct evidence that congenital and otherphysical defects are sometimes due to chromosome aberrations. This important information has been acquired
as a consequence of improved techniques in human
cytogenetics. Because most research in this area is new,the subject will be considered here in some detail.
20. As with those traits caused by the action of specific alleles, there is often considerable variation in theclinical severity of defects caused by chromosome aberrations. For this reason, all the clinical aspects of somespecific defects remain to be described. Different degrees
of mosaicism may be partly responsible for this variationin expression. Many associations of physical impairmentwith chromosome aberrations are now being reported
and it must be suspected that some of these associations
are due to chance. Reasonably well-established associations are presented in table I, others, necessitating further
confirmation, in table II. All the disabilities noted intables I and II are congenital, but some diseases ofsomatic origin are known to be associated with chromosome aberration. Two of these are granulocytic chronic
leukaemia 3 and Waldenstrom's macroglobulinaemia.'
Such diseases are discussed in anne_ic D.

26. Sterility is a frequent consequence of chromosome
aberration. Males with sex-chromosome abnormalities
are almost always sterile. 38 A study of men attending
an infertility clinic showed that about 3 per cent of thepatients were chromatin-positive. 3 ' Among sixty-eight
women with a presumptive diagnosis of primary amenorrhoea, 28 per cent were found to have sex-chromosome
anomalies. 35
27. Some cases of still birth and abortion are attributable to chromosome aberration. In a survey for se..xchromosome anomalies in still-born children by nuclear
sexing, none of fifty-two females was found to be abnormal. but two of forty-nine males were chromatinpositive. 86 In two instances of miscarriage the embryos
have been shown to be triploid. 37 • 38 Here it was possible
to culture material from foetal remnants.

· 21. The fact that some well known defects occur as aconsequence of anomalies in the number of autosomes
was discovered in 1959, when it was demonstrated that
Down's syndrome is associated with trisomy of one of
the small acrocentric chromosomes (number 21 under
the Denver Convention). 5 • 6 There are two other wellestablished instances of trisomy syndromes. One involves a member of the 17-18 group, 7 the other a memberof the 13-15 group. 8 All three kinds of trisomy areassociated with mental retardation.

22. Some detrimental traits are attributable to anomalies in the number of sex chromosomes. This wasestablished when it was shown that a condition known as
Klinefelter's syndrome can be caused by an XXY constitution.9 Related clinical symptoms have now been
attributed to XXXY,1° XXXXY 11 and XXYY 12 karyotypes. Turner's syndrome has been associated with an
XO constitution. 13 Females with XXX and XXXX
karyotypes have also been described. 14• 15

28. A general picture of the prevalence of defective
traits caused by gross chromosome anomalies is beginning to emerge despite the newness of this field of research. Some specific traits are extremely rare. However, the frequency of Down's syndrome is about 1.5 per
1,000 total births in Europe, North America, andJapan. 3041 Comparative figures from other parts of theworld are rather scanty. Current data on the frequencyof sex-chromosome abnormalities have recently beensummarized.33 Cases of Klinefelter's syndrome (XXY),
or at least karyotypes containing a Y and more than one

23. Defects attributable to the presence of chromosome rearrangements have also been detected. Some86r
X, are relatively common, whereas cases of Turner's
syndrome (XO) are rare. Three surveys by nuclear
sexing of buccal mucosa, have been made among consecutive live-born. A frequency of 2.65 /1,000 ( 18/6,801)
chromatin-positive males was found in the combined
data. Chromosome studies of seven of the anomalous
cases showed that four were XYjXXY mosaics andthree had an XXY complement. The frequency of abnormal nuclear sex among females was 0.90/1,000 ( 6/6,642). 36, 42, 43

sion, a simple mode of inheritance has been postulated
for some of them. However, their frequency in the faceof strong selection and their distribution in families are
difficult to reconcile with a monomeric hypothesis. As aconsequence, simple modes of inheritance are not usuallyassumed. 49 Each of these traits is common and prevalent over most of the world. They were collectively estimated in the 1958 report to affect at least 1.5 of all
adults, but this estimate is very uncertain.

29. It is now estimated that about 1 per cent of all
live-born have some harmful trait determined by chromosome aberrations sufficiently gross to be detected bypresent techniques. Many of these individuals aremosaics. Rather more than half of the aberrations areanomalies in chromosome number. The rest are intrachromosome changes, translocations or combinations ofthese with numerical changes. Only a small fraction ofthese aberrations are transmitted to subsequent generations. It is likely, however, that estimates of the frequency of transmissible chromosome aberrations would
be greater with more refined techniques since theseaberrations, being less gross, are more difficult to detect.

Category IV

36. This category includes harmful traits which are
determined at single loci, but it is highly unlikely that thefrequency of the alleles is substantially influenced bymutation.
37. The frequency of these traits tends to be high inlocalized areas of the world. This high frequency is aconsequence of the fact that each of the traits e.xists as apart of a system of balanced polymorphism; selection
pressures maintain the related genotypes in a state ofbalance. Included in this category are sickle-cell anaemia
and thalassaemia. Many other traits, such as fibrocystic
disease of the pancreas, probably belong here. On theother hand, a change in environment at some time in
the future might remove some traits from the category.
Except in certain localized areas in the world, the prevalence of these traits as currently recognized is extremely
low. The subject of balanced polymorphism will be discussed in greater detail in a later section (paras. 47-52).

Category II

30. This category includes developmental malformations whose mechanism of inheritance is ill understood.
Environment is influential in the aetiology of these
traits. Drugs, certain infections, and radiation are known
to be teratogenic at critical stages of organogenesis, andmaternal (intra-uterine) environmental factors are also
known to have a great influence on prevalence. The roleof mutation in maintaining the frequency of these traits
has not yet been ascertained. They often show somefamilial concentration, but this fact does not necessarily
prove the existence of a genetic component.
31. Some of these malformations may be caused bychromosome aberrations. However, no cytological evidence of this has been found in many of the more commonly-occurring malformations. 4 4""' 6 It is of course possible that chromosome changes too small to be identified
by current techniques are responsible. Alternatively,
comple..x genotypes and unusual environments may becausal factors; it has been suggested that a fraction ofcongenital malformations are caused by an insufficientdegree of such heterozygosity as is necessary to ensure
normal development.40 • 47 However, it is difficult to distinguish between conditions due to individual recessive
genes of low penetrance and any that may arise becauseof a deficiency of heterozygosity at a multiplicity of loci.
32. Many of these traits are detectable at birth. The
frequency of live-born so affected is now estimated to beabout 1.5 per cent, but is higher if still births are included. At the age of five years, an additional 1 per centof affected children can be detected. 40· ' 8

ROLE OF HEREDITY IN PREMATURE DEATH

38. Abortions, still births and neonatal deaths present
special problems in a survey of hereditary defects; notonly is the frequency of these defects greatly affectedby environmental factors, but the role of heredity intheir cause is difficult to ascertain because they are nottransmitted to the ne..xt generation. In consequence, withthe exception of those cases known to be caused by grosschromosome aberration, these defects are not consideredin categories I-IV. Nevertheless, breeding experiments
in animals have shown that simple genetic mechanisms
contribute to their incidence. In other instances the additive effects of several genes with slight individual effects
may be responsible.
LETHAL AND DETRIMENTAL EQUIVALENTS

39. All the genetic damage within a population is not
expressed phenotypically in any one generation. To alarge extent, this is because many detrimental traits are
partially, if not completely, recessive; complete e.xpression occurs only in the homozygote. The amount of thisrecessive damage is an important measure of the genetic
health of a population. It can be estimated indirectlyfrom a knowled~e of the increase in mortality and morbidity observed m the progeny of consanguineous marriages; in these circumstances the hidden genetic damage
can be described in terms of lethal and detrimental
equivalents. A lethal equivalent has been defined as agroup of mutant genes of such number that, if dispersed
in different individuals, it will cause one death on the
average.~ 0 This death occurs with homozygosity. In thesame manner, genes leading to visible recessive defects
can be defined in terms of detrimental equivalents.51

Category III

33. In this category have been placed serious "constitutional" disorders in which the mechanism and contribution of inheritance are ill understood.
34. Included here are mental illnesses such as schizophrenia and manic depressive reactions as \vell as disorders such as diabetes mellitus, pernicious anaemia andsome affecting the thyroid gland.
35. There is general agreement about the e.xistcnce ofa major genetic component in these traits and, on occa-

40. The procedure outlined above is a powerful toolwith which to estimate the amount of recessive genetic
damage within a population. However, lethal and detri87

It is known that few dominant diseases and defects arecompletely dominant and it is becoming increasingly
clear that many recessive traits may not be, in fact,completely recessive. This. partial dominance can reflect
on the genetic fitness of heterozygotes. The effect thateven a minor change in heterozygotic fitness may haveon the estimated mutation rate required to maintain thefrequency of a defect at a constant level can be illustrated with a trait such as phenylketonuria. This trait
occurs with a frequency of 25 X 1~ in the populationof England and the genetic fitness of the homozygote isnearly zero.H Under the assumption that the heterozygote has the same fitness as the homozygous normal,
a mutation rate of 25 X 1~ per locus per generation isrequired to maintain the gene at its present level in the
population. If, however, the fitness of the heterozygote is
1 per cent, 2 per cent, or 5 per cent lower, as has beensuggested, then the corresponding mutation rates would
be three, five and eleven times the previously mentioned
rates. 50 • 51 • 58 In contrast, if a slight heterozygous advantage is assumed, a very different estimate is obtained;with only a 0.1 per cent or 0.2 per cent advantage infitness, the estimated mutation rate would be only 4/5 or
3/5 that of the original rate. 39 With an advantage of
0.5 per cent, mutation would not be required to compensate for the loss of genes due to deleterious homozygotes ; in fact, the gene frequency would increase to ahigher level.
46. Genetic fitness of heterozygotes cannot be treatedas an invariable property of the two alleles under consideration. Rather, fitness can be influenced not only by
the remainder of the genotype, as in the intricate situation involved in populations carrying genes for boththalassaemia and glucose-6-phosphate dehydrogenase deficiency, 55 but also by the external environment. For
such reasons an individual estimate of fitness may bevalid for the immediate future but less valid when applied
over several generations.
47. One of the advances in human population genetics
has been the discovery of several balanced polymorphic
systems (category IV). The term polymorphism, as
used here, describes "the occurrence in the same habitatof two or more discontinuous forms of a species maintained by a balance of selective forces, as opposed tomaintenance by recurrent mutation". 56 Such systems
arise when a gene confers reduced genetic fitness insome circumstances and increased fitness in others. The
increase in fitness may be a consequence of a shift in themacro- or micro-environment or it may be a consequenceof heterozygosity as contrasted with homozygosity. The
role of mutation in supporting the frequency of polymorphic traits is minor. To predict the over-all consequences of an increased mutation rate it is therefore
essential to know the extent to which balanced polymorphic systems contribute to the burden of detrimental
hereditary traits. It is also essential to know what fraction of new mutants are equivalent to alleles that are
already part of a polymorphic system.

mental equivalents do not represent genes determining
any special category of recessive detrimental traits;
when expressed phenotypically in the homozygote, thetraits may fall in any of the lists of defects in paragraphs 13 to 38. Furthermore, an estimate of thefrequency of equivalents does not provide any direct
measure of that fraction of genetic damage within a population which is expressed in the heterozygous condition.
Nor does a knowledge of the size of the pool of recessive
lethal and detrimental genes, by itself, indicate the mechanism by which these genes are maintained in a population.
41. Estimates of lethal equivalents obtained fromavailable surveys are presented in table III. The surveys
are of very unequal scope and reliability, the one carried out in Japan being by far the most extensive. In spiteof inconsistencies in the results, including some between
the two cities in Japan, it seems reasonable to conclude
that individuals in human populations carry from two
to four lethal equivalents which are expressed, in homozygotes, before the age of twenty to thirty. In addition,
each individual carries approximately the same numberof detrimental equivalents.
ID. The role of mutation in supporting theprevalence of hereditary disabilities
42. Mutation may be broadly defined as any change
imposed in the genetic constitution of a cell. In the present annex, mutation is considered in terms of the two
fundamental units of heredity, the gene and the chromosome. Natural mutations are generally referred to as
spontaneous though in fact it is understood that there
are causal factors over which we do not usually haveany direct control. One of these factors is undoubtedly
naturally-occurring ionizing radiation. Other physicaland chemical variations that occur in nature, and thegene complement itself, probably influence mutability.
43. Two mechanisms are involved in maintaining theprevalence of detrimental hereditary traits within a population. One of these is recurrent mutation. The other isdirect transmission of the basic genetic faults throughsuccessive generations. The role of transmission is generally e.."\:pressed in terms of genetic fitness of the relevant genotypes, i.e., the number of their progeny whichreach maturity. The importance of mutations in humanpopulations cannot be considered independently ofgenetic fitness because reliable estimates of specific natural mutation rates and of the over-all contribution of
mutation to ill health are frequently dependent on accurate information about this fitness.
RELATIVE GENETIC FITNESS

44. The relationship between mutation, genetic fitness,and the prevalence of hereditary disabilities is concisely
expressed by the principle which holds that each mutation, whether fully lethal or slightly detrimental, will on
the average, result in the death of a descendant or in a
failure to reproduce. 52 • 53 The more genetically unfit ofthese mutations, as for instance dominant lethals, will beeliminated quickly, and occasionally without provoking
any suffering or undue hardship on the population.
Mutations which have less drastic effects on fitness willusually be transmitted through many generations and~eir phenotypic effects will be expressed in correspondmgly more descendants.
45. Genetic damage can affect the phenotype of individuals in either the homozygous or heterozygous states.

