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

UNITED NATIONSNew York, 1988

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

UNITED NATIONS PUBLICATION
Sales No. E.88.IX.7
ISBN 92-1- 142143-8
09000PANNEX E
Genetic hazards

CONTENTSParagraphs

Poragrophs

INTRODUCTION .......................
.4.

B.

I.

Germ cell stages and radiation
conditions relevant to genetic risk
evaluation ....................

3-4

General assumptions ...........

5

BRIEF HISTORY O F T H E APPROACHES TO GENETIC RISKASSESSMENTS .................
A.

B.

1-2

The doubling dose method ......
1. Reports by different scientificbodies including UNSCEAR
in the period 1956-1966 ....
2. The UNSCEAR 1972 andBEIR 1972 Reports.. ......
3. The UNSCEAR 1977 Report
4. The BEIR 1980 Report.. ...
5. The ICRP Task Group 1980
Report ...................
6. The UNSCEAR 1982 Report
7. The NUREG 1985 Report . .
8. The UNSCEAR 1986 Report
9. The doubling dose method
in retrospect ..............
The direct methods ............
1. Direct methods used between
1956and 1972 ............
2. The UNSCEAR 1977 and
BEIR 1980 Reports.. ......
3. The UNSCEAR 1982 Report
4. The NUREG 1985 Reportand other publications .....
5. The UNSCEAR 1986 Report

11.

I

RELEVANT NEW HUMAN DATAPUBLISHEDAFTERTHE
UNSCEAR 1986 REPORT ........

77-78

111. RISK COEFFICIENTS FOR GENETIC EFFECTS .................

79-80

IV.

ESTIMATES OF DETRIMENT ...

81-83

V.

UNCERTAINTIES AND PERSPECTIVES ..........................

84-103A.

9.

Prevalence of mendelian, chromosomal and other diseases.. ......
1. Mendelian diseases ........
2. Chromosomal diseases .....
3. Congenital anomalies andother diseases of complex
aetiology .................
Mutational mechanisms and DNA
repair .......................

85-91
85
86-87
88-91
92-97

C. Nature of spontaneous and radia-

tion-induced mutations .........

98

Fragile sites and spontaneouschromosome breakage.. ........

99

E.

Oncogenes: genetic aspects .....

100

F.

Other work in progress

G.

Suggestions for future research . .

D.

......... 101-103
104
Poge

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

392

References ............................

401

Introduction
1. The evaluation of genetic hazards associated withthe exposure of human populations to ionizing radiation is one of the major areas in uhich the Committee
has been active since its inception. Its first comprehensive Report on this topic was published in 1958 [UI],
and this was followed by six Reports of a similar
nature published in 1962 [UZ], 1966 [U3]. 1972 [U4],1977 [U5], 1982 [Ub] and 1986 [U7]. This time span ofover a quarter of a century has witnessed a number ofmajor advances in radiation genetics, human genetics,
cptogenetics and epidemiology; it also represents aperiod during which, from the standpoint of genetic
risk evaluation. there have been changes in concepts
a n d methods and shifts in emphasis necessitating
revision of views and quantitative estimates of genetic
risks. The paucity of direct data that bear o n the
induction by radiation of genetic effects leading todisease states in man continues to remain a major
drawback; however, the prodigious amount of literatkeo n such effects in other species makes it prudent andreasonable to believe that exposure of human germ
cells to ionizing radiation will cause mutations andchromosomal aberrations, which in turn may lead todiseases. So far. there has been no alternative but touse data generated from experimental organisms as
the main basis for predicting expected effects in man;in fact, the estimation of genetic risks to man fromexposure to ionizing radiation remains a major exercise
in extrapolation.
2. The aim of this document is threefold: (a) toprovide a general background of the principles andmethods that are used in the evaluation of genetic
radiation hazards in man; (b) to trace the evolution of
the conceptual framework, the data-base, the assumptions and the extrapolations involved in genetic risk
estimation. from about the mid-1950s to the present;and (c) to indicate in which areas research is inprogress or needed in the years to come. While theemphasis will be on the Committee's continuing
efforts in this direction. the work of other scientificbodies will also be discussed where appropriate.
A.

GERiM CELL STAGES A N D RADIATlOh'
CONDITIONS RELEVANT T O GENETIC RISKEVALUATION
3. From the standpoint of hazard evaluations, it isthe effects of radiation on two particular germ cellstages that are considered important: (a) the mitoticallydividing stem-cell spermatogonia in the male, whichconstitute a permanent germ cell population in thetestes and which continue to multiply throughout the
reproductive life span of the individual, and (b) the
oocytes, primarilv the immature ones, in the female.
Female mammals are born with a finite number ofoocytes, formed during embryonic development. These
primordial oocytes, as they are called, grow andbecome surrounded by follicles but are arrested at aparticular stage (diplotene o r dictyate) in meiosis. This
arrest lasts from late pre-natal life until shortly before
ovulation in the mature female. Because oocytes are
not replenished by mitosis during adult life andbecause they only have to complete the meiotic
divisions before pronuclear fusion, these are clearly
the cell stages in the female whose irradiation has
great potential significance for hazard evaluations.
3 . The radiation exposures received by human populations are i~silallydelivered as small doses at highdose rates (e.g., exposure during diagnostic radiology)o r they are greatly protracted (e.g.,continuous exposure
to nntilral and man-made sources). In therapeutic
radiology. doses as high as several Gy may bedelivered, and at high dose rates; howekrer, such
exposures are warranted on medical grounds and are
given only to selected individuals for the treatment ofspecific cancers. In estimating genetic hazards to the
population, the relevant radiation conditions are,therefore. low doses and low-dose rates.

B.

GENERAL ASSUhlPTIONS

5 . In using the data from mouse studies (the principal
model in this context) o r studies of other suitablemamnials (such as non-human primates) to makequantitative estimates of genetic r i ~ k sin man, threeimportant assumptions are made unless there is
el-idence to the contrary: (a) the amount of genetic
damage induced by a given type of radiation under agiven set of conditions is the same in human germ
cells and in those of the test species used as the model;(b) the biological factors (e.g., sex, germ cell stage a n dage) and physical factors (e.g.. quality of radiationand dose rate) affect the magnitude of the damage insimilar ways and to similar extents in the experimental
species from which extrapolations are made a n d inhumans: and (c) at low doses and at lou-dose rates of
low-LET irradiation, there is a linear relationshipbetween dose and the frequency of genetic effects.
Other more specific assumptions and considerations
will be discussed in the appropriate sections of thisreview.

C.

METHODS

6. The methods that have been used so far inquantitative genetic risk assessments can be broadlygrouped under two headings: the doubling dose
method (or the relative mutation risk method) and the
direct methods. The aim of the doubling dose method
is to provide an estimate of risks in terms of theadditional number of cases of genetic disease due toradiation exposure using the natural prevalence ofsuch diseases in the population as a frame ofreference.
7. The doubling dose is the amount of radiationnecessary to produce as many mutations as those that
occur spontaneously in a generation; it is obtained by
dividing the spontaneous rate by the rate of induction
per unit dose. Thus, for instance, if the average
spontaneous rate is m , per locus and the average rateof induction is m2 per locus per unit dose of radiation.
then the doubling dose c = m,/m,. The reciprocal ofthe doubling dose, I/c, is the relative mutation risk
per unit dose. i t is easy to see that the lower thedoubling dose, the higher the relative mutation risk
a n d vice versa.
8. The doubling dose method is generally used to estimate risks to a population under continuous irradiation.
The general concept is that, under normal conditions in
the absence of radiation, there is an equilibrium between
those mutations that arise spontaneously and those thatare eliminated by selection in every generation. Underconditions of continuous irradiation (with the influxof new mutations that it entails), the population will
eventually reach a new equilibrium between thosemutations that enter the gene pool and those that are
eliminated.

9. In practice. what is done is to: (a) estimate
the doubling dose@) from experimental data on
spontaneous and induced mutations and chromosomal
aberrations and (b) estimate the expected increasea t equilibrium as a product of prevalence, p, ofspontaneously arising diseases, relative mutation risk.
I/c. and the dose sustained by the population. The
increase in the first generation is then estimated fromthat at equilibrium, using certain assumptions. It
bears mentioning that the risk at equilibrium underconditions of continuous irradiation (say, a t a rate ofx mGy per generation) is numerically equal to theintegrated risk over all future generations following asingle (i.e., one time only) dose of s mGy to theparental generation.

locations) in mammalian and human germ cells. With
certain assumptions. the doubling dose method cantherefore be used to estiniate risks from the inductionof at least certain kinds of structural chromosomal
anomalies.
13. The estimation of risks associated with theinduction of congenital anomalies and other diseasesof complex aetiology (whose spontaneous prevalences
are much higher than those of Mendelian and chromosomal diseases) poses a different problem. F o r anumber of well-studied conditions belonging to thisgroup, the evidence is consistent with the assumptionthat their aetiology is multifactorial, depending on
polygenic genetic predisposition and environmental
factors that may also be multiple. In order to be able
to estimate risks of induction for this group of
diseases, the B E l R Committee [B I] introduced theconcept of "mutation component" in its 1972 Report(see also [CI] and [C2]). In that Report [BI], themutation component of a disease was defined a s "theproportion of its incidence that is directly proportional
to the mutation rate". For Mendelian diseases andchromosomal anomalies, the mutation component is 1,
except if there is some selective advantage in theheterozygote; for the diseases of complex aetiology
mentioned above, it was assumed that this component
is less than 1 (in the range 0.05-0.5). Therefore, for theestimation of risks of inducting this group of diseases.
the principle is the same as that for autosomal
dominant and X-linked ones, except that the productof p. I/c a n d x (see paragraphs 7-9) is t o be further
n~ultipliedby the mutation component.

10. In principle, the doubling dose method can beused t o estimate risks from the induction of mutational
events, irrespective of whether they are operationally
14. In addition to the doublingdose method discussed
classified as dominants o r recessives, as well as
above. a number of other methods, called direct
chromosomal aberrations. The major application of
the above method, however, is to simple. b o m i n a n t ~ ~ methods, have been used over the years for theestimation of genetic risks: these are discussed later.
inherited traits whose equilibrium frequencies (i.e.,
The advantage of these methods is that they express
those of the responsible mutant genes) can be assumed
absolute risks in terms of effects expected in theto be directly proportional to the mutation rate [B I ,progeny for the different kinds of genetic damage on
Dl]. The assumption is almost as good for sex-linked
the basis of experimental data. However, it has nottraits [B I].
always been possible to bridge satisfactorily the gap
between the estimates of rates of induction a n d theI I. An increase in mutation rate of autosomal
actual effects expected in terms of genetic disease.
recessive genes will not lead to a corresponding
increase in the frequency of recessive diseases for two
reasons: (a) when recessive mutations first arise (or are
induced). they are present in heterozygous condition
1. BRIEF HISTORY OF THE APPROACHES
and their fate depends strongly on the way selection
TO GENETIC RISK ASSESSMENTS
acts [BI] and (b) a recessive mutation has to combinewith an already existing recessive allele o r become
homozygous to manifest the disease, and this may
A. T H E DOUBLING DOSE M E T H O Dtake from many to hundreds of generations, depending on a number of factors.
1. Reports by different scientific bodies. including
UNSCEAR, in the period 1956-1966
12. Evidence for the radiation induction of numericalchromosomal anomalies resulting in live births, either
15. The general radiation genetic principles thatin experimental mammals or in man, is insufficientguided the BEAR Committee [B2], the British Medicala n d equivocal, apart from XO induction in mice.
Research Council Committee [MI] and UNSCEAR
Consequently. the use of the doubling dose method to[Ul] in the preparation of their respective reports inestimate risks for chromosomal diseases is subject tothe mid- and late 1950s were those that emerged fromconsiderable uncertainty, although it was used by thethe extensive work with Drosophila (primarily mature
Committee in the UNSCEAR 1977 Report [U5].
sperm irradiation), ongoing work with experimental
However, there is definite evidence for the induction
mammals (primarily with the mouse) and the few sparseof structural chromosomal anomalies, particularly
human data. Of these principles, the following deserve
reciprocal translocations (but not Robertsonian transmention: (a) mutations. spontaneous o r induced, areusually harmful; ( b ) any dose of radiation. however
small, entails some genetic risk; ( c ) the number ofmutations produced is proportional to the dose. sothat linear extrapolation from high-dose data provides
a valid estimate of the low-dose effects; and ( d ) the
effect is independent of the dose rate at which theradiation is delivered and o i the spacing between the
exposures.
16. In its 1956 Report. the BEAR Committee [BZ]
estimated that the doubling dose was probably between
30 R and 80 K and that it would be reasonable to use
40 R in computations. I t also assumed that about 2%of all live-born children are, or will be. seriously
affected by defects of "simple genetic origin". Under
the further assumption that for this fraction of humangeneric defects the incidence is proportional to themutation rate, the effect at equilibrium after acontinuing exposure to the then-recommended limit of
10 R per generation was computed. The conclusion
was that there ~vouldbe about j.OOO new instances of"tangible inherited defects" per million births, with
about one tenth of this number in the first generation
after the beginning of radiation exposure. The generalphilosophy, the range and the best estimates of the
doubling dose arrived at by the British Medical
Research Council Committee [ M I] and by UNSCEAR[ U l ] were roughly similar.
17. With increasing reliance on mouse data. attentior;
was focused on collecting more extensive information
after irradiation of spermatogonia and oocytes, thecell stages mosr at risk from the standpoint of genet:crisks. The results that became available (after the
publication of the three reports mentioned earlier)demonstrated that ( a ) chronjc gamma-irradiation of
spermatogonia was mutationally less effective (by afactor of about 3) than the same total dose of highdose-rate x-irradiation [R I , R3]; f b ) following acutex-irradiation at high doses, the mutation rate inmature and maturing oocytes was higher than in
spermatogonia: and (c) the dose-rate effect in females
was even more pronounced than in males [R-l].

18. On the basis of' these results. the UXSCEAR
1962 Report [UZ]suggested that for chronic Ion-LET
irradiation of males. the doubling dose tvas probably
3-4 times the value of 30 R used in the USSCE.AR
1958 Report [UI] and also noted the possibility that.
for similar radiation conditions. the doubling dose forfemales could be higher than for males. It was pointed
out that ". . . a permanent doubling of the mutation
rate would ultimately double the prevalence of thoseserious defects determined by the unconditionallyharmful genes which are estimated to affect about 15of those born alive".
19. By the time of the UNSCEAR 1966 Report [U3],the earlier mouse results had been amply confirmed
and extended and new data had been obtained infemales showiilg that there was 'a dramatic effect of
the interval between irradiation and conception: in thefirst seven weeks after irradiation, the mutation
frequency was high; subsequently, however. n o mutations at all were recovered [R5]. In view of the wealthof mouse data that by then had accun~ulated, theCommittee abandoned the doubling dose approach infavour of a more direct approach, using primarily themouse specific-locus data as a basis. This aspect will
be discussed later.
2.

The UNSCEAR 1972 and BElR 1972 Reports

20. In the UNSCEAR 1972 Report, the Committee
revived its interest in the doubling dose method but
gave i t a low profile. Part of the reason for thisreneived interest was that Liining and Searle [LI] hadsummarized a number of estimates of doubling doses
for different kinds of genctic damage in the mouse(semi-sterility, specific locus mutations. dominantvisibles, mutations affecting the skeleton and autosoma1 recessive lethals). They all fell within a range of
16-51 R, averaging about 30 R for spermatogonia
exposed to high acute x-ray doses. On the basis of thedose-rate studies on the induction of specific locus
mutations in male mice, it was inferred that the
doubling dose for chronic low-LET irradiation conditions could be about three times the above value, i.e.,
100 R. Liining and Searle [L 11 gave no doubling dose
estimates for females. since very little information on
spontaneous rates was available in the literature.
21. On the assumption. based on the Northern
Ireland survey [SI], that in Inan about 3% of live bornare affected by deleterious traits maintained by mutation (now including simple dominants, some traits ofuncertain genetic origin and chromosomal anomalies)
and that the doubling dose is 100 R. Uh'SCEAR [U4]estimated that there would be about 300 extra cases
per million live births for each rad of low-dose-rate.
low-LET radiation to the males of the parental
generation. It argued that. . the great majority ofthese will be (the result of) gene mutations with an
unknotvn degree of dominance. . . if, however, therange observed in Drosophila (2-5%) is used as anupier limit to the average dominance in man as
expressed by the frequency of deleterious traits among
liveborn. then 6-15 affected individuals per million
liveborn \vould be espected in the first generation
following irradiation. t h e rest of the damage being
expressed in subsequent generations".

".

