SOURCES AND EFFECTS
OF IONIZING RADIATION
United Nations Scientific Committee on the Effectsof Atomic Radiation
UNSCEAR 1993 Report to the General Assembly,
with Scientific Annexes

UNITED NATIONSNew York, 1993

NOTE
The report of the Committee without its annexes appears as Official Records of theGeneral Assembly, Forty-eighth Session, Supplement No. 46 (N48/46).
ll1e designation employed and the presentation of material in this publication do not imply
tl1e expression of any opinion whatsoever on the part of tlie Secretariat of the United Nations
concerning the legal status of any country, territory, city or area, or of its authorities, or concerning
tl1e delimitation of its frontiers or boundaries.
The country names used in this document are, in most cases, those tliat were in use at thetime the data were collected or the text prepared. In other cases, however, the names have been
updated, where tliis was possible and appropriate, to reflect political changes.

UNITED NATIONS PUBLICATION
Sales No. E.94.IX.2
ISBN 92-1-142200-0

ANNEX G
Hereditary effects of radiation

CONTENTS

Pogc. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 730
I. GENETIC DISEASES IN HUMANS . . . . . . . . . . . . . . . . . . . . . . . . . . 731
A. SINGLE-GENE DISORDERS . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
1. Dominant traits ..................................732
2. Recessive traits ..................................732
3. X-linked traits ..... ;..............................733
B. CHROMOSOMAL ABERRATIONS ....................... 733

INTRODUCTION. MULTIFACTORIAL AND POLYGENIC INHERITANCE ....... 733
1. Determining factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733
2. Risk of recurrence within families . . . . . . . . . . . . . . . . . . . . . 734
D. NON-TRADITIONAL INHERITANCE . . . . . . . . . . . . . . . . . . . . . 735

C

E

.

1. Mosaicism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
2. Genomic imprinting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737
3 . Uniparental disonly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 738
4. Cytoplasmic inheritance . . . . . . . . . . . . . . . . . . . . . . . . . . . . 739
5. Anticipatio~~and allelic expansion . . . . . . . . . . . . . . . . . . . . . 739
6. Gene amplification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740
7 Transposable elements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 740.
SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .741.

MONITORING THE BACKGROUND INCIDENCE
741
OF GENETIC DISEASEA REGISTRIES OF CONGENITAL ANOMALIES .............. 741
1. Types and incidence of congenital anomalies . . . . . . . . . . . . . . 741
2. Scope of monitoring . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 743
B. CONSIDERATIONS ON BACKGROUND INCIDENCE . . . . . . . . 744
1 Sentinel Mendelian diseases ......................... 744
2 Autosomal recessive diseases
745
3 Chrornosornal diseases
746
4 . Congenital anomalies and nlultifactorial diseases ........... 746
C MOLECULAR AND BIOCHEMICAL STUDIES OFSPONTANEOUS AND RADIATION-INDUCED MUTATIONS ... 748
1. Location and effecls of mutations ...................... 748..................................

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.
.
.

.

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

2 . Protcin studics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 751
D. SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 752

111. GENETIC RISK ESTIMATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 753
A . HUMAN STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .754
1 . Gcnctic follow-up studies oa thc
survivors of the atomic bonibi~~gs. . . . . . . . . . . . . . . . . . . . . .754
2. Epidemiological study o i lcukacniia rases a t Scllaficld . . . . . . . 757
3. Epidemiological studies on other hun~aa~)opulations . . . . . . . . 759
B METHODS OF RISK ESTIMATION: ANIMAL STUDIES . . . . . . . 760
1. The doubling dosc (indirect) method . . . . . . . . . . . . . . . . . . . 761
2 The direct mcthod ................................ 762
C EXPERIMENTAL STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . 767
1 . Ncw cxpcrimc~~taldata rclcvant to risk cstin~;~tion. . . . . . . . . . 767
2. Studies of mutations in mouse oocylcs . . . . . . . . . . . . . . . . . . 768
3 . I~iductionof translocations in prin~atcs . . . . . . . . . . . . . . . . . . 769
4. Induction of dominant mutations
causing congenital ~nalforrnations. . . . . . . . . . . . . . . . . . . . . . 769
5 . Results of thc dircct neth hod to cslimatc risk . . . . . . . . . . . . . . 770
6. Mousc vcrsus human genes . . . . . . . . . . . . . . . . . . . . . . . . . .771
D GENETIC RISK ESTIMATES . . . . . . . . . . . . . . . . . . . . . . . . . . .772
1 Estimates of UNSCEAR . . . . . . . . . . . . . . . . . . . . . . . . . . . . 772
2. Estimates of BEIR. lCRP AND NUKEG . . . . . . . . . . . . . . . . 773
3 . Re-evaluation of doubling dose cstiruatcs
in nlicc and humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 774
4 . Molecular biological dcvclopn~cnts. . . . . . . . . . . . . . . . . . . . . 775
E. SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 776

.

.

.

.

.

IV. FUTURE PERSPECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 777
A . MOLECULAR INVESTIGATIONS . . . . . . . . . . . . . . . . . . . . . . . 777
B THE HUMAN GENOME PROJECT . . . . . . . . . . . . . . . . . . . . . . 778.

CONCLUSIONS........................................... 779

Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 782
Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 786
Rcfcrc~~ccs. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 796

INTRODUCTIONh a t cannot bc answered givcr~the prcscnt slate of1.
Evaluation of the hcrcditary hazard associaled
with the cxposurc of human populations to i o ~ ~ i z i r ~ g knowlcdgc
radiation has been a major concern of thc Cor~i~~iittcc
Attc~nl~ts
at risk csti~llntio~~cntail uncer~aintics.
2
sincc its inccptio~l. Meny approaches have bccr~uscd
in part hcci~usci t bas not been possible to dircctly
to formulate optimal predictions ofthc cxtcnt to which
confirln radial ion-induccd mutations in hu~nanpopua givcn dose of ionizing radiation will incrcasc thc
lations Gcactic risk cstin~atcshave rclied on a gcncna~urallyoccurring nlulation rate of germ cclls and ofral knowlcdgc of hunian genctics and on tbe cxtrapolahow such an incrcasc will aficcl the health of futuretion of results from animal cxpcrimcnts . Limited data
hunian populations . However. an exlrcmcly coniplex
from long-tcrni studies on thc children of radiationset of problems rcniai~~s.
and thcre are rnariy questions

.

.

.

ANNEX G: IIEREDITARY IFFECIS OF W I A . I l O N

exposed parents, parlicularly those cxposcd to theatonlic bombings ofl-liroshi~llaand Nagasaki, may be
used to set outside linlils oe gcnctic risk es~in~ales.
These data indicate that t l ~ chcrcditary cffccb of
niodcratc irradiiition of a large 11u11la1lpopulation arc
minimal, at lcasl for acutc exposure.

3.
Progress is being made in scvcral areas of human
gcnctics. Thcrc have been major advances in theknowlcdgc of non-traditional inheritance and so-called
multifactorial disease in humans. Prcvious UNSCEAR
Rcports raised the queslion of whether, and how, toinclude cstiniatcs of gcnctic risk for mu!tifactorialdiseases. This category of disease represents a hetero.
geneous group for which the underlying mechanisms
are poorly understood, although they clearly have agenetic component Multifactorial diseases are related
in a complex way to other risk factors and to population structure and living conditions. Radiation damage
may affect the regulation of genes involved in multifactorial inhcritance by many different niechanisn~sand may also affect the structure and function of
singlc gcnes. Thesc n~ultifactorial discases and nontraditional mechanisms of inhcritance arc discussed inthis Annex in order to emphasize the complexity ofhuman genetics and biology, as well as the difficultyof obtaining accurate risk estimates from studies of
only a few well-defined disordcrs in animal models.

I.

-

4.
The understanding of human gcnctics on a~nolccularlcvcl is incrci~singcxtrcr~~cly
rapidly. As
disc~~sscd
in this AIIIICX,
new laboratory tccllniqucs
allow a more prccisc aniilysis of the typc of genetic
damage causcd by various i~gcnts,includillg radiation.
Eventually, thc scquc~lcingand identification of cvcry
gcnc oa cvery cl~ron~osomc
will provide a rllctl~odof
direct access to the cffccL$ of radiation on humall
gcnes at t l ~ emolccul:~rlevel. Knowledge of population
genetics, gaincd frorn rcgistrics of birth defects, isimproving estimates of the current incidence of serious
birth dcfects, wilh which any cstimate of risk fromradiation may be compared.
5.
The knowlcdgc gained from the Japanese expericncc, from advanccs in human genetics, and fromanimal studies should allow uncertaintics of risk
estimates to be gradually reduced. However, as thedifficulties inherent in Lhc estinlation procedures
beconic even rnore apparent, there is increased uncertainty and/or inability to specify appropriate andrealistic values. Practical solutions arc needed. In thisAnncx, the cornplcxitics irivolvcd in making humanrisk estiniates using animal models are pointed out, thebest estimates of genetic risk that can be made at thistime are discussed, and ways of obtiiining infonnationthat could lead to Inore rcliablc genetic risk estimatesarc suggcstcd.

GENETIC DISEASES IN HUMANS

6 . Genetic diseases occur because of alterations tothe structure or regulation of DNA in the cells of anorganism. Genes are units of heredity, comprised of
specific sequences of DNA and carried on the chroniosomes and in mitochondria. Mutations (changes in
DNA structure, arrangement or amount) occur spontaneously or are caused by physical or chcmical agents.
Genetic disorders have traditionally been classi7.
fied into three categories: (a) single-genc disorders, (b)chromosomal aberrations, (c) multifactorial disorders.
Although many recent dcvelopn~cnts in molecularbiology and new concepts rclating to mechanisms of
disease processes have made these distinctions lessclear, the classification will be rctaincd for the
discussion that follows.

A.

73 1

SING1,E-GENE DISORDERS

Single-gene disorders are usually recognized by
8.
their clinical nlanilestatio1~5,but research is now identifying many disorders on the rnolecular level. Disease

traits occur bccausc of mutations to the normal gene.
Alleles are alternative forms of a gene at a particularlocus, or position on the chromosonie. Thcre are two
levcls on which the genetic constitution of an individual may be considered: the gcnotype, or particularalleles of a given gene carried by an individual, andh e phenotype, or the physical, bio-chemical or physiological characteristics dctcrrnincd by these allclcs.
These si~lglegene dcfccb arc often called Mcndclian,aftcr Mcndcl, who first described thcsc unib of
hcrcd ity.

9.
Simplc Mcndclian trails are inherited by autosomal transmission (LC. the gcnes for then1 are carriedon one of the 22 pairs of autosomcs, or non-sex chromosomes) or by X-linked tra~lsnlission(i.e. thc gcnes
Wit11 autosorl~alare carried on tlle X-chro~nosoa~e).
gcnes, one copy ofthe genc is ~ronnallycol~tributcdby
Ule mother and olle by the father. X-linked gcnes will
always come lrom the motl~crin a male (as he has
rcccivcd a Y-chro~noson~efrom his father), or fromboth parents in a fe~nale(since she has reccived an
X-chroniosonie from each parent).

U N S C M R 1993 WPOll'f732

10. Dominant disorders are those in which tl~ereis aclinically recognizable abnonl~alityproduced, even if
only a single copy (allele) of the gene is abnonnal, i.e.
in the heterozygous state. On average, the autosolnal
dominant gene (kc. the abnonnal allele for the trait)
will bc transmitted to 50% of the offspring of anaffected individual. Unaffected individuals will not
usually carry or transmit the abnormal gene. Affectedindividuals will have an affected parent, except in theevent of a new mutation of the gcne.
11. Autosomal doniinant Lraits are not always
expressed to the same degree in all individuals whocarry them. In complex genetic and environmental
interactions, some mernbcrs of a family may be scverely affected and others only mildly so. There may
even be transmitters of a dominant allele who appear
phenotypically normal. T o describe this phenomenon,
the terms penetrance and expressivity have beendeveloped [T9].

1 2 Heterogeneity is the term used to describe
situations in which the same or nearly the same
phenotype is produced by different mechanisms. There
are many situations in which heterogeneity appears toexist. For instance, homocystinuria can produce a
symptom complex that strol~gly resembles Marfan
syndrome [B7].

Conversely, it is possible that two different
mutations in the same gene will produce different
phenotypes. This niay occur when the mutations lie in
different domains, or regions, of the protein productand thus affect different functions of the same protein.
For example, ostcogcncsis imperfccta types 1 and I1
and some occurrences of Ehlers Danlos syndrome may
be caused by murations in the alpha 1 chain of type I
collagen, but depending on which portion of thecollagen molecule is altered, markedly different
diseases occur [B7].

know11as a n X-liltked disorder. Hcniizygosity can also
occur ill autoso~nalgenes if there is a deletion of partof tllc cllro~nosonieor if one of a pair of chromosomes is lost. When an autosoma1 recessive condition
is present ill a family, cases usually occur among
siblings. Tllc itb~~ornial
copy of the gene (the abnonnal
allele) ~nily ~ I I S O be carricd by other relatives, offspring and parents, but the trait or disease will appear
only in t l ~ coffspring of two individuals who cany theabnornial gene. This type of pairing is rare in thegeneral population.
15. Frequently, honiozygotes for autosomal recessive
disorders do 11ot reproduce, because the homozygous
state of l l ~ edeleterious gene reduces their biologicalfitness. For tbis reason, some autosomal recessive
traits must have conferred a sclcctive advantage on theindividual during the course of evolution, otherwise
tbe mutation would not be as j~rcvalentin the general
populittion as it is. A niutatio~~
may be maintained atrelatively high rrequency in it population by tbis kindof selective advantage or because of a founder effect,
or because of genetic drift (see glossary) [VlO].
16. Consanguineous marriages may also play a rolein producing a homozygous individual for a rare autosornal recessive condition. In a consanguineous
marriage, the parents of an affected individual are
related (e.g. first cousins), which makes them more
likely to have inherited the same abnormal allele [L5].
Some human populations have higher rates of consanguineous marriage than others.

13.

2.

Krcessive traits

14. Recessive disorders are those that are usuallyclinically expressed only when both copies of the geneare abnormal (homozygosity). If hvo diffcrent
abnormal alleles of the gcnc are present, the individualis said to be a compound I~eterozygote.A recessive
disorder will also be clinically expressed when there
is one abnormal copy and no normal copy of the gcne
is present (hemizygosity). Hemizygosity occurs
normally in males for the X-chromosome; this leads todisease when the single normal copy of a gene carriedon the X-chromosome is lost or damaged. This is

Occasionally, each parent niay carry two different itlleles of a particular gelre; in this event theoffspring could inherit two differently abnonnal copiesof the gene. This might result in a disease characterized by a combination of the symptoms of two somewhat different diseases. Alternatively, each of the two
defective alleles could compensate for the other,resulting in a normal phenotype. This is called
complementation.
17.

18. Mutatioas occur on a regular but unpredictablebasis. They are most frequently observed as donlinant
mutations, since the dominant nature of the gene
allows expression and inimediate recognition. However, new rnulations must be occurring in genes forrecessively inherited traits as well. It is estimated that
he mutation frequency for some genes is in the rangeof 1 in 30,000 to 1 in 50,000 live-born individuals, but
most mutiltion rates are probably lower. Some hurnan
disorders, sucl~as neurolibromatosis I, have far higher
mutation frequencies (1 in 6,000). This difference inmutation frequencies may be influenced by the size ofthe gcnc, its vulnerability, its exact position on achroniosorne (e.g. at a mutational hot spot) (V3, W3],
or by orher as yet undefined faclors [V5].

A N N M G: IIEREDITARY EFFECIS OF RADIATION

19. X-linked trails, as mcntioacd above, are those inwhich the gene producing the abnorn~irlplrenotype islocated on tlre X-chromosonre. Because ~iralesdo notpass their X-chromosome on to their sons (i.e. thesons are niale because they have inherited heir
father's Y-chromosonie), there will bc no male-tomale transmission of an X-linked trait in a pedigree.
Females, with two X-chromosomes, may or may not
manifest an abnormal phenotype for an X-linked trait,
depending on whether the trait is dominant or recessive. In addition, the mariner in which rrornial X-inactivation (lyonization) occurs may affect expression.
Thus, if by chance the normal allele is on an X-chromosome that is inactivated in more than 50% of thecells, a carrier female may express some features ofeven a recessive disorder.

B. CHROMOSOhlAL ABERRATIONS
20. Each species has a characteristic chromosomal
constitution with respect to number and morphology.
This is called the karyotype and can be visualized
under the microscope at the stage of the cell cycle
where condensation occurs. Normally, a human being
carries 46 chroniosomes in each somatic cell. Thesecomprise 22 homologous pairs of autosomes and one
pair of sex chroniosomes. The menibers of a homologous pair are matched with respect to the genetic
infomiation that each carries, although they may
contain different alleles of the same genes.

21. There are two types of cell division. Mitosis is
the usual type that occurs as the body grows andreplaces cells. Mitosis involves Lhe precise duplicationof each chromosome so that h e daughter cells will beidentical to the original cell in terms of genetic
information. The second type of cell division ismeiosis, the specialized process of producing gametes(ova and sperm). During n~eiosis,the diploid numberof 46 chromosomes is reduced to the haploid number,in which only one copy of each chromosome pair will
be present

2 2 The union of the egg and the spemi at fertilization reestablishes the norn~al diploid number ofchromosomes. Abnormal numbers of chromosomes,
breaks, or rearrangements of chrornosomes or of segments of them can produce ~najorabnormalities in theaffected individual. The presence of abnormal numbersof chromosomes is called ancuploidy (i.e. not euploid).
Certain chromosomal rearriingernents are not compatible with viability or are selected against by thegrowth of more vigorous normal cells during development. However, a wide variety of rearrangements(translocations, inversions etc.), breaks and extra or
missing chromosome s e g m c ~ ~mayt s be tolerated.

733

C. MUI,TIFACTORlAI, AND I'OLYGENICINHERITANCE

23. The ternis polygcrric arrd multifactorial refer tothose traits, diseases or co~rgcnitalanomalies whose
developnlerrt has a genetic coniponelrt but whose inheritance does not follow standard Mendelian patterns
for autosonial do~ninant,autosoma1 recessive, or sexlinked transmission, suggesting that more than one
gene is involved. Rather, many genes acting in concert
are thought to be responsible. If environmental factors
appear to play a role in the developliicnt of the trait ordisease, it is described as multifactorial. These socalled multifactorial disorders are a very heterogeneous group, including about 95% of conditions
having a genetic predisposition. They are observed at
all ages and in all human populations. Their aetiology
is complex, heterogeneous and poorly understood. It is
important that this term be used only when referring
to a single condition or trait (e.g. clubfeet, not multiple
contractures) and that all disorders due entirely to a
defect in a single gene be excluded.

24. Observations suggest that there is a gradation offactors contnbuti~igto the devclopmcnt of a multifactorial trait and that a certain number of such factors
are necessary to produce the trait. If an individual has
a susceptible genotype and is exposed to a predisposirig environment, the likelihood that he or she will
manifest the bait depends upon the accumulation ofboth genetic and environmental factors beyond a certain threshold. The threshold is the point on a liability
scale below which individuals are not affected andabove which they are affected [F7].

25. Numerous environmental factors may affect thedevelopnient of multifactorial trails. Environmental
factors include the milieu in which the embryo andfetus develop, including both intrinsic and extrinsic
factors such as drugs, airborne toxins, viral or bacterial
agents and radiation; abnormalities of maternal
metabolism, such as diabetes mellitus, malnutrition, ormaternal hyperthermia, may also be a factor [n,F8].

26. In calculating the recurrence risk for such
multifactorial disorders, it is first essential to determine, along with the family pedigree and the preconceptional arid pre~ratalhistory, whether there are othercases of such disorders in unrelated fanlilies who livein the same geographic area. A case cluster of thistype would suggest that erivironmental factors may beparticularly important in the aetiology of the defectIB81.
27. Human susceptibility to teratogenic or mutagenic
agents, including radiation, may differ between individuals and between hu~iiansarrd mice. Likewise, there

734

UNSCEAR 1993 REPOH

are el1111icor strain differences within a single species.
CleR lip with or wilhoul clcft palate can be i~lducedin
100% of offspring of N
J strain nice when prcg~~ant
fcmalcs arc treated wit11 corticostcroids on days 11-14
of gestation. By contrast, o~lly20% of the offspring of
C53B1/6 mice given the salnc trcilln1cnt will haveclefts [F7].Direct coml~i~risons
between humans andmice are not possible; however, clhnic diffcrcnces are
known to exist for n~ultifact~riirl
co~lditiorlsin humans.

28. Both gcnctic and cnvironnicntal factors caninfluence the development of a given enibryo relative
to a particular threshold by acting at any point during
development. Whcn different strains of mice arecrossed and interbred, the picture is further complicated by new combinations of genetic backgrounds.
The same is most likely true for humans wilh different
ethnic and genetic backgrounds.
29. Thus, in applying the mouse model to humanstudies, it must be borne in mind that the embryo's
teratogenic (or mutagenic) susceptibility can be
influenced by its normal developmental patterns andinteractions. Thus an ethnic (strain) or regional groupdifference in the frequency of an induced malformation could occur even if the primary effect of thetcratogen or mutagen was the same in the two strains.
This is a very importa~ltaspect of the threshold modelof multifactorial inheritance.
30. It should also be kept in mind that two or moremutations (or cxten~al mutagens) can act together
either additively or synergistically on any dcvelopmental process. Furthermore, multifactorial systems
are heterogeneous, i.c. two individuals who are similarly liabile to develop a particular disorder may be so
as a result of completely different genes andlor
mechanisms.

31. In humans, there are numerous cxamples of differences in incidcncc between diffcrent ethnic groups
and different geographic regions, as can be observedin studies of neural tube defects. Neural tube defects
are a heterogeneous group of anomalies h a t involvethe developing brain and spinal cord. Tbc
epidemiologic characteristics of neural tubc defects
include a higher incidence in females, in lower socioeconomic groups, and in people of Celtic or East
Indian ancestry, and prevalcncc rates that vary
substantially in different geographic regions [H4].
While neural tube defects arc generally registered asa single category of defect, their causes areheterogeneous and c;~n be i~~flucnccd
by tcratogcnic
exposure or niatcrnal nutritional deficiency or illness.
In some families recurrence is frequent, in others only
sporadic. Each of these c o m p o ~ ~ c nof~ sthe overall
category "neural tube defect" is likely to bedifferentially affected by exposure to various

rnutagc~lic agcnls IV121, and, as wit11 ott~cr
multifactoriiil disordcrs, nutrilioa and lifestyle, i.e.
cnvironmeat, ciln II;IVC iI ~~rotcctivc
effcct as well as adarnaging clTect. For c x a ~ ~ i p l cColic,acid supplementation I1i1s been shown to rcduce tllc rccurrcnce ofncurnl tubc defects [W4].
32. I t is also i~l~portsntto rcnieniber that multifactorial disordcrs often m;~nifcst with different
gradations of severity. Thus if a new mutation simply
increased the scvcrity of a disorder, it would probably
not be noted as a change ill the incidcncc of the disorder in the population.

33. In exploring the relationship between environmental factors and the occurrence of congenital anomalies, one is confronted with an extremely complex
situation. In multifactorial disordcrs, an environmental
factor or factors interacts with a susceptible genotype
to produce the defect. The ur~iquenessof this interaction in a given fa~nilyniay preclude generalization
to the populatio~~
as a whole. As a result, it is perhaps
not surprising that it is so difficult to define specificenvironnlental factors that correlate significantly andconsistently with particular congenital anomalies inhumans. This difficulty is particularly relevant to any
attenlpt to predict the cfCccts of radiation exposure on
multifactorial disordcrs.

2.

Risk of' I-ecurrellce within fanlilies

34. Whcn determining the risk of recurrence forcommon multifactorial disordcrs, empirical data areused, as no single niodcl explains the observed variables. But even empirical data from a large random
sample will not take into account the uniqueness ofeach family, its cnviro~mient,or the particular eventsof a given pregnancy that might affect the outcome.
Thus, only generalizations can be used for dealing
with questions of risk and rccurrcnce. The models
developed to describe multifaclorial inheritance arejust that, models. In no case have all of the specificbeen defined.
genes involved and their i~~tcractions
Thus it becomes very difficult to predict the effects ofa particular type of mutation (e.g. radiation-induced),much less the multiple er~viro~~r~iental
agcnts involved[F8,FlO].

35. In general, the risk oC recurrence for multifactorial disordcrs is directly related to he scvcrity ofthe disorder in the 11robi111dor index case. This is, ina sense, a dose-rcspo~rscphc~~omcaon,i.c. [he more
~ dgenes thi~tiire irlvolved i l l causing the defect a ~ themore environnicnhl factors that contribute, Ihc more
likely the defect is to occur with a severity proportional to both genetic and c~~viror~mental
contributio~ls.
Assuming that the potential gene pool of a couplercniains colisla~~la ~ tl~at~ d 111cyc o ~ ~ t i ~to~livc
u c in t l ~ csamc cnviro~~mcnt,
t l ~ crisk of a C O I I ~ C I I ~ I anomaly~IIrecurring will bc grcntcr if tlrc irrdcx casc cllild is
scvcrcly affcctcd t1ra11 if il is niildly iiffccl~d [Fa,FlO].
~factors arc
36. Bccausc in niost cascs I I ~ : I I Iu~rk~rown
involved in rccurrcncc, figurcs for rccurrclicc risk
reprcscnt avcragc prob;~biliticsrather th:~nccrtai~~tics.
Thus, if only one child in a family is affcctcd, t l ~ eaveragc risk of rccurrcncc is 3 7 ~ 5 %for most multifactorially inhcritcd birth dcfccts. If two siblings arc
aiicctcd, thc avcragc risk of rccurrcnce is usually 5%
10%. Aftcr thrcc siblings arc affcctcd, the risk for a
fourth child is 1 0 5 2 5 % . As thc nunibcr of affectedchildren in a family i~lcrcascs towards a 25%
recurrence ratc, it bcconics csscntial to ask whclhcr
onc is perhaps dcaling will] a spccific autosomal
recessive trait having variable pcnctrancc rathcr thanwith a multifactorial cor~tinuum[FlO].

37. Mathematical n~odcls arc available for the
distribution and risk of recurrcnce of many multifactorial disordcrs [B8]. But it must be made clear thateach disordcr requires a scparatc modcl, and Lhcrc is
no guarantee that rccurrcncc risks will rcniain thesamc froni o ~ i cfanlily to anotlicr. T l ~ cbasic principles
of recurrence risk asscssmcrlt for a niultifactorial
disordcr are as follows:

liability bctwccn I?rst-dcgrcc rclalivcs call be cstin~atcdby thc aicthod of Bo~raitic-Pcllicct al. [BS]. Thisnrcthod ~ 7 k c sillto i ~ c c o u ~difl'crcnccs~tin f r c q u c ~ ~ c ybctwccr~ sexcs and diffcrc~~tscvcrity-age classcs.
Con~putcrprogr;lInrllcs arc avail;~hlcto dcrivc t l ~ criskesti~liatcs(c.g. [B8]).
39. It niust bc rccmphasizcd that i t is at present
difficult, if trot impossible, to discri~ninatcbctwccn aniultifactorial modcl and a ulrifactorial ~nodclwith
incon~plctcpcnctrancc for most multifactorial conditions in hurnans, sincc thc diffcrcnt modes of inhcritance lcad to similar frcqucncics in relatives [FlO].
Understanding of such disordcrs in humans is primarily empirical at this stage; cascs arc obscrved andrccordcd, but the uridcrlying niolecular niccbanisms
rcmain obscurc. Gradually, niorc arid more human
gcnctic disordcrs arc yielding to new nioleculartechniques.