48. The existence of balanced polymorphism is suspected when excessively high mutation rates must be
postulated to maintain the frequency of a detrimental
trait under the assumption that the heterozygote isneutral. An example of heterozygous advantage in genetic fitness is provided by sickle-cell anaemia, a trait
which is fatal in the homozygote. The distribution of thesickle-cell trait has been investigated over large areas of
the world and is very uneven: the trait is completely
absent in a number of populations, yet the homozygote
88alleles at loci involved in polymorphic systems are unconditionally harmful in contrast to those alleles which
support the polymorphic systems in nature. In thesecircumstances it is important to know the average reduction in fitness of the heterozygote, since this value determines the number of generations over which a temporary
increase in mutation rate would be felt by a population.
It also determines to some extent the magnitude of thetotal damage. There is no general information about thisvalue in man. In Drosophila, e."<tensive studies have indicated that the average reduction in fitness of heterozygous lethals and semi-lethals is about 2 per cent.50• 68
It would probably be larger in poor environmental conditions. 69 • 1°

bas a frequency of 3 to 4 per cent in some populationsof Asia and Africa.57 It has now been demonstrated thatheterozygous ii;dividuals .have an increased resistance. tomalignant tertian malana and a consequent selective
advantage in a malarial environment. 57 • 58 It is likely that
other serious haemoglobinopathies, including thalassaemia, are maintained by a similar mechanism. Current
world-wide measures to eradicate malaria will have theeffect of reducing the genetic fitness of heterozygotes.
As a consequence, a reduction in gene frequency is to
be expected. However, the rate of reduction will be slow
and the trait will continue to be carried for many generations. It has been suggested that the ine."<plicably highfrequencies of some detrimental traits are a consequenceof relatively greater genetic fitness of heterozygous carriers at some time or place in the past. 89
49. The frequency with which balanced polymorphic
systems occur in human populations has yet to be determined. Relevant to this problem are two contrasting
but not mutually e."<clusive hypotheses that have been
proposed for the construction of e.xtreme models of gene
behaviour. One has been termed the classical, the otherthe balance hypothesis. 59 Under the classical hypothesis,
it is assumed that genetic variability is maintained byrecurrent mutation. Furthermore, it is assumed that
almost all mutations are unconditionally deleterious andsubject to selective elimination; heterozygous advantage
is restricted to a small number of loci although it may
contribute greatly to existing genetic variability. Thebalance hypothesis, on the other hand, assumes thatgenetic variability is to a large e.""<tent maintained byheterozygous advantage; mutation may not be unconditionally deleterious and a certain level of heterozygosity
is essential to high fitness.
SO. Using the concepts of lethal and detrimental
equivalents, it is possible to deduce the relative importance of these two models. It has been calculated that an
inbreeding depression of such a high degree as has been
detected experimentally cannot be expected from systemsof balanced polymorphism ; this has led to the conclusionthat most hereditary defects revealed by inbreeding are
maintained by recurrent mutation.60 A similar conclusion
has also been reached from different evidence ; an analysis of the frequencies and modes·of inheritance of deafmutism, limb-girdle muscular dystrophy and low grade
mental defects has suggested that the mean genetic fitnessof a population would be impossibly low if the prevalence of these and other traits were not maintained bymutation. 51 On the other hand, in a recent study of two
Japanese populations, the detected inbreeding depression
was so slight as to indicate that the role of balanced polymorphic systems in maintaining the prevalence of hereditary effects is greater in those populations than in others
previously studied.61
51. Investigations \vith irradiated experimental organisms have also produced conflicting evidence, 0 2-6 1 a factwhich may well reflect the importance of strain differences and environment in the phenotypic expression of
genotypes. It is also possible that a variation in frequency of gross chromosomal aberrations with different
doses of radiation contributes to differences between
results.
52. In the absence of complete information about therole of balanced polymorphic systems it is usually assumed that most of the genetic damage within populations is mutation-maintained ; this avoids the risk ofunderestimating radiation damage. Even if this assumption is incorrect, it is possible that most new mutant

NATURAL MUTATION RATES AT INDIVIDUALLOCI IN MAN

53. The frequency of mutation at a locus can only be
studied when the mutation determines a specific detectable trait. Mutation is always an uncommon event; afreshly-arisen specific mutation seldom occurs with afrequency of more than one in fifty thousand gametes.
It follows that very large populations must be studied
to obtain a reliable estimate of this rate.
54. In many respects man is a very ·suitable organism
for the observation of mutation rates because large freeliving populations can be defined and close relatives areeasily identified. Furthermore, the high efficiency of
medical diagnostic procedures renders relatively easy
the identification of many traits in man that might bemissed in e.xperimental animals. For these reasons, moreestimates of natural mutation rates are available for man
than for most species other than micro-organisms. There
are, however, difficulties in relating traits to specificmutant alleles in man. These difficulties do not arise as
frequently in animals, because planned breeding andgenetic analysis can be employed.
55. Some of these problems are specific to dominant,some to sex-linked, some to recessive gene mutations,and some are common to all three. Those common to all
three derive from the following circumstances :(a) Certain mutant gene traits are mimicked byphenocopies. These are identical or nearly identical traits
determined not by the genotype but by abnormal development in the embryo of foetus in utero. However, careful clinical study often serves to distinguish such phenocopies, as for example in the case of certain cataracts,
and in cases of congenital deafness;( b) Certain traits which are difficult if not impossible
to distinguish clinically, are sometimes determined bymutations on different chromosomes. For example,
ichthyosis vulgaris is determined by an autosomal dominant gene and also by a recessive gene on the X-chromosome;( c) Some clinically identical traits seem to be inherited as if they were autosomal dominant at sometimes and recessive at other times. Examples are achondroplasia and a number of degenerations of the choroid
in the eye. This variation may be a consequence of mutations to different alleles at the same locus, of mutations at
different loci on the same chromosome, or of mutations atloci on different autosomes;( d) Some traits, though apparently inherited in thesame manner, show differences between families whichsuggest that the causal mutations are different in kind.
Although different loci may be involved in these cases,
it is conventional to e.xpress mutation rate in terms of a89

single locus. Such difficulties lead to over-estimates ofmutation rates.
56. Precision in the estimation of the mutation rates
of genes determining harmful traits in man depends
upon the completeness of ascertainment of the characterin a large defined population. High precision can only beachieved where the medical and social services for the
population are well organized. Even so, complete ascertainment is virtually impossible and can never be assumed as certain. Incompleteness of ascertainment tends
to result in under-estimation of mutation frequency.
57. In generalizations of the mutation rates per locus
in man one further factor must be considered. If themutation rate of a gene is very low the trait may arise
too infrequently to be recognized as of genetic origin,or even if so recognized, it may not attract study becauseof the great difficulty of collecting a sufficient numberof cases. In consequence, only those traits occurring witha sufficiently high frequency to give a reliable estimateof mutation rate are selected for investigation.

Autosomal dominant traits
58. A direct method is applicable for estimating rates
of mutation to dominant traits. This method attempts to
identify all cases of a certain trait in the offspring ofparents not affected by the trait. If it is assumed thatthe gene is fully manifested, then each case must represent a mutation in the germ cells of one parent. As
each birth results from two gametes, the mutation rate
per gamete is one-half the frequency per birth. Thismethod can seldom be employed and can be fallacious if
unrecognized phenocopies occur.
59. An indirect method can also be used. This metl1od
assumes that an equilibrium has been reached in which
the frequency of the trait is more or less constant. At
this equilibrium, the number of fresh mutations arisingin the population in each generation is approximatelybalanced by the number of mutations eliminated by
selection. The equilibrium equation is µ. = ~ (1-f) %,where µ. is the mutation rate per gamete per generation, xis the trait frequency in the population, and f is therelative fertility of ilie individuals bearing the trait. In
such an equilibrium the value off is of great importance.
It is, however, difficult to estimate with accuracy. If f iszero then the condition is not recognized as genetic in
origin. On the other hand, relative fertility of the affectedindividuals can be estimated only if it is as low as 85 percent. As a result, estimates of mutation rate tend to bemade for traits with a value of f between 0.0 and 0.8. A
number of estimates are listed in table IV.
Sex-linked traits
60. Estimates of the recessive mutation rate at locion the X-chromosome must be made by an indirect
method. The equilibrium equation is µ. = 73 (1-f) %. In
tllis case, it is assumed that the fertility of heterozygous
females is the same as that of homozygous normal females in the population.
61. The most reliable estimates of mutation rates fora sex-linked recessive gene are those for Duchenne-typemuscular dystrophy. However, there is some evidence
that even this trait is clinically heterogeneous. In consequ~nce, current estimates may represent the sum of mutations at more than one locus.
62. No reliable estimates of the mutation rate forhaem?philia ~ have beer; ma.de since haemophilia B(Christmas disease) was identified as a separate entity.

The proportion of haemophilia types A and B varies indifferent countries. Possibly the older estimates of themutation rate for haemophilia, if reduced by about onetenth, serve as reasonable estimates for ilie locus determining haemophilia A. However, ilie trait can be so mildthat ascertainment is almost certainly incomplete. This
tends to produce under-estimates of the true mutation
rate. Some estimates are presented in table V.

Autosomal recessive traits
63. Only indirect estimates of autosomal recessive mutation rates can be made and these are of very uncertain
reliability. The equilibrium equation is µ. = (1-f) x.
In man, the value off is zero or extremely low for thegre~t.majority of recessive homozygotes. Exceptions arealbm1sm and some forms of recessive deaf-mutism. Even
with these conditions, however, the value of f is not over
0.5. If f has a value of zero then ilie estimate of mutation
rate corresponds to the trait frequency. Here, however,there are many difficulties. It is assumed, as for sexlinked genes, that the fertility of the heterozygote is thesame as. the average in ilie population. However, a highproportion of all mutant genes in the population are inheterozygotes. For this reason any selection in favour ofor against the heterozygote has a much greater effect on
the prevalence of a trait at equilibrium than has the loss
due to homozygosis. Furthermore, a shift in the environment can upset the population equilibrium by affecting
the genetic fitness of the different genotypes. When thishappens, many generations may pass before equilibrium
is restored. Again, changes in marriage customs canaffect the frequency of different genotypes. A decline in~e amount of inbreeding has been noted in Europe durmg the last century or two; such a circumstance is likely
to lead to estimates that are too low.11 Some estimates ofautosomal recessive mutation rates are presented intable VI.
64. In spite of all the reservations, there is a large
group of grossly harmful mutations, autosomal dominant, recessive, and sex-linked recessive, whose estimatedmutation rates cluster around 10 X 10-S per generation.
However, this clustering may be conditioned largely byilie selection of traits for study.
NATURAL MUTATION RATES AT INDIVIDUAL LOCIIN EXPERIMENTAL ANIMALS

65. With experimental animals it is possible to estimate natural mutation rates with methods that involve
test matings. In the mouse, the rates of natural visible
mutation have been estimated at seven loci. These loci are
identified by recessive visible alleles namely: a (nonagouti), b (brown), c (chinchilla), d (dilution), p (pinkeye), s (piebald spotting), and se (short ear). The lociare distributed on five of the twenty chromosomes. Thereis linkage between d and se and between c and p. These
alleles were selected for various radiation studies andshould not be considered a random sample. The over-all
mean mutation rate is estimated to be about 7.3 X 1()-6
per locus per gamete (table X).
66. Estimated values of natural mutation rates at specific loci in Drosophila were discussed in ilie previous
report and in a recent review .'2
NATURALLY-OCCURRING CHROMOSOME ABERR.~TIONS
IN l'l!A.."'i'67. Man has a relatively stable karyotype; the diploid
chromosome number is forty-six. 73 • H Nevertheless,90with the development of improved techniques in mammalian cytology, examples of aberrations already wellknown in plants and insects are bein~ accumulated. The
detection of chromosome anomalies m man is aided by
the relative ease with which associated abnormal phenotypes can be recognized. On the other hand, cytogenetic
techniques are not yet far enough advanced to permit thedetection of less obvious aberrations. Those which are
not now detectable include reciprocal translocations ofnearly equal size, inversions and either small duplications
or small deletions having a length less than 10 per centthat of the affected chromosome. Other aberrations may
be undetected because they are lethal at a very early stage
in embryo development. 33

nate maternal and paternal derivations of the X chromosome) the relative frequencies are 0.7 per cent and 0.02
per cent, and on the fact that primary XO's are notrandomly distributed. 86 • 87 Deficiencies and monosomies
that would have been detected in e..xtensive e..'Cperimentson certain genetically marked autosomes in the mouse
have so far not been found. 85 • 88 Spontaneous translocation has been observed in the rat. 89
72. In Drosophila, maternal non-disjunction andmeiotic loss of whole chromosomes from dividing cells
both operate to produce abnormal eggs. This information
has been deduced from the fact that the frequency ofeggs with two X chromosomes is less than that of eggs
with no X chromosomes. The frequency of abnormal
eggs that arise as a result of non-disjunction has been
estimated at 0.08 per cent and the frequency of thosearising as a result of meiotic loss of the X chromosome
at about 0.12 per cent. This produces an XO :XXY ratio
of about 4 :l.90 There is also a considerable rate of nondisjunction of se..'C chromosomes in males; the ratio ofscored XHO to XUXPyP individuals is 2.8 :l.91 Monosomy and trisomy of the small fourth chromosome occurs
spontaneously but non-disjunction or loss of the second
and third chromosomes has not been detected by genetic
or cytological methods of analysis. It is probable thatthese events occur but that monosomy or trisomy of longautosomes leads to elimination in embryonic stages. 00 An
early study showed that aging of females by itself has noeffect on the natural rate of non-disjunction, although thefrequency of non-disjunction following irradiation ofvirgin females increases through the first ten days. 02
More recent studies have confirmed that maternal age
per se has no appreciable effect on the frequency of spontaneous non-disjunction. 93 In view of the recognized increase in frequency of Down's syndrome with advancing
maternal age 39 and similar observations on the two otherautosomal trisomies, 9 ' this observation shows the difficulty of comparing natural chromosomal mutation rates
of flies and man.