22. In 1972, the BEIR Committee published its
Report [El]. In that Report, the doubling dose wascalculated using an assumed range for the rate of
spontaneous mutations in man (0.5
to 0.5 lo-'
per gene) and an induction rate from mouse specificlocus data (0.25 lo-' per locus per rem, an averagerate trtking into account both sekes and assumed to
appl! to low-dose-rate, low-LET irradiation conditions). The range 20-200 rem thus derived represents a"hybrid" doubling dose range. On the basis of theNorthern Ireland survey [SI] (as may be recalled. thiswas also the basis for UNSCEAR's figures), the BEIR
Committee assumed that the prevalence of genetic
diseases in the human population is about 6%(including 1% dominant and X-linked diseases. 1%
chromosomal and recessive diseases and 4% congenital
anomalies and other diseases of complex aetiology), andthey estimated the effects of 5 rem per generation on a
population of 1 million live births.

23. Further considerations or assumptions used inthat exercise were the following: (a) since the incidenceof dominant and X-linked traits is essentially proportional t o the mutation rate. their frequency will be
increased by the relative mutation risk per rem
multiplied by the dose: ( b ) the incidence of recessive
diseases is only very indirectly related to the mutation
rate; (c) diseases caused by chromosomal anomalies
are not likely to be very much increased by low-level
irradiation: ( d ) for diseases of complex aetiology. themutation component is likely t o be in the range of
5-50'5 (see paragraph 13): (e) for dominant and Xlinked diseases, the expected increase in the first
generation is likely to be about 20% of that at
equilibrium (based on the finding. in the Northern
Ireland survey. that the population incidence was only
four fifths of the incidence in new-borns. and this isroughly equivalent to assuming that the averagemutant persists in the population for five generations);(f) for diseases of complex aetiology. the firstgeneration incidence uill be about one tenth of that at
equilibrium.
24. The estimated effect of 5 rem per generation on a
population of 1 million live births was 300-7.500 new
cases of genetic disease at equilibrium and 60-1,000
cases in the first generation, relative to the assumed
prevalence of 60,000 cases of spontaneous origin per
million live births. To facilitate comparisons with theorher estimates. the recalcuiated figures for 1 rem per
generation are summarized in Table I .
3.

The UNSCEAR 1977 Report

25. At the time of the preparation of the UNSCEAR
1977 Report [U5], the Committee had access to (a)detailed analyses of mouse data obtained after chronic
gamma-ray exposures and estimates of doubling doses
therefrom [S3, S3]; ( b ) the results of the continuing
studies o i mortality rates among children born tosurvivors of the atomic bombs in Hiroshima andNagasaki, published by Neel et al. [N I]; and (c) new
data on the prevalence of Mendelian and chromosomal
diseases, as well as on the prevalence of diseases ofcomplex aetiology, from an extensive sur\*ey carriedout in the Canadian province of British Columbia andpublished by Trimble and Doughty [TI].

that it would be prudent to continue to use thedoubling dose of 100 R for estimating human radiation
hazards. I t also appraised the British Columbia
prevalence figures, taking into account, among otherthings. the results of the Northern Ireland survey, of
several ad hoc surveys for specific dominant conditions and of new-born surveys for chromosomal
anomalies, as well as the uncertainties involved in the
aetiology of the multifactorial diseases. The following
figures (expressed per 10') that were arrived at wereused for hazard evaluation: 10.000 dominant and Xlinked diseases: 1,100 autosomal recessive diseases(excluding t hose maintained by heterozygous advantageof the relevant genes); 4,000 chromosomal diseases(including sel-chromosomal aneuploids. autosomal
trisomies and unbalanced forms of translocations, but
excluding mosaics and balanced structural rearrangements); and 90,000 diseases of complex aetiology-a
total of 105,100 diseases per 10' live births.
28. Using a doubling dose of 100 rad and theprevalence figure of 105,100 per lo6 mentioned above.
UNSCEAR [U5] estimated that. if the population\\?ere continuously exposed to low-LET irradiation at
a rate of I R per generation, there would be a total of
about 185 cases of Mendelian. chromosomal andother diseases Der million live births at eauilibrium. ofwhich about o'ne third would be expressid in the first
generation (0.17'3 versus 0.06%. respectively. of theassumed prevalence of 10.5%) (see Table 2). Thesefigures were arrived at using the following assumptions: ( a ) for dominant and X-linked diseases, thefirst-generation increase will be about one fifth of thatat equilibrium: (b) for recessive diseases, there will beno perceptible increase; (c) for chromosomal diseases,
all those due to numerical anomalies and three fifthsof those due to unbalanced structural rearrangements
will be expressed in the first generation: and (d) the
mutation component of diseases of complex aetiology
is probably about 5%. and the first-generation increment in the frequency of these disorders is probably
10% of that at equilibrium.
4.

The BEIR 1980 Report

26. The estimates of doubling doses for the mouse fordifferent genetic end-points fell in the range 80-249 R[SZ,S3]. Analysis of the Japanese mortality data by
Neel and colleagues showed no significant effects ofparental exposure on the mortality of children throughthe first 17 years of life but suggested that the
doubling dose for this kind of damage is about 46 rem
for farhers and about 125 rem for mothers. for theacute radiation conditions that obtained during thebombings. Neel et al. suggested that. on the basis ofmouse data, the gametic doubling dose for humanbeings would be expected to be 3-4 times the value of
46 rem for males and as much as 1,000 rem forfemales.

29. Subsequently, the BEIR Committee published its
1980 Report [B3]. Its summary of risk assessments is
reproduced in Table 3. I t should be noted that (a)prevalence figures for Mendelian, chromosomal andother diseases are essentially the same as those used in
the UNSCEAR 1977 Report; (b) the calculation ofrisks is based on an assumed doubling dose range of
50-250 rem (instead of 20-200 rem used in the BEIR
1972 Report); (c) the risks are expressed for a
population exposure of 1 rem per generation (instead of
the 5 rem per generation used earlier); and (d) whereas
in 1972 the doubling dose method was the preferred
method of expressing risks at equilibrium and in thefirst generation, in the 1980 Report only the equilibrium
values were obtained using the doubling dose method(the first-generation values given in Table 3 werearrived at using a direct method, to be discussed
later).

27. UNSCEAR examined both the mouse data andthe Japanese data mentioned above and concluded

30. Concerning the new doubling dose range
50-250 rem used in the BEIR 1980 Report, theCommittee stated: ". . . this is based mainly on ourbest substantiated estimates of the doubling dose:
namely. 114 R for mouse spermatogonia: we approximately halve and double this to get our range of 50 to
250 rem". Moreover. although a direct method wasused to obtain first-generation figures, i t is stated in
the Report thar such figures can also be arrived atusing the equilibrium values (estimated using the
doubling dose method) and making assumptions
similar to those made in 1972 (namely. for dominant
and X-linked diseases. the first generation increase
will be one fifth of that at equilibrium and for
disorders of complex aetiology about one tenth of thatat equilibrium).

5. The ICRP Task Group 1980 Report
31. In 1980, Oftedal and Searle [OI] published theconclusions of a Task Group of lCRP on "genetic risk
estimates for radiological protection". Their risk
estimates are reproduced in Table 4. While the basic
data and several of the assumptions used by the Task
Group were similar to those used by UNSCEAR in
1977. the numerical estimates of risk by the former
were different. The important differences pertain torisk estimates for diseases of complex aetiology andfor diseases stemming from unbalanced products of
induced balanced reciprocal translocations. These will
now be considered in turn.
32. As may be recalled (paragraph 28). it wasestimated in the UNSCEAR 1977 Report that the riskof induction of diseases of complex aetiology is a
product of their prevalence (taken to be 90,000 perlo6 live births, on the basis of the results of the British
Columbia study); their average mutation component(assumed to be 5%); the relative mutation risk
(estimated as 1/1W on the basis of the doubling dose
estimate of 100 rad); and the dose sustained (assumed
to be 1 rad per generation). t h e figure arrived at was
45 cases per lo6 live births (i.e., 90.000 X 1/100 X 0.05)
at equilibrium. Under the assumption that the increasein the first generation would be about 10% of theabove, the Committee derived a figure of 4.5 cases per
10"ive births in the first-generation progenj.
33. The Task Group did not, however, use any
prevalence figure for the above class of diseases tomake risk estimates. Instead, (a) they split up thediseases of complex aetiology into (i) dominants ofincomplete penetrance and multifactorial diseases
maintained by mutation (i.e., those that respond to
induced mutation) and (ii) multifactorial diseases not
maintained by mutation (i.e., those that do notrespond to induced mutation) and (b) they assumed
that the expected increase in the frequency of group (i)above (as a result of radiation exposure to the
population) is unlikely to exceed the sum of expected
increments in Mendelian and chromosomal diseases;in the Task Group's calculations, this amounted to
160 cases per lo6 live births at equilibrium. Thus. theestimate of 160 cases per lo6 live births was arrived at
in a way different from that used by UNSCEAR.
34. In the UNSCEAR 1977 Report the risk of production of unbalanced gametes leading to congenitally

malformed children (stemming from the induction ofbalanced reciprocal translocations in males) on thebasis of combined marmoset and human cytogenetic
data. The estimate was 2-10 affected children per
106 live births in the first generation per rad ofpaternal irradiation. The lower limit of the above
range was for chronic gamma-irradiation and theupper limit was for low-dose-rate x-irradiation. The
risk for the irradiation of females was considered to be
low, but no quantitative estimates were given.
35. The Task Group's estimate for the above class ofgenetic damage was 30 cases per 106live births per radof parental (i.e., both sexes) irradiation with lowdoserate x rays and was based on the same set of
marmoset and human cytogenetic data. However, theTask Group assumed that the risk from translocationinduction would be the same in both sexes (whereas
UNSCEAR assumed that it would be lower infemales).
6.

The UNSCEAR 1982 Report

36. The risk estimates of the UNSCEAR 1982
Report [U6] are reproduced in Table 5. They arebasically the same as those derived in the UNSCEAR
1977 Report [US], except for two changes: (a) for
dominant and X-linked diseases, the first-generation
increment was assumed (in 1982) to be 15% of that at
equilibrium (instead of the 20% assumed in 1977).
based on the calculations of Childs [C3], and (b)diseases due to chromosomal anomalies were split up
into those due to numerical anomalies and those due
to structural anomalies; it was assumed that theincrease due to the induction of numerical anomalies
would probably be quite small and that the firstgeneration increment of those due to structuralanomalies would be about three fifths of that at
equilibrium. Consequently, the expected total increases
at equilibrium (-150 cases per million live births) andin the first generation (-22 cases per million live
births) are lower than the corresponding values
estimated in 1977 (185 and 63 cases, respectively).
37. It is worth pointing out thar at the time the
UNSCEAR 1982 Report was prepared, the Committee
had at its disposal the papers of Keel et al. [NZ] andSchull et al. [S4, S5]. They contained an analysis of all
the available genetic data obtained in the continuing
studies of the Hiroshima and Nagasaki populations (afollou8-up of the material presented by Nee1 andcolleagues in 1974 [N2]). These new data pertained tountoward pregnancy outcomes (i.e.. those resulting inchildren with major congenital defects. still births anddeaths i n the neonatal period), survival throughchildhood, incidence of sex-chromosomal anomalies
and incidence of biochemical variants (erythrocyte
and plasma protein variants, analysed using onedimensional electrophoresis). In all the calculations,
the T65D dosimetry was used and an RBE of 5 forneutrons was assumed. As Schull et al. [SS] pointed
out. ". . . in no instance was there a statisticallysignificant effect of parental exposure. . . but for all
indicators, the observed effect was in the direction
suggested by the hypothesis that genetic damage
resulted from the exposure."38. Doubling dose estimates were made only for the
first three indicator traits since the data on biochemical~ ~ a r i a nweret s considered too preliminary. The gametic
doubling dose estimates presented bq Schull et a\. [S5]were the following: untoward pregnancy outcomes,(69 93 rern); survival through childhood (F!mortality ),(1712388 rern); and sex-chromosomal aneuploids,(535 2 2,416 rem). The weighted average of theseestimates is ( 139 1 157 rem). Schull et al. [S4] considered that the doubling dose estimate for low doses
and low dose rates might be higher by a factor of 3.
39. The main message from these papers is that the
doubling dose for human genetic effects may be about
4 Gy, i-e., about four times the value used by
UNSCEAR. which would mean that the relative risks
estimated by UNSCEAR are too high by a factor of 4.
The Committee examined these data and the analysis
presented and concluded that, in view of the lack ofstatistically significant effects and the high standard
deviations associated with the doubling dose estimates.
it would be premature to use these results for genetic
risk assessments at the present time. Therefore, theearlier doubling dose estimate of 1 Gy (based entirely
on mouse data) was retained.
7.

The NUREG 1985 Report

40. In 1985, a report prepared for the U.S. Nuclear
Regulatory Commission entitled "Health effects modelfor nuclear power plant accident consequence analysis"
was published [E7]. This report, hereinafter to bereferred to as the NUREG Report, included (among
other things) esrimates of genetic risk arrived at by the
doubling dose method for low-dose-rate, low-dose,
low-LET irradiation conditions. Important aspects ofthese estimates are the following: (a) the basic data on
the prevalence of autosomal dominant and X-linked
diseases and of irregularly inherited diseases are thesame as those used by UNSCEAR in 1982 and by the
BElR Committee in 1980; (b) the doubling dose used
is 1 Gy (the same as UNSCEAR used in 1982 butdifferent from the 50-250 rem range used by the BEIR
Committee in 1980); (c) the mutation component of
irregularly inherited diseases was taken to be in therange 0.05-0.5 (the same as in the BEIR 1980 Report,
but different from the value of 0.05 used by UNSCEAR
in 1982); (d) the risk estimates were made for a total
population of lob persons with 16.000 live births per
year (or 480.000 in a 30-year generation). basedon 1978 demographic data from the United States(UNSCEAR's estimates were for a population of10" live births): and (e) estimates of risk for the first
generation were derived not from the equilibrium
values but by using a direct method (UNSCEAR's
estimates were derived from equilibrium values as well
as by using a direct method). The relevant table fromthe NUREG Report is reproduced here as Table 6.
8. The UNSCEAR 1986 Report
41. The risks estimated by the Committee in the
UNSCEAR 1986 Report (with some additions) are
given in Table 7. The additions pertain to risk fromrecessive diseases and for second generation effects(see footnotes c, e and f of Table 7). I t can be seenthat (a) the estimates of prevalence and of risk for
Mendelian and chromosomal diseases are the same as
those used in 1982 and (b) no risk estimates areprovided for diseases of complex aetiolog?. (i.e., forcongenital anomalies and other multifactorial diseases),although they had been provided in 1982. The reasonsfor this departure are set out below.
42. New data on diseases of complex aetiology that
became available subsequent to the UNSCEAR 1982
Report provided grounds for believing that theirprevalences may need upward revision. First. thecompilation and analysis of the extensive results oncongenital anomalies in the Hungarian population[C5] suggested that their prevalence is about 60,000
per 106 live births (compared with 43,000 per lob.
based on the British Columbia study and used in the
UNSCEAR 1977 and 1982 Reports); on the basis of
their aetiologv. the congenital anomalies can beroughly subdivided into those due to major genes (6%of the total of 60,000 per lo6);multifactorial causation(50% of the total); chromosomal anomalies (about 5%of the total): environmental. including maternal.
factors (about 6% of the total); and aetiology as yet
unknown (the remaining 3070, approximately, of thetotal) (see UNSCEAR 1986 Report, Annex C. paragraphs 51-58).
43. Second, in the same population, the prevalenceof other irregularly inherited diseases, most of them oflate onset (in middle age and later), was estimated to
be about 600,000 per lo6 of the population (seeUNSCEAR 1986 Report for a discussion of thesedata). Relative to the prevalence used in the UNSCEAR
1977 and 1982 Reports (47,000 per lo6 live births,
based on the British Columbia study), the Hungarianprcvalencc for these diseases is at least an order ofmagnitude higher. One must hasten to add, however,that (a) the British Columbia figure relates to thosemultifactorial diseases with onset before the age of 21,
whereas the Hungarian figure pertains to lifetime(taken as 70 years) prevalence. and (b) in Hungary,
the actual frequency of affected individuals will be
fewer than 600.000 per lob because many of them will
suffer from more than one of these diseases. One
further point relates to the fact that the diseases
included in the Hungarian list (at least 25 entitiesa)
are by no means homogeneous, either clinically oraetiologically; the same is true of those included in the
British Columbia list.
44. During the preparation of the UNSCEAR 1986
Report. the Committee discussed at length these data.
the question of a new risk estimate for these diseases
and the appropriateness of the assumptions usedearlier (i.e., a doubling dose of I Gy. a mutation
OThyrotoxicosis, diabetes mellitus. gout, schizophrenia, affective
psychoses. multiple sclerosis. epilepsy. glaucoma. essential hypertension. acute and sub-acute myocardial infarction. varicose veins,allergic rhinitis, asthma, gastric ulcers, idiopathic proctocoliris.
cholelithiasis, calculus of kidney and urcter, atopic dermatitis andrelalcd conditions. psoriasts and related conditions, systemic lupus
eryrhema~osus,rheumatoid arthritis. ankylosing spondylitis, juvenile
osteochondrosis of the spine and adolescent idiopathic scoliosis.

component of 5% and 10% expression in the first
generation). If these assumptions were valid (which
seem very doubtful), then, the estimate would be
330 cases of diseases of complex aetiolog? per 10" atequilibrium (i.e., 660,000 X 1/100 X 0.05 = 330) underconditions of continuous irradiation at a rate of
0.01 G y per generation. The expected increases in thefirst and second generations would then be. 33 and30 cases, respectively, per lo6. These estimates areabout se\fenfold higher relati\le to those arrived at in1977 and 1982, on the basis of a prevalence figure of
90,000 per lob. Although there is no reason to believethat the actual risk from these diseases would be lessthan those arrived at in 1977 a n d 1982, there are atleast three reasons why the reliability of the estimates
based on the prevalence of 660,000 per 10" is open toquestion: ( a ) the prevalence figure of 600.000 per lob
for multifactorial diseases refers t o the number of
diseases per lob of the population rather than to theactual number of affected individuals; it also includes
conditions of less severity such as allergic rhinitis andpsoriasis: ( b ) the applicability of the doubling dose of
1 G y (which is based entirely on mouse results forclearly defined genetic end-points) to diseases ofcomplex aetiology remains questionable in the absenceof information on the mechanisms of maintenance of
these diseases in the population a n d what effect. if
any, radiation would have on their prevalence: and( c ) the assumption of a 5% mutation component forthe diseases included in the new data-set cannot bescientifically defended in the absence of a systematic
analysis. These considerations led the Committee toexpress the view that it is at present unable to provide
a reliable estimate of risk for these diseases. However.
there is some hope (see paragraphs 90-91) that thedifficulties will be at least partially resolved in the not
too distance future.

not any real breakthrough in the understanding of thegenetic sensitivity of human germ cells to ionizing
radiation.
B.
I.