D. NON-TMDITIONA12 INHERITANCE
40. Many newly recognizcd n~cchanisnisof genercgulatio~~and gcnctic disease in humans were notknown to classical geneticists and thus have riot been
considered in previous cstir~iatcsof eilbcr backgroundincidence or risk of hcritablc disordcrs following irradiation. Sincc thcy could, howcvcr, be significantly
affected by radiation, thcy arc discussed in this S c c t i o ~ ~in sonic dctail, wilh the caveat that any cstiriiatiori ofrisk must iricludc an uridcrstanding and considcrationof thcsc additional potential sources of hereditarydisease.

the corrclatio~rof phcnotypc bctwccn rclativcs is
proportional to tbc nunibcr of allclcs in common:
UIC correlation for offspring is halfway between
the risk for parcnts arid that for the general
population;
if a disordcr is morc frcqucnt in one scx, therecurrence risk depends on the sex of subsequent offspring;if the population frequency is p, the risk among
41. Mosaicism rcfers to the presence of both normal
first degree rclativcs is the squarc root of pcells and cclls carrying a nuta at ion within a singlc(whcn heritability is high);
individual. Somatic niosaicisrri results froni a gene
the rccuncrice risk is highcr when more than one
nlutation or c h r o ~ n o s o ~ ~anomalyialarising in a somatic
member of the family is affcctcd;
cell. Sincc tlic nunibcr of cclls in thc hunian bodythe more scvcrc a ~nalforniation,the highcr lbe(approxi~natcly 10") cxcccds thc magnitude of therecurrcnce risk;
mutation ratc for alniost all gcnctic disordcrs thus far
the risk to rclatives drops off rapidly withrecognized, it sccnis likcly lt~atduring the course ofincreasing rcnioleness of rclation;embryonic, fetal and postnatal life, virtuallyentiremonozygous twins arc scvcral timcs more likcly
repefloirc of known mutations might occur within all
to bc concordant than dizygous twills, but connormal human b c i ~ ~ g11-131.
scordance is ncvcr complc~c(it is usually ICSS
than 40%) (S341;
abnorconsanguinity incrcascs Lhc risk of polygcnic a ~ ~ d 4 2 Mosaicisn~tr~ayrcsult frcln~rlrro~noson~alsofmalitics ( r ~ ~ i s s i ror~ gcxlrir c l ~ r o ~ ~ i o s o ~orn cpartsniultifactorial conditio~~s.
chromosomes), l'ro~nsingle gcnc mutations or fromchanges in gcl~c control, sucl~ as X-inactivation,
38. To estiniatc rccurrcncc risks with the multigenoniic imprinting or loss of impri~~ling(scc bclow).
factorial modcl, two picccs of ir~fonnation are reIt may also result fro111 u~~iparcntaldisomy (seequired: h e frequency of Ojc c o ~ ~ d i t i oint ~the populabclow), gcric amplification (sec bclow) or from thc
tion and the empirical Gcqucncy in first-degreeincorporation of extrachromoso~nalDNA.
relatives of affcctcd individuals. The correlation ill

UNSCMR 1993 REPORT

736

43. The expected eflects of somatic mosaicism
would depend on a number of factors, including (a)the type of mutation (deletion, point mutation etc.), @)the type of gene in which the mutation occurs(housekeeping, structural, regulatory etc.), (c) the l o c ~ ~ s(or loci) at which the mutation occurs, (d) the domain
involved (intron, exon, regulatory region), (c) whether
the mutation has led to heterozygosity or homozygosity of the mutant or wild-type allele, ( f ) the specificcell type(s) involved and the tissues and organs
affected, (g) the stage of development in which themutational event occurs, and @) the fate of theparticular cell lineage in which it arose (migration,
mingling, selection etc.). Very different effects would
be expected if the mutation occurred in a growing anddeveloping organism rather than in an end-stage
differentiated cell.
(a)

Chromosomal mosaicism

44. With the advent of chorionic villus sampling in
prenatal diagnosis, some interesting and unexpected
types of chromosomal mosaicism have been reported,
such as confined placental mosaic aneuploidy infetuses who have intrauterine growth retardation anda normal karyotype [Kl]. In some cases, when thefetus is aneuploid, the presence of a normal cell linein the placenta may even explain why a small minorityof fetuses afflicted with lethal chromosome anomalies
are able to survive to term. This has also been shownin fetuses with altered chromosomes 18 and 13 thatsurvive to term [K2].
45. It seems quite possible that there are genetic
reasons why mosaicism is tolerated in someindividuals and in some tissues. The mechanisms
involved are unknown at this time but could be
affected by radiation, making an individual moretolerant to mosaicism and thereby more likely todevelop abnormal tissues.

(b)

Gem-line mosaicisnl

46. There have been a number of reports suggestingtbat mosaic mutations of the germ line niay be present
in phenotypically normal individuals. Families with
Duchenne muscular dystrophy [H3], pseudoachondroplasia [H5], Apert syndrome [A3], osteogenesis
imperfecta type I1 [Bll], tuberous sclerosis [H5] andmany other disorders [H3] whose transmission isnormally either dominant or X-linked have beenreported in which parents are phenotypically normal
by all known tests but more than one of their children
are affected by the disorder.

Germ-line mosaicisni is a mechanism of mutation that may produce transgenerational effects, as thegerm cells of the carrier parent are formed in embryo47.

genesis during the grandniotl~er'spregnancy. Alternatively, if ii parent carried mosnicism for a n~utationlhat
involved a niullifactorial trail, it could be passed
througl~!he children and not manifest with visible
pltenotypc uatil the grar~dcl~ildren's
generation or laterPI.
48. With regard to recurrence risk, the data available
on single-gene "new" mutations from the disorders so
far cllaracterized on a biochemical or DNA level
suggest that many (at least 5%) of what appear to be
new mutations may actually represent a substantial
parental germ-line mosaicism [H3]. One implication of
U~isis that there may be a real risk for the recurrenceof a new dominant niutation in subsequent offspring inwhat had previously been thought to represent a riskfree situation.
49. Depending on the particular tissue and mutation,
sonic chron~osonialanomalies and single-gene mutations niay be lethal to the cells, others may betolerated if they do not have a severe effect on thattissue, while still other mutations may actually have aselective advantage, as in the case of malignancies
F5]. For example, observations on patients withmosaicism for trisomy 8 and tetrasomy 12p support
this concept, since mosaicism for these aneuploidies
appears to be much better tolerated in fibroblasts thatin lymphocytes [P2].

50. Normal cells may occasionally arise in dominantlethal disorders via back-mutation, gene conversion,
mitotic crossover, suppressor mutation or double mitotic nondisjunction. They then outgrow the mutant
cells, iliterspcrsing Ihemselves throughout the bodyand allowing survival of what would otherwise be alethal condition. Such may be the explanation for theoccasional survival of males with X-linked incontinentia p i p e n t i [HlO] and Melllick Needle syndrome [D6].

51. Mosaicism is a pervasive phenomenon that almost
certainly affects all multicellular organisms. When
expressed in sornatic cells, it can be an important causeof neoplasia and possibly other aspects of tbc aging
process [H3]. Somatic mosaicism can also be an
important and sometimes dramatic cause of phenotypicvariation in the expression of genetic traits[m].

52. It should be kept in mind that if a mutation
occurs in a DNA repair function, then somatic
mutations, and therefore mosaicism, will occur far
more frequently (as seen in DNA repair disorders suchas Fanconi's anaemia etc. wl~ichpredispose to cancer).
Thus, a radiation-induced lr~utationwould have a very
different effect in fiiniilies with a DNA repair defectthan in other people. Likewise. a radiation-induced
mutation in a DNA repair gene would affect manyother genes as well.

ANNEX G: HEREDITARY EFFECrS OF RADIATION

53. In the past, only in the case of cl~ron~osonialabnoniialitics has it h e n possible to confinii the existof nios;iicism, but the dcvelopence and sigr~ificar~cc
mcnt and application of molecular genetic tecl~niquesshould provide several appro;ichcs for idelltilying andanalyzing a wider range of mos;lic states ill hu~nans.

54. Genomic imprinting is a newly recognized
genetic phenomenon in humans. It appears to be a
regulatory mechanism by which certain genes aredifferentially expressed, and thus convey different
phenotypic effects, depending on whether they are
inherited from the mother or the father. An "imprinted" gene is inactivated. Thus, a paternallyimprinted gene would be expressed in a child only
when it has been inherited from the mother; thepaternal copy would be inactivated [H4].
55. A mechanism such as imprinting might further
complicate efforts to cstimate hereditary risk fromradiation, as paternal vs niatcrnal irradiation could
have different influences on the phenotypes of F1 offspring, even if damage to the genetic material was
identical [V6]. I11 addition, imprinting effects may
remain hidden for several generations. This is due tothe fact that a mutation in an imprinted gene may
remain silent (i.e. inactivated) through many generations before it is actually expressed in offspring.
56. As with the DNA repair genes discussed above,a mutation in a gene that regulates the imprinting
process could have pleiotropic effects at multiple geneloci, causing them to be improperly expressed or improperly silenced. Imprinting appears particularly toaffect early embryonic development and growth and toplay a role in cancer. In other words, if a particulargene inherited from one parent is damaged, it may
result in overgrowth or tun~ourdevelopment, while
loss of the same gene from the other parent may haveno effect
57. Another line of evidence to support the existenceof parent-of-origin differences in gene expression has
developed from the study of hunian chromosome
deletion syndromes. There are indications that theparental origin of the chromosome that carries thedeletion or translocation may be associated with ormodify the clinical nianifcst;itio~~sof a number ofobserved syridrorr~es[H6].
58. Two striking examples are h e Pradcr-Willi andAngelman syndromes. Both are associated with deletions of the same region of the proximal long arm ofchromosome 15. The clinical features of the two syndromes are remarkably different. On a cytogenetic

737

level, i t has been deternlincd that in Pradcr-Willi
patients with visible chro~nosornaldeletions, the deletion is always of tllc paternally derived 1 5 q l l - 1 3
region, whereas in Angclnia~~patie~llswith visible~ always of the niatemallydeletions, the d e l c t i o ~ isderived 15q11-13 region [H6]. The deletions in thetwo syndromes tlii~s;ipparcndy involve the criticalregion(s) of chrornosonic 15 but result in different
phenotypes, depending on the pare~~tal
origin of thechromosome.
59. These observations strongly suggest that thisregion of chrorriosome 15 is imprinted. Presumably
there is a gene or group of genes in this region that isexpressed only from the maternal chromosome,resulting in Angelrnan syndrome when deleted, while
a second gene or group of genes in this region isexpressed only from the paternal chromosonle, resulting in Prader-Willi when deleted. A deletion or translocation in this region of chromosonle 15 will havequite different effects in different generations,depending on the parent of origin [H6].
60. The concept of checks and balances between theparental contributions is further supported by recent
studies on endogenous mouse genes. It has been foundthat in mice, only the paternally inherited gene forinsulin-like growth factor 11 (Igf-2) is expressed [ D l ]and only the maternally derived gene for the Igf-11
receptor (Igf-21) is expressed [B6].
61. A second group of chromosomal deletions whose
phenotypic effect5 are now recognized to have a nonrandom pattern of parental origin are those involved inoncogenesis [H2]. Familial cancer syndromes usually
behave as dominantly inherited traits. Loss of thewild-type allele in individual cells is thought to resultin loss of a suppressor gene function, which in turnallows oncogenic transformation and the developmentof tumours. It has recently been recognized that in alarge number of sporadic Wilms' tumours there is lossof all or part of chromosome 11. Now that DNA
markers allow identification of parental origin, it has
been determined that those deletions or losses of chromosome 11 almost always involve the chromosome ofmaternal origin [S9]. The Philadelphia chromosometranslocation associated with leukaemia and otherhaemopoietic neoplasms has recently been shown todemonstrate parcnt-of-origin effects, with chromosome 9 always being paternal in origin and chromosonic 22 always rnaternal [H16].
(rb) gene also sug62. Work on the retinohlasto~~iagests that there nre tissue-specific. parent-of-origin
differences in the expression of niatcrnally and patcrnaily derived genes [H2]. For instance, new mutations
resulting in retinoblastoma are almost always paternal
in origin, whereas sporadic sarcomas or rhabdomyo-

UNSCMH 1993 REPOIIT

738

sarcolnas with deletioris of Uie rb gene alaiost always
involve loss from the maternally derived chromosome

13.
63. Imprinting probably involves modifications oflllc nuclear DNA in sn~nirticcells in ordcr to produce
Uiese parent-of-origin diffcre~~cesin the phenotype.
Thus the same nucleotide sequence niay confer different phenotypic effects in different generations,depending upon whether it has been inherited from amale or from a female. I t is not yet clear at which
stage in development gcnomic imprinting occurs.
64. It should be noted that if the imprinting proccss
or part of it occurs during meiosis, this niay be
another mechanism for which mutation would havesuch transgenerational cfiects. These effects would
begin with the radiation exposure of the grandmother,because the formation of an oocyte, which when
fertilized will eventually become a new individual,
occurs during the in irfero life of the mother (i.e.
during the niother's own embryonic development within the grandmother). The effects of radiation thus
might not become apparent for two or more gcnerations following irradiation. Imprintable genes would be
expected to be transmitted in a Mendelian manner, but
their expression would be determined by the sex of theparent transmitting the gene, by way of this epigenetic
fonn of regulation. Thus, studies of irradiation in
fcrnalcs may produce results that are markedly different from those in males, depending on how much of
the human genome is imprinted.
65. Now that niolccular markers are available, theparental origin of various chroniosomes and chromosome segments can easily bc traced, and phenotypes
dependent upon this phenomenon are being recognizedin many areas of biology and medicine. Many humandisorders are now being identified as imprinted [H6].
Disorders whose transmission and inheritance havebeen poorly understood and described as variably
penetrant, mullifactorial or variably expressed should
now be examined for parent-of-origin differences andpossible imprinting effects.
66. Imprinting has obvious implications forunderstanding the hereditary cffech of radiation, sinceparent-of-origin effects would be expected and might
be masked in animal experirncnts, where parenls of
only one sex are irradiated. Also, the effects ofnuta at ions involving imprinted genes niay bc masked
for several generations.

3.

Unipirrnntul disomy

67. Uniparental disoniy occurs when, in a cell witha normal number of chroniosomes, both members ofa c h r o ~ ~ i o s opair~ ~ have~ c beeti i~~hcriled
from a si~igle
parent. Nonni~lly,one c h r o r ~ ~ o s o ~ofn eeach pair ismaternal in origin and the ollicr paternal. Experinicrits
using tm~~slocation
chromosonics in n ~ i c ehave shown
tliat at 1c;rsl seven segments of the rllouse gcnonie
producc 111:lrkcd phcnc>typic differences in growth,bch;~viour; ~ n dsurvival WIICII uliiparcntal disomy ispresent; ill otlicr scgrucnts, IIO diffcrcnce is observed[C5, S14j. 111 other words, for some rcgiolis of the
genome, a totally diffcrcrit phenotype is observed
depending on wliether both segments come froni theniothcr or both from the father. Because of extensive
honiologics bctwecn the mousc and hunian genonies,
it is reaso~i;rblcto cxpcct that the imprinted regions ofhuman chromoson~eswill follow a similar distribution.

68. Not all cases of the Pradcr-Willi and Angelman
syndro~nescarry visible cytogcnetic deletions. Using
molecular ni;rrkcrs, many of these cases can be shownto have rcsultcd from uniparcrital disomy [H6, HIS,
M2]. I n these i~~srallcesof Angclman syndronle, bothnien~bersof'tllc chromoso~nc15 pair have been inherited fro111 the father; in the cases of Prader Willi
syndrome with uniparental disomy, both have been
inherited froni the mother. Uniparental disomy occurs
far rtiore frequently than originally assumed [Eg]. It
may occur through the loss of a chromosome, in thecase of a trisomy, or through the duplication orcomplcmcnt;rtion of the rernaitiirig chromosonie, in thecase of a rnonosoniy (i.e. salvage, since nionosomy islethal) [H6]. Irradiation is known to lead tochromosome deletion and loss arid could therefore be
expected to uncover imprinting and uniparental disomy
effects [C17].
69. An interesting corollary of uniparental disoniy isthat it can, for the following rcason, result in a childbeing affected by an autoson~al recessive disorderwhen only one parent is a carricr for that disorder: if
a parent carries a chromosome that contains an abnormal recessive gene and a son or daughter inherits two
identical copies of this chromosonie (uniparental isodisorny), thc so11or daughter will now carry two copiesof U I ~;rb~ior~ii;llgene, i.c. will bc homozygous for the
mutaot gcae. Thus, he or she will express an autosomal recessive disorder that has been inherited fromonly o ~ i ecarrier parent. Precisely this situation has
beer1 shown to have occurrcd in two cases of cystic
fibrosis [ V l l ] arid a collagen defect [S41]. The
percentage of cases where an autosonial recessive disorder is unipirrcntiil rather than familial is unknown at
this ti~nc,but clcarly thc qucstion descrvcs furthcr
study.
70. The effects of uniparcntal disomy forchromosome 7 (intrauterine growth retardation) arid
chromosome 15 (Angelman and Pradcr-Wilii syndromes) have been described iibove. In addition, a rare,

E P E C I S OF RADIATION

dominanlly inherited human overgrowth syndronle, theWiedeman-Beckwith syndrome, has heen s l ~ o w rto~
occur in cases with paternal disonly for chrolnosome
11 [W2]. When familial, this syndrorne has been
known for some tinle to be nearly always transmitted
through the mother. As discussed above, this again
suggests a role for imprinting in growth disorders, aswell as in human cancer, since patien& with thiscondition frequently develop several types of cancer.

71. Other chromosomes for which uniparental
disomy has been documented are chromosome 4 [C3],chromosome 6 [W6], chro~nosome14 [T2], chromosome 16 [K17]and chromoson~e21 [Wl]. More information will be needed before it can be known if thesechron~osomescontain imprinted regions. Whether uniparental disomy occurs for other chromosomes remains to be determined. The implications for the hereditary effects of radiation are that damage to a chronlosome may lead to loss of part or all of a chromosome, with complementation by the remaining chromosome producing uniparental disomy with increased
frequency.

4.

Cytoplasniie inheritance

7 2 Cytoplasmic components are present in the ova
but not the sperm. Thus, the elements of the cytoplasm, such as the mitochondria (and possibly the
mitotic spindles, endoplasmic reticulum etc.), areinitially derived from the mother by cytoplasmic inheritance. One specific type of cytoplasmic inheritanceis mitochondrial inheritance. The nucleus is not the
only cellular organelle to carry genetic information.
The mitochondria contain a separate genome, comprised of over 16,000 base pairs. This genome iscircular in structure; both strands of mitochondrial
DNA (mtDNA) are transcribed and translated, in contrast to the single coding strand of the nuclear chromosomes, which is usually transcribed in only one
direction [M3].

73. Each mitochondrion contains many copies ofthese circular genomes, and thus each cell (with its
many mitochondria) contains ttiousands of copies ofthe mitochondria1 genome, as opposed to only two
copies of each nuclear chromosome. In addition, themitochondria contain esse~ltial enzyme and otherprotein molecules that are transcribed in the nucleus,translated in the cytoplasm and then transported to themitochondria.
74. The mitochondrial genome is transcribed as asingle messenger RNA ( I ~ R N A that)is cleaved into
various genetic units. The products of the mitochoadrial genes participate in a number of functions, themost important being the energy-generating synthesis739

of ATP via oxidative phosphorylation. (Of Ihe 69
separate polypeptides known to be required foroxidative phosphorylation, 13 are coded for by the
mitocl~o~~drial
DNA [T3].)

75. Asdiscussed above, the inheritance of
mitochondrial DNA follows a strictly maternal line oftransmission. Thus a clue to this cytoplasmic mode ofinheritance is that a trait is passed only throughfemales, but all (or almost all) offspring are affectedor are at risk of being affected (as opposed to Xlinked recessive traits, where only males are aKectedor X-linked dominant traits, where only 50% of theoffspring are affected because there are two
X-chromosomes).

76. Disorders such as Lcber optic atrophy, myoclonic epilepsy with r a g e d red fibres and progressive
external ophthaln~oplegia(alone or as part of KearnsSayre syndrome) have been shown to be due to mutations in n~itochondrialDNA. Mitochondria1 disorders
tend to have a more severe effect on tissues that
require high levels of metabolic energy, such asmuscle aitd brain. The mothers of these cases, and thecases themselves, are often heteroplasmic, meaningthat each of their cells carries some normal and someabnormal mitochondria and thus may appear unaffected. Each offspring (and each tissue of offspring) may
thus also carry varying proportions of abnormal mitochondria.
77. While the n~itochondriahave few genes compared to the approximately 100,000 genes in the
nuclear genome, rnitochondrial genes have a significantly higher rate of spontaneous mutation than
nuclear genes [R2]. Thus the daughter of a heteroplasmic mother may develop additional mutations in
her mitochondrial genome, and so on down the generations, increasing the likelihood that a child will carrya sufficient number of abnormal mitochondria to
become symptomatic and to manifest one of the mitochondrial disorders. It is also likely that the effects ofradiation may be more severe for the mitochondria1
genome than for the nuclear DNA, but because ofheteroplasmy, the effect may not become apparent for
one or more generations (W12J.

5. Anticipation and nllelic expansion
78. Genetic anticipation is a phenomenon in which
the phenotype of a disorder becomes progressively
more severe in each subsequent generation inheriting
the gene. Although until recently this phenomenon was
thought not to occur, a number of studies have iden~ified molecular mechanisms by which it can, and does,
occur [Ha].

740

UNSCEAR 1993 wI'OKT

79. One niechanism that can cause a~~ticipationisfound in the autosomal dominant disordcr niyotoriic
muscular dystrophy (MMD). This disorder is highlyvariable in its expression and is oncn more severe in
the children than in the niildly affectcd parents. Part of
the gene for MMD has recently been isolated andappears to be highly unstable, beconling larger insubsequent generations [H8]. The niutation responsible
for fragile-X syndrome, the most common single-gene
mental retardation syndrome in humans, has also been
identified: it shows a similar instability in bothphenotype and gene size in subsequent generations
inheriting the mutation [Y3].
80. This type of increase in the size of a particulargene is called allelic expansion and can occur either
somatically or during meiosis. In traditional Mendelian
genetics, it has always been assunlcd that genes are
essentially stable units of genetic infomiation, and thateither a normal allele or a mutant allele carried by theparent will be passed to offspring unchanged. When
allelic expansion occurs, however, it has been foundthat patients with the most severe symptoms have thegreatest enlargement of the defective gene, owing toan increase in the number of units of a repetitive
sequence in the DNA. The number of repetitive
sequence units continues to increase from generation
to generation and is associated with a worsening ofsymptoms, i.e. anticipation [F9].
81. A siniilar increase in gene size has also beenfound in the fragile-X syndrome, with expansion of a
CGG repeat [Y3],
Huntington disease, with expansionof a CAG repeat [H17], and in X-linked spinal bulbar
atrophy, also with an expansion of a (CAG)n repeat
which occurs in the coding region of the gene for the
androgen receptor [Ll]. When amplification occurs at
the fragile-X site, it is always when the mutation ispassed by a female to her children [Y3]; when the
Huntington expansion is passed from a male, it can
expand rapidly. Thus it seems likely that parent-oforigin eflects could play a role in the transniission andexpression of the fragile-X phenotype [L2]. Olher disorders are likely to involve allclic expansion. or asimilar mechanism. For example, unstable sequences
called microsatellite DNA have been shown to be
associated with familial colorectal cancer IA8, P4.

n1.
82 The iniplications of allelic expansion forradiation are as follows: if certain rcgions of the
genome nre more sensitive than others to allelic expansion, radiation damage niight cause this sorl ofmutation to increase at a different rate than classicalmutations. There may also be differences between theeffects of irradiation of the mother and those of irradiation of the father. Many familial cancers have been
demonstrated to have widespread alterations in shortrepeat DNA scqucnccs, which niay predispose to oncogeriic e v e ~ ~IA8,
t s W l l ] . In addition, the spontaneous n l u t ; ~ t i orate~ ~ in tllcse regions may be ~~nusuallyhigh; thus csti~ii;~tesof background incidence of mutations niay be difl'crcnt llla~ifor other genetic disorders.

83. In gene amplification, an entire gene or portionsof it are duplicated. This may lead to an increased
expression of gene product, either normal or defective,
or to disruption and loss of gene function. Amplification can produce a selective advantage, as in cancer
cells that are able to survive chemotherapy by virtueof having i~mplifiedthe multi-drug resistance (MDR)
gene to gain nlnlly active copies [S30]. Alternatively,
it can produce a disease phenotype, such as LcschNyhan syndrome, in which an internal amplification
has bee11 fou~ld to disrupt a normal allele for thc
enzyme hypoxn~ithine-phosphoribosyl transferase(HPRT), causing loss of gene function and thus
leading to the disease [S32].
Aniiplification differs from allelic expansion inthat the latter tern1 refers to an increase in the lengthof a fragment consisting of multiple copies of a short
repetitive sequelice (for example, [CGGIn) [H8]. Suchshort rcpctitive sequences are found throughout the
genome, usually flanking structural genes. They arealso referred to as a variable length polymorphisms, as
the sequences alter the restriction fragment size for aparticular gene. Amplification refers to an increase in
the number of copies of a longer nucleotide sequence
unique to a particular gene. The molecular mechanisms for each may or may not be similar and may or
may not be affected by radiation w 3 ) .
84.

7.

l'runspasubie elements

85. Tri~nsposablcclements are sequences of DNA
that intcgrstc unstably into the genonic at random (orpossibly by homologous rccombinatiori at specificsequences). These i~lcludcthe Alu and LINE elenien~s[U,
S331. This integration, if it occurs in the middle
of a structural gene or regulatory sequence, can disrupt
gene fu~lctionand produce a mutant phenotype. Transposable elements have long been observed in a number of lowcr orgnnisnis, including yeast, maize anddrosophila (L31. They were suspected in the huriian
il
had not been provcn.
genomc but u ~ ~ t rccently
However, Do~t~broski
el al. [DS] have identified
a LINE-I tra11sl)osable elenient disrupting thc factor
VIII gcnc in two I~aeniophiliapatients. This elenient
also contains a full-lc11g1hcopy of a gene for reverse
transcriptase, making i t possible, after the elcmc~itis86.

copied to RNA, for the transpos;ible scqucr~ccto becopied back into DNA, which can then integrate backinto the genoltle at a new site, often disrupting functional genes [M6].It is thought that this typc ofelement may have originated with retroviral ir~tcgration
into thc human genome. Sinlilar LINE-1 tra~lsposablc
elements have caused mutations in the neurofibron~atosis typc 1 gene [WlO] and the cholinesterase gene[M12].
It seems likely that radiation should be able tomobilize or destabilize such elements, which lead toincreased mutation or gene disruption in later generations.