68. The most common of detected aberrations are
trisomies of the smaller autosomes and either monosomy
or polysomy of the sex chromosomes. It seems likely thatmonosomy and trisomy of autosomes other than that
producing Down's syndrome, are rare or usually lethal. 75
Triploidy has been detected, 37• 38• 76 and translocations andother aberrations are frequently reported (tables I andII).
69. Whole-chromosome anomalies may be a consequence of either chromosome loss or "non-disjunction".
Monosomy can result from either process, but polysomy
is attributable only to non-disjunction. It seems likelythat the majority of whole-chromosome aberrations occur
in meiotic divisions of a parent or in early cleavage divisions of the zygote. Little is yet known about the relative
importance of non-disjunction and chromosome loss
during meiosis. However, there is considerable evidence
that one or both of these processes frequently occurs inmitotic divisions following fertilization. This evidence is
supplied by the existence of mosaics16-a: and of exceptional nvins. 83 The occurrence of whole-chromosome
anomalies during mitosis may be more frequent thanpresent data suggest ; mosaicism is not likely to be detected when it does not originate in early cleavage divisions. Moreover, selection pressures may eliminate oneof the stem lines. The possibility that the processes leading to mosaicism tend to recur in a cell line is suggestedby the fact that two or three types of cells are sometimes
present in the growth from a single biopsy of bone marrow or even of skin.84
70. For one reason or another, most individuals withdetrimental traits caused by gross chromosome aberrations fail to produce progeny. Exceptions so far recognized are those phenotypically normal persons withbalanced translocations. The general incidence of suchtranslocations is, however, low. As a consequence, theincidence of gross chromosome aberrations in a population tends to correspond with their mutation rate. For
estimates of frequency, see paragraphs 28 and 29 above.

FACTORS AFFECTING THE FREQUENCY OF
NATURAL MUTATION

73. It has long been observed that the frequencies withwhich natural mutations are found may vary in different
circumstances. This variation provides an opportunity
to identify and study individual causal or influencing
factors. In man, some of these factors can be detected
because a relatively long childhood and reproductive span
permit the factors to work over a prolonged period oftime.
74. With some hereditary diseases and defects it has
been observed that mutant frequency among offspring
increases with parental age. Such conditions are epiloia,
neurofibromatosis and retinoblastoma. This effect of timesuggests a simple dependency of mutation frequency on
the accumulated dose of the causal factor. Here, by implication, some cumulative influence is involved. 39 In
other conditions, such as Down's syndrome, an increasein mutant frequency accompanies rising maternal age but
not rising paternal age. Again, a contrasting situation
holds with achondroplasia, where the increase in theoccurrence of the anomaly is associated only with risingpaternal age. Each of these latter examples suggests thepresence of influencing factors which are not common
to both sexes. Thus, when paternal but not maternal age
affects mutant frequency, a dependence of mutation on
frequency of cell division in gametogenesis may be
involved.

NATURALLY-OCCUIDUNG CHRO:MOSOME ABERRATIONSIN EXPERIMENTAL ORGANISMS

71. In the mouse, non-disjunction of se..x chromosomes
has been shown to occur in meiotic divisions. However,non-disjunction in the first meiotic division is rare in themale and possibly non-existent in the female. In contrast
to man, XO karyotypes occur much more frequently thando XXY karyotypes. 85 There is evidence that XO individuals most often result from the loss of the paternal sex
chromosome some time between sperm entry into thevitellus and the first cleavage. This evidence is based on
the observation that when XMO and XMXPy mice arescored simultaneously (the superscripts M and P desig-

9175. A number of factors are known to affect natural
mutation frequency in experimental organisms. One of
the most studied of these is se.x; the spontaneous mutation .rate to sex-linked recessive lethals is apparently
lower in females than in males of Drosophila. 95 • 96 An
effect of sex on mutation frequency in the silkworm has
been noted. Here locus specificity is a factor; at one locus
the frequency of mutation is higher in the male, at another it is lower. 97 In the mouse, the data on seven lociunder detailed study provide some indication that mutation frequency is lower in females than in males (table
X). Females have yielded one mutant among 98,828 offspring. In contrast, males have yielded thirty-two
mutants among 544,897 young. However, in man, a studyof mutation to the sex-linked trait, Duchenne-type muscular dystrophy, has provided no evidence of a sex difference.98

environmental changes. This concept has been formulated as a mathematical model by introducing what iscalled the principle of minimum genetic load. 115 A species
must adapt itself to progressive changes in the environment and the ability to do so comes from genetic variation, the ultimate source of which is mutation. The importance of new mutation for the future adaptation of thehuman species is problematical.
IV, The induction of mutation by radiation

81. For obvious reasons, most of our information on
the induction of mutation by radiation comes from experimental organisms. However, there is ample evidence
that the mutation process is fundamentally similar in all
forms of life and there is no reason to suppose that man
is exceptional in this respect.

76. Genetic constitution can also affect the frequency
with which naturally-occurring mutations are found. A
number of specific genes in Drosophila have long been
known to modify the natural mutation rate by a factorof ten or more over at least a segment of the entire
genome. 99 A difference between two geographical races in
the frequency with which sex-linked lethals are produced
has been demonstrated.100 In addition, there is no doubtthat the mutation rate varies with different loci. The
mutability of a gene is also affected by its position in thechromosome. 827 • 828

FACTORS AFFECTING THE FREQUENCY OF
RADIATION-INDUCED MUTATION

82. The genetic hazards to populations cannot be determined in the absence of a knowledge of the relationship between frequency of mutation and dose of radiation. It is now well recognized that many factors caninfluence this relationship. The foundation for our
knowledge in this field was laid through investigations
with Drosophila. More recently, studies with mammals
have yielded significant information.

77. In man, tendencies towards diverse chromosome
aberrations in the same individual and towards familial
occurrence of diverse chromosome aberrations have been
noted. For example, cases of Down's syndrome ( trisomy21) and Klinefelter's syndrome (XXY) in the same individual have been described. 101-1° 5 Associations of XXY
with a translocation between chromosomes 14 and 1510•
and of XXX with trisomy 18107 have been reported.
Trisomy for the 13-15 group and an XO constitution has
been noted in two sisters.108 Trisomy 21 has been reported in the progeny of a female carrying an autosomaltranslocation.109 Such clustering of gross chromosome
aberrations has led to the suggestion that the cells of someindividuals may be labile in this respect, 21 or that theoccurrence of a first aberration predisposes the chromosomes of a cell towards a second. 84

Li11earity of the dose-effect relationship and absence ofa threshold

83. The assumption of a linear dose-effect relationshipdown to zero dose, and thus of an absence of thresholdfor mutagenic effects has been considerably strengthenedby the results of investigations with Drosophila. Studies
of mutations at more than fifty loci which affect minutebristles have indicated that acute doses as low as 5 r havea significant mutagenic effect and that the dose-effectcurve is linear from lower to higher doses.117 A linear
relationship in the low dose range down to 5 r has also
been found for radiation-induced recessive lethals.118
However, in germ cell stages such as spermatogonia andoocytes, where the repair of some of the pre-mutational
damage is possible, the effect at low doses may tum out
to be somewhat less than expected on a linear basis fromthe mutation frequency at high doses.119 A departurefrom linearity has been found for mutations induced withhigh doses of acute radiation in mouse spermatogonia. A
dose of 1,000 r produced significantly fewer mutations
than expected on the basis of linearity with results atlower doses. 120 The view that this effect might be due tocell selection gains some support from the finding thatfractionation of the dose gave a higher mutation rate
which was consistent with linearity.121 In E.coli, evidenceof a linear relationship down to doses as low as 8.5 r
has been presented. 122

78. There is evidence that natural mutations occur atdifferent rates in cells in different stages of gametogenesis. Relevant investigations in Drosophila have recently
been reviewed. 72 Some loci are more mutable in the germline than in the soma, while for others the reverse
applies.110
79. No doubt other as yet unrecognized influencing
factors exist. For instance, a significant increase in thefrequency of sex-linked recessive lethal mutations has
been reported in each of two strains of Drosophila as aconsequence of space flight. 111 Similar circumstances arealso reported to result in an increased frequency of chromosome anomalies (non-disjunction) in germ cells of
Drosophila. 112 The intensity of cosmic radiation during
flight was insufficient to account for these phenomena,
and an influence of some other factors must be suspected.

The dose-rate effect

84. The rate of delivery of ionizing radiation has now
been demonstrated to affect the frequency of mutations
induced by a given dose. This has been shown for bot11
mice and insects.
85. In mice, the effect of differences in dose-rate on
the frequencies of mutations induced at seven specific locihas been studied.119• 1 21 • 1~ 3-127 It has been observed that(tableX):

80. It has been hypothesized that the genetic responseof a species to the factors influencing mutation rate isitself modified through selection. This concept presupposes the existence of an optimum mutation rate for survival of a species ;11s-115 if the mutation rate is too highthe species may be crushed under a heavy mutational load
and if it is too low the species may not be able to adapt to92

(a) When spermatogonia are exposed to doses of300-600 rat a rate of 8.5 X 10-3 r/min (90 r/week), thefrequency of induced mutations is less by a factor of
about four than is the frequency following the same dosedelivered at a rate of 90 r/min;( b) There is an even more pronounced .dose-rate
effect in parallel studies of irradiated oocytes ;( c) The dose-rate effect for spermatogonia is notdemonstrably greater when the lower rate of delivery is
reduced from 8.5 X 10-3 r/min to 1 X 10-3 r/min;( d) Most of the dose-rate effect in spermatogonia isdisplayed within the range of 24 r/min and 0.8 r/min,whereas in females the range of effectiveness appears to
be greater;(e) As in Drosophila, no dose-rate effect is evident inspermatozoa.

However, there are several lines of evidence including
the shape of. 0e dose-effect curve, that sugg~st that, alt~ou~h multi-hit aberrations are easily induced by radia~on m ~ouse spermatozoa, the specific-locus mutations
11?-duced 1;I1 mouse spermatogonia are almost never associated with such multi-hit effects. .Most mutations in
Droso P!iil~ sperma~ogonia c:Iso appear not to be a resultof mulh-hit a?errations. Th1s.evid~nce supports the viewthat. the specific-locus mut<3:t10ns mduced in spermatogoma of the mouse are pomt mutations or extremely
small deficiencies, ss, 136• 1 37 and that it is repair of the
pre-mutational damage associated with this type of mutation that is involved in the dose-rate effect. 1 ~ 1 Current
investigations in other organisms confirm the e..x.istenceof processes of natural repair or elimination of premutational (primary) damage at low dose rates. The
subject of repair will be discussed in detail in the next
section.

86. In Drosophila a significant dose-rate effect on
lethal mutations in chromosome II has been reportedwith irradiation of oogonia 128 and spermatogonia. 129 In
spermatogonia, a lowering of the intensity from 0.10
r/min to 0.01 r/min at a total dose of 200 r results in asignificant reduction in mutation frequency. However, adose-rate effect for contrasting doses of 2 r/min and2000 r/min at a total dose of 3,000 r gamma radiation has
not been observed. In the silkworm there have beenfound two different types of dose-rate dependence ofmutations affecting egg colour and induced during earlylarval development. 97 In one type the mutagenic effectiveness of chronic irradiation at 0.15 r/min is lower thanthat of acute irradiation at 320 r/min, and in the otherthe mutagenic effectiveness is higher with chronic irradiation than with acute irradiation. The former is observed
only in the very young larval stage_ when primordial cells
are prevalent in the gonads, whereas the latter is foundwhen germ cells are irradiated in later stages of development. This latter result, which is opposite to the expected
effect of dose rate, may not be a dose-rate effect on themutation process, for it is suspected that cell selection is
reducing the yield of mutants at the high dose rate. In any
case, it resembles an effect observed at a high dose ratein the mouse, where a dose of 1,000 r gave fewer mutations than a dose of 600 r. 12° Cell selection was invokedto account for this odd result also. In the chalcid wasp
Dahlbominus no significant dose-rate effect on mutations
affecting eye colour has been found when female larvae
receive a total dose of 1,000 rat 1,000 r/min and at 0.17
r/min.130''Repair'' of pre-mutational damage

88. Studies of a variety of organisms have indicatedthat the process of induction of mutation is not irreversibly fixed at the time of irradiation, but that there isa limited interval between the absorption of radiationenergy and the completion of the mutation process during
which, depending on the physiological state of the cells,
modification of pre-mutational damage is possible. Repairof broken chromosomes by restitutional unions of the
breakage ends has been known for a long time and has
been studied in some detail. The subject has recently
been reviewed. 138 Though there are some reasons to thinkthat restitution and recovery from pre-mutational damage are separate though analogous phenomena, this distinction has not been established by e.."'\:perimental means.
89. In Paramecium, post-irradiation treatments are
known to alter the e..'<:tent of recessive damage from agiven radiation exposure, provided they are applied before a certain critical stage has been reached in thesubsequent division cycle. Moreover, in cells not receiving post-irradiation treatment, the effect of irradiation isincreased the later it is administered prior to that criticalstage.139- 141 It was shown earlier that a large fraction of
the mutational effect of exposure of bacterial cells toionizing radiation can be reduced by post-irradiation
treatment with chemical reagents in certain circumstances.14~ A similar pattern of results has been observed
when investigators have worked with UV instead ofionizing radiation.14 3-150 It now appears that all theseresults are consistent with the hypothesis that the terminal event for fixation of some major part of the potential mutation corresponds to the first post-irradiation
replication of DNA.1 H,H 7 • 148 • 151
90. Recent data obtained with Drosophila show thatmodification of pre-mutational damage is possible inspermatids, meiotic stages, and late spermatogonia. 152- 157
In cells with peak sensitivity, spermatids and spermatocytes, post-treatment with cyanide following exposure to
X-rays at a high dose rate may lead to either an increaseor a decrease in radiation-induced mutation frequency.
Inhibition of oxidative respiration by means of posttreatment with nitrogen causes an increase in mutation
frequency in spermatids, meiotic stages, and spermatogonia. On the other hand, fractionation of a dose given
at an intensity of 55 r/sec results in a decrease of themutation frequency in exactly those stages where cyanide
is effective. Inhibition of protein synthesis by means of
pre-treatment with either chloramphenicol or ribonuclease leads to a significant reduction in the frequency ofmutation in spermatids, and in the case of chlorampheni-