The doubling dose method in retrospect

45. The rationale for the continued use of the
doubling dose method for risk evaluation is that it
permits one to express risks in tangible terms and thatwhole classes of genetic effects can be handled as aunit in the absence of information about. for instance,
the number of loci involved o r their individual
mutation rates. The early estimates of doubling doses
fell in the range 10-100 R (then, for acute. high-dosee
rate irradiation). and the possible r e p r e ~ e n t a t i \ ~values
lay between 30 and 40 R. With the discovery, in 1962.
of dosc-rate effects in the mouse. UNSCEAR adopted
1 Gy as the best estimate. a n d this value is still being
used. However, ( a ) individual estimates for different
kinds of genetic damage vary from about 0.8 to
2.4 G y in the mouse a n d ( b ) the analysis of theHiroshima and Nagasaki data suggests that the value
may be higher than I Gy. The principal reasons foradhering to the I Gy estimate are that the humanevidence is far from conclusive and that caution andprudence are the guiding principles in this endeavour.
The changes in the estimates of relative risks from themid- 1950s to the present thus reflect increasing knotvledge on the prevalence of these diseases in the humanpopulation and the evolving assumptions o n their
possible responses to an increase in mutation rate andDirect methods used betseen 1956 and 1972

46. Some of'the basic radiation genetic principles thatguided the BEAR Committee [B2]as it prepared its 1956
Report were briefly alluded to earlier. In addition.
advances in radiation genetics and in theoretical a n dexperimental population genetics had even by thattime documented the thesis that the changes due tomutated genes are seldom fully expressed in the firstgeneration progeny of irradiated individuals and thatthese mutant genes persist in the population for
shorter o r longer periods of time, depending o n theirdeleterious effects on fitness, until they are eventuallyeliminated from the population. The concept ofgenetic death enunciated by hluller [M2] was current
and influenced much of the thinking of geneticists. I t
seemed logical, therefore. to apply the concept to theestimation of genetic risks. This point of view was
succinc~lystated by the 13E.4R Comnlittee [BZ] as
follows: "One way of thinking about this problem ofgenetic damage is to assume that all kinds ofmutations on the average produced equivalent damage.
whether as a drastic effect on one individual who
leaves no descendants because of this damage, o r awider effect on many. Under this view. the total
damage is measured by the number of mutations
induced by a given increase in radiation, this number
is to be multiplied in one's mind by the averagedamage from a typical mutation."I t was thought, therefore. that the total risk due
to induced mutations could be obtained as the
product of three factors (i.e.. the number of genes atwhich mutations can occur, the radiation dose a n d therate per gene per unit dose) and that the expression ofthis risk in the first and succeeding generations could
be estimated by population genetic methods. Somelimlted data were available on mutation rates in mice:the main difficulty was the lack of reliable gene
numbers for humans. T o circumvent this problem. theBEAR Committee used Drosophila data. dividing thetotal mutation rate (for recessive lethals per gamete)by that for individual genes. multiplied this ratio by
2 to 3 lo allow for m ~ ~ t a t i o nwithsless-than-lethal
effects and arrived at a figure of about 10': this figure
was then used along with the mutation rate inferredfrom mouse studies to estimate the "total number ofmutant genes that would enter the population in thenext generation if everyone in the United States ofAmerica received a dose of 10 R to the reproductive
glands" ( 5 lo6 mutant genes) [B2]. It is thus clear that
this estimate was for "a hypothetical organism whose
mutation rate per gene is [hat of the mouse and ~vhose
gene number is that of Drosophila" (see [BI] for a
discussion). The BEAR Committee concluded. however. that ". . . this kind of estimate is not a meaningful one to certain geneticists . . . their principal reservation is doubtless a feeling that, hard as it is t o estimate
the number of mutants, i t is much harder still, at the47.

9.

T H E D I R E C T METHODS

present state of knowledge. to translate this over intoa recognizable statement of harm to individual persons" [BI]. The method was then abandoned [BI, B3].
48. In its first Report of 1968, UNSCEAR did notuse any direct methods. In 1966, it used a variation of
the method used by the BEAR Committee. It wasargued that (a) if it is assumed that the average rateof induction of recessive mutations in the mouse(estimated as 1 lo-' per locus per R from dataobtained for specific locus mutations, following highdose, high-dcse-rate s-irradiation of spermatogonia) is
applicable to man and (b) if, for the purpose ofcomputation, the total number of gene loci in man
were assumed to be 20.000 (range: 7.000-70,000). then
the total risk from the induction of point mutations
will be 2 lo-' mutations per gamete per R. This estimate
was higher than the one arrived at using the limited
data on the induction of autosomal recessive lethals inmouse spermatogonia as a basis (0.5 10-' mutations
per gamete per R), although not significantly so. The
expression of this risk in the first and succeeding
generations was then estimated using the average
degree of semi-dominance of recessive lethals in
Drosophila.
49. For estimating more directly the risk from theinduction of dominant mutations. the Committee
toassumed that the rate is likely to be fromper locus per R and that the number of locidetermining dominant diseases in man ranges from 50
t o 500. The total risk was thus estimated to be from
5 10-Qo 5
mutations per gamete per R. Similar
estimates of risk from the induction of chromosomal
aberrations (translocations and deletions) were arrived
at using the limited data on the induction of heritablesemi-sterility in the mouse and data on the inductionof dicentrics and deletions in human peripheral blood
lymphocytes. It was pointed out that all the risks
would be lower for chronic irradiation conditions.
50. In the UNSCEAR 1972 Report [U4]. the Committee approached the problem of estimating gene
numbers in the following way. In the mouse, there areabout 20 functional units per cross-over unit [R6] andthere are some 1.250 map units in the entire genome[GI]. This gives about 25.000 functional units in themouse genome. The DNA of the mouse and human
diploid genomes were estimated to contain 4.7 IOY and5.6 lo9 nucleotide pairs, respectively. Thus the estimateof the total number of functional units in the humangenome was 25,000 X (5.6/4.7) = 30,000. By assumingthat the rate of induction of specific locus mutations inmouse spermatogonia under conditions of chronic
gamma-ray exposure (0.5 10-- per locus per rad; average
estimate based on the 12 loci studied) was applicable toman, the total risk from the induction of point
murations in man was estimated to be 1.500 mutations
per rad per million gametes (i.e., 0.5 lo-' x 30,000)(Table 8). This tvas considered an overestimate,because specific locus mutations may involve morethan one functional unit.
L,

51. The estimate of total risk based on the newmouse data (discussed in the 1972 Report) on the
induction of autosomal recessive lethals (sperma-

togonial irradiation), after correction for DNA content. was 36 mutations per rad per million gametes.
and this was considered a possible underestimate. The
first-generation expression of these risks (computed
using, as before, the degree of semi-dominance ofrecessive lethals (2-5%) inferred from Drosophila
studies in conjunction with the total rate of 1.500)
amounted to 36 mutations per rad per million
gametes.
52. .A modified version of the gene numbe: approach
was also used in the UNSCEAR 1972 Report for
estimating the rate of induction of dominant mutations in man. For this purpose. the rate of inductionof dominant visible mutations in mouse spermatogonia(4.96 lo-- per rad per gamete) was used. Since this rate
was for acute. high-dose-rate s-irradiation. it was
divided by 3 to correct for effects at 10% dose rates
and divided by 75 (the then-presumed number of lociin the mouse that mutated to dominant visibles).
giving a rate of 2.2
per locus per gamete per rad.
53. The 1971 compendium of McKusick [M3] listed
415 autosomal dominant loci in man plus another 528
for which the evidence was inconclusive. Assumingthat there was "good reason t o predict that the
number will not be less than 1,000 based on progressof research in this area", the Committee multiplied
2.2
by 1,000 and obtained an estimate of about
two dominant mutations per rad per million gametes[U41.
54. In its 1972 Report. UNSCEAR also provided an
estimate of risk from the induction of reciprocaltranslocations in man. using a direct method. This wasdone by assuming that (a) the rate of induction ofbalanced reciprocal translocations in man ivould betwice that in mouse germ cells (i.e., 2 X 0.3 lo-' per
gamete per rad, based on the arm number hypothesisof Brewen et al. [B4], which was then, but 1s not now,
considered valid); (b) at low doses or low, dose rates.
the rates in males would be reduced by factors of 4 o r 7,
respectively; (c) the ratio of balanced to unbalanced
products would be 1:2: and (d) only about 6% of theunbalanced products would result in liveborn children
with multiple congenital anomalies. Taking all theseassun~ptionsinto account. i t was estimated that therisk was 1-2 congenitally malformed progeny per
million live born, following irradiation of males. (It is
worth mentioning that in its 1972 Report, the BEIR
Committee also provided an estimate of risk from theinduction of reciprocal translocations: using the same
basic data and a different set of assumptions, it
arrived at an estimate that was an order of magnitude
higher than the estimate of UNSCEAR.)
55. In retrospect, despite gallant efforts to weld theprinciples of population genetics, the concept ofgenetic death and the principles of radiation genetics
in order to arrive at risk estimates for the induction of
mutations, the hopes that, until 1972, had been raisedby the gene number method proved illusory. Apartfrom the difficulties of reliably estimating gene numbers. the conceptual difficulties of bridging the gap
between the dynamics of mutant genes in the population, on the one hand, and genetic disease, on theother, were so numerous that the method fell short of
expectations and faded into oblivion. Furthermore,
the degree of semi-dominance of recessive mutant
genes, used to extract first-generation effects from thetotal risks. referred in reality to the effects of thesegenes on biological (reproductive) fitness and not togenetic diseases as such.
2. The LSSCEAR 1977 and B E I R 1980 Reports

56. In the UNSCEAR 1977 Report, a major conceprual change was introduced. At the time of
preparation of the above Report. the Committee had
at its disposal the earlier data collected by Ehling (E I,
E2] on the induction of dominant mutations affecting
the skeleton of the progeny of irradiated male miceand the new data on these collected by Selby and
Selby [S7]. The data of the latter authors establishedthat these skeletal mutations were in fact transmissible
and also showed that they had incomplete penetrance
and variable expressivity for many o r all of thephenotypic effects they caused and, besides, that someof them behaved as recessive iethals when madehomozygous. Doubtless, some of the properties ofthese mutations are similar t o those of rare dominants
a n d rare. irregularly inherited dominants in man.
57. However, in order t o convert the rate of induction of mutations causing skeletal abnormalities in themouse into an overall rate for all mutations withdominant phenotypic effects in man, information isneeded on ( a ) the proportion of dominant conditions
in man whose main effect is in the skeleton and (b) the
proportion of skeletal abnormalities studied in themouse that, at the human level, is likely to cause aserious handicap. After careful deliberation. UNSCEAR
arrived ar values of 10% for item (a), taking into
account the proportion of clinically relevant autosomal
dominants in man whose main effect is in the skeleton(which was assessed at 20%) and the ease of diagnosisof skeletal defects (possibly higher by a factor of 2)
relative to defects in other bodily systems. The
proportion of skeletal anomalies in the mouse thatmight cause a serious handicap (item (b) above)should they occur in man, was assessed as one half.
58. In risk estimation, the frequency of skeletal
mutations observed after high fractionated or highacute x- or gamma-ray doses was corrected by suitablefactors t o arrive at a rate that would be applicable forlow-dose-rate, low-LET irradiation conditions. The
resultant rate of 4
was multiplied by 10 anddivided by 2, to give 20 lo-". which is the probabilityof induction of mutations causing dominant effects inany of the bodily systems in man. In other words,
following 1 R of paternal (spermatogonial) irradiation,
20 per million progeny would carry mutations causing
one o r another kind of dominant genetic disease, inthe first generation (see Table 9).
59. In its 1980 Report. the BEIR Committee, startingfrom the same data-base as that used by UNSCEAR.
gave a different estimate (5-65 cases per million perrem; see Table 3). There are two reasons for thisdifference. First, to convert the rate of induction ofskeletal mutations in mice to an overall rate invol\.ing
all bodily systems in human beings, UNSCEAR used afactor of 10, as mentioned in the preceding paragraph;this was divided by 2 to exclude mutations whose
effects were slight.
60. The BEIR Committee. by contrast, multiplied by
5-15 t o make the first conversion and multiplied by
0.25-0.75 to make the second conversion: these operations gave the range of 5-45 cases per million births.
Second. to take into account the effects of irradiationof females, the BEIR Committee multiplied the upper
limit by 1.44 (the UNSCEAR 1977 Report assumed
that the risk for irradiated human females would be
negligible and did not give any quantitative estimate).
The rationale for the multiplication b> 1.34 was statedas follows: "The mutational response of the resting
oocytes in mice is negligible. compared with that ofspermatogonia, and mature and maturing oocytes inmice have a mutation rate no greater than 0.44 times
that found in spermatogonia. We d o not know whichof the two classes of oocytes would have a mutational
response more similar to that of the arrested oocytes
in women. T o incorporate this range of uncertainty
into our risk estimate for the combined effects ofirradiation of both sexes, we have simply kept thelower limit of our estimate the same as it was(assuming a negligible mutation frequency in resting
oocytes) and multiplied the upper limit by 1.44
(assuming the maximal estimate of the mutation
frequency in mature and maturing oocytes). This gives
an estimate of 5-65 induced serious disorders per
million liveborn as the first generation expression. . . ."61. In 1977, as may be recalled, using marmoset andhuman cytogenetic data [B5] as the basis for estimating
the risk from the induction of reciprocal translocations.
UNSCEAR arrived at an estimate of between 2 and 10
congenitally malformed children per million births per
rad of low-LET irradiation of males. Brieflv.
- . thecalculations were the following: 7 lo-' (rate of translocation induction; spermatocyte data) X 0.25 (factor
to get the rate for heritable translocations in theprogeny) X 0.1 or 0.5 (factors to account for dose-rate
effect after chronic gamma-rays and low-dose x rays,
respectively) X 2 (factor to estimate the rate of production of unbalanced products of reciprocal translocations) X 6% (the proportion of unbalanced products that was assumed to give rise to viable. butcongenitally malformed, progeny). The risk for theirradiation of human females was considered to besmall. but no quantitative estimate was given.
62. In its 1980 Report, the BEIR Committee used themarmoset cytogenetic data for estimating the risk
associated with the induction of balanced reciprocaltranslocations in human males. Its estimate was
0.5-5
per rem (compared to that of UNSCEAR,
2-10
per rad, as reported in the preceding
paragraph). The BEIR Committee's procedure was thefollowing:(a) Basic rate
7.7 10-4e/m/spermatocyte(marmoset cytogenetic data)(b) Rate of potentially trans4.7 10-'e/m
missible rearrangements(multiply (a) by 2/3)

(c) Correction for low total
2.3 10-4e/m
doses and for low dose rate (multiply (b) by 0.5)(d) Correction for the
1.3 10-'e/m
probability of adjacent(multiply (c) by 0.55)
segregations(unbalanced gametes)(e) Correction for proportion
6.5 10-be/mof unbalanced gametes(multiply (d) by 0.05)
that would result incongenitally malformed
live births(0 Correction for the prob1.6 10-6e/m
ability that only one of(multiply (e) by 0.25)
the four kinds of aneuploid
segregation products will
be viable in zygotes(g) Correction for uncertainty
0.5-5 10-be/m(multiply (f) by 0.3-3)
63. For estimatingrisksfor irradiated human females,
the BEIR Committee made the same assumption as inits 1972 Report; namely, that the risk would be thesame as that in males. Thus "the expected frequencyof viable aneuploids for both sexes is assumed torange from 1
to 10
per rem". The BEIR
Committee also used "an alternative and independent
approach based on litter-size reduction observed after
acute irradiation of mouse germ cells" and pointed
out that "the upper limit of 10
for both sexes
combined may be an overestimate, and that the true
value could indeed be near to zero".
3.