E. SUMMARY

88. Pheootypic diversity within a single heritable
disorder call be caused by (a) environmental factors,(b) allclic series (an individual with two alleles o f asingle gene with two different mutations), (c) genetic
c o m p o u ~ ~ d(mutationssin two different genes), (d)~ ~ ~ u t a t i oinr i sdiffcrcnt domain coding regions of thesame gene and (c) interaction with the products ofother genes in that individual. Similar phenotypes canbe caused by the action of any one of several different
genes. This is called heterogeneity of disease.
Multifiictorial traits and disorders are those where asingle condition (i.e. not complex disordcrs or multiple
anomalies) is thought to have a genetic component but
whose inheritance cannot be explained by single-gene
inheritance.

87. Genetic diseases occur because of alterations(mutations) lo the structure or regulation of genes in
the cell. Traditionally, genetic disorders have beenclassified into one of three categories: single-gene
disorders, cl~romosomalaberrations and multifactorial
disordcrs. Single-gene traits and disordcrs arc either
recessive (i.e. a normal copy of Lhe gene will preventthe disease phenotype) or do~ninant(i.e. one abnormal
copy of the gene will result in expression of thedisease phenotype). A single gene can have multiple
and apparently unrelated effects on niany different
tissues; this is called pleiotropism.

89. Modes of non-traditional inheritance include
cytoplasmic inheritance, mosaicism, imprinting anduniparental disomy. These mechanisms may prove to
be increasingly important as causal factors in diseases
whose inheritance does not follow standard Mendelianpattenls of inheritance, and they may well be affectedby radiation. Gc~lcticdisorders, particularly severe
ones h i l t interfere with reproduction, may be the resultof new, as opposed to inherited, mutations. Humangene mapping using family pedigrees and restriction
fragment length polymorphisms is being used to
localize and isolate genes related to specific disorders.

11. MONITORING THE BACKGROUND INCIDENCEO F GENETIC DISEASE
90. The term genetic disease has been used to refer
to any disorder (anato~niciil or metabolic) that issevere enough to interfere with a normal life and thathas a genetic component, regardless of the age at
which it occurs. The term congenital means present atbirth. Congenital anomaly is a more precise term thanbirth defect and refers to structural anomalies present
at birth. There are three nii~jor types of structuralanomaly that may be apparent at birth [S35]:
(a)
@)

(c)

malformation, a defective or abnormal formationof a structure from its origin;deforniation, an improper formation of astructure because of some physical i~npcdirnent(e.g. too litlle amniotic fluid causes restricted
fetal movement, which in turn results in joint
contractures);disruption, an injury to a formed structure causedby an extrinsic or intrinsic force (e.g. amniotic
bands disrupting circulation to a limb or digit).

A. REGISTRIES OF
CONGENITAL ANOhIAI.IES
1. Types end incidenceof congenital anomalies
91. Congenital anomalies are not usually theconsequence of Mendelian or chromosomal disorders,which they greatly outnumber. They have the advantage of being easy to document, as birth, surgery anddeath involve recorded events; moreover, in earlier
days, when their nature was less clear, they wereconsidered useful genetic markers. It is now possible
to assess fairly accurately whelher a congenital
anomaly represents a significant problem and whetbcr
treatment is available. The anomalies can be classified
as major (e.g. hydrocephalus, achondroplasia, amelia)
or minor (c.g. skin tags. pigmented nevi, supernumerary nipples, mini~nalpolydactyly).

732

UNSCMR 1993 REPORT

9 2 Access to niulliple rcgistries allows the development of fairly accurate backgrour~drates for congenital anomalies. Some registries reflect concentrationsof specific elhnic groups or high rates of consanguinity. Different registries have different illcidences ofat~omalies, reflecting regional, ethnic and temporalvariations. However, taken :ill together, they allow
establishing fairly accurate background incidence of
anomalies. Anomalies that are subvarious congc~~ital
ject to environmental influcr~ces,such as neural tube
defects, can be identified as varying with social classand region.
93. There is a consistent finding in all populations
that 2%-3% of the scrious congenital anomalies thatwill alter the length of life or ability to function
normally without nicdical intervention are ascertainedin neworns and that another 2%-3% of serious congenital anomalies are ascertained by 5 years of age[B2]. An additional 5%-13% of minor anomalies arc
found in all populations [B2, Nll]. Efficacious treatment is available for at least one half of the defects,
allowing an affected individual to become functional,
independent and a contributing member of society.
However. the remaining one half of congenital
anomalies presently leave the affected individual withconsiderable disability in spite of therapy.
94. A study by B;lird et al. [B3], conducted since
publication of the UNSCEAR 1988 Report [Ul], useda database of niorc than 1 million consecutive live
births, followed from birth rough' the age of 25
years, obtained from the British Columbia Health
Surveillance Registry through 1983. A hierarchicalapproach ensured that individuals were not counted
more than once. Although the authors generally
followed the approach of Trinible and Doughty [T6],they chose to proceed from single-gene disorders(autosomal dominant, autosomal rccessive, X-linked)
to chromosome disorders and then to niultifactorial
disorders. Congenital anomalies were considered last.
Their analysis was restricted to those relatively
common conditions that are generally accepted ashaving a major genetic component The aetiologicalcategory "genetic unknown" was used when it wasevident that the condition had a genetic basis but theinheritance pattern was not known.
95. It is recognized that this approach yields minimal
estimates of irlcidencc rates, since cases with relatively
mild manifestations [nay not be diagnosed or may notcome to the attention of the ascertainment sources. In
addition, the count of multifiictorial cases was assumed
to he falsely low, bccause of an inherent bias in the
counting process that could be present whenever acase had more than one diagnosis. Only those caseswith a single diagnosis were counted as multifactorial.
This means that the chance occurrence of a second
non-multifactorial diagnosis or a second, unrelated

multifactori:ll dingnosis in tllc same i~~dividual
wouldcausc that case to be oniittcd from the niultifactorialcategory, occurring in the same individual. Baird ct al.
discussed an adjustcd value for this ratc that would
correct this problcai in the n~ctllodology.
96. T l ~ cstudy found that l~cforethey reached the ageof 25 years, more than 53 of 1,000 live-born
individuals can be expected lo llave diseases with animportant genetic coniponcnt (see Table 1). The breakdown was as follows: 3.6 per 1,000 for single-gene
disorders, col~sistirlgof autosonial dominant (1.4 per
1,000), autoso~nal rcccssivc (1.7 per 1,000) and
X-linked recessive disordcrs (0.5 per 1,000); 1.8 per
1,000 for chrol~iosonialanomalies and 46 per 1,000
for multifactorial disorders, including those present atbirth and those whose onset was before the age of 25
years. If all co~lgenitalanonlalies are considered aspart of thc gcnctic load, thc total rises to 79 per 1,000
live-born individuals.
97. It was found that if all cases of congenital
anomaly (non-genetic as well as genetic) were considered, irlcludil~gthose to which no genetic aetiology
was attributed, the combined rate of all congenital
anomalies was approximately twice that for genetic
anomalies alo~re(LC. 52,808 per 1 million live births,
or 5.3%). If irlguirlal hernia was added, approximately
6.1% of the live-bon~ in this population had acongenital anomaly (recent Hungarian data found 7.2%[B2]). Howcver, inguinal hernias are easily corrected
and arc not considcred a serious congenital anonialy.
The study by Nelson ct al. [ N l l ] in Massachusetts
found the same level of incidence and genetic
distribution as the study by Baird et al. [B2, B3].
98. The point was made that in urero diagnosis ofgenetic abriorrnality has becorrle increasingly common
in recent years, and that tl~iscould bias the estimatesof genetic defect in live-born children, since a positive
test may lead to tcrminatior~ of the pregnancy. The
potential inipact was calculated from the records of the
British Columbia Provilicial Prenatal Diagnosis Programme [B2], and it was concluded that the impact ofpregnancy termi~~ationon the rates in the study was
extremely small, with an incidence of approximately
0.027% in the mid-1980s.
99. Baird ct al. notcd that the present records of the
British Colun~biaHealth Survcillance Rcgistry lnake
it possible 10 identify tl~osecases within the co~~genital
anomaly group t11;it were judged to have a gel~ctic
actiology. This is a col~sidcr;ibleadvance, bccause
many earlier studies did riot attempt to quantify the
relative iniporta~ice of the genetic versus the
non-genetic categories wiU~inche broader "congenital
anomaliesn grouping. The other advantagc of thisstudy is that it provides follow-up data to age 25 years
for at least a portion of the study population; thefollow-up data rcvcal that many co~~gcnitala~~onialies
arc not ascertained during tlle first few nionths of life.

2.

Scope of n~onilorinji

100. There arc two approitcl~esto ~nooitoringcongenital anomalies: epidemiological, i.c. the detection ofoutbreaks or clusters of predefined conditions bystatistical methods, and tentological, which stresses
the importance of clinical details in tlic scarch forunusual events, either rare malforrnations or unusual
combinations of malformations, that may indicate theintroduction of a new tcratogcn [W8].
101. In attempting to calculate the genetic conscqucr~cesof any agent, be i t a drug, e clic~nicalor
radiation, it is essential to begin with an accurate
estimate of the background incidence ratc for a given
genetic disease or congenital anomaly. Previous reports on the genetic effects of radiation [ C l , C2, U1,
U2, U3, U4] raised the issue of background incidence.
These reports relied heavily on data that arc now
almost 20 years old. and that were derived primarily
from two sources [C13,C141. A 11u111bcrof dcvelopmcnts in recent years should make i t possible toin~provethe accuracy of background estimates and toaddress the question of which genetic disorders andcongenital malformations are most i~~fonnative
andworthy of inclusion in the study. There are now
numerous registries of birth defects worldwide, eachwith unique features and each with advantages anddisadvantages; these should all be taken into accountwhen attempting to assess background incidence forhuman populations in general. Likewise, the accuracyof specific diagnosis has been greatl y inlproved andrefined in reccnt years, providing more precise
definitions of significant dcfccts.
102. There are bound to be regional, ethnic andtemporal variations in the incidence of congenital malfonnations. For example, a study comparing congenital
malformations in Aboriginal and non-Aboriginal newborns using the Western Australia Congenital Malformations Registry found that although the birthprevalence of ail malformations was 3.5% for bothgroups, nervous system and cardiovascular defects andcleft lip and palate were significantly more prevalent
in Aborigines and pyloric stenosis and urogenital
defects were significantly less prevalent [B9]. In
ariothcr example, Sikhs in British Colu~nbia were
found to have a significantly higher ratc of neural tube
defects than the general population, which is lzrgely ofnorthern European extraction [H4].Many alarms
generated by the International Clearinghouse for BirthDefects Monitoring Systems [W8] have, upon further
investigation, yielded negative results.

103. Storliastic tc~nporalvariations in incidcncc may
result in apparent clusters of a particular co~~gcnitalanonialy or group of anomalies. While it is important
to investigate such increases, it is probably riot iippropriate to rcly on registries containing substa~rti;~ldcviat i o ~ ~fro111s(he majority of regislrics is cstirnatingbackgrolrlld i ~ l c i d c ~ ~ cofc scongenital tnalformations.
However, if tllc concern is for a specific rcgion, c.g.
the Ukr;~iac,where the reactor accident occurred, theincidcncc of genetic disease for that partibackgrou~~dcular population should be used, if it is available, toprovide the baseline from which to calculate any increase in risk. Japan has regional monitoring programmes [KlS]. It should be kept in mind, however,that any effect fro111a specific mutagen is likely to be
obscured by the effccLs of social disruption, as someof the commoner ~nalformations, c.g. neural tube
defects [N4],arc known to be greatly influc~iccdby
diet and sti~ndardof living [S16].
104. One other point to bear in mind is that, within acategory of congenital malformation, there arc often
multiple subcategories wilh divergent causes and incidences, i.e. heterogeneity. For example, neural tube
defects are generally classified as a single calegory,
yet the cause of this defect can be single-gene niutation, chromosomal anomaly, teratogenic exposure,nutritional deficiency or ethnic predisposition. In somefarnilics rccurrcnccs are frequent, while in others thecascs arc sporadic; some cases can be caused by physical disruption such as amniotic bands. High lesions(anencephaly and thoracic spina bifida) differ fromlow lesions (lunibosacral spina bifida), and cases tbat
occur in the presellce of other birth defects differ fromthose that occur alone [H4]. Each of these componentsof the ovcrall category "neural tube defect" could be
differently affected by exposure to various mutagenic
agents, and yet hey are usually grouped together.
105. Registries may also differ in other aspects. I t isimportant to consider the following sources of variation
when comparing them: (a) exclusion or ir~clusion ofstillbirtl~s,(b) effects of prenatal diagnosis (ratcs ofincidcncc may bc lower owing to increased prenatal
diagnosis and sclcctivc abortion for particular anomalies), (c) number of people contained in the registry (toosmall a sample may not yield statistically significant
results), (d) ascertainment, as mentioned below arid (c)duplication of reporting (multiple congenital anonialies
may be reported singly as well as collectively).
106. According to Cordcro [C9), ifregistrics arc to be
useful in S U ~ V C ~ ~ ~ ~ Iepiden~iological
IICC,
and otllcr kindsof studies, they must contain four critical clcn~cntsof
informalion: who, what, when and where. Once these
elenicnts arc specified, i.e. number of cascs (what),
divided by the population (who), in a specified area
(where) and for a specific time period (when),incidence rates can be calculated [C9].

744

UNSCFAR 1993 REPORT107. The collection of data can be either active or
passive. With an active system, the registry has trained
staff who follow a particular methodology to ascertain
infants with birth defects and to collect data. With apassive system, the registry relies on reports fromsources such as physicians, hospitals or vital records
departments [C9].
108. Active systcnls have several strengths: (a) they
have fairly complete ascertainment, @) they can obtaindata in a timely fashion, (c) they can include quality
control measures for the data gathering process, (d)they define the type of data to be collected and (e)they usually allow for the follow-up of cases. A disadvantage of active systems is their cost, which tends
to limit the sample size of the population to bestudied. This, in turn, limits the registry's ability tocollect sufficient data for some types of
epidemiological studies [Cg].

109. Passive systems have one major strength, lowcost, which allows them to cover larger populations
with a minimum of resources. Their disadvantages
include a lack of diagnostic specificity, little control
over time delays in obtaining data and measurable
underreporting of data. In some passive systems, thequality of the data cannot be evaluated. Moreover, few
systems provide a means to track cases, making
follow-up studies impossible.
110. The process of finding persons with the disease
under study is referred to as ascertainment. It is
important to bear in mind that methods of ascertainment are bound to differ between registries, often
resulting in the under- or overreporting of a particularbirth defect in a particular population. For example,
physicians in Hungary were paid for every instance ofcongenital hip dysplasia they reported; this malformation subsequently comprised an artificially high percentage of overall birth defects in Hungary. It is also
important to bear in mind that many birth defects do
not become apparent until after the first few months oflife. Thus, a registry that reports only birth prevalence
may be underreporting.

111. An alternative approach for complete ascertainmerit is to review medical records. In the UnitedStates, every baby born in a hospital has a medical
record that generally indicates if birth defects arepresent. The strengths of this approach include nearlycomplete ascertainment, the ability to achieve population-based ascertainment and a lower cost than ifevery baby were examined independently,i.e. not by its
own physician. Its disadvantages include labour intensiveness, inefficiency and cost [Cg].
112. Some programmes, e.g. those in Sweden, Australia and Atlanta, Georgia in the United States, do not
routinely record possible exposures during pregnancy.

Such programmes are usually found in areas where it
is relatively easy to go back lo nlcdical records and tocontact the parents of the damaged infant if exposure
infor~natiorr is thought to be of interest. In otherprograrnlnes, sucll as llie Central-East France
progranlmc and the large hospital-based programme in
Italy, information 011 possible exposures during
pregnancy is collcctcd at the same time the malformed
infant is reported, but no similar data are collected fornormal infants. A third group of programmes, including one in Mexico, Spain arid South America, has ongoing case-control data collection, in which information on possible exposure is obtained for each malfonned infant and for a control (normal) infant born at
the same hospital. Each teclinique has its advantages
and disadvantages, but in areas of the world where it
may not be possible to follow up an observation byinterview at some time after birth, collecting exposure
data on a case-control basis seems the most effective
technique [Cg].

B. CONSIDERATIONSON BACKGROUND LNCIDENCE
1. Sentinel Mendelian diseases

113. The concept that certain phenotypes were so
obvious that they could not be missed led to the ideathat their frequencies could be easily monitored forsudden increases. It is not difficult to establish thebackground incidence of autosomal-dominant disorders, especially those that have a strong selective
disadvantage, the prevalence of which is maintained in
the population by an equilibrium between constantmutation pressure and selection (see [VS,VlO]).
114. Theoretically, in situations where illegi~imacy
can be ruled out and g e ~ ~ e l iheterogeneityccan berecognized, this method should lead to reliable
estimates of the spontaneous mutation rate and its
increase because of a mutagenic agent. Such mutations
are called sentinel mutations, because they are
expected to indicate mutation rate increases caused bya new agent in the environment. Czeizel [C13, C14]
enumerated 15 sentinel anomalies that are thought tobe caused by dominant new mutations and that can be
diagnosed at birth or shortly thereafter. However, themolecular aetiologies of these disorders, which are
beginning to be defined, appear to be very heterogeneous. Thus, i t may not be valid to apply one
estimate to the group as a whole, as each subgroup
might be expected to have a different rate of mutation.
Moreover, as suggested by Strobel el al. [S39], suchsentinel mutations are too rare to easily provide
realistic mutation rate increases. Furthermore,
col~tirluousscreening of very large populations would
be required.

ANNEX G: HEREDITARY EFFECTS OF W I A T I O N

115. From Ure cxpcricnce accumulated so far, it isI
will everextremely unlikely that I I U I I I ~ Ipopulations
be exposed to nlutagcnic agents that will cause anobservable statistically sig~~ifica~rt
i~rcrcascin tlris typeof disorder above tllc naturiil rate of mutation (seeparagraph 213). Tllc Hungaria~rdata wcrc used to test
whether the Chernobyl accident in April 1986 had led
to any increase of new rriutations [C15]. No evidence
was found that it had. This is, however, not surprising,
because according to Strobcl [S39], for a mutation
incidence of 3 per 10,000, it would have been necessary to screen of a population of almost 2 nlillion
newborns distributed in two samples of equal size
(before and after irradiation) to recognize an increaseof 30% in 95% of instances. A smaller increase would
require an even greater sample size. Down's syndrome
alone (7.02 per 10,000) is nlorc common than all thesentinel mutations taken together. But even for it, apopulation of approximately 1 nill lion newborns would
be necessary to recognize a statistically significant
change, and Hungary has only about 150,000 live births
per year [C14, C15] (see paragraphs 213 and 338).
116. Many autosomal-dominant disorders, especiallymany rarer ones, are thought to be maintained in the
population by an cquilibriu~r~
between mutation andselection. This may be true for such disorders as
neurofibromatosis, Marfan syrrdrorrle and autosomaldominant types of osteoge~icsisimperfects. Other disorders, such as bilateral reti~~oblastonlaor haemophilia,
were probably maintained by such an equilibrium inthe past, but successful theri~pyis very likely to havc
upset this equilibrium in recent decades. Assuming
constant mutation rates, the incidence of such disorders is bound to increase until a new equilibrium has
been reached unless there are counteracting circumstances, for example, artificial selection.
117. It is, however, very unlikely that the morecommon disorders are maintaincd by an equilibrium
between mutation and selection. The mechanisms thathave caused the present-day incidence of many dominant diseases arc unknown. It follows h a t dominant
and X-linked diseases cannot be subdivided easily into
those whose incidence is maintained by an equilibrium
between mutation and negative selection and those in
whicb a selective advantage under certain living conditions has been the decisive factor. More complicatedsituations may occur and the equilibrium conditions
may change over time, depending on living conditions.
118. There are, of course, a great number of fairlyrare and, irr ri~ostcases, very rare disorders that may
indeed be maintained by an cquilibriurn between mutation and selection, but for an overall estimate of themutational component, it is not the number of these
disorders but their combined incidence Itla1 is important in calculating risk. Since they are mostly lethal atan early age, fertility is 0 and there is a 100%745

mutationel component, i.c. all cascs arc caused by a
new mutation, ratlrcr than inherited from tile parents.
These disorders comprise only about 1/30 of lhe entire
group of dorni~rarlta ~ ~X-linkedddisordcrs. In otherdisordcrs, tlrc rn~tiitior~al
cornpollclrt is snlallcr, and forsome of tllc most common ones, it nray not exist atall. In sorlic earlier UNSCEAR Rcports, the Committee estinratcd Ihc ~nutationalcomponent of the entire
group as 15%. In Uris, the nicdical geneticists niay
have been persuasive, having in mind Ure more severe
and debilitating forms of genetic disease (this would
be understandable, since these diseases are the ones
most frequently seen in daily practice), but in thegeneral case, the estimate is high.
119. To place an increase in morbidity due toautosomal dominant and X-linked radiation-induced
mutations in proper perspective, it should b eremenlbcrcd that the natural spontaneous mutation
rate, the causes of which are unknown, is not a
constant. The best known factor that influences themutation rate is paternal age. For some autosomaldominant anonlalies, such as achondroplasia, acrocephalosyrrdactyly (Apert syndrome), Marfan syndrome, rnyositis ossificans and probably many others,
the mutation rate at a paternal age of 40-45 is four to
six times higher than at a paternal age of 20-25 [V8].
Modell and Kulieve [MlO] havc calculated how mucha given shift in the distribution of paternal agcs in a
population would change mutation rates. Thcy compared the mutation rates expected with the present
paternal age distributions with those expected if all
fathers were less than 30 ycars old at the time of birthof their child. Thcy found that even a relatively small
shift in the distribution of paternal ages, and especiallya reduction in the fraction of older fathers, could
influence the mutation rate for such paternal-agedependent niutations appreciably.
120. Not all known do~iiinantmutations show such astrong increase with patenral age (for details see[V8]). In recent decades, and with a decrease in the
average number of children per marriage, a decreasein the fraction of older fathers has been observed inmany populations, and a corresponding reduction in
the number of such patemal-age-dependent new
mutants has to be assumed in h e developed countries.
Hence, evcn a relatively small shift in paternal age
distribution, especially an increase or a reduction ofolder fatlrcrs, could irrflucnce the mulation rate forsuch patcmal-age-dependent mulalions appreciably,probably nluch more than could a change in exposure
to mutagenic agents, e.g. ri~diation.

2.

Autosomnl recessive diseuses

121. Searle and Edwards IS161 stressed Urat thedegree of inbreeding influences only the immediacy of746

UNSCEAR 19B W.POIC1'

the cffccls and that in t l ~ cabscncc of a strong hctcrozygotc disadvantage it will afl'cct only slightly thc totalnun~bcrof casualties. That is, in a population with ahigh rate of inbrccdiag (LC. consanguinity), damage
due to honiozygosity of n~utationsbeconlcs visible
sooecr. The ai~thorsassu~ncdfor their calculi~tior~sarate of 1% first-cousin malings.
122. Estimates of thc n~anifcstationof homozygotcs infuture generations depend critically on consanguinity
rates. In industrialized countries, the ratc of lintcousin malings has droppcd to one or a fcw per
thousand in recent dccadcs. Sincc this reduction iscauscd on the one band by grcatcr mobility and on theotl~cr hand by smaller nurl~bcrs of children (and,hence, a reduction in thc number of available cousins),
the decrease will probably continuc and also occur inthe populations of countries only now becorningindustrialized. Howcvcr, cven if consanguinity can bc
ncglectcd in the future, it is open to q u e s t i o ~wl~cthcr~
effects distributcd to thousands of gcncrations should
bc considcrcd at all in genetic risk cstimatcs. It may
be rliost reasonable to assurnc that civilization willdevelop in about the samc direction as it has in rcccnt
centuries and that gcnc Ihcrapy and/or prcnatal
diagnosis at the zygotc lcvcl will eventually becomeroutine, especially for autosomal rccessivc diseases
that involve mostly simple enzyme defects.

123. In humans, few data on phenotypic deviations inheterozygotcs of autosomal-recessive discascs arc
availablc p 5 ] , and chose that are relatcd primarily tocnzymc studics. As a rule, hcterozygotes have about
half the activity of normal homozygotcs for the
product of the genc affcclcd by the mutation, which inmany cases is an cnzymc. This rcduccd activity is,however, in most cascs sufficient for normal function.

radiiitio~r sl~ould be vicwcd, since any attempt todcrivc a n csti~natcof incrcascd risk will depend on
population slruclurc.

125. n ~ c r cis gcncral agrccnlcnt that cstimatcs ofchro~noso~nel
discase ir~cidcnceat birth disregard thegreat ~najorityof (~~umericaland unbalanced, structural) c l ~ r o ~ ~ ~ o saberrations
o~nal
in human gem] cells andearly zygotcs. Most embryos and fetuses with chromodie sornc time during embryonicsomal abcrr;~tiol~slifc. TI scclns vcry unlikcly that niore th>n 1% of allconceptions wit11 rccognizablc, chromosomally aberrant phc~~otypcssurvive to birth [VlO]. This is arcasor~ablcbut cautious cstimatc, i.c. the true fractionof survivors might well bc lowcr. The number ofzygotcs dying ie the first days after fertilization,
bcforc in~plantation,cannot be cstiniatcd, but it may
be appreciable. I n studics of cl~ronioson~esof hu~nansperm, t l ~ cfr;~ction of thosc sl~owingchro~nosonicaberrations is high [B12, K13, K14, K15, K16, M4,
M5, S421. It is, of course, unknown which of d ~ e s cchromosornally abnornial cclls are still able tofertilize; but the use of this rncthod o r spermkaryotyping for mutagenicity testing, especially in men
exposcd to high doses of niutagcnic agents, such asradiation, should bc encouraged. Studies of ova usedduring it1 virro fertilization suggest that human ova
also have a high fraction of spontaneous chromosomal
abcrra lions.

126. Calculations similar to thosc for paternal age
cffccts in autosomal-dominant and X-linked recessive
diseascs have been performed for nunicrical chromosomal abcrratio~~s,such as Down's syndrome, todctcrn~inc ~narcr~lalage cffccts. The baselinc is
especially variablc for triso~nics,because the spontancous mulalion ratc increases with the age of themother: thc risk for niothcrs abovc 40 is 10-20 times
higher than Illat for 20-ycar-old mothers [H12]. Thc
conclusion reached is thcrcforc the samc as forpatcrnal age and dominant mutations: even a small
shift in t l ~ cdistributiol~of matcr~~alages in a humanpopulation, ~ I I cspcciallyI ~ill the fraction of mothers
abovc 35, will alter thc i~~cidenceof trisomy
syndromes at birth ~nuch Inore than any probablc
increasc causcd by radiation.