87. Although some of the factors that affect the doserate phenomenon have been uncovered, investigation has
not yet proceeded far enough to elucidate the mechanism
involved. Nevertheless, there is strong evidence that it is
the mutation process itself which is affected. Thus, cellselection, which may at times play a role, can, in somespecific instances, be eliminated as the causal factor. For
example, the effect is observed in those mouse oocyte
follicle stages in which cell-killing by the doses of radiation used is negligible.11 9 • m Furthermore, the amount ofspermatogonial killing induced by radiation is approximately constant over a range of dose rates in which thedose-rate effect on mutation is evident.125 • 1 31 •m If themechanism for the dose-rate effect does indeed involvethe mutation process itself, then it seems likely that somekind of "repair" of pre-mutational damage must be taking place at the lower dose rates.119 It has been suggested133 that many of the mutations observed at theseven loci under study may be a consequence of multi-hit
chromosomal aberrations which would be e.."'\:pected tooccur with reduced frequency at low dose rates. 134• 135
93

col, in the earlier stages as well. Since a ring-shaped X
chromosome has been used in such experiments, thereported changes refer to lethal gene mutations and pos~sibly to small deletions. These results have been explainedby assuming that, in analogy to the findings in Paramecium, two contrasting processes are involved, one
associated with the rate of disappearance of pre-mutational damage, the other with the time or rate requiredfor its fixation. 141 Thus, the enhancement of mutation
frequency after post-treatment with nitrogen is thought
to result from an inhibition of the metabolic repair
process. On the other hand, the reduced mutation frequency observed after pre-treatment with both chloramphenicol and ribonuclease suggests that inhibition ofprotein synthesis prolongs the time-span available forrepair of pre-mutational damage. Although it is notknown at present what process is involved in fixation ofpre-mutational damage in spermatids, the reported findings suggest a correspondence of repair mechanisms insuch. widely difierent organisms as Drosophila and Para-

all thirty-ei~ht at the locus s were lethal. In contrast, of
t:I;ose at loci b, c and p, twenty out of thirty-eight wereviable.

S ez and stage of gametogenesis
94. The frequency of radiation-induced mutations canbe influenced both by sex and by stage of gametogenesis.
Th~ c.ell stages of greatest importance in determining
ra~at10n hazards to man are the oocyte and spermatogomal, and the genetic effect of ionizing radiation onthese stages of the germ cells of mammals has received
considerable attention. 166-168 The most extensive investigations have been concerned with the mouse.
~5. ¥ale i;nice i~r_adiat~d with doses as high as 1,000 r
mamtam their fertility briefly, and then undergo a periodof sterility. Near-normal fertility is then resumed. The
temp?rary sterility is a consequence of the fact thatcertam spermatogonial stages are eA-tremely sensitive toirradiation. 169 • 17° Cells in these stages have an LD 50 of
20 to 40 r. However, a few of the early type A spermatogonial cells survive high radiation doses ; these cells
repopulate the germinal epithelium and are responsible
for the resumption of fertility of the irradiated animal.
The existence of the sterile period aids in distinguishing
between genetic effects induced in spermatogonial andpost-spermatogonial stages.

mecmm.
91. The interaction of oxygen and X-rays in the production of genetic damage, as detected in the progeny oi
irradiated males of Drosophila, has been studied extensively.158-165 Dose-fractionation experiments, in whichpart of the dose is delivered in nitrogen and part in airor oxygen, indicate that X-irradiation destroys a protective oxygen-sensitive system. It has been variously postulated that this system acts to reduce the initial amow1tof damage and that it acts to increase the amount of
repair. The system affects both recessive lethals andchromosome aberrations.
92. Table VII summarizes some of the phenomena andmaterial studied both before and since the drafting of
the Committee's 1958 report. The similarity of the effects
observed is striking, considering the wide range of organisms observed. From these data it can be concluded
that a proportion of radiation-induced mutational or premutational changes are subject to natural repair for a
finite but relatively brief period after they occur, and thatthe natural repair process itself is subject to interference
by radiation and by metabolic inhibitors. It is important
to determine whether this effect is applicable to man, andif so, the single dose-levels or continuous dose-rates atwhich the natural repair processes are effective, and thecritical period of tin1e and the circumstances under which
they act. It is emphasized that probably not all premutational damage is reparable and that a linear dosemutation relationship independent of dose-rate is to be
expected at low doses which do not appreciably affect the
repair process.

96. Irradiation of female mice with doses as low as
50 r can result in permanent sterility after an initialperiod of post-irradiation fertility. A dose-rate effect on
this induced sterility has been detected.171 The permanency of induced sterility is attributable to the fact thatthe majority of oocytes are in early stages of folliculardevelopment, and are extremely sensitive to radiation ..
Since there is no new formation of oocytes in the adultmouse ovary, sterility sets in when the supply of radioresistant oocytes in older follicles is exhausted.
97. It has been possible to distinguish two kinds ofradiation-induced cell death in different types of germ
cells in mouse gonads. Most spermatogonia die immediately after irradiation, while spermatocytes show no
response until they reach the meiotic divisions. In bothcell types, chromosome damage in the classical sense of
aneuploidy can, at most. account for only a small part ofthe cell loss.172 A similar situation has been found in the
rat-kangaroo. 173 These studies suggest that chromosomal
damage is a minor cause of cell death in spermatogonia
irradiated with moderate doses. The subject of the radiosensitivity of the gonads is treated more fully in annex D.
98. Peak sensitivity to the induction of dominantlethals and recessive visibles in the mouse has been foundin spermatids and spennatocytes11'°"178 for the male, andmetaphase primary oocytes for the female. 179 With anacute dose of 300 r of X-rays, the mean frequency formutations at specific loci following irradiation of postspennatogonial stages is twice that induced in spermatogonia.178 It has also been shown that exposure of adultfemales to an acute dose of 200 r of X-rays results inmore mutations than a similar e..xposure of 17~ day old
foetuses. In males the induced-mutation frequency has
also been observed to be higher in adults than in foetuses,
but the difference is not statistically significant. 175

Lorns specificity
93. Both the natural and induced rates of mutation
have long been known to vary markedly at different lociin various organisms. This observation has now been
firmly established in the mouse. 85•136 Among the sevenloci under study, the lowest and highest rates for mutations induced in spermatogonia differ by a factor of
thirty. This information is based on 174 mutations induced with doses of 300-1,000 rand high-dose rates. Of
these, seventy-one mutations were induced at locus s,ninety-nine were induced among the four loci, b, c, d andp, and only four were induced at the two loci, a and se.
Ninety-two of the mutations were analysed for viabilityof the homozygotes. Seventy-one (i7 per cent) were
lethal prior to maturity and twenty-one were viable.
There was some variability among the seven loci in thisrespect also. All the t\velve mutations at the locus d and

99. The ratios of induced mutation frequencies at theseven loci under study in mice differs with irradiationof spermatogonial and post-spermatogonial stages. 88 •13"
Deficiencies large enough to involve both the d and seloci (with cross-over value of 0.16 per cent) are common
among the mutations induced in post-spermatogonial94

cells, but irradiation of spermatogonia yields such deletions only with extremely low frequency, if at all. Such
deficiencies are, however, induced in oocytes. It thus
seems that mutations contributed to progeny as a resultof spermatogonial irradiation differ systematically fromthose due to post-spermatogonial and oocyte irradiation.
100. In Drosophila, the influence of se.x and stage of
gametogenesis in radiation-induced mutations is well
documented. 12 •1 50 • 1 81 •329 The lowest and highest freguencies of induced mutation for a given radiation dose varyby a factor of fifteen. Spermatogonia and oogonia are theleast sensitive; oocytes are somewhat more sensitive thanoogonia. In contrast, spermatocytes and spermatids areseveral times more sensitive than spermatogonia. Spermatozoa -vary in sensitivity depending on their stage ofmaturity. The difference in radio-sensitivity between
Drosophila sperm and spermatids is attributable both todifferences in 02-tension 164 • 182-186 and to changes associated with protein synthesis.m-155

guide to those effects which might be e.xpected. They arebriefly summarized here.
.104. Most of the Drosophila information has been obtamed through irradiation of spermatozoa. Aberrations
are de~ect~d in ~i~er the first or subsequent generationsf<;>llowmg 1rrad1ation. Cytological as well as genetic techniques can be used for this purpose.
105. V~ble aberrations resulting from chromosome?reakage mclude duplications, deficiencies, and intra- or
1i:ter-chro?1osome rearrangements. The ability of individuals :v1th deficiencies or duplications to survive thisaneuplo1dy d~pends upon the length and genie content of
the segments mvolved. Both duplications and deficiencies
upset genie balance, and tend to lower viability and to betransmitted as recessive lethals. Viable intra- and interchromosome rearrangements include inversions andtranspositions of segments within chromosomes as wellas translocations between chromosomes. These' aberrations do not involve aneuploidy, and affected individuals
are phenotypically normal if "position effect" is not involved. However, their progeny may be geneticallynormal, or again contain the balanced rearrangement, orbe aneuploid.

Species specificity
101. Species differ widely in their genetic sensitivity
to radiation. The induced rate of mutation at the sevenloci studied in mice is about fifteen times that for a comparable group of loci in Drosophila. 181 Comparisons ofdominant lethals in mammals and Drosophila188 and ofchromosome mutation in plants189 have likewise indicatedthe existence of species specificity. Radio-sensitivity indifferent species of rodents has been determined in termsof the number of chromosome rearrangements in the
nuclei of spermatogonia exposed to a low acute dose of
4 r.uo, i 9 i Such measurements are difficult to make because the frequency of chromosome breakage varies
greatly in different cell stages, a fact which can lead tothe confounding of species and cell-stage differences.
Nevertheless, the percentage of cells with rearrangements
has been reported to vary from 2.6 in guinea pigs to 0.6
in rats, 0.2 in mice, and 0.1 in rabbits. A comparison of
the cytogenetic radio-sensitivity of germ cells of themonkey and mouse at doses from 50 to 400 r has suggested that sensitivity of monkeys is twice that ofmice.1ss, 1s2106. At low doses, the frequency of individuals withaberrations caused by single breaks tends to increaselinearly with dose. In some instances it has been notedthat small intercalary deficiencies also increase linearlywith dose. The frequency of individuals with aberrations
caused by two breaks, such as inversions and translocations, increases more rapidly than the first power of thedose, approaching the second power of the dose at lower
levels of treatment.
107. Whole-chromosome aneuploidy in Drosophila isalso caused by ionizing radiation. The induction of primary non-disjunction was first reported in 1921.19'• 195
Using irradiated females of Drosophila virilis it has been
demonstrated that there is a linear increase in the occurrence of primaryXO males in the dose-range400-l,200 r,
and that the induced rate of occurrence of XO males isapproximately 1 X 10-5/r/egg.196•197 The rate of occurrence of XO males is approximately fifteen times that of
XXY females. The ratio of XO :XXY flies is thus
greater than the naturally-occurring ratio which is about
4:1. l\fore recently a similar investigation has been carried out with Drosophila melanogaster.93 With exposure
to doses of 600 r, 2,400 r, and 3,600 r, the frequency of
non-disjunctional males increased at a rate of approximately 2.5 - 3.0 X 10-5/r. Non-disjunctional males
were more frequent than non-disjunctional females by
about one order of magnitude.