The UNSCEAR 1982 Report

64. The estimates of risk arrived at in the UNSCEAR
1982 Report are given in Table 10. They are basically the same as those arrived at in 1977, except
for the following additions o r changes: (a) an additionala n d independent estimate of risk from the inductionof mutations having dominant effects in the F, progeny
was presented. using the new data on the induction of
dominant cataract mutations in male mice following
spermatogonial irradiation; (b) the probable magnitudeof risk for irradiation of females was arrived at very
indirectly by assuming, on the basis of specific locus
data, that the rate in females is likely to be either close
to .zero (on the assumption that the mutational
sensitivity of the human immature oocytes may besimilar t o that of the mouse immature oocytes) o r not
more than 44% of the spermatogonial rate (see [R7]);
and (c) for estimating risks from the induction ofreciprocal translocations, all the then-available primate
data (i-e.. the marmoset data, the rhesus monkey data
and the limited human data) were used.

65. The mouse cataract mutation data were obtainedin experiments involving high acute o r fractionatedgamma-ray exposure [E3, E4, KI]. From these results,
a rate applicable to chronic gamma-ray exposure wasderived, using empirical correction factors derived
from specific locus studies. This rate was about
2.6 lo-' per gamete per rad. In man, about 2.7% of all
known and proven dominant mutations are associatedwith one o r another form of cataract. The reciprocalof this (i.e., 100/2.7 = 36.8) was used as a factor bywhich to multiply the rate of 2.6 lo-', to arrive atapproximately 10 X
per rad. In other words, forevery rad of low-dose-rate, low-LET irradiation,
about 10 individuals per million born will be affectedby one o r another kind of serious, clinically important,genetic disease. It is worth pointing out that thesecalculations did not use either the multiplier of 2 o r
the divisor of 2 that had been used in analogous
computations with skeletal mutations to account forease of diagnosis and severity of effects, respectively.
66. The extensive cytogenetic data on translocationinduction in male rhesus monkeys show that the rateof induction, at least for highdose-rate x-irradiation
conditions, is much lower than that in marmosets(0.86 lo-' versus 7.7 lo-' per rad per gamete) (see[B6]). Since it is not known whether human spermatogonial sensitivity is more like that of the marmoseto r that of the rhesus monkey, the rates for both these
species were used, one to define the probable upper
limit of risk and the other, the lower limit. The
correction factors used to convert the rhesus monkey
acute rate into the rate applicable to human radiation
conditions are the same as those used in the 1977
Repon. Other correction factors and the underlying
assumptions are explained in the footnotes to Table 10.
4.

The NUREG 1985 Report and other publications

67. The direct estimates of risk presented in the
NUREG Report [E7] (Table 6) differ in some respects
from those in the BEIR 1980 Report. First, the
NUREG Report assumes that both sexes have thesame sensitivity to the induction of dominant rnutations (the BEIR Committee assumed that the sensitivityof females is no more than 0.44 times that of males).
The consequence of this assumption is that forirradiation of both sexes. the risk of induction of
dominant genetic disease is twice that estimated for
exposure of males; namely, 2 X (5-45)
per 0.0 I Gy,o r 10-90
per 0.01 Gy. The geometric mean of thisrange (central estimate) is 30. As may be recalled(paragraph 60). the BEIR Committee multiplied theupper limit of the range 5-45 by 1.44 and came up
with the range 5-65
per 0.01 Gy for irradiation ofboth sexes.
68. Second. the NUREG Report employed the gene
number method (which is no longer used by either
UNSCEAR or the BEIR Committee) to arrive at arisk estimate for X-linked genetic diseases. Assumingthat the rate of specific locus mutations in male mice
(7.2 lo-' per locus per 0.01 Gy) is applicable for Xlinked mutations as well, and that the number of lociin man at which X-linked mutations occur is 250, an
estimate of 1.8
per 0.01 Gy was obtained forirradiation of males or females.
69. To obtain a "single central estimate" for induced
translocations and the unbalanced segregation products, some of which produce viable but seriously
affected live born, the NUREG Report used thefollowing calculations:(a) Basic rate
7.4 104/.0 1 Gy/spermatocyte(marmoset cytogenetic data)(b) Correction for
3.7 10-'/.0 1 G!/spern~atocyte
low-dose-rate(multiply (a) by 0.5)
x rays(c) Correction of
1.48 10-'/.0 1 Gy/spermatocyte
gamma-ray RBE(multiply ( b ) by 0.4)(d) Correction for expected
0.74 IO-~/.OI ~yfrequency of unbalanced(multiply (c) by 0.5)
products(e) Correction for
0.74 10-6/.01 Gy
proportion of viable(multiply (d) by 0.01)
unbalanced products
For irradiation of females. the rate was assumed to be
the same as that in males (i.e., 1.48 lo-' per 0.01 Gy).
and since the oocyte will contain the reciprocal translocation distributed between two tetrads of chromatids,
the probability of recovering unbalanced products wasestimated as nine sixteenths of the above; namely.
5.6 lo-' per 0.01 Gy. Assuming further that about one
tenth of this ~ o u l dlead to viable aneuploids, it wasestimated that the risk for irradiation of human
females would be 5.6
per 0.01 Gy; for irradiationof both sexes. therefore. the total risk from induced
translocations would be about 13 cases of abnormal
progeny per million live births per 0.01 Gy of parental
irradiation.
70. In addition to risk estimares for low-dose, lowdose-rate. low-LET irradiation conditions. the NUREG
Report also provided estimates of genetic risk for theirradiation conditions that would prevail in nuclear
accidents. As would be expected, the risks are higher
under the latter conditions, but this case will not be
further considered here.
71. The NUREG Report also sought to determine
whether its risk estimates were consistent with the lackof detectable genetic effects of radiation in the genetic
studies of Hiroshima and Nagasaki. In its analysis of
the Japanese data, i t used ( a ) the paper of Schull et al.
as a basis [S13: specifically, Table 7. in whichmortality up to age 17 for 16.173 children of exposedparents is correlated with the distribution of parental
doses]; ( b ) the linear-quadratic model as the one
applicable for the induction of gene mutations andchromosomal aberrations at high doses and high dose
rates (developed independently of the Japanese data. on
the basis of the experimental results discussed in thepreceding paragraph); and (c) average doses for eachexposure group (parents), i.e.. 0.05 Gy (0.01-0.09 Gy);
0.295 Gy (0.10-0.49 Gy): 0.745 Gy (0.50-0.99 Gy); and2 Gy (>I Gy). These values were introduced into theequations to project the number of cases of eachgenetic event relative to the child sample size in eachof the 32 sectors of exposure in the matrix of Schull etal. [SI?].
72. The important conclusion that emerged from thisanalysis \\,as that "the central estimate of prediction ofcases should lead to a statistically insignificant. i.e.,
undetectable increase in genetic disorders among the
16,713 progeny of irradiated parents. For example.
there were 1,040 deaths in this group of 16.7 13 progeny
up to the age of 17 (6.22%); in the unexposed groups,
there were 2.191 deaths among 33,976 progeny produced (6.45%) and the two frequencies are notsignificantly different. nor would they have been even
if 50 additional cases were added to the exposed group[E7]."
73. Abrahamson [A21 and Ehling [E8] independently
reached similar conclusions. I n his analysis, Ehlingused the estimate of the genetically significant dose(sustained by the survivors of Hiroshima and Nagasaki)of 1.1 lo4 man Sv arrived at by WHO in its report
entitled "The effects of nuclear war on health andhealth services" [ W I]. The projected increases amongthe 19.000 children in the sample were less than
one dominant cataract mutation and about I I dominantskeletal mutations; the total number of expected
dominant mutations was estimated to be 20-25 (on thebasis of niouse cataract data) or about 56 (on the basisof mouse skeletal data). Ehling argued that, given thekinds of end-points used in the Japanese studies, (a) it
is not surprising that no clear-cut positive evidence forthe induction of genetic damage could be obtainedand (b) the Japanese results are not inconsistent \viththe expectations based on the dominant cataract andskeletal data.

5. The Uh'SCEAR 1986 Report
74. The most recent estimates of risk, those of the
UNSCEAR 1986 Report, are given in Table 11. Thechanges with respect to the estimates of 1982 are
the following. First, on the basis of litter-size reductions observed in niouse studies involving acute, highdose-rate x-irradiation, chronic gamma-irradiation or
chronic fission neutron irradiation (in all, sperniatogonial irradiation; these data are discussed in the1986 Report), the Committee estimated that, following
irradiation of male mice, between 5 and 10 per lo-' Gy
per million live born (in the first generation) would die
between birth and weaning as a consequence of
induction of dominant sub-lethal effects. In vie\!, of
the uncertainty as to whether and to what extent littersize reduction in mice can be extrapolated to mortality
in humans between birth and early childhood, theabove estimate has been appended to Table 11 asfootnote b.
75. The second change (see footnote e in Table 11)
pertains to the risk of induction of autosomal recessive
genetic disease as a result of radiation esposures. In
the past, the Committee's view has been that although
recessive niutations are expected to be induced, nocases of individuals affected with recessive disease will
occur in the first generation; it therefore made no
attempt to present a quantitative estimate of risk inthe subsequent generations following one-time or
generation-after-generation radiation exposure. Searleand Edwards [S9] have now provided a numericalestimate of risk for autosomal recessive disorders.
Basing their calculations on a combination of datafrom observations in human populations and in mice,these authors have estimated that (a) a geneticallysignificant dose of lo-' Gy of x- or gamma-irradiation
received by each parent once in a stable population
with I million live born would induce up to 1,200
additional recessive mutations; (b) from partnershipeffects (i.e., partnership with another recessive mutation

either induced or already present in the population),
about one extra case of recessive disease would be
expected in the following 10 generations; (c) homozygosity resulting from identity by descent would notnormally occur until the fourth generation after
exposure, but on certain assumptions. about 10 extra
cases would be expected from this cause by the tenthgeneration; and (d) in the same period. about 250
recessive alleles would be eliminated as heterozygotes.
on the assumption of a 2.5% heterozygous disadvantage. Such elimination through heterozygotes
may occur through, for example. an increase indisease susceptibilities, malignancy or a decrease inintellect.
76. The third change pertains to risks associatedwith the induction of balanced reciprocal translocat i o n ~ .In its 1982 Report, the Committee used thecytogenetic data collccted in studies with the rhesus
monkey and the marmoset Saguinus fuscicollis, aswell as some limited human data. as a basis for its
risk estimates. The rates of unbalanced products ofreciprocal translocations expected to be generated(estimated from the corresponding rates for balanced
reciprocal translocations) were used in conjunction
with the assumption that 6% of unbalanced zygotes
might result in congenitally malformed children,
giving the range 0.3- 10 per lo-=Gy per 10h live births(the lower limit was based on the rhesus monkey data
and the upper one on the combined marmoset andhuman data). New data at low doses and low dose
rates have since then become available from experiments involving the rhesus monkev and the crabeating monkey: further, the estimate of conceptions
uith unbalanced products that may survive birth has
been revised upwards, from 6% to 9% (discussed in
the UNSCEAR 1986 Report). As a result, the estimated risk is now 1-15 cases of congenitally malformed children per lob live births per lo-? Gy ofpaternal irradiation and 0-5 cases per lo6 live births
per
Gy of maternal irradiation. Further details
are given in footnotes f and g to Table 11.

11. RELEVANT NEW HUMAN DATAPUBLISHED AFTER THE UNSCEAR 1986
REPORT77. The most recent results from the Hiroshima andNagasaki genetic and cytogenetic studies again show
no significant effects of radiation. The mutation tvork[S 121 involved examining 13.052 children of' proximally
exposed parents and 10.609 children of control parents
for rare electrophoretic variants of 30 blood proteins;
three mutations were detected in each group in
725.587 and 539.170 equivalent locus tests. respectively.
The mutation rates can therefore be estimated as
0.4 lo-' per locus (exposed group) and 0.6 lo-' perlocus (control group). In a subset of 4.983 children of
exposed parents (= 55.689 equivalent locus tests) and
5,026 control children (= 59,269 equivalent locus tests)
who were studied for deficiency variants of nineerythrocyte enzymes, one mutant was encountered in
the first group (rate: 1.80
per locus) and none in
the second.

78. In cytogenetic studies [All, among 8.322 children
born to exposed survivors. 19 (0.23%) had sexchromosomal anonlalies (3 XYY. 7 XXY. 5 X X X ,3 mosaics and 1 miscellaneous). and 23 (0.28%) had
structural rearrangements (I0 Robertsonian translocations, 7 balanced reciprocal translocations. 1 inversion,
2 unbalanced supernumeraries and 3 miscellaneous
unbalanced aberrations). Of 7,976 control children,
24 (0.309TrI had sex-chromosomal anomalies (5 XYY.
9 XXY. 4 X X X . 3 mosaics and 3 miscellaneous) and 27(0.34%) had structural rearrangements (6 Robertsoniantranslocations. 13 reciprocal translocations, 6 inversions and 2 miscellaneous unbalanced aberrations). Of
the I I balanced structural rearrangements for whichfamily studies were made. one reciprocal translocationin each group was a new mutant. the rest werefamilial.

111.

RISK COEFFICIENTS FORGENETIC EFFECTS

79. All the numerical estimates of genetic risks
discussed thus far have been obtained on the basis ofgenetically significant doses, i.e., on the assunlptionthat the doses are received by individuals before or
during the reproductive period. It is obvious that in
the case of population exposures, the geneticallysignificant doses are markedly less than the total doses
received over a lifetime: damage sustained by germ
cells of individuals who are beyond the reproductive
period or who are not procreating for any otherreason. poses no genetic risks. If it is assumed that themean age at reproduction is 30 years and the average
life expectancy at birth is 70-75 years, the dose
received by 30 years is about 40% of the total dose.
80. To derive risk coefficients for genetic risks to a
population, therefore. one needs to multiply thegenetic risk estimates discussed earlier by 0.40. The
following calculations make use of the most recent
risk estimates presented in Table 7: (a) risk coefficienton the basis o f gonadal dose in the reproductive
segment of the population (from Table 7); for quantifiable damage only, over all generations, per Gy:-12.000 per lob or 1.2% ; ( b ) risk coefficient to the
population: for quantifiable damage only. over all
generations. per Sv ( 1.2 X 0.4 = 0.5): 0.5%.; (c) risk
coefficient for the first two generations under conditions otherwise similar to (a) above (from Table 7):3.100 per lo6 or 0.3%; (d) risk coefficient to the
population for the first two generations. per Sv(0.3 x 0.41: 0.1%,. it is useful to reiterate here thatthese risk coefficients are for conditions of continuous
exposure at a finite rate every generation and that theyalso reflect the total genetic risk from a once-only
exposure of the parents.

IV.