124. Finally, it should not bc forgotten that thebackground incidcncc of rcccssivc mutations, andcspccially of rcccssivc discases, in human populations
is not constant from onc disease or population toanothcr. The human spccics is a patchwork of cxtrcrncly diffcrcnt frcqucncics of rccessivc gcncs. The
breaking up of isolatcd subpc)pulations a ~ ~havingdstrong intermixture bctwccn them will not lead to a
reduction of frequencies of all recessive gcnes in asimilar fashion, but i t will lead to an assimilatior~of
gcnc frcqucncics and cspccially to an appreciablercduction of frcquencics of gcnes that had bcconic
common in one or a fcw populations owing to r a ~ ~ d o m
drift. This, in turn, will lcad 10 a gcncral dccrcasc ofhomozygotes of autosorlial-recessive diseascs, as a127. Thc hackgrou~~di~~cidcnccsof congenitalconsequence of thc Hardy-Weinberg Law IV10). This
anornalics
and multifactorial diseases are not casy to
decrcasc will then be followcd by a very slow increase
establisli.
Thc
UNSCEAR 1986 Rcport [U2l gavc ain gene Gequcncics, bccausc fewer alleles will be
figurcof
60,000per m i l l i o ~for~ congcnilal anonialics
cliniinated in homozygotcs. This is the cornplcx backand
600,000
pcr
millionfor
otherniultifactorial disground against which ally possible effect of addi~ional

eases [U2]. BElR V [ C l ] esliriiated congenital abnormalities as 20,000-30,000 per million and subdivided"other disorders of complex aetiology" into three
categories: heart disease (600,000), cancer (300,000)
and selected others (300,000). These three figures add
up to more than 1 million, so they cannot be nieant tobe mutually exclusive. These discrepancies reflect thedifficulties in attempting to establish reliablebackground incidence mentioned earlier in this Annex.

128. The seemingly simple task of detcnninil~gtheincidence of congenital malformations at birthcontinues to pose problems: results from one study to
the next may show considerable differences, occasionally because of real differences between populations but much niore often because of differences inascertainment and classification. To predict a possible
increase attributable to a spccified radiation doseexperienced by the germ cells of parents, the mutational component of this incidence needs to be estimated. This involves estimating the frequency anddegree of genetic determination of sil~gleanomalies
and their modes of inheritance, which, as discussed
earlier, is very difficult to achieve and must be individualized. Furthermore, any possible selective disadvantages of such anomalies under present and earlier
living conditions (and, if possible, in populations ofindustrialized countries and of developing countries
with poor medical systems) should be known. This
information is needed to estimate which part of thegenetic component of a certain anomaly is lost in
every generation and which is therefore replaced by
new mutants. Even then, the estimate would be of theright order of magnitude only if there were a nequilibrium between mutation and selection [HI].

major histocoml)atibility systeni [T4], have failed topoint to any such association.
130. Sonle aspecls of mamlnalian e~tibryologyshouldbe n~cntioncdhere, since they are relevant to estimation of risk. Mammalian development is not entirely
pre-programmed; rather it is influenced to a significant
dcgree by the c~lvironmcntof chc developing embryo.
~ tphysical or chemical insult, tile en~bryo
In the e v c ~ ofhas an remarkable ability to catch up and correct thedamage. Many buffering effects are built into biologic
systenis, such h a t if one element is disrupted, others
may be able to compensate. In addition, the evolutionof gene duplication has led to a biological system ofbuffering, such that if one gene is knocked out, others
may be able to take over its function. There appear tobe thresholds during the course of development andaging, such that timing is extremely important. Mutations that upset the timing of evenls (heterochronicmutations) may produce unpredictable results [W7].
131. The incidence of all types of multifactorialdiseases given in the UNSCEAR 1986 Report [U2],660,000 per million, was based on the study ofCzeizel et al. in Hungary [C12], which consideredmorbidity up to the age of 70, and some individuals
had more than one disease. The Hungarian study comprised incidence estimates for 26 such multifactorialdiseases, which were classified according to ICD and
subdivided into three groups:
(a)
(b)

(c)
129. In the British Columbia registry. data, 4.6% of
individuals were noted to have a multifactorial conditionby age 25 years (Table 1) [B3]. Many congenital anomalies are consistent with the concept of multifactorial
inheritance. A few are caused by environmental factors
such as teratogenic drugs or, very rarely, irradiation
during pregnancy. For many congenital anonlalies, nocause can be identified; they are attributable to an
accunlulation of random processes during early embryonic development. However, data from radiation experiments in mice suggest that some may also be caused byirregularly manifesting dominant mutations. Their frequency may increase &er the irradiation of fathers. For
example, Ehling [El, E8] and Selby et al. [S21, S24,
S25, S28] have shown that the irradiation of mouse
spermatogonia may lead to occurrence of a wide arrayof skeletal malformations. The genetic variation that
influences some malformations may, indeed, have astrong mutational component. I t is remarkable, on theother hand, that studies on the association of
malformations with known genetic polymorphisms, suchas the ABO blood groups (see [V4, VlO]) and thcvery severe (schizophrenia, niultiple sclerosis,
epilepsy, myocardial infarction);moderately severe and/or episodic or seasonal(Graves' disease, diabetes, gout, affective
psychoses, duodenal ulceration, asthma):less severe (varicose veins, atopic dermatitisetc.).

With the exception of epilepsy, none of these diseases
causes death in h e age group 0-19 years, but they areamong the leading causes of death in advanced age.
Such incidence estimates are extremely useful formany purposes, but in the context of radiation risk
estimation, these prevalence estimates need to be carefully analysed to further identify subsets of conditioru
that may potentially respond to an increase in mulation
rate. Such analysis is necessary because of thefollowing:
(a)

(b)

a niajor parl of morbidity for many of these diseases is not the result of genetic predisposition
or inescapable environmental exposure or bothbut is the result of voluntary and avoidable behaviour. Type 2 diabetes is one example; coronary
heart disease and gout are other examples:in some of these diseases, the quality of life is
not impaired decisively. providing that theindividual finds a way of adapting his or her
lifestyle to the disease;

748

(c)

UNSCEAR 1993 REPOIIT

parameters such as the attitude of the society, thenumber of doctors and the quality of the healthcare system i~lfluencc whether a disease isdiagnosed and how much detriment it causes.

The relative importance of Ulcse factors may vary inand may vary over time withindifferent populatio~~s
the same population.

C. IbIOLECWR AND BIOCHEMICALSTUDIES OF SPONTANEOUS AND
RADIATION-INDUCED MUTATIONS
132. In addition to numerous types of DNA damage
leading to stable, heritable mutations (i.e. single basedeletions, base-pair modifications, strand breaks, basepair substitutions, nondisjunction etc., that lead tononsense, missense, Gameshift, chromosomal mutations etc.), the site of a particular mutation must also
be taken into account when attempting to analyse its
impact on genetic risk. The relevance of various sitesof mutation and their effect on cell function is of
crucial inlportance in understanding the effect ofmolecular damage on phenotypic abnormality. Thus,a knowledge of molecular damage can be important inpredicting genetic risk.

1. Location and effects of mutations
133. Structural mutations occur in the coding regionof a gene, altering the protein product of a single
gene. If the change occurs in a sequence that codes fora non-critical region of the protein, it will have little
or no effect and will be well tolerated (e.g. amino acidsubstitution into the non-active site of an enzyme). If,
however, it occurs in a critical region, it may impair
the function of the protein (e.g. the disruption of thedisulfide bridge in the oxygen-carrying haelnoglobin
molecule, which results in sickle-cell anaemia).
134. While the structure, and thus the function, of thegene product will not be affected by mutations in regulatory regions, the amount of gene product synthesized may be. Loss of promoter function will render agene inactive even though its structural integrity
remains intact, making the mutation difficult to
identify, the loss of other regulatory elements, such as
repressors, enhancers etc. may result in the loss of
responsiveness to environn~entalconditions (e.g. liver
cytochromes, which are upregulated in response to
toxic insult).
135. If the protein serves a single, limited func~ion,its
loss or overproduction may have only a minor effecton the survival of the organism (e.g. the loss of tyrosine hydroxylase, which resulls in albinism). However,if d ~ ge11ee
product is a regulatory protein i~lvolvedina pathway tl~atamplifies its effect, the effects of themutation inay be far-reaching or wen devastating tothe organisn~(c.g. protein kinasc proto-oncogenes, inwhich activating mukitions lead to cancer). Other
examples include niolecules like the chaperonins,which regulate the secondary structural folding ofmany different proteins; p53, which has a dominantnegative effect; the ubiquitins, which regulate the degradation of all messenger RNA molecules such thatthey are not transcribed into protein indefinitely;transport proteins, which carry the gene products totheir proper location in the cell; genes involved ingene inactivation, such as dosage compensation resulting from X-chroniosome inactivation in females [n].

136. Likewise, if the gene product is a structural
molecule essential to the development and maintenance of nornlal anatomy, such as connective tissue
constituents, the loss of this type of gene function will
have far-reaching effects for the organism as a whole(e.g. defective keratin which leads to epidermis
bullosa, and defective collagen, which leads to osteogenesis imperfects). Moreover, any gene involved in
the synthetic pathway of such structural elements will
have major effects (e.g. defective hydroxylase enzyme,
which leads to n~ucopolysaccharidosesand concomitant skeletal changes).
137. In molecules where there is a repeating structure,
any type of mutation in these repeating segments ofthe gene will destroy the structure of the whole
molecule. For example, collagen contains multiple
repetitive elements, such that any mutation in the third
amino acid of the repeat disrupts the entire secondary
structure of the glycoprotein.

138. Recent developments in cancer research suggestthat somatic mutations are responsible for most, if notall, leukaemias, lymphomas and solid tumours [C6,M11, S l l ] . This is generally due to the loss or mutation oS an oncogene suppressor gene function (as, forexample, retinoblastoma or Wilms' tumour) or to an"activating" mutation in an oncogene that renders it
immune to normal regulation (e.g. RAS in coloncancer). Tbere are also many hot spots for mutation
throughout the genome; since these regions show ahigher frequency of mutation than other regions of the
genome, they may be far more sensitive to mulagenic
agents [V3].
139. The failure of crossover during meiosis can leadto non-disjunction, resulting in the loss or gain oflarge regions of chromoso~nal material. Thus, thissingle event can adversely affect many genes (e.g.
triso~ny21 causes Down's syndrome, while most othertrisomies and monosomies are not compatible withlife.) Mutations that disrupt this genetically regulated
process will have major ramifications.

ANNEX G: I IElUtDITARY

140. Mutations in one region of a gene rnay ~)roduce
a phenotype that is completely different fro111 mulations in another region. This is partici~larlytrue forgencs coding for products with multiple domains, suchas connective tissue molecules (for example, dislocatedlens of the eye and rupture of the aorta are bothcaused by mutations in the fibrillin gene) [VlO].
141. It has also become apparent that alternative
splicing of messenger RNA n~olcculcsoccurs (e.g. themessenger RNA for several different hormones can beproduced from one gene); that there are "genes withingenes" (e-g. the neurofibromatosis locus); and lhat
some genes code for precursors that arc tl~ericleaved
enzylnatically to yield the active product (c.g. prothrombin to active thrombin, encephalon to endorphin). Thus, one gcne can, in effect, code for several
products.
142. It is now clear that damage to n~itochondria(including those in ova) must also be considered in
genetic risk estimates. In the past it was assunled thatdamage to DNA was the only concern, but changes toother components of the cell structure, such as mitochondria, may affect subsequent generations [W12].
(a)Nature and origin of spontaneous mutations
in human Mendelian disease

is tl~oughtto be due to the propensity of 5-methylcytosine to undergo sponlal~eousdeamination to form
thyniine [ClO]. I t can be anticipated that each gene
will have its own susceptibility pattern, and it is notknown wlieUicr these pattenis will be similar in huInans and in mice. 0U1er cndogcrious damage to DNA
is thought to come from replication errors and fromby chemical radicals [A9].
oxidative attack ~t~ediated14.5. Examples of non-random point mutations thathave been identified in human cancer biology studies
include the point mutations in codons 12,59 and 61 of
the RAS genes involved in myeloid leukacmia, lungcancer ctc. arid those in codons 110-307 of the P53
tumour suppressor gene in diverse types of cancers.
Such site preferences have long been known to occur
in visible chromosomal changes in neoplasias,
particularly leukaemias and lymphomas, and molecularstudies are now shedding light on these specificities.
146. There is good evidence that the breakpoints oflengtt~~iiutationsare also non-randomly distributed. Of
60 sniall (<20 bp) deletions at the 23 loci studied, 59
had direct repeats of 2-8 bp. For large deletions, sequence homologies and repetitive sequences such as
Alu located within or between genes appear to play
important roles. The mechanisms involved in thegeneration of deletions and duplications are listed inTable 2.

143. A large number of spontaricously arisingmutations that cause disease states in humans havebeen described. Only a few are known at the molecular level. As of 1990, molecular data were available
for some 76 Mendelian diseases in humans [S3]. For
33 of these, the predominant event is a point mutation(base-pair change), and for 39 it is a length mutation(mostly DNA deletions, but sometimes duplications orother gross changes). In the 4 remaining diseases, both
point mutations and length mutations occur. These
relative frequencies may be revised as more data
become available, but for now, it can be assumed thatpoint mutations and length mutations each account for
about half of the Mendelian diseases [S7].

147. Data from a number of well-analysed spontaneous gene deletions are consistent with mechanismsthat assume base mispairing between repeat sequences
and slippage during replication; hon~ologousunequal
recombination between evolutionarily related gencs;
homologous unequal recombination between repetitive
sequences such as N u ; and non-homologous recombination. There is circurt~stantialevidence supporting the
hypothesis that repetitive sequences may play animportant role in chromosome pairing [S3]; if true, thedeletions and duplications lhat have been found to be
associated with spontaneously arising mutations inmany discases may represent the inevitable byproducts of occasional mispairing.

144. In spontaneously occurring mutations, point
mutations (i.e. mutations in which a single base pair isaltered or deleted) do not appear to be distributed at
random throughout the genome. This is thought to berelated to the sequence organization of the gcne andits genomic context [S7]. CpG dinucleotide sequences,when present in a gene, provide hot spots for transition-type mutations (i.e. A to G or G to A and C to T
and T to C). Vertebrate DNA is highly methylatcd atthe cytosine residue, and about 90% of 5-methyl-cytosine occurs within CpG sequences. At the level of thegene, C to T transitions and the corresponding G to A
transitions in the complementary DNA strand occur at
a high frequency within these methylatcd regions; this148. Exaniples of deletio~~sarising as a result of
non-homologous recombination are provided by somealpha-U~alassemias[N12,01], some beta-thalassemias[As, H l l ] and some complex thalassemias [Jl]. In allthese deletions, the 5 ' breakpoints were mapped eithcr
in or close to Alu sequences. The interpretation is thatthese deletions presumably arose during DNA replication (when sequences widely separated in tbe linear
DNA ~~loleculemight be physically close to one another as a result of anchorage to the nuclear matrix
and chromatin loop formation) as a consequence of
non-honiologous intrachroniosomal breakage andreunion events [As, V2]. The models proposed differ
in some details.

UNSCWR 1993 REPORT

750149. Intragcnic partial deletiol~s(well over 300 are
now known) appear to be the nlost conlnlon defectleading to Duchel~neand Becker ~nusculardystrophies
ID2, F6, G5, K8]. Less common are intragenic duplications that appear to duplicate one or a few exons by
the tandem duplication of a portion of the gene,presumably by unequal crossing-over between repeat
elements [H13, K8]. Data have also been publishedsuggesting that duplications can arise as an il~trachromosomal event through unequal sister-chromatid
exchange [H14].
150. Thus, in spontaneously occurring mutations thcre
occur both point mutations (base-pair changes) andlength mutations, which include DNA deletions (small
and large), insertions, rearrangements and duplications.
The length mutations are occasionally microscopicallydetectable as chromoson~alaberrations. Several othermechanisms of mutation are involved in spor~taneously
occurring mutations in humans, including gene conversion and mutation due to h e insertion of mobile, ortransposable, genetic elements. (Transposable elen~ents
are also discussed in Section I.D.) The term geneconversion describes the local transfer of DNA
sequences from one gene to a related gene elsewherein the genome in an event that resembles a double
crossover [MI].Gene conversion events leading todisease phenotypes are now well documented inhumans. One example is congenital adrenal hyperplasia due to 21-hydroxylase deficiency [D7, H7,
U121. There are two 21-hydroxylase genes in humans,
one of which is a non-functional pseudogene; if any of
the inactivating sequences in the pseudogene are
introduced into the functional gene by gene conversion, there will.be a deficiency of the enzyme. Other
examples include spontaneous mutations at the HLA-A
and thymidine kinase (TK) loci in human somatic cells
in vuro, in which gene conversion has been shown toplay a significant role (see [SS]).

(b) Radintion-induced mutations in mnn~malinn
experimental systen~s151. Data from mouse mutation studies (with x- or
gamma- and neutron irradiation) have provided mostof the information on the genetic effects of radiation.
They have been reviewed from time to time [E4, F3,
F4, R8, R9, R10, S1, S3, S4, S5, S6, S7, S13, S19].
Points of interest include the following:
(a)

(b)
(c)

spermatogonia, post-meiotic male germ cells andmature and immature oocytes differ in their
sensitivity to the induction of mutations byradiation;
the yicld of mutations varies between gene loci;a majority of radiation-induced mutations arelethal in the homozygous condition (i.e. twocopies of the same mutant gene);

(d)

(e)

the rclalive frcqucr~cy of various molecular
ch:~ngcs see11 i n 111c ~nutiitionnl event differs
betwccr~ s1)oniancous mucation and radiationinduced mutation; andin mice, tile frequencies of radiation-induced
mutations differ.
recessive and domir~al~t152. Russell et al. [R3], in a detailed genetic andn~olccularcharacterization of large numbers of specific-locus mutations collected at the d, se and c loci,have shown that the simple phenotypic classificationof specific-locus mutations can effectively separate
mutations into Ihe followil~gthree categories: multilocus deletions, presunled intrageriic mutations andviable null mutations. Conlparisons between rnutations
induced in different germ-cell stages, spontaneous
niutations and rllutations induced by low-LET radiation, neutrons aud ethylnitrosourea (ENU) have shownthat there are marked qua1itative differences between
spontaneous and induced n~utationsand between mutations induced by low-LET radiation, neutrons or ENU
in dirfercnt germ-cell types. A total of 264 radiationinduced mutations and 45 spontaneous mutations wereclassified in this way. Most of radiation-induced
rnutations studied in the mouse and in mammalian in~ i t r osystems, however, are either presumed to be or
actually den~onstratedto be DNA deletions; however,
the relative proportions of point mutations versus
deletions vary with the locus and the test system understudy [S7]. In one study [R13], 31 mutations wereanaiysed by Southern blot analysis with a tyrosinase
cDNA clone and with other probes, which identified
13 radiation-induced and one spontaneous mutation to
be deletions or rearrangements ranging from 36 to
2,000 kb. The fact that such large viable deletions canbe recovered suggests that 1 or 2 Mb of DNA including and surrounding the c-locus harbour no genes
essential for viability or fertility.
153. There are also hot spots for radiation-induced
breaks, as observed in the chromosomes of blood
lynlphocytes in human radiotherapy patients. These hot
spots are in T bands, which are very rich in both GC
and Alu sequences, suggesting that at least someradiation-induced deletions may arise by mechanisn~ssimilar to those inferred for naturally occurring
deletions mediated to Alu sequences [R13]. (Tbands,
which are a subset o r R bands, represent only 15% of
all bands, but contain 65% of mapped genes and 42%of x-ray-induced breaks [S7]).
154. The findings in mouse studies are consistent withthe view that in mouse germ cells, most radiationi ~ ~ d u c emutationsdare DNA deletions. This has now
been shown to be the case by molecular rnelhods fora number of mutations [S4]. However, most work
done on the cffects of germ-cell irradiation have been
done in males; remale germ cells may have very

ANNEX G: IIEIEDITARY EFFECTS OF RADIKilON

different susceptibility to difcerc111 typcs of i ~ ~ d u c e dmutation at differci~tstagcs. Surprisingly largc dclclions can bc tolerated in viablc mice [CIX].

155. Data on the i ~ ~ d u c t i ooft ~niutations that lcad toobsenjable congc~~italstructural abnorni;~liticsin thc
progeny of irradiated mice suggest that thcsc abaormalilies are not very sci\sitive cnd-points. In addition,
it should be mentioned that different strains of mice
may have different sensitivities to radiation [N15,N161, although the work of Favor et al. [F17, F18]
suggcsts no strain differences when using radiationand cthylnitrosourea.
156. From available studies that have analyscd thc
molecular nature of mutations, the following conclusions nlay be drawn:(a)(b)

ionizing radiation induccs vcry few point
mutations;whcn ionizing radiation induces mutations inenzymatic proteins, the changcs lcad to altered
enzyme activity or lack of enzyme activity; themolecular changes may include a mixture of
events at thc DNA level, ranging from point
mutations to intragenic DNA deletions, niultilocus deletions, or rearrangements;
the limited data on radiation-induced mutations
at the haemoglobin loci in mice suggest thatradiation induces deletions, duplications andtranslocations, but not point mutations.

The fact that radiation-induced mutations are likely todiffer from spontaneous mutations in thc typc of mutation produced, the frequency and the sites affectedmusl also be considered, and indeed cxpectcd. Thc
above examples offer a convincing argunicnt that asimple, direct correlation between thc number ofmutations and the degree of n ~ u t a t i odamage~~would
bc exccedirlgly difficult, if not impossible, to demonstrate in either animal or human studics.

2. Protein studies
157. Quantitative and qualitative protein variations i n
the children of atomic bomb survivors were examined,
using a variety of methods. Prcsurned new nuta at ionswere verified by carefully cxcluding false paternity.
No increase in comparison with the controls wasobserved. The number of loci scrceried was 6.67 10'
in the exposed group (parents within 2 kni of thc
centre of the atomic bombings) and 4.67 10' in the
non-exposed group. Three ncw mutants wcrc idc~~tificd
in each group. The mutation rates per locus per
generation were cstirnatcd to be G 1 0 ' ~(95% CI:
2-15
exposed group) and 6.4(95% CI:
1-19 loe6: non-exposed group) IN7, N9j.

75 1158. For t l ~ c~ n o ~ ~ i t o rof
i i ~largegpopulatio~igroups,
a~iotllcr;~pproachhas bccu suggested that avoids thelogistir;~lly no st difficult part of protein studies,l ~ a ~ ~ l econhctinglyt l ~ cfa~nilics and collecting tlie
blood snml)lcs IV91. In most counrries, practically all
ncwbonis :ire scrccncd for i ~ ~ l ~ c r imetabolic
tcd
diseasessuch as pl~rr~ylkcto~~uria(PICU). A few drops of blood
are put on a special tcst card that is sent to a screening
ccntre. A rncthod has been developed by whichhacmoglobin (Hb) and othcr protcins can be extracted
from this card and studied by clcclrophorctic mcthods[A4]. In a pilot project in Japan. blood samples from40,003 newborns (for Hb variants) and 30,659 individuals (for other protein variants), were screened,
representing altogether 722,719 gene loci. In three
instances, the transmission tcst was negative but there
was no cvidcnce for non-paternity. These three individuals call be regarded as new mutants. From these
data, the followi~~gmutation rates were estimated:
5.2
per locus pcr generation, 2.0
per codon
and 6.0 loe9 per base. These data are in good agreement with other spontaneous mutation rates (seeIVlOl).
159. Givcn the number of offspring included in the
study by Neel el al. [N9] and the relatively low
gonadal cxposurc of parents in the exposed group, it
would be premature to use these data to speculate on
the biological mechanisms of radiation-induced mutations. But one likely conclusion can bc drawn:
medium- to low-dose irradiation in humans does not
induce an unexpcctcdly large number of rnutations
detectable at the protein level. As discussed later,
radiation does not cause significant visible genetic
darnage in humans in the next generation, and theresult for proteins just noted seems to decrease thelikelihood that radiation could enhance the long-term
genetic load ill the human population by producing
many rcccssive mutations. Mauy radiation-induced
rccessivc mutations in the mouse are deletions, asevide~~cedby studics with thc scvcn rccessivc test lociIm]. From widcsprcad experience in medical genetics
it would bc expcctcd that such dclctiom, if induccd inhuman gene loci coding for hiown enzyme proteins,
would reduce cnzymc activity by about one half. Such
cflects have not bccn observed at a highcr rate illchildrcr~of irradiated parents in Japan.
160. The mcthods for assessing protein variants inchild re^^ of parents exposed to the atomic 1,ombirrgs
tend to be very time-consumii~g and personnel-

intcnsivc. They rnigl~tbe applicable to the mo~~itoringof a limited population group that has becn cxposcd torclativcly high doses of radiation (or any othermutagenic agent), hut they are not suilcd Sor the longterm screening and monitoring of large populationgroups.

UNSCEAR 1993 REPORT

752

D. SUMMARY
161. The estimation of additional genctic risk isnieaningful only in relation to the spontaneous mutation rate. Thus, in attempting to calculate the genetic
consequences of any agent including radiation, it isessential to begin with an accurate estimate of the
background incidence rate for a given genctic diseaseor congenital anomaly.
162. There are now numerous registries of birthdefects worldwide, each with unique features and eachwith advantages and disadvantages; these should all betaken into account when attempting to assess the background incidence for human populations in general.
Access to multiple registries allows the devcloprnent
of fairly accurate background rates for congenital
anomalies. Registries have different incidences ofdifferent anomalies with regional, ethnic and temporalvariations in specific birth defects. However, when
they are taken all together, fairly accurate backgroundincidences for various congenital anomalies can now
be established. Anonialies that are subject toenvironmer~talinfluences, such as neural tube defects,
can be identified as varying with social class andregion.

unlikely Illat I~umenpopuli~tionswill ever be exposed
to ruulagcnic agellts that will cause an observable
incrcasc above the ~laturalrate of mutation.

166. Other factors, such as paternal age, may greatly
inflt~e~lcc
the rate of occurrence of cenain autosonial
do~llinantco~lgcnitalanomalies; thus a shift in paternal
age distribution within a populatio~~
may have agreater effect on incidence llian a change in exposure
to radiation or other mutagenic agents. Maternal age
may i~ifluenccthe rate of chromosomal anomalies suchas Down's syndronle in a similar fashion.
167. Both heterozygote advantage and heterozygote
disadvantage have been observed in autoso~nalrecessive diseases in humans [VlO]. Induced recessive
mutations may cause hann in four ways:
partnership with a defective allele already established in the population;
partnership with another recessive mutationinduced at tile same locus;
the fomlation of homozygous descendants of theinduced mutation; that is, identity by descent;heterozygous effects (i.e. a carrier of the gene
may have adverse effects).

Estimates of the nianifestation of homozygotes in
163. There is a consistent finding in all populations of
2%3% incidence of serious congenital anonialies thatwill alter the length of life or ability to function
normally without medical intervention that are ascertained in newborns. Another 2%-3% of serious congenital anomalies are ascertained by 5 years of age.
An additional 5%-13% of niinor anomalies are foundin all populations.

164. Dominant mutations, together with X-linked
mutations, are usually considered to provide the mostimportant contribution to an increase in genetic discasethat results from exposure to cnvironmcntal mutagens.
Contributions from autosomal recessive mutations
would have less impact initially and would 1101 be
expected to be evident for many generations.