INDUCED CHROMOSOME ABERRATIONS

102. Because some serious hereditary defects in man
have recently been found to be associated with chromosome aberrations, the role of ionizing radiation in producing these anomalies will be considered in detail. The
fact that radiation can cause extensive chromosomechanges has been known for many years; investigations
in plants193 and in animals 90 have been reviewed in detail.
Actually, it is not always possible to make a sharp distinction between gene mutation and chromosome aberration.
Minute chromosome aberrations often cannot be distinguished from gene mutations. Furthermore, rearrangements of chromosome segments sometimes involve"position effects" in which the phenotypic e.xpression ofgenes is altered. 85

108. In mice, gross chromosomal anomalies are rarely
found as a consequence of irradiation of parental premeiotic germ cells. This rarity has sometimes been attributed to failure of transmission rather than to lack ofoccurrence. However, for at least two types of chromosomal aberrations, reciprocal translocations and deletions, this e.-..;:planation does not seem to be correct.
Translocations induced in post-meiotic stages can betransmitted through subsequent meioses to become heritable traits.166 Thus, a more likely explanation for therarity of these aberrations following pre-meiotic irradiation is either that the necessary chromosome breaks do
not occur or that the broken parts do not e.xchange. The
same situation exists for deletions. An exhaustive studyof what appear to be deletions in the d-se region of linkage group II in the mouse has shown that these are produced as a consequence of post-spermatogonial andObservations on experimental organisms
103. One of the most suitable organisms for studies of
induced chromosomal changes is Drosophila,· in thisorganism small chromosome changes can be detected
cytologically by e.-..;:amination of salivary gland chromosomes. Furthermore, detailed information on the linear
sequence of specific loci is available. Although observations made with this organism cannot be used for direct
extrapolation to man, they nevertheless serve as a useful95

oocyte irradiation, but not of spermatogonial irradiation.88 Transmission of the induced deletions ranges
from poor to normal or near normal. Since transmission
is possible, it is apparent that either lack of breakage orrejoining is responsible for the non-appearance of thedeletions following· spermatogonial irradiation.
109. Some types of chromosomal damage are, however, produced with high frequency by irradiation of
spermatogonia. Many abnormal anaphases have beenfound in spermatogonial cells of monkeys two years after
exposure. 198 More recently, cytological evidence of chromosome damage in irradiated spermatocytes has been
noted at the first post-irradiation cell division in mice.172
Those particular types of aberration probably cause cell
death before maturation of the gametes. However, a
recent report suggests that structural changes induced in
pre-meiotic germ cells can occasionally be transmitted toprogeny.100
110. Data on the induction of whole-chromosomechanges in the mouse are at present largely restricted to
sex-chromosome changes. Experimental work in thisfield has developed rapidly in recent years. 85 The availability of useful sex-linked marker genes and improvement in cytological techniques have contributed to thisprogress. The sex-determining mechanism of man has
recently been shown to be much more similar to that of
the mouse than it is to that of Drosophila.
111. In mice, irradiation of sperm increases the frequency with which paternal sex-chromosomes are lost:
1.3 per cent of progeny suffered such a loss after a doseof 600 r as compared with 0.1 per cent in the control.200·201 HoweYer, the bulk of spontaneously occurring
XO individuals are believed to arise from events following sperm entry into the vitellus. 85• 202•203 Irradiation of
the zygote in the interval between sperm penetration andthe first cleavage is particularly effective in inducing lossof a sex chromosome. Thus, 100 r yielded S per cent XO
individuals as compared with 1 per cent for controls. Bothmaternal and paternal losses can be induced by radiation,
whereas only paternal losses have occurred in the controls. No autosome loss has been detected in these experiments in which four and in some cases five autosomes
carried genetic markers. This suggests that such losses,
if they occur with an appreciable frequency, are lethal.
112. Extensive investigations of the in vitro cytogenetic effects of radiation on mammalian somatic cells
have been undertaken. Although from the point of viewof heredity the important chromosomes are those of thegerm cells, these studies of the radio-sensitivity ofsomatic cells provide a direct method for determining theeffect of radiation on chromosomes. It is to be expectedthat they will play an important role in the future. Measurements are usually based on the frequencies of aberrations detected at the first post-irradiation cell divisionbecause many types of aberration are lost in subsequentdivisions. Commonly-used mammals include the Chinese
hamster, 20 4-we the mouse 201- 209 and the monkey.wa
113. Most of the previously known types of aberrations have been detected in these investigations. Breaks
are of the chromatid or chromosome type depending upon
whether the chromosomes are effectively double at thetime of irradiation. Data on the frequency of breaks are
not always in good agreement and it is apparent that oneof the influencing factors is the method by which cells
are cultured. Nevertheless reproducibility of results isgood under standard conditions.
114. As is to be expected, terminal deletions increaselinearly with the dose but total breakage occurs more fre-quently than the first power of the dose. 206 At low dosesa measure based on linearity is of practical use but a moreaccurate measure of damage is the "coefficient of aberration production". 210 Values for chromatid aberrations invitro cultures of epithelioid-type cells of monkeys andChinese hamsters have been found to be in general agreement with those for Tradescantia microspores. 211
115. With experimental mammals it is possible tocompare the in vitro and in vivo rate of induction ofvisible chromosome aberrations. Somatic cells cultured
in vitro frequently have a much higher spontaneous mutation rate than do in vivo cells. 211 However, investigations with Chinese hamsters and with monkeys indicatethat the radiation-induced aberration rate of epithelioidtype cells cultured in vitro is not greatly different fromthat of rapidly dividing cells in vivo. 205• 200

Observations on human cells
116. No measure of the radiation sensitivity of humangerm cells has yet been made. Nor have extensive quantitative measurements been made of chromosomal damage induced in somatic cells of individuals. However, it
has been clearly shown that chromosomal aberrations areproduced.' 6 • 212- 210 This subject is dealt with in annex D,paragraphs 155 to 158.
117. The effect of ionizing radiation on chromosomesof human cells cultured in vitro has received considerable
attention in recent years. 2060211-223 As with e.-x:perimental
mammals, data on the frequency with which breaks occur
are not in good agreement. For epithelioid-type cells theobserved rate at metaphase is about 0.3/cell/100 r2 00 • 217
but for "fibroblasts" the rate is about 2/cell/100 r. 218 • 220
The frequency of chromosome breaks has been reported
to be 0.9/cell/100 r for fibroblast-type cells 220 and 2/cell/
100 r for leucocytes in freshly-drawn human blood. 222
The coefficients of aberration production for chromatid
breaks in epithelioid-type cells in vitro and for chromosome breaks in leucocytes are in remarkably good agreement with those for Tradescantia miscrospores and forchromatid breakage in epithelioid-type cells of themonkey and Chinese hamster. 222
COMPARABILITY OF RADIATION-INDUCED AND
NATURALLY-OCCURRING MUTATIONS

118. Mankind has long been exposed to natural radiation and it is to be e.-x:pected that an increase in the levelof exposure would not result in any mutations whichhave not occurred in the past. Nevertheless, naturalradiation is only one of the causes of "spontaneous"mutation and it is therefore possible that there may bedifferences between the spectra of radiation-induced andnaturally-occurring mutations.
119. Evidence concerning the comparability of thetwo sorts of mutations was presented in the Committee's
last report. 22 • Most of this information came from studies
with lower organisms and suggested that, in general,mutations induced by ionizing radiation are similar inkind to those of natural origin.
120. There is evidence that in Drosophila the radiation-induced and natural rates of se..x-linked recessive
lethal mutations are similarly affected by sex and stage of
gametogenesis.~ 2 Close correspondence between induced
and spontaneous mutations is not found, however, inmice.137 Furthermore. in mice loss of the maternal X
chromosome can easily be induced by irradiation but
spontaneous maternal loss is very rare. 85 There is also
96

'.Lvailable methods for. det~ctir:g induced ~enetic damage
m humans and for estrmatmg its extent. Six such studies
have been reported. 225 • 221• 235 - 235 In interpreting the results, the effect of maternal irradiation is more appropriately considered independently of the effect of paternal irradiation. The effect of maternal irradiation on the
proportion of male offspring is summarized in table VIII.
A consistent reduction in proportion of male offspring
has occurred following maternal irradiation. In terms of
the simplest genetic interpretation, this can be attributed
to the induction, in irradiated women, of se.'<-linked recessive mutations having a lethal effect on the foetus. The
effect of paternal irradiation is summarized in table IX.
These latter data are not amenable to a single interpretation; the proportion of male offspring is apparently increased with higher doses, but, in at least some instances,
reduced with low doses. The former effect is interpretable in terms of the induction of dominant se.x-linked
lethals. However, the validity of such a simple genetic
interpretation has been questioned on the grounds that the
Y chromosome cannot be considered genetically inert. 239
In addition, the induction of XO and XXY karyotypes
may also affect the relative frequency of male and female
offspring. Furthermore, e.xplanations based on the assumption that the effect on sex ratio is due to damage tosex chromosomes cannot be accepted without reservation.
For instance, the drop in proportion of males which has
sometimes been noted could be attributed to autosomal
mutations which further increase the e.icisting higher
mortality of males. The occasionally erratic control
Yalues must also be considered in any interpretation.

very good evidence from E. coli that the natural mutabilities of loci are sometimes not correlated with theirradiation-induced mutabilities.m
V. Effects obsenred in descendants of irradiatedpopulations
INDUCED MUTATIONS IN THE IMMEDIATE PROGENY OF
IRRADIATED HUMANS

121. Direct observations of the genetic consequences
to man of exposure to ionizing radiation are now limited
to observations of first-generation offspring. Such surveys can be expected to detect only autosomal dominantor se.x-linked gene mutations and chromosome aberrations. Among the difficulties of such inquiries are thoseof estimating the gonad doses actually received by parents, and the small absolute and relative increases to be
expected in the frequency of traits determined by suchmutations.
122. In these surveys, the data are usually concernedwith such matters as abortion, still birth, neonatal death,congenital malformation, and shifts in the sex-ratio ofprogeny. Results frequently indicate a detrimental effectof radiation but this is seldom statistically significant.
One study detected a significant effect of radiation on tlle
frequency of congenital malformations in the progeny ofirradiated individuals but interpretation is hampered by
the incomplete response to the questionnaires used.m
Another similar study failed to show this effect. 226 The
most e.xtensive survey was carried out in the Japanesecities of Hiroshima and Nagasaki following the atomic
bombings ; data were collected on more than 30.000 offspring of irradiated parents and on a comparable control
group. 227 Observations were made of still births, neonatal
deaths, birth weight and congenital malformations. Analysis of these data failed to detect a significant effect ofradiation on either the frequency of early death or congenital malformations. It did, however, detect a significant shift in the sex-ratio of immediate progeny. Morerecently, an analysis of the sa.m~ dat~ b~ an independ~t
investigator has produced statistical significance of radiation effects for some other categories of defects and also
for over-all early death of progeny. 228 • 229
123. The comparatively high frequencies of Down's
and Klinefelter's syndromes permit the effect of parental
irradiation on the incidence of these defects in offspring
to be studied with relatively little effort. Three such investigations have already been reported. In one of these
the radiation history was obtained of the mothers ofeighty-one children with Down's syndrome, ninety-one
children with cleft lip and seventy-one children with nodefect. A possible association between maternal irradiation and Down's syndrome was indicated. 230 However,results of the other two investigations, one of which involved fifty-one patients with Down's syndrome andfifty-one controls, 231 the other 197 patients and 197 controls,232 were completely negative.
124. A survey of the incidence of congenital malformations in different regions has indicated that higher incidences are associated with geographical areas with highbackground radiation. 233 Another survey has reported
that the frequency of malformation varies with the geomagnetic latitude to which is related the cosmic-ray
energy flux. 23• However, it is difficult to prove that natural radiation is the direct influencing factor.
125. A shift in the proportion of male offspring of
irradiated individuals has been considered one of the best

INDUCED :MUTATIONS IN THE IYYEDIATE PROGENY OF
IRRADIATED MAMMALS

126. By means of properly controlled e.xperiments it
is possible to detect induced dominant mutations in ~e

immediate progeny of ir!adiate~ m_ammals. Curr~nt mformation has been obtamed pnnopally from mice. In
mammals it is particularly difficult to distinguish between
gene mutations and minor chromosomal changes.
Reduction in litter size, following irradiation of spermatozoa or oocytes, is most plausibly e.xplain~d in terms of
the induction of chromosome aberration, althoughgene mutations may also be involved.
127. Spermatogonial cells and oocytes are of greatest
concern in a consideration of radiation hazards. Oocytes
are not replenished, and it has been shown that there isno significant change in mutation rate with time after
irradiation of spermatogonia.m Irradiation of spermatogonia has much less effect on litte~ size than does irradiation of later germ-cell stages. This no doubt reflects adrastic reduction in frequency of gross chromosome
aberrations. For instance, individuals with deficiencies
involving more than one gene locus ai:e commonlr fou~dafter irradiation of post-spermatogornal cells but irradiation of spermatogonia yields such deletions only withe..'<tremely low frequency, if at all. These aberrations do
occur, however, among progeny produced after irradiation of oocytes. 88 • 137
128. The fact that dominant detrimental mutations are
induced and transmitted after irradiation of post-spermatogonial stages has been demonstrated by a shorteningof the life span in the offspring of male mice exposed toneutrons. 241 In another study, a significant increase incertain types of skeletal abnormalities was found in thefirst-generation descendants of irradiated male mice.m
Evidence that some dominant lethality is transmitted
after irradiation of spermatogonia has been provided by97

analysis of the cause of litter-size reduction following
exposure to 1,200 r. 199 The same data indicate that translocations are occasionally found in progeny following
irradiation of spermatogonial cells.

gators. hai.:-e adopted the procedure of expressing induced
mutation m terms of the resulting increase in the genetic
component of the variance, with or without reference toth~ genetic component ob_se:"ed in natural outbred populat10ns. The. extent of this mcrease has, in general, beenmeasured either directly by variance analysis or indirectly ~y calculation of the capacity of an irradiatedpopulabon to respond to selection. Pertinent informationfrom e..xperiments concerned with natural and radiationinduced mutation rates is summarized in table XL

129. The specific-locus method of detecting mutations
in mice has yielded further information on the dominanceof mutations induced in spermatogonia. About threequarters of all the induced mutations have been recessive
lethals. However, some of these have a visible effect on
the beterozygote. 1ss In a freely-breeding population thesemutations might well produce greater total damage asheterozygotes than as homozygotes.

133. Such experiments are of special value in indicating whether the genes determining polygenic traits differ
in thei; pattern of mu!ability from those individually
recognized through discrete changes. Estimates ofdoubling dose for abdominal and sternopleural bristles in
Drosophila agree well with those for major genes. 252 On
the other hand, the estimated induced rates for polygenes
controlling viability are high. 253

130. In mice, several studies of the effect of paternal
irradiation have not revealed any consistent effect on thesex ratio of offspring.166 • 239• 248 Another comprehensive
investigation has shown that although the presence of
sex-linked recessive lethals in the second generation
progeny of irradiated males can be detected, neverthelesssex-ratio changes do not now provide a reliable methodof estimating the genetic hazards of radiation because of
the comple."\:ity of factors governing this ratio. 244 This
comple.x.ity has been emphasized by the fact that strain
differences in the ratio can be obtained through differential selection for low and high blood pH.m In fowl, asignificant decrease in the frequency of female progeny
resulting after exposure of male birds to 600 r has been
noted. m In Drosophila, most investigations have demonstrated some tendency toward an excess of males among
the progeny of irradiated males. 241 • 2 ' 11 A significant shift
in this direction has been reported recently. 2' 9 Researchon sex-ratio shifts needs to be continued m the hope oflaying a firm foundation for the application of thismethod in analyses of radiation-induced mutation in man.