ESTIMATES O F DETRIMENT

8 1. The estimates of risk discussed in the preceding
sections refer to the expected number of cases ofserious genetic disease due to radiation-induced muta-

[ions and chromosomal aberrations in the progeny ofirradiated parents. The Committee had always realized(although it had not explicitly stated so in Reports
prior to 1982) that presenting numerical estimates isjust one aspect of risk estimation. Without some
objective and quantifiable indicators of severity, it isdifficult to perceive the impact of these on theindividual and on the society at large and to makecomparisons with the risks of induction of otherbiological effects, such as cancer. Therefore, startingwith the UNSCEAR 1982 Report. the Committee
began a systematic review of data bearing on thisproblem, focusing on spontaneously arising Mendelian,chromosomal and other diseases in order to gain someperspective of the detriment associated with these
diseases and hoping to be able to use this knowledge
to assess the impact of radiation-induced diseases atsome later stage.
82. Particularly important in this context are therough estimates of the disability caused and the lengthof life lost by the more common genetically determined(i.e.. Mendelian and chromosomal) diseases provided
by Carter [C4] and discussed in the 1982 Report.
Carter's analysis revealed that for monogenic diseases(autosomal dominants. X-linked recessives and autosomal recessives) and for an estimated total birthprevalence of 12,500 per lo6. about 190,000 years oflife are lost, 300.000 years of life are potentially
impaired and about 150,000 years of life are actually
impaired per lo6 live births. For chromosomal diseases,
Carter's figures are about 89.000 years (lost life).
180.000 years (potentially impaired life) and about
90,000 years (actually impaired life) per 106live births.
The average life expectancy at birth assumed in thesecalculations was 70 years.
83. Czeizel and Sankaranaraanan [C5] extended thisanalysis to spontaneously arising congenital anomalies
in man (these results are discussed in the UNSCEAR
1986 Report [U7]). The data on birth prevalences
for the various conditions considered were derived
from several epidenliological surveys carried out in
Hungary and from the Hungarian Congenital hlalformation Registry. Most of the information on
mortality profiles was obtained from the records ofthe Hungarian Central Statistical Office in Budapest.
Their analysis showed that with an estimated prevalenceof about 60.000 per lo6 live births in Hungary, thecongenital anomalies may cause about 480,000 yearsof lost life, about 3,700,000 years of potentially
impaired life (including congenital dislocation of thehip. whose birth prevalence is 25,770 per lo6; andwhich. if excluded, would reduce the potentially
impaired life figure to about 1.800,000 years) andabout 4.500 years of actually impaired life. In thesecalculations. it has been assumed that the average life
expectancy at live birth is 70 years.

V.

UNCERTAINTIES AND PERSPECTIVES

84. The foregoing discussion amply documents thefact that there have been only a few changes in the
numerical estimates of risk since the UNSCEAR 1977

Report. However, this statement is not meant to imply
that there have been no advances in our knowledge in
the areas relevant to genetic risk evaluation in recenr
years: rather, it reflects the fact that the impact ofthese advances has still not been fully assessed, as
illustrated below..
A. PREVALENCE OF MENDELIAN.
CHROMOSOMAL AND OTHER DISEASES
1. Mendelian diseases

85. There is no need to belabour the point that asound knowledge of the contribution of gene mutations
and of chromosomal aberrations to genetic diseases isof paramount importance. not only because i t affords
a perspective on those diseases to which man islitera!ly heir. but also because it provides a frame ofreference within which to appraise the increases
expected as a result of radiation (or other mutagenic
esposures). Our current estimates of prevalences ofMendelian diseases are based on a total of about
50 entities, the individual birth frequencies of whichrange from about 1 lo-' to about 1 lo-", with someupward adjustment in the total frequency for thosediseases yet to be discovered. For obvious reasons.
these estimates pertain to a very small proportion of
those listed in the recent update of the McKusick
cornpendiurn [M4](i.e.. a total of 1.906 conditions thatare well documented as being inherited in a Mendelianmanner and a further 3,001 for which such evidence isincomplete). The disparity is even greater when one
considers that the total amount of nuclear DNA in thehurnan haploid genome is about 3 lo6 kb, which inprinciple can accommodate between 100.000 and
150,000 genes (on the assumption that an "average"
gene is 20-30 kb long). However, this estimate isprobably roo high, since it neglects introns, pseudogenes, highly repetitive sequences such as satellite
DNA and other interspersed and non-transcribed
DNA sequences [B7, D2, E5. E6, JI]. Judging fromthe phenomenal progress in the understanding of thehuman genome that has been made possible in recent
years by applying the methods of recombinant DNA
technology (reviewed in the UNSCEAR 1986 Report[U7]1. one can confidently look forward to (a) a better
understanding of the relationship between genes andmutations and their effects on health and disease and(b) the application of the knowledge so derived to theevaluation of genetic risk.

2.

Chromosomal diseases

86. At the chromosomal level, the application of
banding techniques to the study of human chromosomes has led to the identification of a variety ofchromosomal defects. particularly deletions and duplications involving every chromosome of the human
complement (reviewed in the UNSCEAR 1977 Report[U7]). However, since most of the currently available
information on these a~iomaliesis in the form of casereports, their prevalences and their contribution todisease states cannot be readily determined. Of particular interest are microdeletions observed in mal-

formed children. especially those predisposed to anumber of cancers. The): provide new ways to localize
and characterize important genes involved in pathology, both at the chromosomal and molecular levels.
They also suggest that a pathological character may
result from the presence of a pre-existing abnormal
allele and a somatic mutation.
87. One exciting development in human cytogenetics
in recent years has been the discovery of fragile sites
on chromosomes. which can be made visible byappropriate culturing techniques (re\iewed in the
UNSCEAR 1982 and 1986 Reports [U6. U71). As was
already mentioned, the fragile site on the X-chromosome (at position Xq27) has elicited considerable
attention because it is associated with one form of
X-linked mental retardation. The prevalence of fragileX-associated mental retardation has been estimated to
be about 4 lo-' both in males and females [S6]: thiswould make the fragile-X the second most common(after Down's syndrome) chromosomal abnormality
associated with mental retardation. It is currently
not known whether this abnormality can be inducedby radiation, so no genetic risk assessments can be
made.

3.

Congenital anomalies and other diseasesof complex aetiology

88. Previous estimates of the prevalence of diseasesof complex aetiology (i.e., congenital anomalies (43,000
per lob) and other multifactorial diseases (47.000 perlob) are based on the results of the British Columbia
survey [TI], in which the follow-up period was frombirth to age 21. Recent studies of Czeizel andSankaranarayanan ([Cl] and Czeizel et al. [C7];discussed in the UNSCEAR 1986 Report [U7]) lend
credence to the view that the above prevalence figures(in particular those of the "other multifactorialdiseases") are underestimates. Their data show that in
Hungary (a) congenital anomalies have a prevalenceof about 60.000 per lo6 live births and (b) the "othermultifactorial" diseases may have a prevalence ofabout 600,000 per lo6 population when all individuals
up to age 70 are included. I t should be made clear thatthe latter figure refers to the number of diseases per
lo6 and not to affected individuals; thus, someindividuals have more than one disease.
89. As was discussed in the UNSCEAR 1986 Report(Annex C, paragraphs 51-58: see also Kalter andWarkany [K2]). the congenital anomalies can be
subdivided. on the basis of their aetiology. into thosecaused by: (a) major genes (6% of the total of 60.000 perlo6); (b) multiple factors (50% of the total); (c) chromosomal anomalies ( 5 % of the total); and (d) environmental. including maternal, factors (6% of the total).
About 30% of the anomalies recorded at birth have noknoun cause at present. One should add. however,that even for those congenital anomalies whosetransmission patterns are consistent with a multifactorial aetiology (i.e.. those resulting from aninterplay of polygenic genetic predisposition andenvironmental factors), little is known of the mech-anisms by which genetic predisposition acts or of theenvironmental factors involved.
90. The same is true of the "other multifactorialdiseases" tvhose population prevalence has been estimated to be about 600,000 per lo6. The question ofwhether and to what extent the prevalence of all these
multifactorial diseases will increase as a result ofradiation exposures remains a matter of conjecture.
Our ability to make reliable estimates for these
diseases depends largely on establishing the role ofgenetic factors in their aetiology. While no quantum
leaps are expected in this area. there are persuasive. if
not yet compelling. reasons to believe that it may soon
be possible to estimate the mutation component in someof the seemingly multifactoriaily inherited diseases. The
use of restriction fragment analysis and the development of more rapid methods for sequencing DNA
will. in time allow a search for mutational variation
at specific loci known to be involved which contributeto the occurrence of these diseases. The following
examples are illustrative.
91. In a large Icelandic family (over 200 members infour living generations) showing Mendelian inheritanceof X-linked secondary cleft palate and ankyloglossia("tongue-tied"), Moore et al. [M 101 localized the geneto Xq13-Xq21; the eventual cloning of the cleft palate
gene could become a starting point for the analysis of
the genetic basis of this developmental abnormality. A
similar analysis using restriction fragment length
polymorphism in an Old Order Amish pedigree madeit possible to localize a dominant gene conferring astrong predisposition to manic depressive illness (aform of affective psychosis) to the tip of the short armof chromosome 1 1 [E9]; however. in three Icelandic
kindreds [H3] and three North American pedigrees[D3] there was no linkage with any of the chromosome I I probes used. The inference is that mutations
at different loci are responsible for the manic depressive phenotype in the Amish and in the other two
population groups studied. Two other areas withparticular promise involve lipid metabolism, where it
is already possible to specify the contribution of
specific loci concerned with the apolipoproteins to thevariation in cholesterol levels seen among individuals(see [B9] for a recent review) and the transport ofsodium and potassium which looms large in theoccurrence of essential hypertension (reviewed in [H4]
and: [WZ]).

B.

MUTATIONAL MECHANISMS
AND DNA REPAIR

92. An increasingly important area of contemporary
genetic research is that associated with the studies on
movable genetic elements, the conceptual framework
for which was laid by McClintock, over three decadesago, with her work on "controlling elements" in maize[M6. M9]. Now, movable genetic elements have been
discovered in a number of prokaryotes and eukaryotes,
and some of these elements have been characterized at
the molecular level. The rapidly accumulating evidenceshows that they play an important role in the genesisof spontaneous mutations and of chromosomal aber-rations: this knowledge, in turn, is altering ourconcepts about mutational mechanisms and the stabilityof the genome (discussed in the UNSCEAR 1986
Report [U7]).
93. Information on mammalian interspersed repetitive DNA sequences and why they are ( o r have at one
time been) considered to be mobile genetic elements
has been the subject of a number of recent reviews[R8, S14. S151. These putative mobile genetic elements
are currently classified into two groups: SINEs (forshort interspersed elements), which are typically lessthan 500 base pairs long and LINEs (long interspersed
elements), ivhich range in length from a few hundredbase pairs up to 7,000. Examples of SINEs are the Alu
in primates and the BI and B2 in rodents: examples ofLINEs are LINE-1 and THE-I in primates. There is as
yet no evidence that these sequences move from one
genomic location to another or that they are associatedwith detectable phenotypic effects in mammals including the human species, but such evidence is good inbacteria, yeast and Drosophila.

34. Skowronski .and Singer [Sl 51 have argued thatthe dispersed positions of LINE-I sequences between
genes, in introns and in interrupting tandem arrays of
species-specific satellites, as well as the target site
duplications associated with many LINE-1 sequences,suggest that the sequences were mobile in the past (inan evolutionary sense); further, these authors havecompiled a list of five instances of mammalian (dog,rat and mouse) polymorphic alleles that differ by thepresence or absence of LINE-1 units. On the basis of
all these data (and some unpublished data on theinsertion of a LINE-] unit into a myc allele in DNA
from a human breast carcinoma). they suggest that theLINE-I alleles are still capable of being inserted into
genomic loci.
95. Concerning the effects. of mutagens, including
x rays, on the mobility of these transposable elements.
the evidence at present is essentially negative, except inyeast: in this species, McClanahan and McEntee [Ml 11
showed that DNA damage induced by UV-irradiationo r 4-nitroquinoline-1-oxide stimulates transcription of
specific genes that share homology with the Tvl (theyeast transposons) element, the inference being that
one o r more members of the Tyl element is (are)regulated transcriptionally by D N A damage. Morerecently, hlorawetz [hllZ] showed that Tb.1 insertion
mutations at the ADH-2 locus could be increased by
UV- o r gamma-irradiation o r by treatment ivith ethyl
methanesulphonate in a dose-dependent manner. thelatter being the strongest agent in this regard.
96. The relevance of the findings in experimental
systems-that
is, that mobile genetic elements significantly contribute to "spontaneous mutations" andthat mutagens have negligible o r no effect on themobility of lhese elements-to genetic risk evaluationin man has been addressed by Sankaranarayanan[S 10, S16]. He argues that (a) if a major proportion of
spontaneous mutations in nlan that lead to diseasestates is due to the insertion of mobile genetic
elements and if the mobility of these is unaltered byradiation exposures, then some of the principal

assumptions of the doubling dose method for genetic
risk evaluation would lose their validity; (b) currently,
however, there is no evidence that documents a significant role for mobile genetic elements in the origin of
spontaneous mutations in man; and (c) consequently,
there is no need to abandon the use of the doublingdose method for risk evaluation on these grounds.
97. In the realm of DNA repair, one of the principal
questions being addressed by current research is theinfluence of function o r activity of a DNA sequenceand its repair following mutagen treatment. All thesestudies have so far been carried out primarily withmammalian cell lines and UV-irradiation. The findingsof interest are (a) there is preferential repair of active(transcribing) genes relative to the genome as a whole[BX]: (b) the regions of active repair, in the system
studied. correspond to control regions and the 5' endsof the transcription unit; and (c) in regions away fromthe 5' or 3' ends of the genes, repair is less efficient[S17 and the papers cited therein]. Indirect evidence
for preferential repair of active genes has also beenpresented by Mullenders et al. [M13, M141. These andother results support the view that ". . . damage insilent regions of the genome may have greater potential
for engendering mutations and Dh.4 rearrangements
than damage in or near transcription units" [SIT]. The
generality of these findings and their implications for
germ cell mutagenesis with ionizing radiation remain
to be established.

C. NATURE OF SPONTANEOUS
A N D RADIATION-INDUCED MUTATIONS
98. The methods of recombinant DNA technology
have enabled the direct detection of the molecular
heterogeneity of spontaneously arising mutational
events that lead to disease states in man, as will beevident from the spectacular progress in studies of theelobin genes (see, for example, [03]). Similar studies
are being carried out to analyse the nature ofradiation-induced mutations in mammalian somatic
cells (e.g., [VI, 7'21). Most of these data have been
discussed in the 1986 Report [U7]. An important
technical advance has recently been made that allows
the cloning and sequencing of small specific DNA
segments from total genomic DNA after in vitro
amplification of those segments up to 200,000-fold(the so-called polymerase chain reaction, or PCR[S18]). The use of this technique in induced mutagenesis studies will allow mutation spectra to be
determined with great precision [V2].

-D.

FRAGILE SITES A N D SPONTANEOUS
CHROMOSOME BREAKAGE

There are suggestive indications for the thesisthat certain autosomal fragile sites may predispose tochromosome breakage. Hecht and Hecht [ H I , HZ]
have adduced some evidence in this regard by analysing
information on the location of breakpoints leading tochromosomal anomalies (deletions, duplications, inversions and non-Robertsonian translocations) found inamniocentesis studies and in studies on spontaneous99.

abortions, still births and new-borns. They caution.
however, that in view of the heterogeneity of thedata-base from which the pertinent information was
extracted. more evidence is needed to determine
whether fragile sites are regions in the chromosome
predisposed to breakage in the germ cell lineage. The
question of whether those fragile sites may predisposethe chromosomes to radiation-induced breakage eventsis as yet unansufered.
E.

ONCOGENES: GENETIC ASPECTS

100. The remarkable insights into oncogenic transformation that have emerged in recent years (reviewed
in the UNSCEAR 1986 Report [U7]) amply testify tothe fact that cancer studies have become an ekciting
area for both geneticists and cancer biologists. Thereis now extensive evidence that mammalian genomes
harbour nucleotide sequences related to the retroviraloncogenes as part of their normal genetic make-up,that several of them play an active role in theregulation and control of cellular proliferation andthat their activation (either spontaneously o r rhroughmutagenic exposures) can initiate cancer. There is thus
no a priori reason to assume that germ cells will be
immune in this respect, especially after exposure to
mutagens. Nomura [N3, N5] has reported high tumour
yields in the progeny of irradiated mice and thus has
highlighted the possibility that genetic changes inducedin the germ cells of parents can cause tumours inprogeny. It would therefore appear important toconfirm these studies independently in experimental
systems. Whether this component of genetic risks
ivould be negligible, small or significant for man isdifficult to say at present.