165. There is general agreement on the backgroundincidence of autosomal dominant disorders. There iseven less difficulty in establishing a baseline forautosomal-dominant diseases that have a strong
selective disadvantage, the prevalence of which ismaintained in the population by an equilibrium
between constant mutation pressure and selection.
These sentinel mutations are expected to indicate
increases in the mutation rate caused by a new
mutagenic agent in the environment. However, sentinelmutations are too rare to provide a basis for estimating
realistic mutation rate increases. Continuous screeningof very large populations would be required, but fromrhc experience accumulated s o far, it is extremely

future generations depend critically on the assumptions
made about consanguinity rates.
168. The incidence of visible structural anomalies or
unbalanced translocations in chromosomal discase has
been based on population studies on newborns; they
do not include data from studies on spontaneous abortions. Most fetuses with numerical chromosomal anomalies (e.g. monosomy or trisomy) do not survive tobirth. Thus, any radiation-induced increase of nondisjunction and/or early chrornosome loss is likely tolead to an increase in the rate of spontaneous abortion
rather than to an increase in chromosomally abnormal
newbor~~s.
Thus, any increase in structural and numerical chrornosornal aberration among newborns attributable to additional radiation of the parents would very
probably be small and would depend on the age structure of the population.
169. I t is important to estimate the mutational
componcnt of the incidence of congenital malformations. This involves estimating tbe frequency anddegree of genetic determination of single anomalies
and their modes of inheritance, which is very difficult
to do, and indeed must be individualized. The complex
genctic basis of most malformations makes it almost
impossible to be sure of the effects of specificchcniical or physical agents such as radiation.

170. In addition to multiple types of DNA damage
leading to Iierikable mutations (i.e. single base dele-ANNFX G: IIEREDITARY EFFECE OF RADIATION

lions, base-pair modifications, strand breaks, base-pair
substitutions, nondisjunction etc., leading to nonsense,
niissense, frameshift, chrornosonial ltiutations etc.), thesite of a particular mutation must be taken into
account when attempting to analyse its impact on
genetic risk. Structural mutations occur in the coding
region of a gene, altering the protein product of asingle gene. Mutations in regulatory regions rnay
affect the amount of gene product expressed or thetime at which it is expressed. The type of gene inwhich a mutation occurs, e.g. a gene with limited
function or a gene coding for a rcgulatory factor, will
influence the extent of the mutation's harm to theorganism. Failure of crossover during meiosis can leadto nondisjunction and may have a serious detrimental
effect on the organism (chromosomal effects). Muta-

753

tions in one region of a gene may produce a phenotype that is completely different from that caused by
a mutation within another region. Mutations that upset
l l ~ etirning of events nlay produce unpredictable results(heterochronic effects).
171. I t h;~dbee11 assumed that DNA daniagc was the
only concern in radiation damage, but it now appears
that chaliges in other components of the cell structure,such as the mitochondria, may have effects that aretransmitted to subsequent generations. Mutations that
affect the non-traditional mechanisms of inheritance(e.g. the methylation that might be involved ingenomic imprinting) could affect numerous genes andhave consequences that might not become visible forseveral generations.

111. GENETIC RISK ESTIMATION
172. Radiation exposure of the germ cells of animals,
and therefore presumably also of humans, causes
mutations and chroniosomal aberrations that in turn
may lead to genetic defects or diseases in the offspringand in later generations. Studies of atomic bomb
survivors, industrial accidents and occupational andmedical exposures have allowed some rough estimates
to be made of genetic effects following human exposure to radiation. However, the paucity of direct
observations regarding the genetic effects of radiationin humans has led to considerable uncertainty in theestimates of overall genetic risk and of the relative
proportions of the various types of mutations that may
occur from radiation. Animal experiments, most ofthem in mice, have been undertaken in an attempt tofurther quantify these effects. Although mice or otheranimals and humans differ in many ways that are biologically important, it has been necessary to assume
similar responses in extrapolating the results of mouseand other animal studies to human populations.
173. In previous UNSCEAR Reports, the Comniittee
described the various methods used to make genetic
risk estimates and applied them to the available data.
The history of these and other attempts to estimate thegenetic risk of radiation has been described by Sankaranarayanan (S2, S3, S4, S5, S8]. Much has beenlearned about the limitations of these mctbods andabout the molecular nature of the mutations that must
be taken into account in estimating risk.
174. In the early 1970s, the following conclusions
were derived from studies of animals, predominantly
mice, and they were thought also to apply to hun~anbeings [S13, V61:

even at a relatively low dose, radiation leads toa sterile phase in males because it kills most of
the spermatogonia; the testicular tissue is later
repopulated by repeated division of a few especially resistant A spermatogonia;@) in the male mouse, a majority of visible
chromosomal aberrations that are present in theF, offspring are induced in the pre-sterile phase,
i.e. in postnieiotically irradiated male germ cells.
Thus, if a human male is irradiated, chromosomal aberrations are not likely in the next
generation unless conception occurs less thanabout 6-8 weeks after irradiation;(c) in the female mouse, chromosomal anonlalies
may be induced, most of which lead to the deathof the zygote at a very early stage of development (equivalent to early abortions in humans).
The same is true for chromosomal aberrations
that are induced in male germ cells and that arepresent in the zygote;(d) in the hours around fertilization there is increased susceptibility to the induction of aneuploidies, especially the loss of single chromosomes, e.g. the X-chromosome;(e) acute irradiation at relatively high dose leads toa considerable increase in recessive mutations inboth sexes;(0 a strong dose-rate effect has been observed inspermatogonia and in oocytcs: chronic irradiationinduces only about one third of the recessive
mutations that are induced by acute irradiation.
A dose-rate effect is also present for predisposition to dominant mutations:(g) many radiation-induced mutations, especiallythose induced in postspermatogonial cell stages,

(a)

75 4

(h)

(i)

UNSCFAR 1993 IlEPOHI'

have bccn idcntificd as dclctions. Many induccd
rccessivc mutatio~~swcrc found to bc lethal inthc hornozygous state;~ s clear-cut phc~rotypic
dominant ~ n u t a t i o ~withcffccls and full pcllctrarlcc arc induced relatively
rarcly; tlorninir~~tcfSccts within r~lultifactorial
gcnctic systca~s,c.g. n~ulationsaffecting thc skcleton, appcar to bc nlorc common. Howevcr, before extrapolating this rcsult to Ilumans, themuch casicr and more dctailcd asscssmcnt of
human anonialics should be considcrcd;
most translocations induccd in spermatogonia areunablc to pass through mciosis; they do not lead
to abortions or to malformcd offspring.

These conclusions have sincc bccn supplemcntcd on
the basis of data t r o r ~further~
studics in animals andhumans. The results of thcsc studies will bc discussed
in the following Scctio~ls.

A. IIUhlAN STUDIES
1. Genetic follow-up studies
on the survivors of the u t o n ~ i cbombings
175. While people who were exposed to radiation
havc becn shown to suffer dircct cffccts from that CXposurc, such as incrcascd cancer rates, the data on thesurvivors of the atomic bombings of Hiroshin~aandNagasaki indicatc that acutc irradiation at modcrate
doscs has a negligible advcrsc effect on the health of
the subsequent generation. Any minor effects that may
bc produced are so sniall that they are submerged in
the background noise of naturally occurring mutational
effects; they havc not bccn dcmonstratcd cven by therefined epiden~iological nlcthods Lhat have been
employed over the last five decades [N7,N8, N9].
176. The first steps towards organizing a genetic
follow-up study at Hiroshinia and Nagasaki wcrc takcn
in 1946, and the full prograllilllc was initiated in 1948.
Now, aftcr 45 years, that programme, co~\ducledby
the Radiation Effects Rcscarch Foundation (formerly
the Atomic Bomb Casualty Comn~ission),has become
the largest and longest-running exercise in gcnetic
cpidcmiology cvcr carried oul. In rcccnt years, thesignificance of the study has bccn greatly enhanced by
the revised radiation dosc cstirnates for survivors that
became available in 1986. All of thc accumulated data
havc now bccn analysed oa the basis of the rcviscd
dosc system.
177. The study has had two pl~ascs.In the early yean
(1947-1954), because of t l ~ cJiipancsc ration system, it
was possible to rcgistcr virtually all pregnant womenin 111ctwo cities at the end of the filth month of theirpregnancy and to arrange that once the child was born,-i t would he cxamincd by a Japnncse physician cspecially instructed i l l tllc diagnosis of congenital malfonnatiors. Thc first phasc of tllc study collcctcd thefollowing data O I I cacl~cl~ild:prcscncc of co~~gcnital
dcfcct, viability at birth, su~vivalthrough the first two
wccks oS lifc, birr11 weight ant1 scx. What n ~ a d cit unusual was that bccausc of tllc prc-birth registration, i t
was a prospcctivc study cn~bmcinga total ncwborn
population; studics of [his typc arc lcss pronc to bias
than rctrospcctivc studics, i n which at some fixcd date
one attcnipts to rccorlstruct I)regllancy outcomes overa prcccding pcriod. About o r ~ eLt~irdof the infants who
wcre cxaniincd undcr this study wcrc reexamined at
the age of 9 months. All childrcn born bcforc May
1946 wcre cxcludcd fro111 thc study of heritable gcnetic cffccts, sincc tiley niay have been conceived prior
to thc bombings and rcccivcd it1 rrfero cxposurcs [N3].

178. In the sccol~dphasc of thc study (1954 to thepresent), the births continucd to bc registered until
1985, but tllc c l i ~ ~ i cprogmmmc
al
was terminated. The
data now collcctcd arc on tlic survival of livcborn
infants, thc occurrcncc of cancer in the children and,for selected subscts of the rcgistcrcd children, physicaldevelopment, the prcscncc of chronlosome abnormalities and the occurrence of mutations that alter certain
characteristics of the proteins of blood scrurn and red
blood cells. The birth rcgistry was also extended~ t s bctwecn
backwards in time, to ir~clutlcall i r ~ f a ~boni
1 May 1946 (i.e. conceived aftcr the bon~bings)andDcccmbcr 1947 (aStcr thc laltcr datc ir1San1.s would
have been registered in the earlier programme). By
now, the cohort of all children born to survivors of theatomic bombings who reccivcd significant exposuresto radiation at the t i ~ n cof Ihc bombings and who still
live in Hiroshima and Nagasaki is thought to be complete. Significant exposure to radiation is defined ashaving becn within 2,000 mctcrs of the hypocentre ofci~hcrbomb; individuals in this catcgory are spokcn ofas proximally cxposcd, whilc those more dislant fromthe hypocentre are rcfcrrcd to as distally exposed. The
cohort of c h i l d r c ~bor11~
to a parent or parents who
wcre proximally cxposcd consisls of 31,150 individuals. An agc- and scx-~nitlchcd control group of
41,066 children was established by sclcction fro111themuch larger group of child re^^ in the two citics born toparents in the distally cxposcd calcgory. Thc nurnberof childrc~~
draw11 from U~csccohorts for the second
phase of tlic study varicd according lo thc indicator.
The average gonadal dosc (parests combined) for theproximally cxposcd catcgory was about 0.4 Sv, theactual dose varying sonicwl~atfrom s ~ u d yto study
dcpcriding 011which r h i l d r c ~wcre~ irlcludcd. The dosc
skcwcd to thc rig111,withcurve is quite asyn~~l~ctrical,
somc parcnts 11avi11grcccivcd combincd gonadal doscs
as high as 2.5 Sv [N7, N8, N9j. T l ~ crcsulls of thevarious end-poi~ils studicd arc summarized in theparagraptis below.

ANNEX G: IIEREDITARY EFFEClS OF RADIATION
179. Unloward pregnancy orrtcorne. Bccal~semajorcongenital defect, stillbirll~ and nconatal death arc
inter-related, thesc cnd-poi~ltshirve been treated as asinplc entity, tcnncd "untowilrd pregnancy outcon~e"and defined ils an o~~tconle
resulting in ii cliild wid1
major congenital dcfcct and/or a stillbirth and/or deathwithin thc first two weeks of life. Bctwcc~l1948 and
1954, data wcre collected on tllcsc outconles for a
total of 76,617 birhs in Hiroshima and Nagasaki; dataon 69,706 of them were sufficic~~tly
co~~iplete
in allrcspects to pcrmit inclusion io the analysis [H3, 021.
In later analysis the category of untoward pregnancy
outcome is separated into stillbirths and congenital
anomalies, giving eight end-points in all for analysis.
180. Pre-reprcxiucfive deaths among livebornchildren (exclusive oJ those resulting Jrom a malignanl fumour). The frequency of death of live-born

children has been analysed through 1985, when themean age of the members of the study groups. if still
surviving, would have bcen 26.2 years. In the twocohorts assembled for the sccond phase of the study,
thcrc are 67,202 individuals, among whom there hadbecn 2,584 deaths by 1985 [K3,N3, Y2].

181. Cancer incidence. Data on nlalignancies
occurring before age 20 have bcen collected on all
children born at Hiroshima and Nagasaki after May
1946, i.e. on all children co~~ccived
following theexposure of their parents and on a suitable set of control children in the two citics. There wcre 43 malignant tulnours in the 31,150 children of proximally
cxposed parents and 49 such turnouts in 41,066 children of distally exposed or unexposed parents. The
incidence of leukaemia (a malignancy of particularinterest because of the study of Gardncr et a]. [G2],see Section 111.A.2) is essentially the same in thechildren of parents one or both of whom were proximally exposed as it is in the children of parcnts who
were not significantly exposed [ Y11.
182 Frequency o/ certain types o j chro~nosomal
abnormaliries (balanced strucfural rearrangements oJ
chromosomes and abnormalities in sex chromosome
number). Among the 8.322 childrcn of the proximally
exposed who were studied, 19 showcd scx-chromosome abnormalities and 23, chromoson~alrearrangements; among the control group of 7,976 childrcn. 24
showed sex-chromosome ab~rormaliticsand 27, chromosomal rearrangements. Since there is no known
instance of a parcnt with a sex-chromosonlc abnormality transmitting it to a child, all children with
sex-chromosome ancuploidy were assu~iled lo result
from a mutation in h e gcnll cclls of thc preceding
generation. With respect to the chro~nosonlalrearrangements, only one child in each group was shown toresult from a mutation in the preceding generationlA6]. It must be noted, howcvcr, that the youngest
children in the chromosome study were 13 years of755

age at thc start of the study, and the study dius could
not bc cxpccted to yield adequate data on h e frequency of cytogcnctic arlon~alics associated withincreased mortality rates, such as unbalanced autosomiil structural rearra~~gcrrlclltsand autoso~naltrisomics. Most paticnts with these aberrations will
already llavc dicd by tllc agc of 13. A possible exccption is Down's syndronlc (i.e. lriso~ny21), but cvcn inthcse cascs, a high pcrceotage of thc paticnts may
have dicd during childhood and early youth, mostly
from rccurrcnt infections but also from congenital
n~alforniationsof the hcart and other organs, given theliving conditions prevalent in post-war Japan. The dataon sex chromosomal abnormalities and balanced autosomal structural rearrangements should, however, be
relatively unbiased.

183. Frequency o/ mutations aJJecfing certain
characteristics oJ proteins. A total of 667,404 tests
were performed for protein mutations that alter electrophoretic mobility or enzyme activity in the childrenof the proximally exposed parents, and 466,881 tests
were pcrfor~nedi n the childrcn of parents who did notreceive significant exposures. The appropriate family
studies on the 747 rare protein variants dctccted
revealed that there wcre four mutations in the childrenof the proximally cxposed and three in the control
children [N4].

184. Sex rafio. The most pertinent data on the effectof parcntal radiation on sex of the child derives fromthe situation where the mother was exposed and thefather unexposed. In this case, the sons would be
expected to manifest the deleterious effects of radiation-induced X-linked dorninant and X-linked recessive mutations as well as loss of the Y-chromosome,whereas the daughters would experience the effect of
only the dominant mutations. A radiation effect should
manifest itself as a relative decrease in male offspring,i.e. the sex ratio (male birthslfemalc births) should
decrease. In fact, at the time the data were last
analyscd, there was an insignificant increase in the sex
ratio, i.e. the data were counter-hypothesis [SIO].
185. Physicul developrrrent of child. The physicaldevelopment of a subsct of the childrcn of exposedand control parcnts was studied at birth and at age
8-10 months IN31 and during the school years [ F l l ,F12, F13, F14, FlS]. The data for the most part pertain to height, weight, and chest circumfcrcnce.

186. A variety of analyses of these seven data sets(and in later publications prcscnted as eight data sets)
has failed to reveal a statistically significant effect ofparental radiation on the indicator. T l ~ eaverage conlbincd gonadal dose of acute ionizing radiation received by lhe proximally exposed parents (0.4 Sv)
approxinlates that which in tbc past had been estimated to bc a gc~lcticdoubling dose for mice. The

756

U N S C M R 1993 REPORT

statistical power of these studies is sucli tllat theabsence of an effect of parental exposure to thebombings on any of the indicators suggests thathumans may not be as sensitive to the genetic effectsof radiation as had for some years been projected on
the basis of the murine doubling dose data.
187. The argument can bc, and was, carried a stepfurther. The investigators of the genetic effects of theatomic bombings accepted the proposition that somemutations did indeed result lrom the exposures to theatomic bombings and that this corpus of data shouldreflect the first-generation impact of these mutations
on the population. The proposition was bolstered by
the increase in chromosomal damage and somatic cell
mutations observed in lymphocytes and red blood cellsof the atomic bomb survivors [A7, Nl], as well as by
the increase in leukaemia and other malignant neoplasms in survivors [P3]. Accordingly, an effort has
been made to estimate from Uiese data the doublingdose of radiation for humans [N7, N9]. The doublingdose (relative) approach was felt to be imperative inthis setting, as it would confer a perspective on therelative risks of radiation that would be lacking withthe direct (absolute) approach. But although siniple inprinciple, the doubli~igdose concept has been difficult
to implement: for the estimate to have maximum
accuracy, it requires the widest possible spectrum ofgenetic end-points, each weighted as to its importancein the total phenotypic burden imposed on a population by spontaneous mutation.

188. The doubling dose approach requires estimating
the contribution of spontaneous mutation in the parental generation to each indicator anomaly or mutation.
For technical reasons, this is not feasible for the sex
ratio and the physical measurements. The approachalso requires deriving a simple linear regression ofeach indicator on dose. This was judged to be notjustified for balanced chromosomal rearrangements,
where only a single mutation was observed in thechildren of both exposed and of unexposed parents.
There remained five indicators from which to derive
the regressions. (Since the data for tbe three indicatorsthat were eliminated from Uie calculation did not suggest a radiation effect, their elimination should notbias the calculation.)189. To derive a doubling dose, the impact ofspontaneous mutation on the indicator in the parental
generation must be estimated for each indicator. The
value for sex-chromosome aneuploids and for lociencoding for proteins may be directly determined fromthe appropriate family studies. The value for the olher
three indicators has been estimated from the genetic
literature. These three estimates are relatively uncertain and should improve with time. The backgroundincidence for these indicators and the parental
mutational component in the indicator, expressed inabsolute ler~nsand as a per ccnt, are given in Table 4[NS). The range given for three of the indicatorsreflects uncertainly as to t l ~ eexact magnitude of thernutatio~ialconiponcnt.
190. Tile data can be used for two different types ofalculations. In Table 4, the doubling dose of radiationin relation to the contribution of spontaneous mutation
to tlie i ~ l d i a t o rhas been calculated lor lower confidence liniits of 99%, 95% and 90%. In principle, such
estimates nlay be conlbincd if it is assumed that thetrue d o u b l i ~ ~doseg is the same for all the phenomena
under study. Such an assumption is not-warranted inthis situation, the radiation literature suggesting thatthe doubli~lgdose lor the genetic phenomena resulting
in untoward pregnancy outcomes, F1(first generation)
niortality and F1 cancer may be lower than the doubling dose for sex chromosome ancuploids and thenucleotide substitutions, which were Ihe predominant
end-points of the protein studies. The minimal
doubling dose at he 95% probability level for the first
three indicators colnbined was estimated to be between
0.63 and 1.04 Sv; for the last two, it was estimated tobe 2.71 Sv.
191. Since these five end-points are essentially independent of one another, the most probable doublingdose for the totality of phenomena measured by these
end-points can be obtained by summing these fiveregressions, summing the estimated contribution of
spontaneous niutation to the various indicators anddividing the latter by the former [Ng].
192. The resulting estimate was between 1.7 and
2.2 Sv, with the range again reflecting some of theuncertainty in estimating the contribution of theparental mutation to the end-point The investigators
considered this estimate conservative, for two reasons:(a) as noted, certain indicators for which there is noevidence for a radiation effect could not, for technicalreasons, be included in the estimate, and @) the dataon socio-econornic status, which were routinely
collected on a subset of the population, suggested aslightly lower status for the proximally exposed
survivors [K3].
This fact might increase the fiequcncy
of untoward pregnancy outcomes arid death among
live-born infants in this group and so give ail upwardbias to the estimate of the genetic effect of radiation.
193. As the investigators pointed out, thc extrapolation of these results to the effects of chronic (orsmall and internlittent) exposures to ionizing radiation
requires ihe selection of an appropriate dose-rate
reduction factor. For the murine data, which was forthe most part collected at doses of 3 and 6 Gy, a dose
rate reduction factor of 3 has been employed. In thelight of the much lower gonadal exposures experienced by proximally exposed survivors a t Hiroshima
and Nagasaki, the investigators elected to employ aANNEX G: IIEREDITARY

dose rate redilctiorr factor of 2 (N61. This resulted ina minimal estimate of the doubling dose for humans
for chronic exposure to ionizing radiation, approximately 4.0 Sv.
194. The error in this estimate is indetcrnlinate but
must be considerable. First, there is the statistical error
inherent in the estimation procedures, which is relatively large in relation to tlie regressions. Next, thereis the error inherent in the present uncertainty concerning the contribution of parcntal mutation to such
indicators as untoward pregnancy outcomes and early
death. In addition, there is a potenrial error in the useof a dose-rate reduction factor of 2 in extrapolatingfrom the effects of acute to chronic radiation. The factthat three additional indicators could not, for technicalreasons, be incorporated into the estimate renders it
conservative, as was already ~nerrtioned,but does not
reduce its error. Finally, the human controls are not as
accurately defined as would be the controls in a similar mouse study. Although the control parelrts weretaken from the distally exposed group (they had been
2.5 km or more from the hypocentre of the bomb), it
is not possible to ascertain that they were 1101 exposed
to radiation from other sources.

195. Some further guidance as to the lower limit ofthis estimate may be derived from the fact that although the average conjoint parental dose of acuteradiation experienced by the proximal survivors was
0.4 Sv (a dose which in past UNSCEAR Reports wasthought on the basis of murine experiments to approximate a doubling dose for acute exposures), it was notobserved to have a significant effect on any of theeight indicators (see paragraph 186). This would bevery unlikely if the true doubling dose for acuteradiation is as low as 0.4 Sv. From the lower 95%
confidence limits cited earlier, it seems unlikely thatthe human doubling dose for acute ionizing radiation
under these circumstances is less than 1.0 Sv, and forchronic ionizing radiation, lcss than 2.0 Sv. The
estimation of the doubling dose for hullians must be
regarded as a dynamic and continuing process, subject
to revision as further data become available. Furthermore, it must be recalled that any estimate of the
doubling dose is time- and place-specific, reflecting
the genotype-environment interaction at a particulartime. This is certainly true of the estimate based on
the Hiroshima-Nagasaki experience.
1%. In evaluating Lhe importance to be accorded to
the results of this study vis-a-vis the results of themore controlled murine experiment (see following
Sections), four considerations stand out: (a) it is based
directly on human data, @) the indicators (congenital
malformation, early death, cancer and syndromes attributable to sex-chromosome aneuploidy) are highly
relevant to human affairs, (c) since the study includes
virtually all the children ever to be boni to exposedparents at Hiroshima and Nagasaki, it provides a total
appraisal of the genetic effects of exposures to theatomic bonlbings rather than a snapshot in time, (d)the findings are of necessity obtained at doses compatible wilt1 human survival and hence do not require thedegree of extrapolation from the much higher (forhumans, unrealistically higher) doses employed in themurine experin~ents.
2.

Epiden~iologicalstudy of leuhernia cases
st Sellafield

197. Marly epidemiological studies have been carriedout 011 populations exposed to radiation [A2, B.5, C7,
C11, C15, D3, K7, LA, S8]. One in particular raised
concern about the harmful hereditary effects of chronic
exposure. In 1990, Gardner et al. [GI, G2] reported
the results of a case-control study of leukaemia andlymphoma among young people near the Sellafield
nuclear plant in the United Kingdom. The study involved 5 2 cases of leukaemia and 22 cases of nonHodgkin's lymphonla. The increased incidence of leukaen~iaamong children near Sellafield was associatedwith recorded whole-body penetrating radiation to thefathers who worked at the Sellafield plant before conception. The authors suggested that the radiation
exposures of the fathers caused mutations in theirgerm cells that, when transmitted to their children,caused those children to develop leukaemia. The
authors pointed out that since low doses were involved, there were important potential implications forradiobiology and for the protection of radiation
workers and thcir children. Those fathers who were
employed at the Sellafield nuclear plant and whosechildren developed leukaemia had received total doscs
of 2100 mSv before conception and doses of 210 mSv
in the 6 months before conception.
198. The implications of Gardner's conclusions, if
correct, would be far-reaching, since they suggest thatas small a dose as 10 mSv, delivered at a low dose
rate to the fathers, is sufficient to cause a large increase in the incidence of leukaemia among theirchildren. The authors point out that their results on
leukaemia conflict with the results available forchildren of parents exposed to radiation at Hiroshima
and Nagasaki; they suggested that the difference might
be explained by the fact that the exposures in Japan
were acute, with a high dose rate, and those in
Sellafield were chronic, with a low dose rate.
199. From extensive studies in mice it has been
known for some time that chronic exposure over a
prolonged period has an important effect on mutational
response to radiation. However, that effect is in the
opposite direction from that hypothesized by Gardner,since protracted radiation induces only one third as
many mulalions in spermatogonia as high-dose-rate

758

UNSCEAR 1993 REPORT

radiation [R6, R121. Recent results on other populations provide no support for the conclusions ofGardner et al. [GI, G2]. Indeed, when Yoshimoto etal. [ Y l ] calculated the slope of the dose-response
curve for the incidence of cancer below the age of 20
years versus conjoint parental dose, using linear
multiple regression, they found negative slopes bod1
for leukaenlia and for all cancers combined. (Thestandard error of the slope, in each case, was larger
than the absolute value of the slope.) The averageradiation exposures of the survivors of the atomic
bombings were much higher than those of the fathers
employed at the Sellafield nuclear plant.