134. Loss of genetic variance per generation in an
unselected, random-mating Drosophila population oflin;U.ted size is ont;v a small p~rtion. of the natural variability of the species. Polygemc traits are evidently wellbuffered against the effects of mutation. Thus the radiation damage from an increased rate of polygene mutation,although possibly considerable when summed over many
generations, is probably small in its impact on the firstfew generations. Variability in these traits may be maintained in part by a balance of selective forces, a possibility which further complicates the estimation of radiation-induced mutational damage to polygenic systems inan organism such as man, that cannot be directly e..'Cperimented on.
135. The learning ability, as measured by a maze test,of a population of rats which were irradiated in eachgeneration has decreased in preliminary experiments. 264
If further experiments exclude other interpretations,these results will support the view that radiation resultsin the induction of many small but deleterious mutations.
Again, a significant accumulation of recessive or sublethal mutations affecting ability to survive irradiation
has been reported in mice after ten generations ofchronic gamma irradiation.m

POLYG£NIC TRAITS

131. The subject of polygenic traits was treated atsome length in the 1958 report \vith special reference tointelligence, life span and birth weight.250 Attention was
drawn to the paucity of information regarding the inheritance of continuously varying, or quantitative, traits.
These traits, which are influenced to varying degrees bymany genes, present a special problem in the estimationof genetic hazards of ionizing radiation to populations.
For example, intelligence is influenced by certain raregenes having major effects and by a multiplicity of genes,
each with a small effect. In those instances where a mutation has a drastic effect on the trait, or concomitanteffects on some other trait, it is individually identifiable
and classed as a qualitative mutation. Mutations resulting
in such conditions as phenylketonuria and mongolism
belong to this category. Where the effect is less drastic
no such identification is possible. Furthermore, the frequency of mutations having minor effects is many times
greater than is the frequency of mutations having major
effects. Finally, a great deal of genetic variability withinthese traits is common in a normal population, and phenotype is, in addition, often strongly influenced by theenvironment. In such circumstances the relative contributions of heredity and environment to the over-alJ phenotypic \·ariability are difficult to determine. A few traits,
such as dermal-ridge count, are relatively unaffected byenvironment after birth; here a more accurate genetic
analysis can be made.251 However, the role of mutation in
supporting the genetic variability of polygenic traits has
defied any simple analysis.

VI. Interpretation
136. The preceding sections of this anne."\'. were concerned with the genetic concepts and information now
available for estimating the hereditary effects of anincrease in the level of ionizing radiation. The present
section considers the practical problems involved in formulating reliable estimates from this knowledge.
DIRECT APPROACH

137. An estimate of the genetic hazards of radiation
to man can, in principle, be obtained by a direct comparison of the descendants of irradiated with those ofcontrol populations. To be reliable, such surveys must be
e..xtensive, since most severe genetic defects tend to be
rare. Furthermore, many aspects of genetic well-being
must be considered and it is desirable to continue theobservations over many generations. These conditions
have not been fulfilled in any study to date. All surveys
made so far have, in addition, been hampered by problems of dosimetry and the difficulty of obtaining proper
controls. In the most extensive of these, that dealing withthe populations of Hiroshima and Nagasaki, the investi-132. Because rates of mutation of the individual genes
in a polygenic system cannot be studied, most investi-

98

gators were unable to detect a significant effect of radiation on either the frequency of early death or the occurrence of malformations. At least, this negative finding
suggests that the human genetic mechanism is not substantially more sensitive to radiation than are those ofother organisms that have been investigated. It has beensuggested that the acute dose required to double thefrequency of mutations causing the defects under study
is probably more than 10 r. 227 The Japanese survey
detected, as did others of lesser scope, a shift in the proportion of first generation male offspring suggestive of
the induction of se..x-linked lethal damage in irradiatedparents. The precise nature of this damage is not knownat present.

gene sometimes conferring reduced fitness, but neverconferring increased fitness, must be maintained entirely
by recurrent mutation. On the other hand, if a gene confers increased selective advantage in some circumstances,mutation may have only a minor influence on its frequency:
142. The extent to which such balanced selective
forces are responsible for maintaining hereditary disabilities in human populations is unknown at present. Of
the defects listed in section II, only among the specificdisabilities now recognized to have a high genetic component is it possible to discriminate between those thatare mutation-maintained (categories la and lb) andthose that are maintained by a balance of selective forces(category IV). At present, traits of category IV provide
but a small fraction of the total amount of serious illhealth of known or suspected genetic origin. Suitably
designed studies will undoubtedly produce more examples in the future. In the meantime, estimates of theimportance of balanced selective forces are dependent on
the use of indirect procedures or are based on conceptsof the genetic structure of human populations which have
yet to be confirmed.
143. 'When the prevalence of defective traits is maintained by recurrent mutation, the genetic hazards ofradiation can be estimated if the factor by which mutation rate will be increased by a given radiation dose is
known. However, when the frequency of induced mutations has been determined at only one dose it is necessary
to know the spontaneous rates to estimate the hazard.
Reliable estimates of spontaneous rates can be made only
when the genetic fitness of both homozygote and heterozygote is known. It is possible to measure fitness where
dominant traits are concerned. However, with recessive
traits it is difficult to determine genetic fitness of heterozygotes; as a consequence, reliable estimates of natural
mutation rates are rare. Point mutation rates so far
estimated cluster around the value 10 X 1~ per locus
per generation. The total mutation rate for grosschromosomal aberrations is now estimated at about 1
per cent per generation.

INDIRECT APPROACHES

138. Indirect approaches attempt to predict the genetic
consequences of e.."posure to ionizing radiations throughan understanding of basic genetic mechanisms and theirreaction to radiation. More specifically, estimates arederived through a knowledge of the prevalence of naturally-occurring hereditary ill health within a population,
the role of mutation in supporting this burden, and therelation between the dose of radiation and the mutation
rate in man.
The prevalence of hereditary diseases and de/ ects

139. There is probably a genetic component in the
aetiology of most diseases. It is now estimated that about
6 per cent of all live-born suffer at some time during theirlives from serious disabilities in which this component iseither known or suspected to be of major importance.
Without doubt the estimate of natural genetic burden will
increase with future research. In about one third of thesedisabilities, those of categories la, lb, and IV, the genetic
component is high and the underlying genetic mechanism
is understood. Of these defects, about half are associatedwith what appear to be specific alleles, and about half
are associated with gross chromosome anomalies. For theremainder of the defects, the developmental malformations and serious constitutional disorders of categories
II and III, neither the size of the genetic component nor
its underlying genetic mechanism is known with any
assurance. These disabilities are almost certainly heterogeneous in aetiology ; some are probably almost completely environmental in origin, but in others genotype
may be an important factor. However, even where theimportance of genetic constitution is suspected, the basic
nature of the fault is not clear; complex constellations ofgenes, specific alleles of low penetrance, or cytologically
undetected chromosome aberrations may be responsible.
140. The amount of recessive damage, that hidden inheterozygotes. has been estimated at 2-4 lethal equivalents and an equal number of detrimental equivalents.per
individual. When e..xposed by homozygosis, the lethal
equivalents are expressed as an increase in miscarriages,
still births and in neonatal, infant. and juvenile deaths.
The detrimental equivalents are associated with viablemalformations and overlap the previous listing to someextent. A comparable measure of genes producing recessive infertility has not been made. No similar method is
yet available for estimating the· amount of dominant
genetic damage within populations.

Dose-mutation relationship144. The genetic effects of ionizing radiations cannot
be understood without establishing a firm relationshipbetween frequency of induced mutation and the dose ofirradiation delivered. Most of the earlier information
about this relationship was accumulated from the resultsof experiments with Drosophila sperm. Past research led
to the working assumptions that: (a) the dose-mutation
curve is linear in the low-dose range, ( b) there is nothreshold dose, and ( c) mutation frequency is not dependent on dose rate over the range under consideration.
Much effort has been put into the task of either confirming or disproving these three assumptions. Recent investigations have strengthened the first two, but havedisproved the last. It has now been conclusively demonstrated that rate of delivery of radiation can have aneffect on the frequency with which mutations are found.
In male mice, low dose-rates of ionizing radiation produce one fourth as many mutations as do high dose-rates.
In females. this phenomenon is even more pronounced.
145. Recent research has increasingly emphasized thefact that radiation-induced mutation frequency can be
drastically affected by circumstances other than dose anddose rates:(a) Radiation-induced mutation rates may vary forgenes in the same species and this variation need not

The role of spontaneous mutation in maintaining thefrequency of hereditary disabilities

141. Various mechanisms by which detrimental traits
can be maintained in a population are well recognized. A
99

correspond to the variation in natural rates. In mice theinduced rates per unit dose in spermatogonia at sevenspecified loci may vary by a factor of thirty.
( b) Rate of radiation-induced mutation per unit dose
varies in different species. Furthermore. it has been reported that the frequency of cytologically observed induced chromosome abnormalities in spermatogonia of theguinea pig is nearly thirty times that of the rabbit, aclosely related species.
( c) It is clearly established that sex and stage of
gametogenesis can have a profound influence on bothspontaneous and radiation-induced mutation frequencies.
The existence of such interactions between radiation
effect and the circumstances of its delivery add to thecomplications of estimating radiation effects in humans.
For example, it increases the possibility that errors may
be involved in extrapolating from one species to another,from non-gonadal tissues to germ cells, and from one
germ-cell stage to another.

mates of doubling dose were consequently based on several other considerations. These included a simple genetic
interpretation of sex-ratio changes in man based on theassumed induction of sex-linked dominant and recessive
mutations having a lethal effect in tttero. Account was also
taken of the investigation of seven specific loci in miceand of extensive observations on sex-linked lethal mutation in Drosophila. As expected, advances in our knowledge have indicated that this estimate is in need ofrevision.
148. The usefulness of se..x-ratio changes in estimatinga doubling dose must be considered doubtful because ofinconsistencies in the sex-ratio change in the progeny ofirradiated fathers (table IX). Furthermore, there is no
significant effect on the sex-ratio in the progeny of irradiated male mice.
149. Recently acquired information has also stressed
the fact that, apart from the radiation dose alone, there
are a number of specific factors which should be taken
into account in calculating the doubling dose. Dose rate,sex, and stage of gametogenesis are all factors which
affect the frequency and quality of mutation in both miceand Drosophila and it must be suspected that they are
effective in man. An example of the influence of rate ofdose on the calculated doubling dose can be obtained fromtable X where the main results of irradiation of spermatogonia and oocytes of the mouse have been summarized.
The most important single comparison is that for males
between the dose rates of 80-90 r/min and 8.5 X l(rll r/
min. The former rate provides a doubling dose of 30-40
rad, the latter 100-200 rad. A significant dose-rate effectis also evident for oOcytes, and the doubling doses for
acute and chronic irradiation show an even greater
spread than in males.

The doubling-dose concept in indirect assessments

146. The indirect methods for assessing the hereditaryeffects of an increase in level of ionizing radiation towhich a population is exposed involve the estimation of"doubling dose" and the assumption of linearity of thedose-effect relationship. The doubling dose for a particular mutation is that dose which will increase the mutation rate to double the spontaneous rate. A prediction of
the phenotypic effect of an increase in mutation rate canbe calculated from the fact that the number of affected
persons arising as a consequence of a doubling dosedelivered in one generation, is equal to the number ofaffected persons normally present in any one generation
as a result of recurrent mutations of natural origin. This
increase in affected individuals will be spread over one ormore generations depending on the genetic fitness which
specific mutations confer on their carriers. The genetic
fitness of the heterozygote is of more importance than thatof the homozygote in most cases, because rare mutant
genes occur much more frequently in the heterozygous
state in a random-breeding population. When genetic
fitness of the heterozygote is very low, most of the impactof the new mutations will be felt in the subsequent generation; if fitness is reduced by one-fifth, most of the effectwill appear within the first five generations; if reduction
in fitness is slight the effect will spread over very many
generations. A permanent doubling of the mutation rate
eventually results in a permanent doubling of the incidence of those traits normally maintained by recurrent
spontaneous mutation. On the assumption of an average
reduction of 2 per cent in genetic fitness of heterozygotes,
most of the impact of a permanent doubling of mutation
rate would be felt in about fifty generations. Where systems of balanced polymorphism are in force, natural
mutation is a relatively minor factor in the maintenanceof genetic variability and a doubling of the mutation ratewould have little effect on the prevalence of the associatedtraits.

150. It is becoming increasingly evident that the spectrum of mutations in man is too wide to be included in asingle category for the purpose of estimating a meaningful representative doubling dose. For instance, thedoubling dose for gross chromosome mutations may welldiffer drastically from that for point mutations. If so, thefrequency-distribution of hereditary defects resulting
from a specific increase in the level of exposure to radiation would not be parallel to the natural spectrum.
151. In view of the undoubted complexities of thedose-mutation relationship, it is evident that this methodof assessing hereditary effects of ionizing radiation caneasily yield imprecise estimates. At the same time it isequally evident that none of these recently discovered
complexities invalidates the doubling-dose concept itself;they merely emphasize that the method must be applied
under carefully defined conditions if accurate estimates
are to be obtained. In particular, it is important to discriminate between the genetic hazards of chronic lowlevel exposures and more acute medical and accidental
exposures.
152. The difficulties of obtaining information on thehazards of ionizing radiation would be reduced if thelarge amount of data collected in other organisms could
be applied directly to humans. Differences in species
introduce into this procedure uncertainties the extent of
which is difficult to estimate. A second approach isthrough the observation of human cells grown in tissue
culture; reproducible results relating to radio-sensitivityof cells can be obtained in this wav. However. here also
extrapolation of information is at present associated withuncertainties. Nevertheless it is clear that in. viva andin vitro research in different organisms will ultimately

147. The usefulness of the doubling-dose procedure
was considered in detail in the 1958 report of the Committee. To a large extent this usefulness stems from thefact that whole classes of mutation can be handled as aunit in the absence of any information about the numberof loci invoked or their individual mutation rates. Tentative numerical estimates of the doubling dose for man
were presented in the 1958 report. It was pointed out
at that time that little direct information was available
on the sensitivity of human genetic loci to radiation. Esti100

provide a valuable source of information. Such investigations must be accompanied by an tmderstanding of thegenetic stmcture of human populations and the respectiveroles of mutation and selection in moulding that structure.

doubling dose is about four times the 1958 value of 30
rad. For chronic low intensity irradiation of females
mutation rates seem to be lower than in males. The corn~bined doubling dose for both se..""Ces cannot exceed twice
the value for males and is not likely to be much lower
than. that value. ~or these est~m'.'ltes, uncertainty due tospecies extrapolation and the hm1ted number of loci usedin experimental studies probably does not exceed threefold in either direction. A permanent doubling of themutation rate would ultimately double the prevalence ofthe serious defects under consideration. These are now
estimated to have a prevalence at about 1 per cent.