F. OTHER WORK IN PROGRESS
10 1. Data on chromosomal abnormalities studied
through direct analyses of the chromosome complement of human spermatozoa (from normal men as
well as from those undergoing radiotherapy) after invitro fertilization of hamster eggs were discussed in
the UNSCEAR 1982 and 1986 Reports [U6, U7]. This
technique has now been considerably improved [K3]and extended to studies using human spermatozoa
irradiated in vitro [K4, M15]. In these studies, whichused spermatozoa from five healthy donors, thefrequencies of spermatozoa with structural chromosomal aberrations were found to increase linearly withthe x-ray dose (0 Gy, 14.1%: 0.25 Gy, 18.9%; 0.5 Gy,
28.5%; 1 Gy, 42.6% and 2 Gy, 68.0%; total numbersof karyotyped spermatozoa: 0 Gy, 2.097; 0.25 Gy,
49 1; 0.5 Gy, 543; 1 Gy, 8 19; 2 Gy, 1,009). Most of the
x-ray-induced aberrations were breaks and fragments,
but a f e u translocations (0.03-0.1 per cell) were also
found: there was no decrease in the fertilization rate ofirradiated spermatozoa, even at the highest dose,
2 Gy. Clearly, this kind of study has relevance to theassessment of genetic risks associated with the induction of chromosomal aberrations.
102. Genetic studies on the Hiroshima and Nagasaki
populations are continuing and will remain a major

source of direct human data. An international collaborative programme on genetic effects in the offspringof cancer patients exposed to physical and chemical
agents for therapeutic purposes is being initiated [L2.
021. This is a commendable enterprise: it is hopedthat it will provide information on hazards attributable to genetic damage in human germ cells, and it
upill undoubtedly have practical importance for clinicians who must advise cancer survivors or current
cancer patients who are pregnant or considering
pregnancy. Likewise, the follow-up of persons exposed
to radiation in the Chernobyl nuclear power plant
accident (and their progeny) that is currently underway in the U.S.S.R. is a worthwhile undertaking.
103. The work of Dobson and colleagues over the
past several years has suggested that the exceptionallyhigh sensitivity of mouse immature oocytes to killingby radiation is a consequence of the possibility thatthe target for killing is not the nucleus but the plasma
membrane. More recent results by the same groupsupport this idea [S 19. S201. Furthermore, Dobson et al.
[D4] have now reported, usingmonoenergetic0.43 MeV
neutrons and ="Cf (whose recoil protons have subcellular track lengths of such a nature that theradiation energy can be deposited in the DNA in a
calculable fraction of the oocytes that survive), thatchromosomal aberrations can be recovered from
irradiated immature oocytes and that these are similar
to those from mature oocytes. A similar effect has also
been reported by Griffin et al. [GZ].

G.

SUGGESTIONS FOR FUTURE RESEARCH

103. In this .4nnex, the progress that has been madein areas pertinent to the evaluation of genetic radiation
hazards in man has been reviewed and estimates ofgenetic risks have been presented. The Committee
feels that, in order to increase precision in risk
assessment. more research effort along the following
lines will be useful (the order in which these are listed
does not reflecr the order of importance): (a) molecularanalysis of spontaneous and induced mutations insomatic and germ cells with and without repair;(b) further studies relevant to the genetic radiosensitivity of human oocytes; (c) phenotypic expression
and transmission of induced deletions and otherrelevant genetic changes: (d) a search for mammalianmodels to study human diseases with complex aetiology:( e ) tests o n the validity of the assumptions andcorrection factors used in genetic risk estimation;(0 further in-depth analysis of multifactorial diseases
with respect to the mutation component; (g) mechanisms underlying nondisjunction and chromosome
loss and effects of radiation on these genetic changes:(h) further work bearing on total genetic damage
manifesting in the first generation after radiation
exposure: (i) relationships between radiation dose.
dose-rate and quality and types of induced chromosomal aberrations; (j) development of methods toreveal chromosomal aberrations and gene mutations
in human germ cells in the haploid stage; and (k) theuse of transgenic mice to study DNA repair deficiencies
and mutational mechanisms.

T a b l e

1

Sumnarv of qecetlc rlsks estlmatedIn the BEIR 1912 Deport uslnq tne doubllnq dose method
The eftects a r e those estlmated for a populatlon contlnuously exposed
at a rate of 1 rem per geceratlon (low-LEI, low dose rate)ln a populatlon of 1 mllllon live blrths.
Assumed doubllng dose range: 20-200 rem

Current
tnc ldence
per 1 0 6
llve blrths

Olreare classlflcatlon

Oomlnant dlseases
Chromosomal and recesslve dlseases
Congenttal anomalles
A n m l l e s expressed later
Constltutlonal and degeneratlve
dlseases

]
]

]

Total

Effect of 1 rem per qeneratlon
Flrst generatlon

Equlllbrlum

10000
10000

10-100Relatively sllght

50- 500
Very slow
lncrease

15000
10000
15000

1-100

10-1000

60000

10-20060-1 500l a b l e7

Sumnary of qenetic rlrks estlmatedIn the UNSCEAR 1977 Report uslnq the dnuhllnq dose method
1h1. e l l e r t s are those estlmated for a populatlon contlnuously exposeda t d rate of 1 rad per generatlon (low-LCT, low dore rate)
In a populatlon of 1 mllllon llve blrths.
Assumed doubllng dose: 100 rad

Current
Incidence
Der 106
1l"e births

Olrease classlflcatlona_/Autoromal and X-llnked disease:
Recerslve dlseases
Chromosomal dlseases
Congenltal anomalles
Anomalies expressed later
Constltutlonal and degeneratlve
dlseases
Total
Percentage of current Incidence

a/

1
]

Effect of 1 rad per generatlon
Flrst generatlon

b/

r/

10000
1100

20
Relatlvely sllght

Equlllbrlurn

4000 a/3 8 e/

100
Very slow
lncrease
40

90000 f /5 ¶/4 5 g/

105100

63

185

]

0.06

0.11

Follows that glven In t h e BEIR Report [BI].
Based o n t h e results o f the Brltlsh Columbla Survey wtth certaln
modlflcatlons.
c/ The flrst generatlon increase 1 % assumed t o be about one flfth of theequlllbrlum lncldence for autosomal domlnant and X-llnked dlseases; forthose Included under the headlnq .congenital anomalles etc.' tt Is one
tenth of the equlllbrlum lncldence.
d_/ Based on the pooled values estlmated from cytogenetlc surveys of new-bornchlldren: lncludes mosaics but excludes balanced translocattons.
g/ The flrst generation lncrease 1s assumed t o lnclude all the numerlcal
anomalies and three fifths of the unbalanced translocatlons (the r e m l n l n g
two-flfths belng derlved from a balanced translocation In one parent).
f / Includes an unknown proportton of numerlcal (other than Down's syndrome)and structural chromosomal anomalles.
q/ Based o n the assumptlon o f a 5% mutatlonal component.

b/

5

T a b l e

Genetlc effects of an averaqe populatlon exposureof 1 rem per 30-vear qeneratlon estlmatedIn the 8CIR 1980 Report uslnq the doubllnq dose method
Assumed doubllng dose range: 50-250 rem

Ctfect of 1 rem per generatlon
per mllllon llve-born offsprlng

Current
incldenceper 106
live births

Type of genetlc disease

flrst generationb/a_/Autosomal domlnant. X-linked
Irregularly lnherlted
Recesslve

10000
90000
1100

f/
C h r ~ m ~ S ~ maberratlons
al

6000

lqulllbrlumc_/5-65 d/]]Very few; effects
In heterozygotes
accounted for In
top row
Fewer than 1 0 q/

40-20020-900 g/
Very slow
increase
Increases
only sllghtlya_/Includes dlsorders and tralts that cause serlous handlcap at some tlmeduring llfetlme.
b/ Estlmated dlrectly from measured phenotyplc damage or from observed
cytogenetlc effects.
c/ Estlmated by t h e relatlve mutatlon rlsk method.
d/ No flrst-generatlon estimate avallable for X-llnked disorders; t h eexpectation ls that It would be relatively small.
N.B.: A typographlcal error In the 8EIR Report Is corrected here.
g/ Some estimates have been rounded off t o dlspel an lmpression of
conslderable preclslon.
f / Includes only aberratlons expressed as congenltal malformatlons. resulting
from unbalanced segregatlon products of translocatlons and from numericalaberratlon.
q/ Hajorlty of t h e Sub-Comnlttee feels that It Is considerably closer to zero,but one member Feels that It could be as much a s 20.

T a b l e

4

Cases of serlous qenetlc I11 healthIn ottsprlnq (excludlnq ahortlons) from parents lrradlatcd
ulthl milllon man-rem In a populatlon ot constant slze,
estlmated by the 1980 ICRP Task Group----

Category ot genetlc eftect

Equlllbrlum&/

Unbalanced translocatlons; rlsk
of malformed llve born
Trlsomlcs and XO
Slmple domlnants and sex-llnked
mutations
Domlnants of incomplete penetrance
and multlfactorlal dlsease
malntalned by mutatlon
Hultlfactorlal disease
not malntalned by mutatlon
Recessive dlsease
Total
a_/

b/
C/

Flrst generatlon
plus second
generatton

30

23 +

30
100

30 + 0 = 30
2 0 t 16 = 36

1 6 0 b/

16 t 14

6 : 29

0

0

c/

C/

320

89

L

30

36 = 125

Over all generations followlng the generatlon exposed.
The sum of the three entrles above (1.e.. 3 0 t 30 t 100).
NO esttmates glven.

T a b l e

5Assumed doubllng dose: 1 Gy

Eltect ot

Gy per generatlon

Dlsease classlflcatlon

Current
lncldence
per mllllonb/Flrst generatlong/Equlllbrluma/10000 g/2500 e/15
Sllght100
Slow lntreare

400 I/
3000 q/2.4
Probably very
small

Probably very
small

90000 h/4.5

Autosomal domlnant and
X-llnked diseases
Autosomal recessive d\seases
Chromosomal dlseases
Structural
Numerlcal
Congenltal anomalles. anomalles
expressed later andconstltutlonal anddegeneratlve dlseases

4

4 5 1/

Follows that glven ln the 1972 BEJR Report [BI]. except that chromosomal
dlseases are dlvlded lnto those wlth a structural and those wlth anumerlcal basts.
Based o n the results of the Brltlsh Columbla survey and other studles.
The flrst generatlon lncrement 1s assumed t o be about 15% of theequlllbrlum lncldence for autosomal domlnant and X-llnked dlseases. about
three flfths of the equlllbrlum lncldence For structural anomalles andabout 10% of the equlllbrlum lncldence for dlseases of complex lnherltance.
Includes dlseases ulth both early and late onset.
Also includes dlseases malntalned by heterozygous advantage.
Based on the pooled values from cytogenetic surveys of new-borns but
excludlng euplold structural rearrangements, Robertsonian translocatlons
and 'othersm (malnly mosalcs).
Ext ludlng mosalcs.
Includes an unknown proportlon of numerlcal (other than Down's syndrome)and structural chromosomal anomalles.
Based on the assumption of a 5% mutdtlonal component.

T a b l e

6

Grnetlc risks of low-dose. low-dose-rate. low-LET lrradlatlon
estlmated In the NUREG 1985 Report
Assumes a 0.01 Gy dose t o t h e populatlon.
Note that t h e flrst-generatlon lncreases w e r e estlmated dlrectly frommeasured phenotyplc damage; the entries g l v e n In c o l u m n *all generdtlons'w e r e derlved uslng the douhiing d o s e method a s s u m l n g a d o u t ~ l l n g dose o f 1 Gy.

Risk o f 0.01 Gy b/
Type of d l s o r d e r

NormallncldenceAllgenrratlons

a/

Flrst
generatton
c_/

50900

30

185

Slngle g e n eAutosomal domlnant
X-llnked
Irregularly lnherlted
Chromosome a b e r r a t l o n s f /Aneuploldy
Unbalanced t r a n s l o c a t l o n s
Total (rounded)& / F o r a total populatlon o f lo6 persons ( 1 6 , 0 0 0 llve blrths/year) f o r
3 0 years (480.000 llve blrths).
b/ Cases expected ln each generatlon of c h l l d r e n f r o m a populatlon of lo6
persons, e a c h recelvlng a d o s e of 0.01 Gy; a s s u m e s 3 0 - y e a r lntergeneratlonallnterval a n d blrth rate of 16.000 per year per 1 0 6 persons. or 480.000
chlldren per generatlon; t h e lntegrated rlsk o v e r all generatlons following
a parental d o s e of 0.01 Gy Is the s a m e a s t h e rlsk at equlllbrlum ( t h ecolumn marked 'all generatlons')
when t h e p o p u l a t l o n ls exposed at a rate of
0.01 Gy per generatlon.
c_/ lstlmated d l r e c t l y from measured phenotyplc damage.
d/ flrst g e n e r a t l o n lncrease In lrregularly lnherlted d l s o r d e r s Included u l t h l nthat for autosomal domlnant dlsorders.
p/ Based on a d o u b l l n g d o s e o f 1 Gy and 1 0 g e n e r a t l o n s m e a n perslstence t lme.
uhlch Is very uncertain.
-f/ Includes o n l y aberratlons expressed as congenital malformations resultlng
from unbalanced
translocatlons (2.400/480.000)
andfrom aneuploldy(480/480.000);
equlllbrlum tlme of 1 - 7 g e n e r a t t o n s a n d 1 generatlon.
respectively.

T a b l e

7

Rlsks of qenetlc dlsease per I mllllon llve-blrths
ln a populatlon exposed t o a genetlcallv slqnlflcant d o s e o f 0.01 Gy
per qeneratlon of low-dose-rate, low-dose. low-LCT lrradlatlon
estlmated In the UNSCEAR 1986 Report uslng to the doubltnq dose method
Assumed doubllng dose: 1 Gy
Effect of 0.01 Gy per generatlon
Dlrease classltlcatlon

Autorornal dominant and
X-llnked dlseases
Autosomal recesslve dlseases. tiomozygous effects- Partnership effects
Chromosomal dlseases
due t o structuralanomalles

Current
lnc ldence
per lo6llveblrths

flrst
generatlon

Secondgeneratlon

A1 1
generatlons(equlllbrlum)

a/

b/

c/

d/

10000

I5

13

100

2500
No Increase No Increase
Negllglble Neyllglble
40 0

2.4

1

Subtotal (rounded)

13000

10

14

Early actlng domlnantsq/Congenltal anomallesh/Other multlfactorialdiseases
1/
Heritable tumours
Chromosomal dlseases d u e
to numerlcal anomalies k/Unknoun
60000

I/

bOO000Unknoun
3400

11 e/

4 i/

115

]

1

I
1

Not esttmated]1
1

Based o n the results of the Brltlsh Columbla Study and other studles: fordetalls see [US].
The first-generatlon lncrement Is assumed t o be 15% of that at equlllbrlum
tor autosomal domlnant and X-llnked dlseases and t h r e e ttfths of that at
ec;ulllbrlum for chromosomal dlseases d u e t o structural anomdlles.
Not given In the UNSCEAR 1986 Report and estlmated here; for autosomal
domlnants and X-linked dlseases, It Is calculated as 15% of (equlllbrlum
Increase mlnus the lncrease In the flrst generatlon); a slmllar procedureappller t o chromosomal dlseases due t o structural anomalles.
These values apply If 0.01 Gy Is glven In each generatlon, but they also
express the total genettc d a m a g e Dver all generatlons If t h e d o s e of 0.01
Gy 1s glven ln o n e generatlon.
Frequency of recessives m l n t a l n e d by mutatlon assumed t o be 1100 perlo6 llveblrths.
F r o m partnershlp between lnduced mutatlons and t h o s e already present In
the populatlon, assumtng 2.5% heterozygous dlsadvantage and a mean numberof harmful recesslves per gamete of 1 [S9].
T h e lncldence of t h e s e ln human populations Is unknown because they act
too early t o be recognlred a s transmlsslble domlnants; they Include
domlnant sub-lethals, t h e rate for uhlch has been estlmated t o be 5-10 per
0.01 Gy of paternal lrradlatlon of mice (see Table 2 3 of t h e UNSCEAR 1986
Report [Ul]).
Studies by Lyon and Nomura and colleagues show that, ln t h e mouse, theya r e induced by lrradlatlon of male and female g e r m cells, but theassociated risks appear t o be low.
The prevalence Is much higher than that glven In prevlous UNSCEAR Reports.
because dlseases manifest up t o age 70, lnstead o f mainly t o a g e 21, haveincluded, together utth
some less serlous condltlons.
n o w beenfurthermore, the flgure denotes the number of dlseases per lo6
lndlvlduals and not t h e number of affected lndlvlduals.
There Is
conslderable uncertainty over whether a douhllng d o s e of 1 Gy and amutattonal component of 5% ( a s used prevlously) can be Justlfled. The
UNSCEAR 1982 Report arrived at estimates of 4.5 extra cases per 1 mllllon
In t h e flrst generatlon and 45 per mllllon at equlllbrlum after a parental
dose o f 0.01 G y , o n t h e basts of the prevlous e s t l m a t e of populatlon
prevalence of 90.000 per mllllon.
Nomura has reported t h e lnductlon o f pulmonary and other tumours In the
F 1 generatlon of mtce after lrradlatlon ( s e e [U7] for detalls). butt h e s e have very l o w expresslvlty; thelr llkely effects o n health a r e thus
unclear.
It Is stlll not clear whether germtnal lrradlatlon leads t o slgnlflcantly
lncreased frequencies of non-dlsJunctlon, but any resultant genetlc rlsk
f r o m the production of trlsomlc condltlons Is thought t o be low.