200. In addition, the statistically significant increase
in relative risk of leukaemia found for fathers employed at the Sellaficld nuclear plant was due almost entirely to only four affected children. Most of the otheraffected children had fathers employed in other industries. The conclusions of Gardner et al. are inconsistent with expectations from the risk estimates presented in this Annex, both from the doubling dose
method and the direct method. Although the Gardnerstudy used accepted procedures and appears to havebeen carefully done, it should be kept in mind that its
conclusion is based on a correlation and is not consistent with other observations of exposed parents, and it
may be a chance observation. A correlation alone cannot show causation. Furthermore, this particular correlation is heavily dependent on a very small numberof cases and is contradicted by all of the studies thathave been done in other populations with similar
exposures (see paragraph 208).
201. The chromosomal translocations resulting in
proto-oncogene activation that characterize the earlyphases of many leukaemias and lymphomas would
tend to produce phenotypic effects incompatible withembryogenesis [E7]. For this reason such events areunlikely to be genetic determinants of leukaemia that
muid account for the Gardner et al. [GI, G2] findings.
However, specific gene losses are also believed tocharacterize the early phases of some leukaemias[Wll]. Since predisposition to some solid tumours ofchildhood (retinoblastoma and Wilms' tumour) is
known to involve suppressor gene loss, a germ-line
origin for some fraction of human leukaemias related
to loss of specific genes or loss of suppressor genefunction cannot be excluded as having a possible
causal relationship in childhood cancer. Even in thecase of leukaenlia associated with proto-oncogene
translocation, recent observations imply that germ-linemediated epigenetic events (imprinting) can affect thesubsequent formation of the translocation in somatic
cells of the offspring [H16]. In the mouse there ismore direct molecular evidence of germ-line mutations
resulting in a predisposition to leukaemiaflymphoma.
In one case this predisposition centres on the loss ofthe p53 tumour suppressor geue [D8]; in the other it
centres on changes to the structure of an anonymous~eloniere-likerepeat scqucnce that may represent a
heritable cl~rornosomal fragile site [S43]. None ofthese obscrvatio~isscrve, however, to account for the
extraordinirrily high induced mutation frequency thatis rieccssary to explain t l ~ eepidemiological findings at
Sellaficld. Modern n~oleculargenetic techniques allow
the identification of the parent from whom a particularchro~nosomehas been inherited. If it could be demonstrated that in every case of leukaemia, the defective
cliron~osonie(s)was(were) inherited from the father,
this would at least lend support to Gardner's hypothesis. I-lowevcr, no such cytogenctic or nlolecularstudies have been done on the Sellafield cases [E7].
Had there been such a biological follow-up, it is likelythat some of the children with leukae~niawould havebee11 foulid to have chromosome rearrangements inonly a fraction of their somatic cells. Such a finding
would have bceri more consistent wilh a mutation ofsonlatic origin rather than with the hypothesis that the
mutation w m e from the father.
202. A large number, of individually rare genetic
diseases are known to increase the risk of cancer inboth the homozygous and heterozygous states. Someof these predispose to leukaemia and lympho~naa ~ t dothers to other types of cancer. Leukaemias wquld be
expected to make up only a small fraction of the induced genetic disorders predicted by the risk estimatesdeveloped in this Annex. Thus, if a dose of radiation
as low as 10 mSv induced a cluster of leukaemias, assuggested by Gardner, that same dose would be expected to induce an increase in other diseases in thesame population. Since no such epidemic of genetic
diseases has been reported at Sellafield [E7] or inlong-term follow-up in the Russian Federation [K12,P.51 or around other nuclear plants [A2], it seems
highly unlikely that the conclusions of Gardner ct al.
are correct.
203. There are some data from mice that could support Gardner's conclusion. Studies by Nomura (N13,N14] found that there were significant increases intunlour incidence in the progeny of X-irradiated maleand female mice in some strains, suggesting that thedifferent genetic backgrounds of different humanethnic groups could influence radiation susceptibility.
The dose-effect relationship was clcar-cut for malepost-meiotic stages and less clear-cut for spermatogonial stages. Oocytes at late follicular stages wereresistant to x rays in the range 0.36-1.08 Gy but
highly sensitive to higher doses. At the highest dose,
5.04 Gy, the tunlour incidence in the offspring wasaround 30% following irradiation of spermatids in themale or oocytes in the female. This incidence was six
times higher than the tumour incidence observed in
untreated controls. Matings to the F3 generation

ANNEX G: IIEWDITARY EFmm OF RADIATION

dcnionstratcd that thc tulnours wcrc hcritahlc anddominant, with ahout 40% pcnctrancc on average.
Sonic strains of rnicc had diffcrcnt scnsitivitics tothese hcritablc effects of r;~diation. Other strains,
however, showcd 110i~lcrcascin 11criti1t)lcturnours wit11
cquivalcnt doses of radiation. While ~ h doscc
uscd in
Nomura's studies, 5.04 Gy was far higl~crthan thatcalciilatcd for the Sclli~ficldworkcrs and well above
the doubling dosc uscd in cstiliiating genetic risks, thestudics do indicate that l~critablc turnours can be
induccd by radiation.
204. Nomura IN171 has proposed three possible
reasons for the differences between the Sellafieldstudies and other studics on Irunian populations:
(a)

@)

(c)

diffcrcnt gcmi-cell susceptibility to Icukacmiacausing mutations ill Japancsc arid English
pcoplc (similar to different susceptibility indifferent strains of micc);
different germ-cell stages exposed in the two
populations;different postnatal tuniour-promoting environments.

Nomura noted that lung cancer, for example, had aseven times higher incidence in white uranium niincrs
than in non-whitc miners who had rcccivcd equal
doses, although this was not a hereditary cffc'ct. He
cited mouse studics dcmons~atingthat thc offspring ofmice irradiated bcforc conception show persistent
hypersensitivity to tumorigcricsis whcn cxposed postnatally to tunlour-promoting agents, dcveloping
clusters of tumours.
205. However, there are difficulties with Noniura's
conclusions as well. The UNSCEAR 1986 Report [U2]reviewed the results of Nomura on the induction of
dominant mutations causing tumours, and Sclby IS211
and Sankaranarayanan [S4] also reviewed those resultsin detail. Most of Nomura's results are on pulmonary
adcnomas. A major difficulty in applying Nomura's
rcsults to risk estimation is the high control frequency
found for each end-point studied. Attempts to exlrapolate from mice to humans become cspccially unccrtain if only a few diffcrcnt abnormalities are studied
and if cach of thcm occurs at much higher frequcncics
in mice than in humans. In addition, the high control
frequcncics makc it much more difficult to evaluate
the strcnglh of tlie evidence on transmission andpenctrance.
206. While Nolnura treatcd his data as if cach oSSspring with a tumour rc~)rcscntcda dolni~~arit
mutation,
it seems much more likcly that the tuniours were
threshold traits and that most of the affected offspringwere non-mutational variants (S211. Although it is probable that radiation can induce mutations that predispose individuals to develop tumours, the extent to759

which it docs so is ur~clcnr Crorn Nomura's work.
Thcre is no indicatioll 111at piirelib wcrc ra~ldolnizcdor
that offspring werc codcd in Nomura's expcriincnts,
arid without such ~)rccaulionsit becoriics especiallydifficult to ir1tcrprc.t cxpcril~~cl~ts
for cnd-points having
suc11 11igl1colltrol frcqucocics (for cxaniplc, 4.7% forpulmonary adcnonlas). According to a report of thc
Intcrnatio~~alA g c ~ ~ cfor
y Rcscarch on Cancer 1121,
positivc rcsults in lung tunlour bioassay in susceptible
strains of micc "may be strongly suggestive of carcinogenicity but arc not conclusive by lhcmsclvcs". Thc
report advises that whcn positivc results are found in
this assay, rcplicating them in another laboratory
would greatly increase confidence in thcm, arid a longterm, lull-Ucdgcd bioassay might be necessary to
remove all doubt.
207. Non~ura'srcsults on pulrnoriary adcnomas andleukaemia suggest that the offspring of heavily irradiated lnalc mice should have a high frequency of induced turnours. A recent slnall cxpcrinicnt by Takahashi et al. [TS]on liver tutnours supports this view.
Although it would sccm, Goni this work, that it shouldbe easy to find increased numbers of tumours in progeny carefully autopsied at time of natural death, noeffect was found by Kohn ct al. [Kg] or by Cosgrove
et a]. (C19) in mice cxposcd to 5.3-7.2 Gy or 6.0 Gyof acute x rays, rcspcctivcly. In both studies theoffspring of botli experimental and coritrol groups
developed many tumours, The Cosgrove ct al. study
also found no diffcrcticc in longevity bctwecn expcrimental and control groups.
3.

Epiden~iologicalstudies

on otller h u n ~ a npopulations

208. The Sellafield report stimulated other studies onradiation cxposure in hurnari populations as well as areevaluation of previous studies. In addition to studics
on the Japanese atomic bomb survivors, studies havebccn conducted on paticnls receiving radiation
treatment for discascs such as rheumatoid spondylitis[L4, S81; on populatio~isliving in arcas with elevatedbackground radiation in India [K7], Brazil [BS],Canada [A2], the Russian Federation [B4, K12, P5,
TS] and China [C7, C11, D3]; on che population in
Hungary cxposcd to fallout from the Chcrnobyl accident [C15, C16]; and on x-ray technicians [TI].
209. The only effcct found in children of thcrapeutically irradiated patients alrd in x-ray tcchnicial~swas
a sex ratio shift in the direction cxpectcd if addi~ional
X-linked recessive Icthal ~nutatior~sare induccd in the
X-chromosomes of irradiated fcnialcs and X-linkcd
dominant mutations in the X-chromosomes of irradiated males. However, results from sex ratio s~udies
are not easily interpretcd and have 1101yet bee11 foundsuitable for the estinlariorl of ~ C J I C ~risk.
~ C

760

UNSCEAR 1993 REPORT210. Two areas in southern China (near Yangjiang)
with especially high levels of natural backgroundradiation were studied. The radiation arises fromradionuclides in fine particles of monazite that are
washed down year after year from nearby mountains.
These areas have been inhabited for about 800 years;
the families of about 80,000 present-day inhabitants
have been living there for more than two generations.
The annual gamma-ray exposure is about three times
that of the control population, which is similar to thatof average population groups in other parts of theworld. In this population, parameters such as cancer
mortality, incidence of congenital malformations andother health impairments were studied, generally with
C11, D3]. One result, however,negative results [C7,
is of special interest: Down's syndrome (trisomy 21)
was found to be far more common in the exposed thanin the control group. T o put this result into proper
perspective, a number of factors must be considered.
Incidence in the control group is much lower than in
all other populations for which fairly reliable incidence
figures are available. An incidence of only 1.8 cases
per 10,000 births is without parallel in theinternational literature. Even the incidence of 8.7 cases
per 10,000 births found in tbe exposed group is lower
than the incidences reported in most population groups
outside of China, which have been found to be 13-14
per 10,000. The most obvious explanation is that thediagnosis andlor reporting of Down's syndrome cases
has been incomplete in both series and less completein the control than in the exposed sample. The
incidence of Down's syndrome in six other Chinese
populations was compared with that of these two
population groups. It ranged between 2.7 per 10,000
and 6.2 per 10,000, i.e. between the figures for theirradiated and the control groups. Again comparison
with international figures suggests underreporting ofvarying degrees.
211. It is common knowledge that the incidence of
meiotic non-disjunction, and therefore of Down's
syndrome, increases sharply with advancing maternalage. Thus, first hypothesis of the Chinese scientists
was that the difference between the two groups wascaused by a difference in the age distribution of themothers. And indeed, 12.02% of mothers in the
exposed group, as compared with only 4.44% in thecontrol group, were older than 35 years at the birth ofthe children included in the study. But even in theyounger age group (below 35 years), the difference
between irradiated and control populations remains
significant (3.6 per 10,000 versus 0.5 per 10,000).

212. The observed differcnccs between exposed andunexposed population groups is very probably caused
by a combination of two factors: different age distribution of mothers and underreporting, especially in thecontrol population. In the light of these two biases, thestudy results canrlot dcrnonstrate an additional radiation effect; indeed they cannot even be regarded asl~inting at such an effect. This outcome highlights
some of the problenls erlcoul~teredin assessing large
populations for induced effects. As is described indetail in Section IT.A, the accurate ascertainment ofindex cases is both difficult and crucial.
213. No cllaage in the incidence of genetic disease in
Hungary was detected by Czeizel after the Chernobyl
accident [CIS]. The lack of effects in studies of populations in areas of varying background is only to be
expected, given the low statistical power of the investigations. Although some studies have included large
population groups, the dose differences have been too
small to observe statistically low risk effects (seeparagraph 115). The most useful human data are stillthose collected at Hiroshima and Nagasaki.

B. METHODS OF RISK ESTIhIATION:ANIMAL STUDIES
214. Animal data, especially those collected in mousestudies, still provide a basis for genetic risk estimationin humans. Extensive work has been done to try todevelop accurate animal models for estimating human
genetic risk following radiation exposure. The data on
survivors of the atomic bombings that are becoming
available suggest many additional animal studies thatwould be useful. Thus, despite the criticisms and limitations of each of the methods outlined below, animalstudies are still invaluable and should be continued
and refined as greater understanding of the complexityof the problem is gained.
215. It has been assumed, based on general principles
of radiation genetics, that mutations induced by radiation are more likely to be neutral or harrnhl thanbeneficial and that the frequency of mutations will
increase linearly with increasing dose. Two main
methods are used in animal experiments (primarily
mouse) that attempt to quantify genetic risk: thedoubling dose (or indirec~)method and the direct
method. Si~lcethey have been described and used withvarying emphasis in previous UNSCEAR Reports [Ul,U2, U3, U4], as well as in other reports on radiation
effects, such as those of tbe Committee on the Biological Effects of Radiation (BEIR) of the UnitedStates National Research Cou~lcil[Cl], they are discussed only briefly here, with a mention of theirrespective advantages and disadvantages.
216. Both methods extrapolate from animal data on
induced nuta at ions to risk of genetic disease in humans, although in different ways, as discussed below.
The terms direct and indirect refer to whether theestimate of damage in the first generation is based
directly on phenotypic damage found in mice in first-

A N N W G: I IEREDITARY EFFECTS OF RADIATION

generation progeny (direct nlcthod) or whether it isbased on extrapolatioi~back to the first generationfrom a prcdictio~~at gcrlctic equilibriuni (indirect
method). Although the frcquct~cyof 11ar11ifuleffec~sfrom induced mutations (from tile exposure of a single
generation) would be expecterl to decrease beyond thefirst generation, owing to negative selection, it should
be kcpt in mind tl~atsome of the genetic effects ofradiation, e.g. aneuploid scgrcgants fro111certain translocations or mutations leading to abnornial imprinting
in the gametes of first-generation offspring, might not
manifest until the second or subsequent generations.

1. The doubling dose (indirect) method(a)Concept

217. The doubling dose nicthod is uscd to estimate
expected risk to a population under cortditions of continuous irradiation, expressed in terms of the naturalprevalence of genetic diseases. It is based on the concept that with stable population structure and living
conditions, there is a balance between n~utationsthatarise spontaneously and those that are eliminated by
selection every generation. Wlcn an additional mutation source (such as radiation exposure) is introduced,
the population will eventually (over a number of generations, depending again on mutation rate and selection) reach a new equilibrium between mutation andselection. It is the additional risk at this new
equilibrium that is estimated with this n~cthod.Estimates of risk for the first or subsequent generations
are then obtained from that at equilibrium using
assumptions on the persistence of mutations in the
population.

218. The method involves the estimation of the
doubling dose, which thus is used to designate themethod. The doubling dose is the dose of radiation
required to produce as many mutations in a generation as those arising spontaneously. It is obtained by
dividing the spontaneous rate at a set of gene loci by
the rate of induction by radiation at the same set ofloci. The doubling dose currently used in risk estimation is 1 Gy for low-LET, low-dose-rate irradiation
conditions and is based on mouse data. The choice of
this value has been discussed in previous UNSCEAR
Reports.
219. The risk is estinlatcd from three qua~~tities
uscd
in the following equation:

Risk per unit dose = P F, IDd(1)where P denotes the natural prevalence of the diseaseclass under consideration, F,, the nlutational component and Dd is the doubling dose.

761

220. The doubling dosc in expcrirnental ani~nals,
especially mice, is defined as the radiation dose that
doubles tlic spolltarlcous mutation rate (not theincidence or prevalence of a certain condition). L i i ~ ~ i n g
and Scarle [L6] have reviewed doubling doses forvarious genetic piiramcters. From their report, two
aspects arc obvious:(a) h e r e is an appreciable difference between
esti~natesof doubling doses for various endpoinls. In mice, these end-points are defincd asdominant and recessive mutations leading todefincd phenotypes; don~iuantmutations affecting the skeleton; recessive Icthals; and chromosomal translocations lcading to semi-sterility, It
should be noted that in humans, there may beother more meaningful end-points, and they may
not be s o well defined or consistent;@) the confidence intervals of these cstitnates arc
very large. Earlier UNSCEAR Reports [ U l , U2,
U3, U4) used a doubling dose of 1 Sv for
irradiation at low dose rates. This estimate,based mainly on data from studies of seven recessive mutations in mice, is probably at least of
the correct order of magnitude. The doublingdose might, however, be quite different for otherend-points (i.e. other types of genetic effects),
such as predisposition to cancer. This limitationor possibility should be kcpt in mind.
221. Regarding attenipts to estimate doubling doses
for some of the end-points examined in the offspringof atomic bomb survivors, Ehling [E8]concluded thatthe doubling doses based on data available from theatomic bomb survivors were not significantly different
from estimates of doubling doses based on data frommice (see direct method, below). The absolute effects
in humans are much too small to permit such a conclusion, and the end-points are too different to allow
direct comparison. This does not, however, mean thatno attempt should be made to estimate the doublingdose from human data or to compare it with that fromthe mouse data. In view of the overwhelming difficulties in arriving at rationally founded risk estimates, allreasonable approaches should be tried arid optimized
as far as possible, and the results compared. The
application by Nee1 et al. (N8, N9) of the doublingdose nicthod to studies of human populations was
discussed earlier in this Chapter.
222. Since the doubling dosc method uses the conceptof mutation-selection equilibrium, the method can beapplied to conditions whose prevalence can be attriant
buted to this mechiinis~n.All autosomal d o ~ n i ~ ~andX-linked conditions (combined prevalence of 10,000
per million) have been traditio~~allyconsidered tobelong to this group; they are also d ~ conditionseforwhich the relatio~~ship
betweer~rnulation and diseasecan bc considered straightforward.

762

UNSCEAR 1993 REPORT223. Autosonial recessive discascs require the combination of two mutant alleles to manifest the conditionI
structure, inand arc slrongly dcpcndcnt ~ I populatio~~
addition to selective factors. For these the rcla~ionshipbctwecn mutation and disease is less direcl. For niultifactorial conditions, as ~ n c ~ ~ t i o nearlier,
cd
the coniplexitics of intcractiol~sh c t w c c ~gc~lcs~
and with the environment prccludc ;~ny dircct relationship between
mutation and discasc, and this makes the applicationof the doubling dosc nicthod for tllcsc diseascs very
uncertain.
224. In order to circu~nvcnt at least some of the
difficulties in risk estimation for the rather large groupof multifactorial diseases, the concept of the mutational component was first i~~troducedin the BEIR
1972 report and was subsequently elaborated upon by
Crow ct al. [C20]. Estimates of the mutational component are based on equilibrium theory. Although thisapproach was used in the BEIR V report to es~imatc
the mutational components for co~~gcnitalabnornialitics and with these to obtain tentative risk estimates
for this class of disorders, the Corliniittce [ U l , U2]
refrained from doing so.
225. There has been no new empirical data that would
warrant revision of the risk csti~natcspresented in the
UNSCEAR 1988 Report [ U l ] . However, arguments
questioning dlc validity of sonic of the assuniptions
used and suggesting h a t these risk estimates for
Mendelian diseascs niay be conservative have been
advanced [S6, S7]. Nonetheless, for the present, theCommittee favours the view that it is prudent to retain
the 1988 estimates, if only because it is better to e n
on the side of caution. These estimates are presented
in Table 5.

(b) Stmngths and weaknesses
226. The major strength of the doubling dose mcthod
is that the risks are expressed in tcnns of the background load of genetic diseases, so lbat some tangible
perspective can be derived to indicate whether the
projected increases are trivial, small or large. Furthermore, it has the apparent advantage that wholeclasses of genetic discascs can be handled as units.
Howcvcr, many of the assumptions used seem open to
doubt and have recently been discussed [S6, S7, V6].

risk cquatioa m;~y bc I~igh.For multifactorial conditioas, 111rcsti~niilionof mutational componc~itsis
still fr;~uglltwith considcrahlc unccrhintics.
228. Anothcr significant difficulty ill applica~ionof
the doubling dosc nicthod for gcnctic risk estimation
lies in csti~bli~hingt l ~ cb a s c l i ~ ~ofc spolltallcous niutations. (It should be ~ncntioncdthat use of the term
spontancous docs 1101 IllCilII that tllesc rrlutations occur
without cause. It simply means that in this context
they are not caused by the agent of interest, namely
additional radiation.) The disorders caused by spontaneous nlutations niay be very different and niay occur
in proportions very different from those causcd byradiation. The doubling dose mcthod assumes thatspontaricous mutations have the same rate relative tomechanisms as do radiatioa-induced mutations. As
pointed out above, however, there is evidence that thisis not the case.
229. The use of the doubling dose mcthod to analysehunian populalio~~sassumes a stable population andenvironnicnt. Howcvcr, human populations are constantly shifting, and there arc times, particularly duringwar, when there are shortages of food and health care,with increased i~ifectionand illness. Such conditions
niay well have an adverse effect on the radiation
sensitivity of humans and their susceptibility to themutagenic effects of radiation. Furthermore, humanpopulatio~~s(iscludiag isolated, inbred groups) are
genetically hctcrogcncous in comparison with mouselaboratory strains, which have been bred throughto be highly homogeneous.
multiple gc~~crations

230. Further discussions on the doubling dose method
centre on the data on the niolccular nature, specificities and mechanisms of origin of mutations underlying human Mendelian diseases and on the nature ofradiation-induced mutations in mamnialian expcrimentat systems [S4, S5, S6, S7]. These suggest that (a) the
doubling dose mcthod may be applicable only to asniall proportion of Mendelian diseases, (b) the
doubling dose for autoso~naldominant diseases may
be higher than 1 Gy (i.e. lower relative risk) and (c)risk estimates for thcse presented in the 1988 Report
are conscrvativc, hut provide a margin of safety inradiological protection.

2.
227. The existcncc of a balance bctwecn mutation andcomponent)
selection (and its corollary, tllc ~r~utational
are among the ccetral assumptions of Ule mctliod. As
discussed in Chapter Il.B, even for Mcrrdeliar~conditions, the assumption of mut;~tio~i-selcctioa
cquilibriuni
may be applicable to only a sniall fraction of these.
This means that the prevalence value (for these andX-linked conditions) of 10,000 per million used in the(a)

T h e direct nlethod

Concept

231. The so-callcd dircct ~riclliod for geoc~ic risk
estimation was suggcsled by Ehling ill 1974 [ER], witht i ~ ~ ofg tl~edifficulties
the intention of c i r c u ~ n v e ~ ~manyencountered in the practical iipplication of the doublingdose mcthod. This has allowed tile Committee to makeUNSCEAR 1993 REPORT

764

trance. Many doniinant niutations affect several developmental pathways and call thus influence several
distributions of undcrlyi~rg factors relative to thresholds. Many niutations that cause genetic diseases,
iricluding tl~oseof conlplcx actiology, can be thoughtof as acting in this way in all niamnials.

236. In the dircct method, an attempt is made to
determine the effects of induced mutations on theentire range of underlying factors and distributions thatmust exist in normal development. The genetic
background of the mouse provides a very large
number of different threshold traits on which theeffects of induced mutations can be tested. Mutations
can be detected that occur anywhere in the genome
and that involve any type of molecular damage,providing that the niutation is capable of shifting a
distribution over a threshold, such that a phenotypic
effect is revealed in a first-generation offspring. The
mouse, or other experimental mammal, used in the
dircct method thus becomes a tool for revealing theeffects of induced mutations on the vast array ofthreshold traits present. It is hoped that by carefully
looking for effects on threshold traits in firstgeneration offspring of mice, and by evaluating themfor severity, some idea may be obtained of the likely
effects of radiation in inducing serious genetic diseases
in humans.

Q

Application and qualifications

237. The most recent application by the Committee[Ul] of the dircct method is summarized as follows.
The expected approximate frequencies of induction ofgenetically abnormal children per million live-born,
following 0.01 Gy of exposure of niales, are 10-20 for
mutations having dominant effects, 0 for recessive
mutations and 1-15 for unbalanced products of reciprocal translocations. A foo~noteindicated that risk
from dominant sublethal mutations is estimated to be
5-10. For exposure of the female, the same categories,
reported in the same order, have risks of 0-9, 0 and
0-5. No estimate is available for dominant sublethal
mutations in the female.

238. A difficulty with the dircct method is that risk isestimated for only a small part of the total damage ofconcern to humans. Skeletal malformations andcataracts have been used because they can be
examined in detail in die mouse. A few otherend-points, for example adenomas in the lungs [N13],
have been investigated, but it is not yet clear how toapply such end-points in the direct method. Muchdiscussion and several lines of argument went into the
choice of the niultiplier of 10 to extrapolate frominduced serious skeletal daniage to induced serious
total damage.

239. Several of llle gencticisls most familiar withgenetic diseases in r~iicc nnd humans felt that the
number 10 was a reaso~iablcfigure to use in making
Russell had suggested using 10,
such an extrapolatio~~.
and Sclby IS231 liad s~~ggcstcd
a range of 5 to 20. The
Conimittcc examined McKusick's catalogue of Mendelian inheritance in marl [M7] and concluded thatabout olre fiClh of the disc;~seslisted involved theskeleton [U4]. Al~houghMcKusick's catalogue gives
no indication of the relative i~rcidencesof the diseases
listed, in a rough way tliis ar~alysissuggested that it
might be appropriate to multiply the skeletal effects by
5 to derive total serious damage. However, the Committee noted that because there is a bias of ascertainment for skeletal effects, the true multiplier mustbe larger than 5. Since plciotropy is common forgenetic diseases in both species, it seemed that themultiplier should not be too much larger than 5, and10 seemed to be a useful round number that would
suggest little precision. McKusick [M8] agreed that thefactor of 10 was reasonable, recognizing that thecatalogue does not reflect the human genome inreality.
240. In view of these and other considerations, theCommittee adopted 10 as the multiplication factor, andthe estimate of risk, calculated as it was from data on
mice, was assumed to be approxiniately correct forhumans. Anotl~crli~iiitationin using the direct method
is that both skeletal and cataract mutations areconnective tissue disorders, and it is anticipated thatthe genes involved in other tissues may responddifferently to DNA damage. As more is leanled about
the relationships between DNA damage and phenotypic changes, it is expected that the multiplication
factor will require adjustment, perhaps for each tissue
tY Pea241. The Conimittcc estimated that paternal exposure
to 0.01 Gy per gerleratiorr would lead to 20 serious
dominant disorders per million live-born. According to
the BEIR V report [ C l ] , this figure was estimated tobe between 5 arid 15. Risk from exposure of themother was estimated to be 0%-44% of that frompaternal exposure (see Table 3).
242. Starting with the UNSCEAR 1982 Report [U3],
the Committee included, in addition lo skeletal
malformation, dominant eye cataracts in its direct
estimates. The radiation-induced mutation rate for suchcataracts was established by mouse experiments
mainly by Ehling et al. [ES,E6]. Dominant cataractsof various types are known 10 occur in humans andcan be diagnosed in mice relatively easily. Again, theproblem arises of finding a way of extrapolating froma very limited selection of mutations observed in miceto all loci expressing dominant mutations of clinicalrelevance in humans.

ANNEX ti: I II~HEDITAKYEFFECIS 01: RADIATION

243. The multiplication factor suggested by Ellling toconvert the dominant cataract rate to an overall mutation rate was again based on McKusick's catalogue ofautosoma1 phenotypes [M7].The nuniber of wellestablished dominant mutations, 42, was assu~nedto
be the same in mall and I I I O U S ~ This.
ratio is tllcn used
to convert thc induced niutation rate of dominantcataracts to the estilnatc of the overall dominant
mutation rate. As new knowledge of the human situation is gained, it should be possible to readjust themultiplication factor.
244. Ehling et al. [E8] have recovered rnore than 85
independent dominant cataracts in the mouse. About
one third were observed in radiation gcnctic experiments. Combined experiments with the well-known
specific-locus test (the seven specific recessive
mutations) [E3] showed that the yield of domiliarit
cataract mutations was one fourth that of specificlocus mutations.
245. Using an argument similar to that mentioned
above for skeletal mutations, the dominant cataract
mutation frequency was estimated to be 0.45-0.55
mutations per 0.01 Gy per gamete for high-dose-rate
exposure. For low-dose-rate exposure, this estimate wasdivided by 3, yielding an estimate of 0.15- 0.18 lom6
mutations per gamete. Again using the McKusick catalogue listings m7]and a multiplier of 36.8, a risk
estimate of 6-7 1 0 . ~serious donlinant disorders per
0.01 Gy of paternal exposure was derived. Bothestimates, that based on skeletal mutations and thatbased on cataract mutations, are similar, considering themultiple assumptions they require. The Committee
decided in favor of a rough estimate of 10-20 serious
dominant disorders per million live-born [U3].