Conclusions

153. Sufficient information is not now available tocalculate with a useful degree of accuracy a representative dose which would double the mutation rate (doublingdose). Nor is it yet possible to predict directly the quantitative or qualitative effects of such a dose on populations. Nevertheless, information regarding some aspectsof the genetic hazards of ionizing radiation can beobtained by the doubling-dose method. This involves thecalculation of separate doubling doses for different dose
rates, and, in addition, for different specific categories of defects. The complexity of the calculations is
reduced by the fact that differential sensitivity of germcell stages within each sex can be largely ignored; as far
as the genetic hazards of radiation to man are concerned,
the significant germ-cell stages are the spermatogonia
and the oocyte. This is true whether irradiation is chronic
or acute.

155. The doubling dose for the defects of category lb,
those due to gross chromosome aberration, cannot now
be estimated for lack of data. However. the effect ofradiation on the frequency of gross chromosome mutation is amenable to study, and it can be expected that
continued research in this field will enable estimates tobe made in the near future. A doubling of the mutation
rate in one generation would almost certainly double theprevalence of these defects in the next generation. Thisprevalence is now estimated to be about 1 per cent.
156. It is not possible to estimate the doubling dose forthe genetic changes contributing to developmental malformations and serious constitutional disorders of categories II and III. The prevalence of these defects might
be doubled by a doubling dose but the increase would
probably be much less; environment is suspected to havea strong influence on their aetiology, and unrecognizedbalancing selective mechanisms may also be effective inmaintaining their frequency.

154. The group of disabilities to which the doublingdose can, at present, be most usefully applied are those
severe defects maintained by recurrent point mutation(category la). Calculations of the 1958 report suggested
that the over-all representative doubling dose for man
might well lie between 10 and 100 rad, with 30 rad as themost probable value. This estimate was based on studies
which involved acute irradiation and the production ofpoint mutations. In the absence of better evidence, thedoubling dose for acute irradiation of males does not
require revision. However, there is evidence that thisvalue is lower in females; experiments with mice haveshown that oCicytes are somewhat more sensitive to acute(but not to chronic) irradiation than spermatogonia. The
doubling dose for the two sexes combined must therefore
be lower than that for males and may well be about half
this value. For chronic irradiation of males, new information from mouse e..xperiments suggests that theTABLE l.

157. Significant progress towards an understandingof the genetic effects of ionizing radiation has been madein the last four years. The Committee emphasizes that:(a) all research has confirmed the fact that ionizing
radiation produces genetic damage at all doses and dose
rates so far tested, and ( b) further progress in understanding the genetic hazards of radiation will come not
only from ad hoe research in radiation genetics but froman increase in all types of genetic research in man and inexperimental organisms.

CHROMOSOME ABERRATIONS ESTABLISHED IN MAN

Associated clinical condition

Chromosome complmwo1

Chromosome
numberFirsl
re/tTe>IU

47
47
47
47

6

I. Anomalies related to chromosome mm1ber
Down's syndrome (mongolism) .....•• Autosomes: Trisomy-21
Trisomy-(17-18)
Complex congenital malformations....
Trisomy-(13-15)
Complex congenital malformations....
Klinefelter' s syndrome ............... Sex-chromosomes: XXY
Klinefelter's syndrome...............
XXXY
Klinefelter's syndrome.,.............
XXXXY
Turner's syndrome..................
XO
Mild mental defect.... . .. .. .. .. .. .. .
XXX
Mental defect .....................•
xxxx
II.

48
49

7
8
9
10
11

48

13
14
15

46

16

45

47

Struct11ral anomalies
Down's syndrome with trisomy-21 .... 21 ,...., (13-15)

101

TABLE II. DISABILITIES WHICH HAVE BEEN ASSOCIATED WITHABNORMAL KARYOI'YPES, EXCLUDING KNOWN MOSAICS
Clinieal anulition

I.

II.

Anomalies related lo chromosome number
Klinefelter's syndrome ......••..•.••..•••.••••. XXYY
Klinefelter's-Down's syndrome ...•.....•...•...• XX:Y, trisomy 21
Prenatal death ................................ Triploidy
Mental retardation •••.•••.••.••••...•..••••••• Trisomy 6(?)
Facial anomalies .............................. Trisomy 22(?)
Structural anomalies
Polydysspondyly .............................. 22,..., (13-15)
Familial mental and speech defect ...•......•.... 22,..., (13-15)
Primary amenorrhoea ......................... X
partlydeleted X
Down's syndrome ...••.............•....••...• 21 ,..., 22
Down's syndrome •.•••..•..•••.•...••••.•.•.•. 21 ,..,,, 21, or
trisomy 19 andmonosomy 21
Convulsive disorder ........................... (1-2),..,,, (6-12)
Klinefelter's syndrome .....•....•...•....•..... XXY and 14-15
Congenital abnormality .•... , ••..•..••• , ••••••. 16,..,,, 21, or
trisomy 21 andmonosomy 16
Pseudo-hermaphroditism ............... , •••.••. 21 ,..,,, Y
Turner's syndrome ..••••••..•••••..••...••.... Enlarged X
Familial Marfan's syndrome .................... Enlarged satellite
Transmissible hypospadias •.•.............••••. Y deletion
Gonadal dysgenesis .• " ..•...••..•......•••..•• X or Y deletion
Auricular septa! defect ......................... 2 ,..., (6-12)
Familial malformation of central nervous system .. Enlarged satellite+

TABLE III.

48
48
69
47
47

12
102
37
256
257

45
45
46

258
109
259

46
46

18
21

46
46
46

260
106
261

46
46
46
46
46
46
46

262
263
264
265
266
267
268

LETHAL AND DETRJME!ITAL EQUIV.AI.a.IS DERIVED FROM STUDIES OF OFFSPRING FROM FIRST-COUSIN MARRIAGES(Modified after Newcombe 2 G9)Consanguineous(first eousin 011ly)(3)

equi!NllenJR.efeUf'.U

16.01
11.62
12.89
2.98
0.61
9.82

6.92 ± 1.50
5.20 ± 1.55
1.63 ± 3.29
0.35 ± 1.73
5.73 ± 1.81
6.33 ± 2.91

2.21 ± 0.48
1.66 ± 0.50
0.52 ± 1.05
0.11 ± 0.55
1.83 ± 0.58
2.03 ± 0.93

270
271 '

16

837
3,184
194
196
164
163

84
182
227
176

4,094
4,010
3,822
4,094

2.05
4.54
5.94
4.30

2.07 ± 0.65
4.32 ± 0.96
5.80 ± 1.12
11.90 ± 1.18

0.66 ± 0.21
1.38 ± 0.31
1.86 ± 0.36
3.81 ± 0.38

273
274

2,091 63,145
808 17,33131
567
651 63,796

3.31
4.66
5.47
1.02

1.16 ± 0.40
1.91 ± 0.88
6.18 ± 1.96
0.40 ± 0.17

0.37 ± 0.13
0.61 ± 0.28
1.98 ± 0.63
0.14 ± 0.05

40
275

2,778
672
248
212
205
192

22.93
16.82
14.52
3.33
6.34
6.15

134
370
25
5

43
87
104
169

1,043
982
886
1,043

4.12
8.86
11.74
16.20

125

2,798
822
352
4,845

4.47
6.57
11.65
1.42

637
113
36
7
14
31

FranceStill birth ..................
Infant death •••...•....•...
Death from 1 to 30 years ....
Abnormality• ...•..........
Japan
Still birth; neonatal death ....
Infant death ...............
Juvenile death ..............
Abnormality* ..•............

DiffutnU

Total

U.S.A.
Infant death; juvenile death .•Death under 20 years •...••.
Miscarriage ••..•.•.•.•. , .•.
Still birth; neonatal death ....
Infant death; juvenile death .•Abnormality .......•.•..•.•

54
41
69

LttMI ordetrimental

FrtfJ!:iney

AJ!eckd

Total

Condition

Fre{%)"'

3)

Affected

Plau

Co111rol•Indicates some overlap with the preceding classes.
•• Controls drawn from offspring of sibs of the consanguineouspair.
See also Book:r.1 who found no significant difference in themortality in small samples of offspring of first-cousin and control
marriages, but a considerably greater proportion of the cousin

3)

212••

offsering having hereditary diseases (16 versus 4 per cent), andhaving lower than average intelligence (26 versus 15 per cent).
Since the individual offspring were observed for varying periodsof time the mortality data are not readily presented in the above
form. An average of three recessive deleterious genes per person
is estimated from these data.

102

TABLE !V.

ESTIMATED MUTATION RATES AT LOCI DETERMI?-t"ING AUTOSOMAL
DOMIN ANT DISEASES IN MAN(Modified from Stevmsoii 277 and Penrose39)
Trail

Estima~d ra!e/lccus/ten.

Region(X 10-<)

Epiloia

England..........................

8

Achondroplasia

Denmark.. . • . . . • . • . . • • . . • . . . • . • . •Sweden..........................
Northern Ireland..................
Denmark.........................
Michigan ...•...••.•• ,............

43*
68*
13

Aniridia
Microphthalmos

278
279
280
281
282
283

5
4

Neurofibromatosis
Huntington's chorea

Sweden..........................
5
England •.•......•.•• ,............ 15
l'vlichigan......................... 23
Northern Ireland........ . . • • • . . . . • 29
Germany, Fed. Rep. of.... . . . • • • • • • 4••
Michigan ...•.••••.•.•••.•••••••.. 100+

285
286
287
288
289

~lichigan.........................

5

290

Arachnodactyly
Acrocephalosyndactyly

Northern Ireland •••.• ,............

6

291

England..........................

3292

Retinoblastoma

0284• This estimate probably includes phenocopies.
This figure is adjusted for presumptive phenocopies.

TABLE V.

EsnMATED MUTATION RATES AT LOCI DETERYnfING
SEX-UNKED DISEASES IN MA."i(Modified from StevensonZ11)
Basis of estimation Estimakd rak/loeKS/ten.

Trail" - 1/J (J - 0 x*

(X 10 ...)

&ference

Englandf = 0.25
Est:: = 0.8 X 10-•

20

293

Haemophilia... . • • . . . . . . • • Denmarkf = 0.286
Est x = 1.33 X 10-•32

294, 295

j = 0.333
x == 489/4,092,025

27

296

f=O

95

297

f""' 0

59

298

f=O

39

299

f=O

47

300

Limb girdle muscular
dystrophy ...........•... Northern Ireland

••

34

51

Recessive deaf-mutism ...... Northern Ireland

••

13

51

Denmark andSwitzerland

Utah, USAx = 18/63,000

Northern Irelandx = 48/271,896

Duchenne typemuscular dystrophy ...•.
Englandx = 16/138,403

Englandx = 15/105,310* µ. = Mutation rate/locus/generation.
f = Relative genetic fitness.
0x = Frequency of trait in population.

Estimates made by special methods. 11

103

TABLE VI.

ESTIMATED ~!UTATION RATES AT LOCI DETERMINING
AUTOSOMAL RECESSIVE DISEASES IN MAN(Modified from Pe11rose3 9 )TrailBasis of estimation(µ - (1 - f) x*

RegionEstimated rate/l«us/len.
(X JO-<)

Rtfertnu

38

301

28

302

f=O

Juvenile amaurotic idiocy ...... Sweden

Est x = 3.8 X 10-1
f = 0.5
Est x = 5.5 X 10-t

Albinism ..................... Japanlchthyosis congenita ........... Japan

f=O
f = 0.5

11

302

28

302

f=O

11

302

23

280

45

280

49

303

25

54

Est x = 1.1 X 10-t

Total colour blindness ......... JapanEst x = 5.5 X 10--1
Infantile amaurotic idiocy ...... JapanEst x = 1.1 X 10--1
f =0:c = 1/44109

Amyotonia congenita .......... Sweden

f=O

Epidermolysis bullosa .......... Sweden

x = 2/44109
f = 0.02
Est x = 5 X 10-1

Microcephaly .•............... Ja pan

f=O

Phenylketonuria .............. EnglandEst x = 2.5 X 10--1* p. = Mutation rate/locus/generation.

f = Relative genetic fitness.
x = Frequency of trait in population.

TABLE VII.