T a b l e

8Sumnary of qenetlc rlsks estlmatedln the UNSCEAR 1972 Report uslne the dlrect method
The estlmates are per rad of low-LET, low-dose-rate radlatlon exposure.

Expected rate of lnductlon
aer mllllon
End polnt

Recessive polnt mutations
Domlnant vlslbles
Skeletal mutatlons
Reciprocal translocatlons d/

Spermatogonta

Oocytes1500 a/( 3 6 ) b/

Very low

2

4

15 g/

X-chromosome losses

Very low

Other chromosome anomalies

Very low

Total genetlc damage

Very low8

txaresslon In F I
per mill ion conceptions
after spermatogonlal
lrradlatlon
30-15(1 - 2 )2C/
2 congenltally
malformed chlldren.
19 unrecogntzed early
embryonlc losses.
9 recognizedabortlons L/
8 early ernbryonlc
and/or abortlons
Very low

1521 q/( 5 7 ) !!I

Total genetlc damage' l/

3 0 0 1/

6-15 i/

Note: Dashes lndlcate that Inadequate or n o lnformatlon 1s avallable.
Estlmate based on mouse speclflc locus data.
b/ Estlmate based o n the per genome rate for recesslve lethals Induced \ nmouse spermatogonla.
c/ Included under recesslve polnt mutatlons.
/:Figures apply t o low-dose x-lrradlatlon.
Estimates for chronlc gamnalrradlatlon are 50% lower.
e/ Balanced products.
-f/ For low-dose x-lrradlatlon; For chronlc gamna-lrradlatlon. flgures should
be halved.
q / Obtalned by addlng 1500+2+4+15 In the column.
h/ Obtalned by addlng 36*2+4+15 In t h e column.
I/ Relatlve t o spontaneous lncldence of genetlc dlseases among llve born,
based o n a n estlmated 'doubllng dose' o f 1 0 0 rad.
1/ In terms of lncldence of genetlc dlsease among llve born (doubllng dose
method).
a/-

T a b l e

9Sumnary o f q e n e t l c r l s k s e s t l m a t e d
I n t h e UNSCEAR 1977 Report u s l n g t h e d l r e c t method
The estimates a r e p e r r a d o f low-LIT,l o w - d o s e - r d t e r a d l a t l o n exposure.

fxpected rate of lnductlon
per m l l l lon
Ind point
Spermatogonla

1. Autosomal m u t a t l o n s a_/
2 . Dominant v l s l b l e sb/
3 . S k e l e t a l m u t a t l o n s c/
4 . Balanced r e c l p r o c a ltranslocatlonsg/
5 . Unbalanced p r o d u c t s o f
e n d - p o l n t 4 above
6. X-chromosome l o s sh/7 . Other chromosome a n o & l l e s

a/
b/

c/

d/

e/
f/

p/

h/

Oocytes

Cxpresslon I n f l
p e r m l l l t o n conceptionsa f t e r spermatogonlal
lrradlatlon

60
Very lorc17- 87

Lou

34.174
Very lowLou-

Note: Dashes l n d l c a t e t h a t inadequate o r no l n f o r r n d t l o n I s a v a i l a b l e .
Presumed t o I n c l u d e s m a l l deficiencies.
Based on r a t e o f l n d u c t l o n o f
m u t a t l o n s I n m l c e t h a t a r e l e t h a l I n t h e homozygous c o n d l t l o n , u h l c h I S
doubled t o g l v e the o v e r a l l rate.
Based on t h o s e s c o r e d l n t h e c o u r s e o f s p e c l f l c - l o c u s e x p e r l m e n t s l n mlce.
D e t e c t e d l n m l c e by domlnant e f f e c t s .
Overallr a t e o f domlnant e f t e c t s .
based on s k e l e t a l m u t a t i o n s andp r e s u m a b l y l n c l u d l n g domlnant v l s l b l e s
and h e t e r o z y g o u s
e f f e c t s ofautosomal m u t a t l o n s .
D e r l v e d f r o m human and marmoset c y t o g e n e t l c d a t a under t h e assumption t h a tt h e f r e q u e n c y o f t r a n s l o c a t l o n s I n t h e F1 progeny l s one f o u r t h o f t h a tobserved l n spermatocytes.
t f f e c t s such as t h o s e g l v e n f o r e n d - p o l n t 5 I n t h e n e x t f o o t n o t e w t l lbecome m a n l f e s t I n g e n e r a t l o n s following t h e f l r s t .
Expressed as c o n g e n l t a l malformations. I n a d d l t l o n , t h e r e would be 11-55
recognized a b o r t l o n s and 22-109 e a r l y embryonlc l o s s e s .
D e t e c t e d I n m l c e by X-chromosomal markers.

T a b l e

10Sumnary of genetlc risks estimatedln the UNSCEAR 1982 Report using the direct method
The estimates are per lo-? Gy of low-LET. low-dose-rate radlatlon exposure.

Rlsk assoclated wlth

Expected frequency (per lob)of genettcally abnormal chlldren
In the flrst generatlon
at ter lrradlatlon of
-

Males

-

Females

Induced mutations
havlng domlnant eftects a/-10t o -20 b/

Unbalanced products o flnduced reclprocal translocattons-0.3

t o -10g/

0 to -9 c_/
0 to -3 g/

a/ Includes the rlsk from the inducttcn of domlnant mutatlons, as uell as ofrecessive mutations, deletlons and balanced translocatlons wlth domlnant
effects.
b/ The lower llmlt of - 1 0 1s derlved from data on cataract mutatlons andthe upper llmlt of -20 per lob 1s derived from data on skeletal
mutatlons and Is the same as the one arrlved at In the 1977 report. A
multlpllcatlon factor of 2 has beer used in t h e skeletal estlmate but not
In the cataract one; thls factor Is an attempt t o allow for the Ilkellhoodthat many domlnant mutatlons (especially those affecting systems other than
the skeleton) remaln t o be detectea. A correction factor o f 0.5 to allow
for skeletal mutatlons whlch are not cllnlcally slgnlflcant 1s not required
for the cataract estlnbte.
E/ The lover llmlt of zero 1s based on the assumption that the mutattonal
sensltlvlty of human l m t u r e oocytes 1s stmllar to that of mouse lmnature
oocytes; the upper llmlt of 9 per 106 Is based on t h e assumptlon that t h esensltlvlty of the human oocytes 1s slmllar t o that of the mature andmaturing oocytes and that the latter Is 0.44 tlmes that of spermatogonla.
See text for further detalls.
a/ The lower llmlt of -0.3 per 1 0 6 is based on rhesus monkey cytogenetlc
data; the upper llmlt of -10 per 106 Is based on comblned marmoset andhuman cytogenetlc data.
p/ The lower llmlt of zero Is based on t h e assumptlon that t h e sensltlvlty o f
the human l m t u r e oocytes to the lnductlon of herltable reclprocaltranslocatlons wlll be slmllar to that of the mouse Immature oocytes ulthrespect t o t h e lnductlon of chromosome aberratlon phenomena; the upper
llmlt of -3 per 106 1s based on t h e assumptlons that the sensltlvltyof the human Immature oocytes t o the lnductlon of translocatlons wlll be
one half that of the human and marmoset spermatogonla (based on results
ulth mlce on herltable translocatlons), that the frequency of unbalanced
products wlll be slx tlmes that of recoverable balanced reclprocaltranslocatlons and that 6% of the unbalanced products wlll result In
congenitally malformed chlldren.

T a b l e

11Rlsks of lnductlon of qenetic damaqe ln man per lo-? t y
at low dose rates of low-LET radlatlon
estlmated In the UNSClAR 1986 Report uslnq the dlrect method

Experted frequency (per lo6)
of genetlcally abnormal chlldren
In the Ilrst generatlon
alter lrradlatlon of

Rlsk associated ulthHales
induced mutatlons
havlng dominant effects

a/ b/Induced recesslve mutatlonse/Unbalanced products of induced
reclprocal translocatlons- 1 0 to - 20 c/rema 1es

0 t o -9 d_/00- 1 to - 15 f /

Oto

5

q/

Note: These estimates are the same as those made In the UNSCEAR 1982 Report
except for changes lndlcated ln footnotes b/ and g/.
a_/ Includes rlsk from the lnductlon of domlnant mutatlons. as well as ofdeletions and balanced reclprocal translocatlons wlth domlnant effects.
b/ Does not Include the rlsk of mortality (between blrth and early llfe)
estlmated on the basls of data on lltter slze reductlon In mlce (about 5-10
cases per mlllion conceptlons); see text for detalls.
L/ The lower llmlt ls derived from the data on cataract mutatlons and theupper llmlt from those on skeletal mutatlons (both In mlce); the latter Is
the same as that arrlved at In the UNSCEAR 1977 report [US].
A
multlpllcatton factor o f 2 has been used In the skeletal estlmate. but notln the cataract one. Thls factor Is a n attempt to allow for t h e llkellhoodthat many domlnant mutatlons (espectally those affecting bodlly systems
other than the skeleton) remaln t o be detected. A correctlon factor of
0.5, whlch allows for skeletal mutatlons that a r e not cllnlcallyslgnlflcant. ts not requlred for the cataract estlmate. See UNSCfAR 1982
Report [ U b ] for detalls.
d/ The louer llmlt of zero Is based on the assumptlon that the mutational
sensltlvlty of human \ m a t u r e oocytes ls slmllar to that of mouse lmnature
oocytes; the upper llmlt of -9 Is based on the assumptlon that thesensltlvlty of the human oocytes Is slmllar to that of mature and maturlngmouse oocytes and that the latter 1s 0.44 tlmes that of spermatogonla. See
UNSCEAR 1982 Report for detalls.
g/ Although the rlsk (of recesslve dlsease from the lnductlon of recesslve
mutatlons) Is zero In the flrst generatlon, about 1 extra case per mllllon
llve blrths would be expected In the folloulng 10 generatlons (frompartnershlp effects) and on certaln assumptlons. about 1 0 extra cases per
1 mllllon would be expected by the tenth generatlon (from effects due toldentlty by descent). See text for further detalls.
f / The louer llmlt Is based on comblned cytogenetlc data from chronic low-LET
lrradlatlon experlments lnvolvlng the rhesus monkey and the crab-eatlng
monkey. and the upper llmlt. on the comblned human and marmoset (Sagulnus
lusclcollls) cytogenetlc data (see UNSCEAR 1986 Report for detalls).
It
has been assumed
that 9% o f unbalanced products of reclprocaltranslocatlons wlll rerult In blrth of congenltally abnormal chlldren.
q/ The lower llmlt of zero Is based on the assumptlon that the sensltlvlty of
the human lmnature oocyte to the lnductlon of herltable reclprocaltranslocatlons wlll be slmllar to that of mouse lmnature oocytes wlthrespect to the lnductlon of chromosome aberratlon phenomena; the upper
llmlt Is based on the assumptlons that ( a ) the sensltlvlty of the human
lrnnature oocytes to the lnductlon o f reclprocal translocatlons wlll be one
half that of t h e human and marmaset spermatogonla (based on results wlth
mlce on herltable translocatlons); (b) the frequency of unbalanced products
dl11 be slx tlmes that of recoverable balanced reclprocal translocatlons;and (c) about 9% of unbalanced products ulll result In congenltally
malformed chlldren. See UNSCEAR 1982 Report for detalls.

REFERENCES
Awa, A.A.. T. Honda, S. Neriishi et al. Cytogenetic
study of the offspring of atomic bomb survivors,
Hiroshima and Nagasaki. p. 166-183 (Chapter 8) in:
Cytogenetics (G. Obe and A. Basler, eds.). Springer
Verlag, Berlin. 1987.
Abrahamson, S. Risk estimates for genetic effects. p.
223-250 in: Assessment of Risk from Low Level
Exposure to Radiation and Chemicals: A Critical
Overview. (A.D. Woodhead et al., eds.). Plenum
Press. New York, 1985.
BEIR Report. The Effect on Populations of Exposure
to Low Levels of Ionizing Radiation. Report of theAdvisory Committee on the Biological Effects of
Ionizing Radiation. National Academy of Sciences,
National Research Council. Washington. D.C.. 1972.
BEAR Report. The Biological Effects of Atomic
Radiation. National Academy of Sciences, National
Research Council. Washington, D.C., 1956.
BEIR Report. The Effects on Po~ulationsof Exposure
to Low ~ e v e l sof Radiation. ~ a t i o n a l cad ern^ of
Sciences. National Research Council. Washineton.
".
D.C.. 1980.
Brewen, J.G., R.J. Preston. K.P. Jones et al. Genetic
hazards of ionizing radiations: cytogenetic extrapolations from mouse to man. Mutat. Res. 17: 254-254(1973).
Brewen, J.G.. R.J. Preston and N. Gengozian.
.Analysis of x-ray induced chromosomal translocations
in human and marmoset spermatogonial cells. Nature
253: 468-470 (1975).
Buul, P.P.W.V. Dose-response relationship for x-ray
induced reciprocal translocations in stem cell spermatogonia of the rhesus monkey (Macaca mulatta).
Mutat. Res. 73: 363-375 (1980).
Britten, R. and D.E. Kohn. Repeated sequence inDNA. Science 16): 529-540 (1968).
Bohr. V.B.. C.A. Smith. D.S. Okumoto et al. DNA
repair in an active gene: removal of pyrimidine
dimers from the DHFR gene of C H O cells is much
more efficient than in the genome overall. Cell 40:
359-369 (1985).
Breslow, J.L. Apolipoprotein gene mutations, dyslipoproteinemia and coronary heart disease. p. 336-341 in:
Human Genetics. Proc. 7th Int. Coner. Hum. Genet.
(F. Vogel and K. Sperling, eds.). Springer-verlag,
Berlin, 1987.
Crow, J.F. and C. Denniston. The mutation component of genetic damage. Science 212: 888-893(1981).
Crow, J.F. and C. Denniston. Mutation in humanpopulations. Chapter 2. p. 59-123 in: Advances in
Human Genetics, Vol. 14. (H. Harris and K. Hirschhorn, eds.). Plenum Press, New York, 1985.
Childs, J.D. The effect of a change in mutation rateon the incidence of dominant and X-linked disorders
in man. Mutat. Res. 83: 145-158 (1981).
Carter, C.O. The relative contribution of mutant
genes and chromosomal abnormalities to genetic illhealth in man. p. 1-8 in: Progress in Mutation
Research, Vol. 3. (K.C. Bora et al., eds.). Elsevier
Biomedical Press. Amsterdam, 1982.
Czeizel. A. and K. Sankaranarayanan. The loadof genetic and partially genetic disorders in man.
I. Congenital anomalies. Estimates of detriment interms of years of life lost and years of impaired life.
Mutat. Res. 128: 73-103 (1984).