246. Several correction factors are needcd to estimate
risk by the direct method. All estimates of phenotypic
damage are based on high-dose-rate exposures, eventhough risk is estimated for low-dose-rate exposures.
It is necessary to assume that the dose-rate effect forserious dominant damage is the same as that seen for
specific-locus mutations, which are recessive mutations
at one of seven genes in the mouse. (The predictive
value of the specific-locus data seems stronger in thisregard because many of the mutations at the s locus,
which is one of the seven genes studied in thespecific-locus test, are associated with reduced sizc,
suggesting an associated dominant effect [RS].) Most
data used in the direct method also come fromexperiments using fractionated exposures, which wereadministered with the expectation of increasing themutation frequency. These experimcnl% require
correction factors, again based on specific-locus data,
for the fractionation effect.
247. The estimate of genetic risk to the female depends on the assumption that the relationship for in-765

duced d o n i i ~ ~ adamagel~t
and specific-locus mutations
will be the same as that for thc male. No experiments
have been conducted studying the induction of skeletal
anomalies or cataraclr following the irradiation of
female micc, and qualitative differences in themutations in the two scxcs could affcct the level ofextent.
induced damage to an iniporta~~t248. Evcn though many large experinlents have beer1
conducted to learn about the induction of mutations inmamnials, the direct method still rests upon relatively
few experiments including few mutations. The total
includes only 42 dominant skeletal mutations and 12
domiria~~tcataract mutations [S8, U3, U4], a small
number on which to base such an important application, particularly when the mouse and human disorders
may be quite different It would be reassuring to havemuch more data collected on different swains or
species; this would provide some indication of whether
the frequency of induced dominant damage is highly
dependent on the genetic background of the animals
being examined. It would also be helpful to confirm
the conceptual rnodel on a niolecular level. Thc direct
method has only been used to estimate the genetic riskof serious genetic diseases, but since this is theinformation about genetic risk that is most needed, thisis not a serious limitation of the method.

249. Although

the direct method requires noinformation on the incidence of genetic diseases in aparticular human population, it is important to havesuch an estimate to help put the mouse estimates into
perspective. The incidences presently used in the
doubling dose method (see above) are probably notvalid for this purpose, however, for two reasons: (a)they include many conditions that are probably far lcss
serious than those used in the direct method and (b)they are based on the incidences of disorders insteadof the incidences of i~~dividualswith disorders.
Concerning the latter point, it is relevant to note thatmany of the dominant skeletal mutations causc
numerous cffects, sometimes on other body systems aswell [S24]. In spite of h i s , when estimating risk by
h e direct method, the number of affected individuals(which corresponds to the number of induced nlutations) is used instead of the total nunlber of malfonnations. This would seem to be a reasonable approach,since only one individual is disabled as the result ofeach mutation.

250. The principal advantage of the direct method ofrisk estiniation is that i t makes no assumptions
regarding spontaneous mutations with similar genetic
mechanisms or phenotypic effects, and no assumptions
are necessary regarding the mulational component incomplex diseases or malfontiations. The method rclics,

766

UNSCEAR 1993 REPORT

however, on extrapolations fro111 mice to humans andirom a small fraction of doniinant mutations, forexample those affecting the skeleton or tile lens, to ail
dominant mutations. In these repects, the so-called
doubling dose (or indirect) method is much more
direct: doubling doses have been estimated not only in
mice, with subsequent extrapolation to humans, butalso in humans, Gom the results of studies on aton~ic
bomb survivors. In addition, estin~atesof the spontaneous incidence of dominant mutations and theirincrease in relation to a certain radiation dose werebased not only on certain categories but on all suchmutations.

251. The indirect method requires two main steps. In
the rust, the absolute number of mutations in relation
to a certain dose and quality of radiation is estimated.
This estimate is compared in the second step with the
spontaneous mutation rate (or the assumed mutational
component of cornplex conditions). The direct method
requires only the first of these steps. The logicalrelationship between the two approaches should be
kept in mind when the so-called direct approach is discussed in the following paragraphs. Selby IS221 correctly distinguishes between the indirect method as amethod of relative risk estimation and the direct
method as a method of absolute risk estimation. Moreover, an absolutc risk estimate should always be put
into perspective by relating it to spontaneous mutations, i.e. by transforming it into a relative estimate.
252. Many of the criticisms of the doubling dose
method also apply to the direct method. In addition,
there are a few points of criticism from the viewpointof medical genetics. It is certainly too simplistic tocalculate the multiplication factor from the number ofdifferent dominant skeletal nialformations and cataracts in humans in comparison with the total numberof known, dominantly inherited hunian phenotypes.
The phenotypes enumerated in McKusick's catalogueof 1975 [M7] are a mixture of moderately common,
relatively rare and extremely rare phenotypes. There
have been many changes and additions to the catalogue since 1975. Many new entries in the category of
confirmed human skeletal and cataract disorders, aswell as many additional multiple anomaly disorders
involving skeleton and cataracts should be included insuch a calculation. One purpose of McKusick's catalogue is to permit the medical geneticist a quickorientation in the vast area of genetically determinedhunian phenotypes. It has never been McKusick's intention to say anything about the incidence or prevalence of such phenotypes or their mutational origin.
253. The life expectancy of a mouse (approximately
two to three years) is very much shorter than that ofa human being. Certain genetic defects that lead tohereditary cataract in humans later in life simply haveno time to m:inifcst lhcniselves in mice. Thus, only
cataracts ~naeifestingat birth or a short time afterwards can be assun~edto be genetically honlologous
to the r~lousec;il;iracls recorded for use with the direct
method. I t must also be kept in mind that all experinicrlts considcrcd in the direct method have been doneon male mice. The genetic risk for the offspring of
irradiated feniale mice could be considerably different.

254. The estimate from skeletal anomalies may be
criticized on similar grounds. For example, it is wellthat minor, and sometimes not s oknown to a~rato~nists
minor, variations of the human skeleton arc widespread. Many, if not most of these variants have noclinical significance at all. In this context it should berenlenibcred that human pol~ulationsare mixed genetically, whereas the mouse populations used in experiments are often inbred strains. The best way to arrive
extrapolations to relevant mutation rates
at reaso~~ablein humans would be to compare the patterns of manifestation of skeletal mutants and cataracts in theniouse with h o ~ ~ i o l o g odominantlyu~inherited diseases
in the human skeleton and eye, as documented and described in the medical genetic literature. For example,
as Sclby suggests [S22], it would be particularly
reassuring if mouse mutant [S31] involving cleidocranial dysplasia could be identified for which there isa homologous hurrian syndrome .

255. Selby [S22] suggested that clinical geneticists
could help to classify animals as to clinical severity.
In his opinion, the biggest advantage of the direct
method is that it i ~ ~ c l u d cwithins
its scope the irregularly inherited disorders, which constitute 85% of theserious genetic disorders in humans. The direct
method requires no assumption that spontaneous andinduced mutatio~uhave approximately the same likelihood of causing harm, no knowledge of the current
incidence of serious genetic disorders in the humanpopulation, no estirnate of how many of the irregularly
inherited disorders are niultifactorial or dominant disorders with low pcnetrance and no knowledge of thepersistence of rnutations in the population. However,these advantages are offset by the fact that it does notallow correlati~iga possible increase in mutations ofknown incidence with the spontaneous occurrence
rates of relevant traits in human populations.
256. Another difiiculty with the direct melhod is thatrisk is measured for only a small portion of the total
damage of concern to humans. Skeletal nialfonnations
and cataracb are used because they can be examined
in detail in Uie niouse. Much discussion, and several
lines of argument, went into the choice of the niultiplier of 10 to extrapolate from induced serious skelelal
darnage to induced serious total damage. However,both skeletal and cataract ~ ~ ~ u t a t i oaren s disorders ofconriective tissue, and it is likely that the DNA

damagc in thcsc tissues will bc somewhat diffcrcnt
from that in othcr tissucs. As nlorc is lcarncd about
the rclationsl~ipsbetwccn DNA damage and phcnotypic damagc, it would not be surprising for tile ~nultiplicadon factor to rcquirc sonic adjustnicnt hccausc oftissuc diffcrcnccs. Multifactorial disordcrs andtlisordcrs of coniplcx actiology arc probably far niorc
colnlnon than is accounted for by a multiplier of 10.
257. A major shortcoming of the dircct nicthod has
becn the uncertainty about the inclusion of risk fromserious disorders of multifactorial (complcx) actiology,
which make up the great majority of the hurnan genetic load. Bccausc radiation-induccd mutations often
havc incomplete pcnctrancc [S23, S241, i t would not
be surprising if many disordcrs of complcx actiology
involve mutations with incomplctc penctrancc. Othcr
important classes of induccd damage for which theactiology is not presently understood might be ovcrlooked if only those mutations are iricludcd that have
proven transmissibility or nlcct particular presumed
mutation criteria, as has been done thus far i n applying
thc dircct method. In addition, generations beyond the
Fl could exprcss visible effccts of induccd mutations
that involve non-traditional n~cchanismsof inhcritancc,
such as gcnomic imprinting, not all of which will bevisible in the F1 generation.
258. In conclusion, thc dircct n~cthod,at least in its
prcscnt form, does not allow estimating the expcctcd
increase of dominant phenotypes overall in humans.
Howcver, it has provided an enormous amount of information in carefully controlled conditions. In
addition, it does not contradict the doubling dose
cstimatcs from data on the atomic bomb survivors andseems to be a uscful altcniative approach lo the
problem of estimating gcnctic damagc in humans. If
rnolccular analyses arc uscd, the method could probably bc dcvclopcd to provide additional interesting
information on the gcnctic basis of some irregularly
inherited anomalies and on genctic effccts in humans.

C. EXI'ElllhIENTAL STUDIES
1. New experimerlhl data relevlint
to risk estimation
259. Basic data on the gcnctic cffccts of radiation
continue to be derived from earlier aninial cxpcrimcnts. A major study in progress. assessing do~ninantdamagc in mice, is intcndcd to havc direct rclcvancc
to the estimation of genetic risk in humans. This study
and others on thc gcnctic cffccts of radiation arc
reviewed in this Section.
260. The results of studics of dominant skeletal andcataract mutations in mice remain the foundation of

the dircct ~ncthodof gcnclic risk estimation. Ehling[E2] rcportcd h a t U~rccof his prcsumcd dominantniutalions wcrc indccd shown to transmit lhcir c f f e c ~ .
in a donlina~itnianncr. Sclby and Sclby IS23, S24,
S25] conducted a largc breeding-test cxpcrimcnt
whosc aii~inpurpose was lo dclcnninc conclusivcly
u ~ a ttlc
t do~ninantskclctal mutations induccd by cxposure of stcm-cell spcrmatogonia to low-LET radiation
wcrc indccd don~inantniuta~ions.It is noteworthy h a tniany of tllc dominant mutations wcrc shown to haveir~coniplctcpcnctrance and variable cxpressivity (andfius might or might not bc truly autosomal dominant).
Sclby IS201 latcr dcnlonstratcd thc statistically significant induction of dominant skclctal mutations instem-cell spcrmatogonia following acute x-irradiation
with 6 Gy or 1 Gy + 5 Gy (24-hour interval) or cxposure to cthylnitrosourca [S26].
261. Ehling ct al. [E3, KlO] dcmonstrated that acutc
gamma radiation induces dorninarit cataract mutations
in mousc stem-cell spcrmatogonia and in post-spcniiatogonial stagcs. This fractionated cxperiment and two
latcr oncs that yicldcd induccd n~utationfrcqucncics
that wcrc not significantly higher than in controls wcrc
used in the UNSCEAR 1982 Report [U3] to apply the
direct mcthod to cataracts. Tbc resulting risk estimate,based on cataract data, was 10 genetically abnormalchildren pcr 0.01 Gy of patcrnal exposure to lowdose-rate, low-LET radiation. It was used in the
UNSCEAR 1982 Report [U3] and in the UNSCEAR
1986 and 1988 Reports [ U l , U2] as thc lower boundof the risk estimate made by h e direct method. Ethylnitrosourea has also been shown to induce dominantcataract mutations [Fl]. Many dominant cataract mutations exhibit incomplctc pcnclrance and variable
cxprcssivity IF2, G6].
262. Sclby ct al. IS201 arc using the assessment of
dominant damage approach IS221 to invcstigatc thc
induction of dominant mutations in stem-ccll spcnnatogonia, with c~nphasis on skclctal and cataract
mutations. Results to date IS291 arc prescrited for6 Gy of low-LET ionizing radiation, dclivcrcd cithcr
as 0.04 ~ n G ymin-' 13'cs ganinia radiation (chronic)
or 0.89 Gy min-I x radiatio~~(acute), and for amatchcd control. The frcqucncics of mice with possibly serious cataracts in the diffcrcnt groups wcre as
follows: chronic irradiation, 511,502 (0.33%); acutc
irradiation, 411,290 (0.31%); and matched conlrol,
511,693 (0.30%). The frcqucncics of mice with scvcrc
skclctal r~ialfonnatior~swere as Lbllows: chronic irradiation, 1 1/1,791 (0.85%); aculc irradiation, 2011,193(1.68%); and matchcd control, 2311,457 (1.58%).
When lcss scvcrc skclctal mallonnations wcrc includcd, thc frequencies wcre chronic irradiation,
2511,291 (1.94%); acutc irradiation, 3711,193 (3.10%);and matchcd control, 5111.457 (2.81%). No significant
differcnccs wcrc obscrvcd.

UNSCEAR 1993 REPORT

768

263. Graw et a]. [G6] conducted experiments on the
induction of dominant cataract mutations in stem-cell
spermatogonia in mice, as detected in first-generation
ol'fspriag produced ill ntatings with untreated females,
and found no significant effect of radiation up to
5.1 Gy + 5.1 Gy (24-hour interval). The rcason forthis lack of effect is not known, but at least the results
are consistent with a low frequency of induction of
cataract mutations. Specific-locus data collected in thesame experiments showed that both treatments wereclearly effective in inducing other typcs of mutations.
264. Selby [S21] reanalyscd the published data ofGraw ct al. to assess whether there had been a significant increase over control in the frequency of cataracts. The findings led Selby to suggest that many of
the cataracts found in such experiments may result
from induced mutations with such low penetrancc that
proof of transmission is unlikely.

2.

Studies of mutations in mouse oocytes

265. For many years estimates of the genetic risk tooffspring of exposed women have been more uncertain
than those of the risk to offspring of exposed men.
Large-scale experimcnts using neutrons or x rays do
not show that specific-locus mutations are induced in
the immature arrested prirnary oocytes in the mouse(i.e. oocytes ovulated more than six weeks after irradiation). Russell [ R l l ] presented a series of argumentssuggesting that it might be reasonable to apply theapparently negligible risk for this germ-cell stage inthe mouse to immature arrested primary oocytcs inwomen, even though the arrested oocytes of mice are
in diffuse diplotene (dictyate stage) and those in
women are in a more condensed state (typical diplotene). Russell [ R l l ] also argued, however, that for thesake of caution one might want to consider the
possibility that the human arrested oocyte could be as
mutatiorially sensitive as the most sensitive oocyte
stages in the mouse, namely, the maturing and mature
oocytes. To provide a basis for such extrapolation, he
provided four different fits for the low-level radiation,
specific-locus experiments in female mice. Only thehighest frequency (0.44 times that in spennatogonia)
was significantly above the control value. Russell
concluded that genetic risk in the female is probably
less than that in the male, and the Committee hasapplied the value of 0.44 in the direct method whencalculating the upper limit for risk following maternal
exposures [ U l , U2].
266. Dobson and Straume [D4] suggested that it isinappropriate to base risk estimates for human arrested
primary oocytes on the specific-locus data collected
for arrested primary oocytes in the mouse. They
demonstrated [S37] that che target for cell death inarrested primary oocytes of mice is not the DNA but
rather the plasma rnc~nbraneor something siniilar to
it in terlns of geometry and location in the cells. They
lave suggcstcd that in Russell's large 0.5 Gy specificlocus expcriruent using x rays [ R l l ] , which provided
most of the bi~sisfor concludi~igthat risk for this stage
might he negligible, thc oocytes that survived [liemembrane damage would have received doses substantially lower than 0.5 Gy. They suggested that theestimate of risk based on a 0.5 Gy exposure might bemuch lower than it should be. In the UNSCEAR 1986
Report [U2] it was noted that current concepts of
microdosimetry agreed with Russell's view that the
distribution of ionizations from x rays would be so
diffuse that the dose to the large nucleus of an oocyte
could not difler appreciably from the exposure of
0.5 Gy administered.
267. Many more details of the Monte Carlo calculations by Straunie el al. have now been published[S38], however, and those calculations suggest that
there is a very small fraction of oocytes in the 0.5 Gy
x-ray experiment that received as little as about 0.2 Gy
to their DNA and there is a very small fraction of theoocytes that received as little as about 0.1 Gy to theirplasma membrane. Furthermore, their calculations
i~tdicated significant coupling between the plasma
membrane and nuclear doses, such that when the doseto the membrane was lower tl~anaverage, the dose to
the nucleus tended also to be low, and vice versa. In
the view of Straume et al. [S38], only oocytes with thelowest dose to DNA (presumably about 0.2 Gy) survived, so Russell's finding of no mutations in 92,059
offspring [ R l l ] was for a dose of only about 0.2 Gy
instead of the 0.5 Gy administered. In their view,
Russell's data do not suggest as low a mutation frequency as he estimated. Even if the interpretation ofStrautne el al. is accepted, however, it should be notedthat the data Goin Russell's large 0.5 Gy experiment
provide no basis for concluding that arrested primaryoocytes are highly mutable, or even mutable, because
no specific-locus mutations were found.
268. Besides providing evidence that the arrested
primary oocytes in Russell's 0.5 Gy experiment may
have received a lower dose than had been tliought,
Straume et al. [S38] demonstrated the induction ofgenetic damage in those oocytes by exposure tomonoenergetic 0.43 MeV neutrons. They selected thisform of radiation because of its short track lengths,
which they say p e r ~ n i uthe recoil protons to deposit
ettergy in the nucleus without traversing the plasma
memhrane. As a result, there would presumably belittle or no correlation between energy deposilion in
Ute plasma m e m b r a ~ ~ande the DNA, and oocytes
receiving higher doses could survive. The two types of
induced genetic damage detected in mice that had
been superovulated using honnonal injections 8-12

ANNEX G: IIEREDITARY EFFECTS OF RADIATION

weeks after irradiation were (a) chro~nosomeaberrations, detected in oocytes arrested at metaphase 1, and@) dominant lethals, detected by the success withwhich cultured two-cell embryos survived to themorula or the blastocyst stage or tiatclied from thezona pcllucida arid fonncd a sl~ectof trophectodern~with a proliferated inner cell mass. The i~tductionof
both types of genetic damage was reported to beaberrations andsignificant, with 6.0% chror~~osome
16.9% dominant lethality at 0.25 Gy.
269. Although the authors denlonstrated the inductionof genetic damage in arrested primary mouse oocytes,
it is not clear whether these types of genetic damage,detected following superovulation, are relevant to thegenetic damage that would be seen in the offspring of
irradiated females. They referred to the work of
Griffin and Tease (next paragraph) and to much earlier
work by Brewen et al. [BlO] on the induction ofchromosome aberrations in maturing mouse oocytes,
and they state that the intrinsic mutational sensitivityof mouse immature oocytes is not very different fromthat of maturing oocytes. They claimed that theirresults make it possible to estimate genetic risk for
women more confidently using the substantial amountof genetic data previously available for maturingoocytes in the mouse. The risk estimates presented in
the UNSCEAR 1986 Report [U2] ranged from thelower limit of zero, based on the assumption that the
mutational sensitivity of immature human oocytes issimilar to that of immature mouse oocytes, to theupper limit of about 9, based on the assumption thatthe sensitivity of the human oocytes is similar to thatof mature and maturing niouse oocytes. The latter is
0.44 times that for spermatogonia. Thus, theCommittee took the position that risk in the female
could be as high as Straume et al. now suggest that itshould be.
270. Griffin and Tease [G7] provided the tint clear
evidence of the induction of genetic damage inarrested primary mouse oocytes by radiation (or by
any agent, for that matter). Young (4-5 weeks-old)female mice were exposed to whole-body gamma
radiation at a mean dose rate of 0.1 mGy mid1 until
they received a total of 1, 2 or 3 Gy. Eight weeks
after the end of the treatment, they were induced tosuperovulate by hormonal injections, and metaphase Il
oocytes were screened for numerical and structural
chromosome anomalies. Hyperhaploidy (i.e. thepresence of an extra chromoson~e)was used to assess
the effect of the radiation on chromosome segregation.
Several kinds of structural anomalies could also be
detected in these cells. Again, the extent to which thisgenetic damage seen in superovulated oocytes would
affect the health of the progeny of such females is
unknown. The cliromoson~eaberrations reported areprobably not compatible with survival, but they may

769

indicate a low level of induction of srnaller types ofrearrangenlents Ulat might be viable.
271. Returning to studies on immature oocytes, Selby
el al. IS281 found Uiat fernalcs acutely irradiated nearbirth latcr produced as rilariy as four or five litters, insharp contrast to adult females, which becanle sterile
after one or two litters followirig such an acute exposure [R7]. Based on the known radiosensitivities tocell killing of the different oocyte stages present near
the time of birth, it seems likely that this experiment
provided the mutation frequencies for pachytene andperhaps diplotene oocytes. Unlike in the adult female,the mutations found following an acute exposure were
not restricted to the first six weeks after treatment; infact all mutations were found later or much later than
this. No evidence was found for induction of mutations when females were exposed to 3.0 Gy at amoderately low dose rate near the time of birth.

272. As discussed above, it is uncertain whether thefinding of no induction of specific-locus mutations inarrested primary oocytes of adult female mice can beextrapolated to women. If the degree of condensationof the chromosomes has an important bearing on themutational response, .those immature oocytes withcondensed chromosomes that are present near the timeof birth, which were studied by Selby el al. [S28],
may be more comparable to the vast majority ofoocytes in women than any other oocyte stage studied
in the mouse. The finding of no nlutation induction in
those oocytes at moderately low dose rates suggests
there may be no reason to abandon the view that
mutation induction in female mice could be negligible
compared to that in male mice.

3.

Induction of translocations in primntes

273. Van Buul [ V l ] and Adler and Erbelding [ A l l
conducted studies on the induction of reciprocaltranslocations in various strains of monkeys. Based onthese results, there appear to be significant strain
differences in monkeys. The frequency for s t u m p
tailed macaques represents the lowest induction rate
per gray ever recorded for an experimental mammal[Vl]. This may raise questions about differences
between primates and mice and about the validity ofusing mice to study radiation risk for humans. Generoso et al, [G3, G4] also found strain differences inmice for the induction of reciprocal translocations.

4.

Induction of don~inuntmututio~iscausing congenital mulfom~utions

274. Mutation studies aimed at dctectilig anomalies
present at birth in mice and rats often examine fetuses

UNSCMR 1993 REPORT

770

late in pregnancy instead of soon after birth, to avoid
the probleni of niothers eating grossly abnormal offspring. Earlier work was discussed in previous
UNSCEAR Reports [ U l , U2, U3], and recently there
has been a detailed review of these studies [S21].
Wl~ilesome experinients have shown clear-cut effects
of mutagens, others have shown weak effects or noeffect at all for strong mutagens. Because of this inconsistency and the high levels sometimes found incontrols, Lyon and Renshaw [LlO] concluded that, inhumans, the incidence of nialformations is likely to bea relatively insensitive indicator of an increased
mutation rate. Many of the congenital malformations
are probably threshold traits (see Section I.C), andsome of them are fairly common in the strains used.
There is also reason to believe that some of the anomalies might result from spontaneous mutations withlow penetrance that are segregating in the stocks[S21]. Selby pointed out that the randomization ofparents in such studies, which does not appear to be
standard practice, would help to guard against
misinterpretations and improve the usefulness of theresults [S21].

275. Nomura [N16] has almost doubled the sizes of
his saniples for studies of the induction of congenital
nialformations in mice by x-rays. The statisticallysignificant induction of congenital malformations wasshown for acute irradiation of post-spermatogonialstages, stem-cell spermatogonia, oocytes in adultfemales that were ovulated within 6 weeks after
irradiation and oocytes present in 21-day-old mice.
Nomura reported that frequencies of congenital
malformations increased with dose for spermatozoa,
stem-cell spermatogonia and mature and maturingoocytes of the adult. However, the slope of the siniple
regression line of dose versus frequency wasstatistically significantly above zero only in the matureand maturing oocytcs. While much importance wasgiven to the clear linear relationship between dose andmutation frequency found in spermatogonia between
0 and 2.2 Gy, the much lower mutation frequency
reported for 5.0 Gy was ignored. In the total datareported, 42% of the anorrialies found by Nomura
were open eyelid, 25% were dwarfism and the rest
were tail anomalies or cleft palate. Most of the micewith open eyelid showed only a small unilateral gap,
and it was felt that had they been born, most would
have been indistinguishable from normal mice by a
few days after birth.

5.

Rrsulb of the direct method
to estimate risk

276. The experiments of Ehling [El) and of Selby el
al. IS231 both yielded estimates of an induced
dominant skeletal mutations
frequency of about 4

per galtietc per 0.01 Gy Sor low-dose-rate irradiation,
after applying correction factors derived from
specific-locus experiments. As explained in describing
the concept of the direct metlrod, this frequency was
multiplied by 0.5 (for severity), by 10 (multiplication
factor for total damage) arid by 1 ~iiillion,to yield theestiriiatc that 0.01 Gy of patenlal exposure would
result in 20 genetically abnonnal children per million
live birtlis. In Ihe UNSCEAR 1982 Report [U3],risk
in the fernale was considered possibly negligible or, at
most, 44% of that in the male, yielding the range 0-9
for 0.01 Gy of maternal exposure. The correction
factors used to estimate maternal risk came from thesuggestion of Russell [ R l l ] , based on specific-locus
data in mice. Data on the induction of dominantcataract niutations were used in that same report toderive an estimate of 1 0 genetically abnormal children
per 0.01 Gy of paternal exposure to low-dose-rate,
low-LET radiation as the lower bound of the risk
estimate made by the direct method.
277. Selby et al. [S29] point out that the preliminary
results of assessment of dominant damage experiments
in progress show no large error of underestimation in
the direct estimate of genetic risk following paternal
irradiation, even if that estimate is applied to all
genetic disorders causing serious handicaps. Theysuggest that the data from an assessment of dominantdamage experi~nentusing protracted exposure [S29]
could be used to derive an estiniate of genetic risk asfollows: subtraction of control results from experimental results will yield the frequency of induced
serious genetic disorders. The estimate of genetic risk
per 0.01 Gy could be calculated by dividing theinduced frequency by 600 and then by multiplying it
both by 10 (to expand to all body systems) and by 1
million to obtain an estiniate of genetic risk expressed
per inillion live births. Many of the correction factors
and assumptions used before in applying the direct
method would thus no longer be needed. Multiplication by the correction factors of 0 and 0.44, derived
from specific-locus results, would yield an estimate ofmaternal risk, as was done previously.
'

278. If a ~ ~ ~ o diesu s e during the first few weeks oflife, most of the types of phcnotypic damage discussed
above would not be detected. The omission of early
deaths from induced dominant mutations would be aserious deficiency in a risk estimate. The assessmentof dominant damage experiments IS291 are specificallydesigned to circumvent this problem by including
extraordinary efforts to examine the skeleton of every
mouse living beyond three weeks of age. Thiseliminates overlooking serious niutations because ofearly deaths. In the UNSCEAR 1986 Repod [U2] theCommittee made an estimate for protracted gamma
radialion of the frequency of induction of dominant
mutations causing death between birth and early life.