STUDIES OF TIME-DISTRIBUTION OF DOSE-MODJPICATION OP PRE-MUTATIONALDAMAGE AND ASSOCIATED PHENOMENA

Radiation

Mouse spermatogonia ...•.............. X, 'Y.l\fouse oOcytes .•••••••••••••••••••••••• X, 'Y

Drosophila oogonia .....•............... 'Y

Silkworm, early stages of spermatogonia
and oogonia ...................•..... x. 'Y
Dahlbominus, wasp <>Ogonia ............. 'Y

Plaenmmnon

Remarks

RLferenee

Recessive visibles
and letbals atseven selected lociRecessive visibles
and letbals atseven selected loci

Fourfold reductionin effect at low
dose-rate
1\fore than fourfold
reduction at low
dose-rate

Differential viabilityof cells, radiation
quality eliminatedInter-cell selection
differential
viability, radiation
quality eliminated119,124,
127,132

Sex-linked
recessive lethals

Reduced effect at
low dose-rate

Egg-colour mutants
at two specificloci
Eye-colour
mutants infemale larvae

Reduced effect at
low dose·rate

Mutations

Drosophila spermatogonia •...........••. 'Y

2nd chromosome
recessive letbals

Drosophila spermatogonia ............... 'Y

2nd chromosome
recessive letbals

Drosophila spermatogonia ..•.•••.•. , .... X

Sex-linked
recessive lethals

Drosophila spermatogonia .......... , .... X

Sex-linked
recessive lethals
in ring-X
chromosome

Drosophila spermatogonia (?) ............ X

Sex-linked
lethals104

No effect at
intensity
differences of
1,000 r/min and
0.17r/min
No intensity
effect at
2,000 r/min and
2.0 r/min
Reduction at
intensity
differences from0.01 r /min to
0.10 r/min
Reduced (?) effectof fractionateddose

121,123304
128
97

After elimination ofcell selection andlater stages
Probably oc)gonia

130

Total dose 3,000 r

129

Total dose 200 r

129

Shifts in brood305
pattern of mutation
rates cannot be
excluded
Intensity of
153,154,
radiation for
155, 156
fractionation and
N: post-treatment
55 r/sec

No effect of dose
fractionation;enhancement by
post-treatment
with N~; reduction
by pre-treatment
with chloramphenicol
Decrease by
Stage not defined,feeding of larvae
probablywith actinomycin D
sperma togonia
and penicillin

306,307

TABLE VII.

MakrialSTUDIES OF TIME-DISTRDIUTION OF DOSE-MODIFICATION OF PRE-MUTATIOXALDAMAGE AND ASSOCIATED PHENOMENA (continued)

Radiation

MutationsPhenomenon

Remarks&Jere nu

Drosophila spermatids and spermatocytes .. X

Sex-linked
recessive lethals
in ring-X
chromosome

Reduced effect ofGene mutations anddose fractionation
possibly small
and of predeletions;
treatment withradiation given at
chloramphenicolhigh dose-rates;
and ribonuclease;inhibition ofenhancement by
metabolic repair
post-treatment
and delay ofwith N,; both
mutation fi....ation
increase anddecrease by posttreatment with HCN

152,153,
154,155,
156,157

Drosophila sperm ............•......... X

Sex-linked
recessive lethals
in ring-X
chromosome

Increase by pretreatment withribonuclease andchloramphenicol153, 154

Drosophila sperm ...................... X

Reduced (?) effectSex-linkedof doserecessive lethals;
fractionation inchromosome breaks
absence of 02

Drosophila sperm ...................... X

Chromosome breaks

Drosophila oc5cytes ..................... X

Critical period~ 40 min; criticaldose for breaks

158, 161

01 affects bothbreakage andrejoining ofchromosome
fragments; nosaturation of Os
sensitivity systems

Radiation given in
N~. air, or at
1 At of 02

163

Half-translocations,detachment of
attached
X-chromosomes

02 alTects bothbreakage andrestitution of
breaks

N: between X-ray
fractions, or as a
post-treatment
increase halftranslocation
frequency

308, 309

Habrobracon oocytes .................... X

Hatchability ofeggs treated infirst meiotic
meta phase

Drosophila spermatids .................. X

Translocation

310
Realization of
Post-treatments
potential radiation
with N. and CO
damageincrease radiation
damage152, 311
After both low andCyanide posthigh dose-rates;
treatment increases
CN delaysfrequency
restitution of breaks,
more translocations
139,140
Effect of various
Effect of timepost-treatments
between irradiation(nutrition,and chromosome
metabolic inhibitors)
duplication
143,144,
Pre- and postObserve mutation
145,146,
treatment withfrequency
147,148,
various temperadecline, mutation
149
tures, nutritional
stabilization,
factors, andmutation fixation,
metabolic inhibitors,
and mutation
relations to protein,
expression
RNAand DNA
synthesis

Paramecium . .......................... X, UV,aRecessive lethals
expressed after
autogamy

E. coli; Streptomyces spores; SerraJia ...... UV, X

Biochemical
reversions,"EMB colour"

Neurospora ..•.. ....................... UVBiochemical
mutation

Trijolium . .•..........................

Somatic mutationsat leaf marking
locus

Chromosome breaks
Vida ............................... .. X,
Neutron105

Protein synthesis
decreases mutation
at low UV doses,
but increases
mutation at highdoses
Reducing effect ofdose fractionation
Process ofrejoininginhibited byradiation

RNA derivatives
increase mutation
frequency at low
doses only

150

312
Protection by doseof 12.5 r, dependent
on 0.-tension andtemperature
313,314
Repair requires
cellular metabolism
and protein
synthesis

TABLE VITI.

EFFECT OF IRRADIATION OF MOTHERS ON THE PROPORTION OF
MALE OFFSPRING
CMltrol

Irradi4Ud

No.
birthsIi••

Per cenlJapan • .........•... {43,544

52.085Countr;ymak

U.S.A . .............. Control not available
355
54.6
674
50.1
225
53.3

Franee.· · · · · · · · · · · · · {Netherlands.... . . . . . . .

TABLE IX.

Dose ra,.ge
rads

No.Ii'<
birthsPer Unlmak&fcre"ceea. 8
ea. 75ea. 200
50-200
20Q-400
2-10
JOQ-600

19,610
3,958
2,268
407
161
797
221

51.97951.44051.190
49.1
44.7
52.2
48.0

227,315

Japan •••••.,. ••••...

Irradi4Ud

No. livebirthsPer cullmale

43,54452.085

609

51.72

51.24
Averagefor Japan
52.42
U.S.A.. • • . . . . . . .. .. • 3,491p"~··············i

Netherlands •••••••.••

238

EFFECT OF IRRADIATION OF FATHERS ON THE PROPORTION OF
MALE OFFSPRING
CMllrol

Cout1lr;y

235
236

1,185
1,926
828
657

51.5
52.7
46.6
52.3

Dose ranie
rads

No. li•ebirthsPer unimale&ferenceea. 8
ea. 60ea.200Many dosesof unknown
amount

5,168
1,226
753
4,201

51.58753.26352.722
53.64

227,315

Many small
doses
20Q-400
2-20
JOQ-608
1-10

4,277

51.39

225

656
1,394
635
668

56.1
46.0
52.3
53.4

236

237

238

TABLE X. NATURAL AND INDUCED MUTATION RATES AT SEVEN SPECIFICLOCI IN ADULT MOUSE SPERMATOGO!'o'lA AND 00CYTES

De/ails of i"adialion

Source

Total
Dose
(r)

X-ray.................
300
X-ray.................
600
X-ray................. 1000
X-ray ..•.••.•••••..•.• 600 400h
X-ray.................
600
Co'°...................
600
X-ray.................
600
csm..... .............. 600
Cs137 • • • • • • • • • • • • • • • • • • •300
Cs111 •••••••••••••••••••
516
esw................... 861
Co'°...................
603•
Co 1111 and radium. . . . . . . .
37.5d
Cs137 • • • • • • • • • • • • • • • • • • •86+

Alton'""

of rnutalions
per locus
per garr.,,te(X 10-')

Dose Rat<:(r/min)No. ofojfspri11i

No.of
mutalions

80-90
80-90
80-90
80-90
60-70
24
9
0.8
0.009
0.009
0.009
0.007-0.009
0.0011-0.0078
0.001

40,408
119,326
31,815
4,904
10,76144,35228,33927,84058,45726,32524,281
10,76363,322
56,993

25
111
23
10
11
33
14
10
10

8.84
13.29
10.33•
29.13
14.60
10.63

5
12
2
6
6

2.71
7.06
2.65
1.35
1.50

119
119
119
121
126
121,316317
125
121,316
121
121
126
318
121

544,89732

0.84

119, 121,316,318

12,85336,083
10,117
27,174

16
13

Control. .............. .

7.06
5.13
2.44

Mula.lions in o6cytes

X-ray.................

esm ..... ·····. ... . . . ..

Co1111 • • • • • • • • • • • • • • • • • • •csw...................

400
400
600•
258

92-96
0.8
0.05
0.009

Control. .....•.........

98,828•For a possible explanation of the low mutation frequency, seeparagraph 83 above.
b The two fractions were delivered 15 weeks or more apart.

17.78
5.15

1

1.41

2

1.05

319
121,123

0.14

121, 123,316• Delivered in 90 12-hr. or 16-hr. days.
d Delivered in 5, 25, or 35 16-hr. nights.
• Delivered in 12 16-hr. nights.

106

121, 123
304

TABLE XI.

Trealmo11l

Material and charatlers

Drosophila mela11ogas/er
Abdominal bristle number .....••.

Drosopltila melanogasler
Abdominal bristle number ...••...

.......

0

POLYGENIC TRAITS: MUTATIONAL DATA

llfelllod

Response to selection for highand low lines

Nil

Analysis of increased varianceassociated with second
chromosome
Ditto

0.0014/generation

0.006/generation

8.7 X 10-1 /radSternopleural bristle number •.....
Drosophila nu:lanogaster
Abdominal bristle number •.......

Nil

Analysis of variance associatedwith second chromosome
Ditto

Sternopleural bristle number ......

?

Regression of variance on dose forlarge chromosomes
Ditto

Rice
Heading date ......•.......•....

Nil

3.3 X 10-1 rad
Not significant hut:I> 0.006/generation

Cmmuents

Refere11te

Natural genetic variance cited as 5 units
for abdominals ancl 1. 7 units forslernopleural320(10/25)Nil'lin gt11eli' variauc'(a) 1,800 r per
generation as
adults(b) NilSternopleural bristle number •••...
Drosophilti mela11ogl1sler
Abdominal bristle number ..•...•.

Drosophila nu:lanogaster
Sternopleural bristle number .••...

ReJults: i11creaJe(a) 3,000 r X-rays
Selection for high no.
every generation (a) Top 15% every generation(b) 3,000 r X-rays(b) Top 15% every otherevery othergeneration
generation

321

0.0004/generation
322

0.002/generation

3.5 X 10-1/rad

Details of X-ray treatment and dose
not given:I> 4.7 X 10-1/rad•323> 2.5 X 10-1/rad*rr suppose inbreeding system leaves

6 or 12,000 r
X-rays to seeds

Variance analysis 5 generations
after irradiation of highly
inbred line

1.5 X 1Q-1(day)2/rad

Plant height. .•.................

Ditto

Ditto

8.4 X JO-l(cm)2/radMaize
9 attributes .•..•...•.......•....

Nil

Analysis of shifts in plot meansover 6 generations of selling
doubled monoploids

Average of 4.5 X 10-1
mutations per attribute per
gameteVariance analysis fnilecl to give significant
results because of high environmental
component

325

2 X 10-1/rad

Variance of flowering data in natural
populations not known. Controls
probably not significantly different from,..., 0.00043: good linearity with dose
obtained

326

Arabidopsis lhaliana
Logarithm of flowering data .....••Secretariat calculation.

0-150 kr X-rays to
dry seeds

324

variance equiv. of 3-5 generationsof spontaneous mutation, can calculatespont. rates of 8-10 X 10-1 (day) 1 /generation for heading date and6-7.5 X 10-t(cm)2/generation forplant heightREFERENCES
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1'L PoHIPieBcKaa, IO. l\L Py&a-r.

BIImmmon II ,lijl., remffiftI8CKaJI pa~IIOtI}'BCTBIITemi­
HOCTb I\.'leTOK paaHii!X: BH,ll;OB M11e&OIIIITaIOm;nx. ,TI;oRyi.teHT OOH A/AC.82/G/L.416.

168. Apcell.bena, l\L A., r. r. Tnnmrnn, II;nToreHeTif!IeCKa.lI

paJJ;II01JY1lCTBIITelbHOCTb

IIOJIOB:bIX:&.JeTO&o6e3l>Jm II Ml>llIIeii Ha ypOBHe Ma..m:x II p;pyrux ,ll;03.
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189. XBocToBa, B. B., .iI. B. HeB3ro.n;1ma, IlpIPirnm pap;rroycroi:l:lJIIBocrn pacTemtii. ,Il;OEJMeHT O;QH A/AC.82/G/L.4L4.
190. Eep1rnc, IO. R., r. :M. P-0HlI'!e1rnr..a.ir, IO. H. HayMeHEo, B.rnmme rerroTIIIIa opra.Hn3~Ia '.Ha 1IJBcTJnrrenbHOc.TI> .ll,U;epHoro aIIIIapam & :r.ra.lThIM ,rr;o3a:1r
nonn3npyrom;ett pa,wr~. )l;oR,y:MeHT OOH A/AC.82/G/L.418.
191. )l;y6IIIDIH, H. II., l\I. A. ApceHoeBa, IO. H. Eep1mc,
renern11ecxaJI onacnocn, MaJiblx µ;03 pa.n;naTI;llll ,n;nH-cie.lIOBem II lIX acpcpeKT na nac:ie.n;cTBeEHOCTI> o6eabmr 11 rpbI3YHOB. ,1!;0Ky.11reHT OOH A/ AC.82/GjL.406.
192. ApcemeBa, i\I. A., r. r. TIIBJIEOB, TI;IIToreReTII1I0ClffiJI pa]J;IIOtJYBCTBilT8JbHOCTI> IIO.IOBbIX :&:IeTOE
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)I;OEYMeHT OOH A/AC.82/G/L.424.
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