Caskey, C.T. and R.L. White (eds.). Recombinant
DNA Applications to Human Disease. Banbury
Report 14. Cold Spring Harbor Laboratory. New
York, 1983.
Czeizel, A., K. Sankaranarayanan, A. Losonci et al.
The load of genetic and partially genetic diseases
in man. 11. Some selected multifactorial diseases:
estimates of population prevalence and of detrimentin terms of years of lost and impaired life. Mutar.
Res. (1988). In press.
Denniston. C. Low level radiation and genetic risk
estimation in man. Annu. Rev. Genet. 16: 329-355( 1982).
Dutta, S.K. Chromosomal split genes. p. 175- 186 in:Genetics: New Frontiers, Proc. XV. Int. Congr.
Genet. (V.L. Chopra et al. eds.) Vol. 1. Oxford and
IBH Publishing Co. New Delhi, 1984.
Detera-Wadleigh, S.D., W.H. Berrettini, L.R. Goldin
et al. Close linkage of c-Harvey-ras-1 and the insulin
gene to affective disorder is ruled out in three North
American pedigrees. Nature 325: 806-808 (1987).
Dobson. R.L., T. Straume and T.C. Kwan. Radiation
damage in oocytes and genetic risk in the female.
p. 202 in: Proceedings of the 8th International Congress on Radiation Research, Book of Abstracts.
Edinburgh, 1987.
Ehling. U.H. The frequency of x-ray induced dominant
mutations affecting the skeleton of mice. Genetics 5 1:
723-732 (1965).
Ehling. U.H. Dominant mutations affecting theskeleton in offspring of x-irradiated male mice.
Genetics 54: 138 1- 1389 (1966).
Ehling, U.H. Strahlengenetisches Risiko des Menschen. Umsch. Wiss. Tech. 80: 754-759 (1980).
Ehling, U.H., J. Favor et al. Dominant cataract
mutations and specific locus mutations in miceinduced by radiation or ethylnitrosourea. Mutat. Res.
92: 181-192 (1982).
Emery, A.E.H. An Introduction to Recombinant
DNA. Wiley, New York, 1984.
Evans, H.J. Structure and organization of the humangenome. p. 58-100 in: Mutations in ,Man (G. Obe.
ed.). Springer. Berlin, 1984.
Evans, J.S., D.W. Moeller and D.W. Cooper. Health
Effects Model for Nuclear Power Plant Accident
Analysis. NUREG/CR 4214 (1985).
Ehling, U.H. Induction and manifestation of hereditary cataracts. p. 354-367 in: Assessment of Risk
from Low Level Exposure. (A.D. Woodhead et al..
eds.). Plenum Press, New York, 1985.
Egeland, J.A., D.S. Gerhard, D.L. Pauls et al.
Bipolar affective disorders linked to DNA markers
on chromosome l I. Nature 325: 783-787 (1987).
Green, M.C., P.W. Lane and J.L. Southard. In 41st
Annual Report of The Jackson Laboratory, Bar
Harbor, Maine (1969- 1970). 1970.
Griffin, C.S. and C . Tease. Gamma-ray induced
numerical and structural chromosome anomalies inmouse immature oocytes. Mutat. Res. (1988). In press.
Hecht, F. and B.K. Hecht. Fragile sites and chromosome breakpoints in constitutional rearrangements. 1.
Amniocentesis. Clin. Genet. 26: 169-173 (1984).
Hecht. F. and B.K. Hecht. Fragile sites and constitutional chromosome rearrangements. 11. Spontaneousabortions, stillbirths and new borns. Clin. Genet. 26:
174- 177 (1984).

Hodgkinson, S., R. Sherrington. H. Gurling et al.
Molecular genetic evidence for heterogeneity in manic
depression. Nature 325: 805-806 (1987).
Hilton, P.J. Cellular sodium transport in essential
hypertension. N. Engl. J. Med. 3 14: 222-229 ( 1986).
Jeiinek, W.R. and C.W. Schmid. Repetitive sequencesin eukaryotic DNA and their expression. Annu. Rev.
Biochem. 51: 813-843 (1982).
Kratochvilova. J. and U.H. Ehling. Dominant cataract
mutations induced by gamma-irradiation of malemice. Mutat. Res. 63: 221-223 (1979).
Kalter, H. and J. Warkany. Congenital malformations: etiologic factors and their role in prevention.
N. Engl. J. Med. 308: 424-43 1 (1983).
Kamiguchi. Y. and K. Mikamo. An improved efficientmethod for analysing human sperm chromosomes
using zona-free hamster ova. Am. J. Hum. Genet. 38:
727-740 (1986).
Kamiguchi. Y., H. Tateno, M. Shirnada et al. X-ra\induced chromosome aberrations in human spermatozoa. p. 117-123 in: New Horizons in Sperm Cell
Research. Japan Scientific Societies Press, Tokyo,
1987.
L~ining,K.G. and A.G. Searle. Estimates of genetic
risks from ionizing radiation. Mutat. Res. 12: 291-304(1971).
Lyon, M.F. Measuring mutation in man. bature 318:
3 15-316 (1985).
Medical Research Council. The Hazards to Man of
Nuclear and Allied Radiations. Cmd 9780, H.M.S.O.,
London, 1956.
bfuller, H.J. Our load of mutations. Am. J . Hum.
Genet. 2: 11 1-176 (1950).
McKusick, V..4. Mendelian Inheritance in Man.
Catalogs of Autosomal Dominant. Autosomal Recessive and X-linked Phenotypes. 3rd Edition. Johns
Hopkins University Press, Baltimore, 197 1.
McKusick, V.A. Mendelian Inheritance in Man.
Catalogs of Autosomal Dominant, Autosomal Recessive and X-linked Phenotypes. 7th Edition. Johns
Hopkins University Press. Baltimore. 1986.
blcClintock, B. Mutable loci in maize. Carnegie Inst.
Washington. Year Book 47: 155- 163 (1948).
hicClintock, 9. The origin and behaviour of mutableloci in maize. Proc. Natl. Acad. Sci. 36: 344-355(1950).
,McClintock. B. Chromosome organization and genetic
expression. Cold Spring Harbor Symp. Quant. Biol.
16: 13-47 (1952).
McClintock, B. lntranuclear systems controlling geneaction and mutation. Brookhaven Symp. Biol. 8:58-72 ( 1956).
bloore, G.E., A. Ivens, J. Chambers et a]. Linkage ofan X-chromosome cleft palate gene. Nature 326:
91-92 (1987).
McClanahan, T. and K. McEntee. Specific transcripts
are elevated in Saccharomyces cerevisiae in response
to DNA damage. Mol. Cell. Biol. 4: 2356-2363(1984).
Morawetz. C. Effect of irradiation and mutagenic
chemicals on the generation of XDH-2 constitutive
mutants in yeast. Significance for the inducibility of
Ty transposition. Mutat. Res. 177: 53-60 (1987).
Mullenders, L.H.F., A.C. van Kesteren, J.M. Bussmann el al. Distribution of UV-induced repair eventsin higher order chromatin loops in human andhamster fibroblasts. Carcinogenesis 7: 995-1002 (1986).
Mullenders, L.H.F., A.A. van Zeeland and
A.T. Natarajan. The localization of ultraviolet lightinduced excision repair in the nucleus and the
distribution of repair events in higher order chromatinloops in mammalian cells. J . Cell Sci. Suppl. 6:
243-262 (1987).
Mikamo, K. and Y. Kamiguchi. Spontaneous andradiation-induced chromosome aberrations in humanspermatozoa. p. 49-50 in: International Workshop on
Re-evaluation of Hiroshima and Nagasaki cases by
Chromosome Aberration Analysis for Dose Assessment and Risk Evaluation. (Abstract). Kyoto (1985).
Neel, J.V., 13. Kato and W.J. Schull. Mortality in thechildren of atomic bomb survivors and controls.
Genetics 76: 31 1-326 (1974).
Neel, J.V., W.J. Schull and .M. Otake. Current statusof genetic follow-up studies in Hiroshima andNagasaki. p. 39-51 in: Progress in Mutation Research(K.C. Bora et al. eds.), Vol. 3. Elsevier Biomedical
Press, Amsterdam, 1982.
Nomura, T. Parental exposure to x-rays and chemicals
induce heritable tumours and anomalies in mice.
Nature 296: 575-577 (1982).
Nomura, T. X-ray-induced germ-line mutations leading to tumours: its manifestation by post-natally
given urethane in mice. Mutat. Res. 121: 59-65(1983).
Nomura, T. Further studies on x-ray and chemicallyinduced germ-line alterations causing tumours andmalformations in mice. p. 13-20 in: Genetic TOXIcology of Environmental Chemicals. Proceedings ofthe Fourth International Conference on Environmental Mutagens (Part B). (C. Rarnel et al.. eds.).
Alan R. Liss, New York, 1986.
Oftedal, P. and A.G. Searle. An overall genetic
risk assessment for radiological protection purposes.
J. Med. Genet. 17: 15-20 (1980).
Oftedal. P. and J. Mulvihill. Possible genetic effectsof cancer therapy, seen in surviving cancer patients'
offspring. p. 351-345 in: Genetic Toxicology ofEnvironmental Chemicals. Proceedings of the FourthInternational Conference on Environmental Mutagens(Part B). (C. Ramel et al., eds.). Alan R. Liss. New
York, 1986.
Orkin, S.H. .4 review of beta thalassemias: thespectrum of gene mutations. p. 19-28 in: Banbury
Report 14. Recombinant DNA Applications Lo Human
Disease. (C.T. Caskey and R.L. White, eds.). Cold
Spring Harbor Laboratory, New York, 1983.
Russell, W.L., L.B. Russell and E.M. Kelly. Radiationdose rate and mutation frequency. Science 128:
1546-1550 (1958).
Russell, W.L., L.B. Russell and E.M. Kelly. Dependence of mutation rate on radiation intensity.
p. 31 1-320 in: Immediate and Low Level Effects of
Ionizing Radiations. (A.A. Buzzatti-Traverse, ed.).
Taylor Francis, London, 1960.
Russell, W.L. Effects of radiation dose rate on
mutation in mice. J. Cell Comp. Physiol. 58 (Suppl.) 1:
183-187 (1961).
Russell, W.L., L.B. Russell and M.B. Cupp. Dependence of mutation frequency on radiation dose rate infemale mice. Proc. Natl. Acad. Sci. 45: 18-23 (1959).
Russell, W.L. Effect of interval between irradiationand conception on mutation frequency in female
mice. Proc. Natl. Acad. Sci. 54: 1552-1557 (1965).
Russell, L.B. Definition of functional units in a small
chromosome segment of the mouse and its use ininterpreting the nature of radiation-induced rnutalions. Mutat. Res. 11: 107-123 (1971).
Russcll. W.L. Mutation frequencies in female miceand the estimation of radiation hazards in women.
Proc. Natl. Acad. Sci. 74: 3523-3527 (1977).
Rogers, J.H. The origin and evolution of retroposons.
111t. Rev. Cytol. 93; 187-280 (1985).
Stevenson, A.C. The load of hereditary defects inhuman populations. Radiat. Res. (Suppl.) 1: 306-325( 1959).
Sankaranarayanan, K. Evaluation and re-evaluationof genetic radiation hazards in man. 111. Other
relevant data and risk assessment. Mutat. Res. 35:
371-386 (1976).
Searle, A.G. Use of doubling doses for the estimationof genetic risks. Paper presented at the EURATOM

meeting "Seminars on Radiation Biology and Radiation Protection". Orsay, France, May 1976.
Schull, W.J.. M. Otake and J.V. Keel. Genetic effectsof the atomic bombs: a reappraisal. Science 213:
1220-1227 (1981).
Schull. W.J.. J.V. Neel, M. Otake et al. Hiroshima
and Nagasaki: three and a half decades of genetic
screening. p. 687-700 in: Environmental Mutagens
and Carcinogens (T. Sugimura et al. eds.). Universityof Tokyo Press, Tokyo, 1983.
Sherman. S.L., N.E. Morton, P.A. Jacobs et al. The
marker-X syndrome: a cytogenetic and genetic analysis. Ann. Hum. Genet. 48: 21-37 (1984).
Selby, P.B. and P.R. Selby. Gamma-ray induced
dominant mutations that cause skeletal abnormalities
in mice. I. Plan, summary of results and discussion.
hlurat. Res. 43: 357-375 (1977).
Selby, P.B. and VI1.L. Russell. First generation litter
size reduction following irradiation of stem cells inmice and its use in risk estimation. Environ. Mutagen.
7: 45 1459 ( 1986).
Searle. A.G. and J.H. Edwards. The estimarion ofrisks from the induction of recessive mutations after
exposure to ionizing radiation. J. Med. Genet. 23:
220-226 (1986).
Sankaranarayanan. K. Transposable genetic elements,
spontaneous mutations and the doubling dose methodof radiation genetic risk evaluation in man. Mutat.
Res. 160: 73-86 ( 1986).
Schrnid, C.W. and K.E. Paulson. Interspersed repeats
in mammalian DNAs. p. 255-267 in: Genetics: New
Frontiers, Proc. XV. Int. Congr. Genet. (V.L. Chopra
et al, eds.) Vol. 1. Oxford and IBH Publishing Co.
New Delhi ( 1984).
Satoh. C., K. Goriki. J.1. Asakawa et al. Effects ofatomic bomb radiation on the induction of genemutation. p. 186 in: Book of Abstracts. 7th Int.
Congr. Hum. Genet., Part I . West Berlin, 1986.
Schull, W.J., M. Otake and J.V. Neel. Hiroshima
and Nagasaki: a re-assessment of the mutagenic
effects of exposure to ionizing radiation. p. 277-303
in: Population and Biological Aspects of Human
Mutation. (E.B. Hook and I.J. Porter, eds.). Academic Press. New York. 1981.
Singer, M.F. SINES and LINES: highly repeatedshort and long interspersed sequences in mammalian
genomes. Cell 28: 433-434 (1982).
Skowronski, J. and M.F. Singer. The abundantLINE-I family of repeated DNA sequences inmammals: genes and pseudogenes. molecular Biologyof Homo Sapiens. Cold Spring Harbor Symp. Quant.
Biol. I (L 1): 457-464 (19861.
Sankaranarayanan, K. Mobile genetic elements,
spontaneous mutations and the assessment of genetic
radiation hazards in man. Banbury Report 30. Cold
Spring Harbor l.aboratory, New York, 1988
Smith, C.A. DNA repair in specific sequences inmammalian cells. J. Cell Sci. (Suppl.) 6: 225-241( 1987).
Saiki. R.K., S. Scharf. F. Faloona st al. Enzymatic
amplification of beta globin genomic sequences andrestriction site analysis for diagnosis of sickle cellanemia. Science 230: 1350-1354 (1985).
Straume, T., R.L. Dobson and T.C. Kwan. Neurron
RBEs and the radiosensitive target for mouse immature
oocyte killing. Radiat. Res. l l I: 47-57 ( 1987).
Straume, T., R.L. Dobson and T.C. Kwan. Size of
Iethaliry target in mouse immature oocytes determinedwith accelerated heavy ions. p. 202 in: Book of
Abstracts. Proc. 8th Int. Congr. Rad. Res. Edinburgh.
1987.
Trimble, B.K. and J.H. Doughty. The amount ofhereditary disease in human populations. Ann. Hum.
Gener. 38: 199-223 (1974).
Thacker, J. The nature of mutants induced byionizing radiation in cultured hamster cells. 111.
Molecular characterization of HPRT-deficient mutants
induced by gamma rays or alpha particles showingthat the majority have deletions of all o r part of the
HPRT gene. Mutat. Res. 160: 263-275 (1986).
United Nations. Report of the United Nations
Scientific Committee on the Effects of -4tomic
Radiation. Official Records of the General Assembly,
Thirteenth session. Supplement No. 17 (A/3838).
New York, 1958.
United Nations. Report of the United Nations
Scientific Committee on the Effects of Atomic
Radiation. Official Records of the General Assembly,
Seventeenth session. Supplement No.16 (A/5216).
New York. 1962.
United Nations. Report of the United Nations
Scientific Committee on the Effects of Atomic
Radiation. Official Records of the General Assembly,
Twenty-first session, Supplement No. 14 (AI6314).
New York. 1966.
United Nations. Ionizing Radiation: Levels andEffects. Report of the United Nations ScientificCommittee on the Effects of Atomic Radiation. withannexes. United Nations sales publication E.X.IX.17
and 18. United Nations. New York, 1972.
United Nations. Sources and Effects of Ionizing
Radiation. United Nations Scientific Committee on
the Effects of Atomic Radiation. 1977 repon to theGeneral Assembly. with annexes. United Nations
sales publication E.77.IX.l. United Nations. New
York, 1977.
United Nations. Ionizing Radiation: Sources andBiological Effects. United Nations Scientific Committee on the Effects of Atomic Radiation, 1982
Report to the General Assembly, with annexes.
United Nations sales publication E.82.IX.8. United
Nations, New York, 1982.
United Nations. Genetic and Somatic Effects of
Ionizing Radiation. United Nations Scientific Committee on the Effects of Atomic Radiation, 1986
Report fo the General Assembly, with annexes.
United Nations sales publication E.86.IX.9. United
Nations, New York. 1986.
Vrieling, H., J.U'.l.bl. Simons et al. Mutations
induced by x-rays at the HPRT locus in cultured
Chinese hamster cells are mostly large deletions.
Mutat. Res. 144: 281-286 (1986).
Vrieling, H., J.W.I.M. Simons and A.A. van Zeeland.
Nucleotide sequence determination of point mutations
at the mouse HPRT locus using in vitro amplificationof HPRT mRNA sequences. hiutat. Res. (1988) (inpress).
World Health Organization. Effects of Nuclear War
on Health and Health Services. Report of theInternational Committee on Experts in Medical
Sciences and Public Health to Implement Resolution
WHO 34.38, WHO, Geneva, 1984.
Williams, R.R., S.C. Hunt, S.J. Hasstedt et al. The
genetics of hypertension: an unsolved puzzle withmany pieces. p. 311-325 in: Human Genetics, Proc.
7th Int. Congr. Hum. Genet. (F. Vogel and K. Sperling,eds.). Springer-Verlag, Berlin. 1987.