ANNEX G: HEREDITARY EFFECIS OF RtUIlATlON

That estimate was based in part on an analysis by
Sclby and Russell IS271 of first-generation litter-size
reduction in 14 radiation experiments involving
158,490 litters. That experilncnt yielded the estimate
illat for 0.01 Gy of low-LET, low-dose-rate paternal
irradiation, illere would be 19 deaths causcd bydominant mutations betwccr~ conception and three
weeks of age for every nlillion F1 mice that would
have lived to that age in the absence of irradiation.
279. The data of Liining [L7],from one large
experiment, yielded a similar cstimate, 24 induced
deaths per million. While the data of Selby andRussell could not be used to partition the total
mortality rate into that occurring before and after
birth, the data of Liining [L7] and of Searle andPapworth [S15] could be used for this purpose. Basedon these three data sets, the Committee estimated thatthe induction rate of dominant genetic changes causing
death between birth and weaning would be 5-10 cases
per million births per 0.01 Gy [U2]. This estimate hassince been referred to as the "frequency of dominant
sublethal effectsn. Although no such estimate has yet
been made for maternal risk, it would seem reasonable
to make a rough estimate by assuming that risk in thefemale is possibly negligible and, at most, 44% of thatin the male, as has been done for other end-points.
Risk in the female would thus be about 0-5 fordominant sublethal effects.
280. It should be noted that the chances that children
with any one of many different serious birth defects
will survive is heavily dependent on the sophisticationof the medical technology available. The risk estimate
for dominant sublethal effects based on the mouse isthus probably especially relevant when considering
genetic risk 6om radiation in countries where
advanced medical technology is less readily available.
Baseline risk estimates are very difficult to obtain insuch countries.

281. Table 3 shows the estimate of genetic risk basedon the mouse model. It is noteworthy that there is nolonger a separate listing for unbalanced products ofreciprocal translocations. Those effects are presumably
already included in the new risk estimate. It is
important to note that research specifically aimed atunderstanding thc induction of translocations in miceor other species, especially primates, must be carefully
followed to see whether the mouse model, as appliedin
3?
lead lo a large underestimation ofrisk. Appropriate additions could be made to the Table
if needed.

282. All modes of inheritance that could lead to
first-generation effccts are presumably included in theestimates given in Table 3, regardless of whether theaedology is understood. Earlier work [S23] showedthat an important part of the total consists of dominant
mutations with full or incomplete penetrance.

77 1283. Studies on skeletal and cataract mutations haveshown that many of these mutations are recessive
lethal mutations that have effects in hcterozygotes[ K l l , S18]. Roughly 10% of the earlier direct estimateof risk based on the skeleton was thought to result
frorrl balanced translocations that acted like dominant
mutations [S18].
284. The equilibrium estimate is the frequency of
induced damage expected in each generation if the
hypothetically increased mutation frequency stays
constant until an equilibrium is reached. The estimateof genetic risk for thc first generation could be extrapolated to an estimate at equilibrium if the persistenceof mutations were well enough known. This is thereverse of the procedure that is necessary to cstimate
first-generation risk from equilibrium risk by theindirect method. Persistence, however, is rather wellknown only for the better understood diseases, such as
those caused by simple dominants. For these, it isthought to be about 5 generations, although this isvery dependent on the specific disorder. In the past,
the Committee assunled that mutations responsible fordisorders of complex aetiology persist for about 1 0
generations [U3], but this is an especially uncertain
estimate. The discussion of multifactorial disease andnon-traditional inheritance in this Annex underlines thedifficulty of understanding the persistence of mutations
that cause serious genetic diseases in humans.

285. In view of these uncertainties, no attempt ismade to estimate risk at genetic equilibrium using thedirect method. An equilibrium estimate is probably
much less necessary for reaching decisions than afirst-generation estimate, since as knowledge of genetics and medicine advances, ways may be found to
reduce future impacts. As noted elsewhere, it would be
useful to extend the direct method to at least a few
later generations by measuring induced dominantdamage following radiation exposure of successive
generations.
6.

blouse versus human genes

286. Comparisons between humans and mice havebeen extremely useful in understanding development
and genetic disease. The homology and sequenceconservation between mouse and human genes is
extensive. However, there are also notable differencesin
expression ofdisuse
Several oftbe
h u m a n discsse mutations (e.g. neure
fibrornatosis) are not observed in mice. The most frequent mouse mutations (e.g. W locus) are rarely seen
in humans. Furthermore, a number of human disease
genes have been isolated, the abnormal mouse homologues of which do not produce any alteration inphenotype (e.g. Ducheme muscular dystrophy and
Lcsch Nyhan disease). Thus, the same mutation may

UNSCEAR 1993 REPORT

772

lead to disease in one species but not in another. Therealso appear to be niarkcd strain differences in micewith regard to Ule severity of the phenotypic defectproduced by a particular gene mutation. This type ofstrain variation in mice is probably comparable to theethnic differences observed in humans [Lll].

287. In addition to differences in disease phenotypes,
there are also significant ditrcrences between mice andhumans in early developmental processes, placentation and types of congenital anomalies. For instance,
monozygous twinning is rare in most strains of micebut occurs quite frequently in humans [N2].

D.

GENETIC RISK ESTIMATES

288. Some new information relevant to estimating thegenetic effects of radiation has been presented in thisAnnex. There has, however, been no reason to revise
the risk estimates, although the uncertainties could
well be widened in view of the many complexities thatare emerging. The genetic risk estimates of theCommittee are summarized here and compared withthose of other groups, national and international.
1. Estimates of UNSCEAR(a)

Dominant and X-linked diseuses289. The Committee has not changed its estimate of
the incidence of dominant and X-linked diseases in the
population since the UNSCEAR 1972 Report [U5].
This value of 10,000 cases per million live births
divided by the doubling dose of 1 Gy, multiplied by amutational component of 100% for these diseases andby a continuing dose of 0.01 Gy per generation gives
an equilibrium estimate of 100 cases per million live
births. The first generation increment (15 cases per
million live births) is assumed to be 15% of that at
equilibrium and the second generation increment (13cases per million live births) is 15% of the equilibrium
less the first generation cases (100-15 cases per
million live births). These results are listed in Table 5.

(b) Recessive diseases
290. The Committee has estimated that autosomal
recessive diseases occur at a rate of 2,500 per million
live births. Calculations based on a combination ofdata from observations on human populations andfrom mouse experiments suggested that an extra doseof 0.01 Gy of low-LET radiation to each parent in astable population with a million live-born offspring
would induce up to 1,200 extra recessive mutations[S16]. From these data it was calculated thatpartnership with an established or newly induced

recessive allele in the population would produce about
one extra child with a recessive disorder in thefollowing 10 gcnerations (per million horn in eachgeneration). About 10 extra cases of recessive diseases
would be cxpectcd fro111 U~is dose by the tenthgeneration, a s s u ~ n i ~about~ g 1% of first-cousin matings.
(c)Chmmosonial disenses

291. Based on extensive cytogenic data from buman
populations, the Conirnittce estimated that visible
structural anomalies or unbalanced translocations occur
at the rate of 400 per inilliori live births [Ul, U2, U3].
The indirect method of estimation (doubling dose of
1 Gy) thus gives an incidence rate at equilibrium of 4
cases per million live births from a continuing dose
rate of 0.01 Gy per generation. The first-generation
increment has been assumed to be three fifths of theequilibrium value [U3], giving 2.4 cases per million
live births, The second-generation increment is Uuee
fifths of the remainder: 3/5 x (4 - 2.4) = 1 case per
million live births.
292. The estimate of genetic risk was based onevidence that about 9% of individuals with unbalanced
chromosome rearrangements survive to birth. The
question of how many such rearrangements can be
induced by radiation is not easily answered. Comparative studies in mice, rhesus monkeys, marmoset
nionkeys, crab-eating monkeys and human males haverevcalcd striking differences (see thc UNSCEAR 1986
Report [U2],Table 21, page 128). One interesting
point should be noted: many spontaneously occurringtranslocations in humans are Robertsonian in type, but
it has been concluded from mouse data h a t radiation
does not induce such Robertsonian translocations[F16].
293. For numerical chromosomal diseases (mainly
trisomies), the Committee has used a figure for thecurrent incidence of 3,400 per million live births [U2].
The increase following radiation exposure could not becalculated but was assumed to be very small, based onmouse data. The human data from the Japanese studies
also support a small risk.
294. Studics in the mouse have shown that the rates
of aneuploidy induction in male and female germ cellsby radiation were of the same order of magnitude(2-7
per Gy) and were not very different fromthose reported by various authors for translocationinduction in spcrmatogonia [PI]. The oocyte, whenirradiated at t l ~ etime of fertilization, is especiallysusceptible to chrornosonic loss, especially loss of thehuman
X-chroniosonie. However, most mo~~osomic
zygotes do not survive early pregnancy; even the great
majority of surviving 45 X-zygotes are thought to be
attributable not to nondisjunction or chromosome loss
during meiosis but to mitotic events during earlyANNID'. G: IIEKEDITAKY EFFECTS 01: RADIATION

pregnancy. Moreover, most trisomics do not survive tobirth [H9]. Hence, in view of the well-known highincidence of chromosomal anomalies among spontarieous abortions, any radiation-induced increase in
noridisjunction and/or early chromosome loss is likely
to lead to an increase in the rate of spontaneousabortion rather than to more chromosornally abnormal
newborns, as explained in greater detail in earlier
UNSCEAR Reports. This conclusion is conoboratcd
by a study in the mouse [Rl], in which the frequencyof chromosomal radiation effects was followed fromzygotes to early and late embryos. The fraction ofchromosomally disturbed gem1 cells, which was very
high at the beginning, was found to be practically zeroin embryos surviving to birth.
295. In the UNSCEAR 1982 Report [U3] (Table 8,
page 525), 1 2 studies were listed that addressed thequestion of whether pre-conceptual irradiation of
mothers increases the incidence of Down's syndrome.
Four studies described a significant increase in thissyndrome; eight studies failed to show such an effect.
The studies included wonlen who had been exposed atsome time in their lives to small doses of radiation for
medical reasons. Obviously, they were not an unbiased
population sample; there is ample opportunity for theaction of confounding variables. On the other hand,the data do not allow dismissing the possibility that
low radiation doses enhance the risk for autosomal
nondisjunction in female human meiosis, at least undercertain conditions (see also the studies of populations
living in areas of high natural background radiation inIndia and China, discussed in Section III.A.2). The
Japanese data do not support an increased risk forlive-borns with trisomics.

(d)Congenital
diseasesanomalies

andmultifactorial

296. In the UNSCEAR 1988 Report P I ] , the Committee estimated the incidence of congenital anomalies
and multifactorial diseases to be 60,000 and 600,000
per million live births, respectively, but did not
estimate the increase caused by radiation [Ul]. In the
UNSCEAR 1977 and 1982 Reports [U4, U3] theCommittee had used a doubling dose of 1 Gy and amutational component of 5%, but the uncertainties did
not justify continuing this procedure, given the higher
estimated incidence of these conditions of varying
seriousness that can arise throughout a lifetime. The
study of the survivors of the atomic bombings inJapan indicates no increase in congenital anomalies ormultifactorial disorders subsequent to parental irradiation [N8, N9]. In theory, a system of continuous
registration of these conditions that is complemented
by ad hoc studies on special problems, such as genetic
data (for example empirical risks in families) or envi-

773

ronniental factors (radiation, drugs and environmental
chemicals), is the best system for answering questionsof incidence and causation. However, in view of thecomplex genetic basis of most malformations and of
multifactorial diseases, it is impossible to estimate
incrcascs caused by radiation, and no such estimate
was attempted in the UNSCEAR 1988 Report [Ul].

2.

Estimates of BEIR. I C R P AND NUREC

297. While the BEIR I11 Committee [C2] reliedmostly on the direct method to estimate firstgeneratio~irisk for genetic disorders and traits thatcause a serious handicap at some time during a lifetime, the BEIR V Committee [Cl] described the direct
method but stated that the "Committee had little
confidence in the reliability of the individual assumptions required by the direct method let alone theproduct of a long chain of uncertain estimates that
follow from these assumptions. Therefore, they did notplace heavy reliance on the direct method in making
their risk estimates, but used it only as a test of
consistency". The BEIR V Committee discussed relatively few of the many assumptions used in the indirect
method, which it did apply. In contrast, the UnitedStates Nuclear Regulatory Commission report [NlO],
in discussing the BEIR V report, noted that the direct
method involved fewer uncertainties than the indirect
and was thus preferable.
298. The BEIR V report presented a much higher
cunent incidence for genetic disorders than the
UNSCEAR 1988 Report [Ul] (Table 5). It concluded
that the current incidence is 1,247,300 genetic effects
per million live-born offspring. Risk was not estimatedfor the 1,200,000 of these effects that consisted ofheart disease, cancer and selected other diseases.
Regarding these three categories, they concluded asfollows: m e magnitude of the genetic component insusceptibility to heart disease and other disorders withcomplex aetiologies is unknown. Because of great
uncertainties in the mutational component of these
traits and other complexities, the committee has notmade quantitative risk estimates for them. The risks
may be negligibly small, or they may be as large orlarger than the risks for all other traits combined". For
the remaining genetic disorders (current incidence of
47,300 pcr million), the estimate of first-generation
risk of radiation-induced genetic effects per 0.01 Sv of
exposure was between 16 to 53 per million live births(Table 5). Of that total, between 1 and 15 were
estimated to be clinically mild.
299. The risk of congenital anomalies was given in
the BEIR V report [ C l ] as about 10 in the first generation and 10-100 at equilibrium for 0.01 Sv ofadditional radiation. These estimates assumed that then4

UNSCEAR 1993 REPORT

relevant malforniations consist of those caused in partby multifactorial inheritance in combination with athreshold and in part by irregularly manifesting
dominant mutations. The overall mutational component
was estimated to be between 5% and 35%. The upper
limit (35%) was then used to estimate the increase(Table 5). The result is quite uncertain. Moreover, theargument is based in part on results of twin studies,
which are misleading for congenital malformations
since the background incidence of most congenitalabnormalities is increased in monozygous twinning,apparently because of the special conditions that
produce monozygotic twin pregnancies [VlO].
300. The ICRP estimated the component of risk for
multifactorial diseases Gom radiation exposure to be
0.5
SV-' and the total for severe hereditary effects
for all generations to be 1 loe2 SV-' (see Annex B inPI]). The ICRP risk coefficients p l , S44] reliedheavily on the UNSCEAR 1988 risk estimates [Ul],with some important additions. The effect of 0.01 Gy
per generation per million live births on the incidenceof Mendelian and chromosomal diseases was taken to
be 120 at equilibrium [S44], as in Table 5. The naturalprevalence of congenital abnormalities was taken to be695, as in Table 5, and of other multifactorial disorders
65%. Assuming a doubling dose of 1 Gy of low-doserate, low-LET radiation, an average mutational component of 5% and a weighting factor of one third forseverity of effects, the risk coefficient for all
multifactorial diseases, including congenital anomalies,
becomes 120 per million live births at equilibrium for
exposure to 0.01 Gy per generation [Il, S44], or
1.2 10.' SV-l. The total risk coefficient for all
Mendelian, chromosomal and multifactorial diseases isthus 2 4
SV-' at equilibrium. However, when the
total population is considered, the genetically significant dose will be markedly lower than the total dose
received over a lifetime. If it is assumed that the mean
age at reproduction is 3 0 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. The risk
coefficient for the total population is thus 0.4 x
2.4SV-', or 1 lo-' SV-' at equilibrium, i.e. whenthe effects are summed over all generations [Il, S441.
The corresponding risk coefficient summed over theSV-l.
f i s t two generations only would be 0.2
301. The NUREG Committee [NlO] expressed genetic
risk per 480,000 live births instead of per million live
births. This figure is an estimate of first generation
offipring in the United States, predicted from the 1978
demographic data of 1 million persons of all ages (i.e.
16,000 live births per year for 30 years). Its combined
first-generation risk estimate for single-gene disorders,chromosome aberrations (including aneuploidy) andcongenital abnormalities was 30 radiation-induced
genetic disorders, and its first-generation estimate forselected irregularly inherited diseases (having a normal
incidence of 576,000 per 480,000 live births, which isequivalent to the current incidences used by the
BEIR V Con~mittee),was 35 radiation-induced genetic
disorders. The Committee stressed the "extremely
tenuous nature of Uiese numerical estimates for diseases of complcx aetiology in light of the very large
uncertainties involved" [Nl 01.
302. The NUREG Committee pointed out that its
estimate of risk from unbalanced translocations, aswell as the estimate in the UNSCEAR 1988 Report[Ul], was based on an estimate of the -frequency ofbalanced translocations at least an order of magnitude
higher than that actually observed cytologically in theoffspring of the atomic bomb survivors [A7]. It thus
may be that the risk estimates in the UNSCEAR 1988
Report [Ul] for this category of genetic disease are
too high.

3.

Resvulltntion of doubling dose estimatesin mice a n d humans

303. It has been suggested that, for humans, thedoubling dose of acute low-LET ionizing radiation of
the gonads is 0.3-0.4 Sv, with limits of 0.1-1 Sv [Cl,U2]. That estimate appears to be based primarily on
the data summarized by Luning and Searle [ M I ,namely, data on semi-sterility (i.e. reciprocal translocation~),the seven-locus (or specific locus) system ofRussell [R4], dominant visible mutations recovered in
the course of specific-locus studies, dominant skeletal
mutations and recessive lethals. The average of thesevalues was 0.31 Sv. When a dose-rate reduction factorof 3 was cmployed for conversion to the effect ofchronic radiation, the doubling dose for chronic and/orintermittent radiation was about 1 Sv, with lower andupper limits of 0.3 and 3 Sv. It has been suggested
that for chronic radiation the doubling dose is not lessthan 1 Sv [Cl]. This estimate was based on a wider
variety of end-points of genetic damage than thoseused by Luning and Searle, and the confidence limits
for some of the additional end-points were very wide.

304. In view of the apparent discrepancy between
these estimates and those resulting from the follow-up
studies on the children of atomic bomb survivors, Nee1and Lewis [N7] compared the findings on mice andhumans point-by-point. They concluded that becauseof biological differences between the two species, aprecise comparison was impossible for many endpoints. For instance, the newborn mouse corresponds
roughly, in terms of development, to a human fetus at
100 days of gestation [N7]. The data on congenital
malformations in mouse fetuses following paternal
irradiation were obtained by sacrificing pregnant miceat day 18 or 19 of gestation, equivalent to less than100 days of hunian fetal dcvelopnicnt [K5. K6].
Because in humans some fraction of the corresponding
defects would be lost through early miscarriage and in
most studies go unrecorded, and bccailsc the very
immature mouse fetus cannot be subjected to the sanic
type of physical examination as a newborn i ~ ~ f ; ~the~it,mouse and human data are not cornparablc. Furthcrmore, the polytocous nature of mousc reproduction
results in pre- and postnatal competition between litter
mates, which does not exist in humans. This compctition renders a cornparison of the two species withrespect to postnatal mortality following radiation
uncertain and complicates any cxtrapolatio~i.Finally,
since several of the mouse strains employed in radiation research were originally dcvclopcd for research on
cancer, it may not be entirely valid to compare theresults of Nomura [N14, N15] on mice with the rcsulls
obtained in Hiroshima and Nagasaki, particularly since
the tunlour types that dominate Nomura's data are notthosc associated with genn-line mutations in humans.
305. Given the mailncr in which the recent estimate of
the human genetic doubling dose resulting from acuteradiation (the Japanese studies) was derived, themouse estimate that would seem to be most comparable to the human would be that based on locus-spccific phenotype studies. In Table 6, the findings foreight different types of locus-specific phenotype
studies in the mousc are compared. These studies areof rather uneven informational content, and sonic notquite congruous studies are combined, particularly
those in which the results had not previously been
incorporated into doubling dose estimates. The simple,
unweighted average of the results of these eight typesof tests is 1.35 Gy. Applying the dose rate factor of 3
customarily applied to such data in the light of the results of Russell et al. [R6], the estimate of the murinc
genetic doubling dose of chronic ionizing radiation
becomes about 4 Gy. As for the human data, it is difficult to develop a precise error term for thcse data.

locus niutability arc beginning to emerge for humans[N7].Thus, it should not be regarded as surprising if
different systems yield different estimates, and there isno objcctivc basis for preferring the results G o n ~onesystcni ovcr thosc dcrivcd lrom another.
308. This sunimary of the mouse data indicates theneed to consider the results from many systems inarriving at a balanced view of the genetic cffccts ofradiation. It should be notcd that the studies in Japan(Section 1II.A.1) irivolve end-points that reflect the
input of many loci. There may, however, be an additional rcason for differences between the results of thedifferent lilouse systems: inadvertent selection in someof the rnurine systcnis of the more mutable loci forstudy. For exa~iiple, the valuable and much uscd
seven-locus test system dcvcloped by Russell [R5]wasdcvcloped on the basis of known, contrasting phenotypes associated with each of the loci in question. This
was the key to developing the test crosses, which
pennittcd rapid locus scoring for mutation. It now
seems possible that this derivation of the system may
have introduced inadvertent selection for loci withrelatively high spontaneous and induced mutation
rates. This and the possible strain differences in miceagain raises the question of ethnic differcnces inhumans: could different genelic backgrounds result inloci with differing susceptibility to mutation?
309. Although the error in both the mouse and humanestimates is, for various reasons, indeterminate but
presumably large, these considerations, in the view of
Nee1 and Lewis, may bring the mouse and humanresults into much better congruence than appeared tobe the case in the past. There is, of course, no rcasoll
why two species differing in as many respects as niice
and humans should have identical doubling doses, butthere is also no rcason 10 think they should beunequal. Given the difference in the end-points uscd
for the two species, this congruence is somewhat
surprising and should be regarded with caution.

306. The potential difference between acute and chronic exposure and between different types of radiationneeds further study. Scarle and Edwards IS161 inparticular have shown an increase in translocations
with protracted exposure to low levels of high-LET
radiation (i.e. alpha particles and fission neutrons).
307. It will be notcd that the results obtained withdifferent test systems appear to vary widely. Since forseveral of these estimates (e.g. clcctrophorctic variants
and recessive visible mutations), only a single mutation has been encountered in the controls, the error of
the estimate is large. There may also be real differences between systems. The data of Russell et al. [R5]
indicate significant differences among the seven lociin their syslem with reference to radiation-induced
rates. Similar data on locus differences in spontaneous

4.

Molecular biological developments

310. Sankaranarayanan [S3, S4, S5, S6, S7] considered at length the impact of molecular biology on
b e estimation of genetic risk from ionizing radiationand made a number of p i n k . In genetic risk estimation, adverse genetic consequences have gcncrally
been vicwcd through the prism of naturally occurring
gcl~etictliseascs. The co~lccpt of radiation-induccd
genetic disease relies on the premise that the types of
events induced are similar to those arising spontaneously; this was supported by the recovery in expcrimental systems of induced mutations at selected geneloci, the phenotypes of which were similar lo thosc of
spontaneous mutations. This idea continues to catalyse

7 6

'

UNSCMR 1993 REPORT

the search for increases in the frequencies of known
dominant or X-linked genetic diseases in human populations exposed to radiation (e.g. as a result of theChernobyl accident [C15] and the atomic bombings ofHiroshima and Nagasaki).

(c)

311. However, as discussed in Section II.C, molecular
data for Mendelian diseases and for radiation-induced
mutations in experimental systems now demonstratethat (a) while the types of events are indeed similar,
those that lead to naturally occurring Mendeliandiseases show specificities both in their distribution
and their mechanisms of origin and @) the overlap inmechanisms between spontaneous and induced mutations may be small. Thus, the probability that ionizing
radiation will induce the specific mutations that resultin known Mendelian diseases is likely to be small. It
is not to be implied that gonadal radiation exposures
have no adverse genetic effects. Rather, the message
is that the frame of reference used, namely naturally
occurring Mendelian diseases, may not be entirely
adequate [S7].

314. Again, as emphasized above, the growing understanding of non-traditional mechanisms by which
genetic diseases may arise (see Section 1.D) has
introduced another dimension of complexity and may
influence estimations of genetic risk, depending on
how these mechanisms respond to radiation.

312. With regard to the two standard methods of risk
estimation using animal models the following may be
noted. The size of the multiplication factor used in the .
direct method is partly based on an understanding of
the relative damage to different body systems fromspontaneous mutations. As noted earlier, the, estimateof this is uncertain. It would be subject to additional
uncertainty if the very large numbers of genes that canmutate to cause damage to different body systems
respond to radiation damage to very different extents.

313. With the doubling dose method, the risk isestimated by multiplying the natural prevalence ofautosomal dominant and X-linked diseases by the
relative mutation risk. A number of arguments suggestthat the value of the natural prevalence may need tobe revised downwards and that of the doubling dose
upwards: as a consequence, the estimate of risk will
be lower than at present. These arguments are as
follows:(a)@)

since radiation generally induces deletions, andassuming that only about 50% of naturally occurring Mendelian diseases are due to deletions,clearly the value of the natural prevalence usedin the risk estimation should be lower, pertaining
only to the subset of genes that are responsive to
induced deletions;the estimate for a doubling dose of 1 Sv is based
primarily on mouse data for recessive visible
mutations at seven loci, which may be moremutable than most genes. Genes that mutate torecessives have been observed to do so at ahigher rate than those that mutate to dominants.

This suggests that if a doubling dose based onrecessives is uscd for estimating the risk of
dominant gcrletic discase, the risk will be overestima ted;
the risk estimation used in the doubling dose
mcthod assumcs lhat genes that mutate at highrates spontaneously will also mutate at high frequencies after irradiation. This assumption is
open to doubt. A high spontaneous rate depends,
anlong other factors, on the size and sequence ofthe gene and on the types of mutational mechanisms involved. A high induction rate is more
dependent on whether a random change in thegene can give rise to the phenotype being
measured [S7j.

315. Two main methods have been used in animal
experiments (primarily mouse) that attempt to quantify
genetic risk from exposure to radiation: the doublingdose (also referred to as the indirect) method and theso-called direct method. Both methods involve collecting similar or identical data on radiation exposures andabnormalities in offspring. However, they use different
approaches in extrapolating animal data to humans.
The terms direct and indirect refer to whether theestimate of darnage in the first generation is based
directly on phenotypic damage found in mice in firstgeneration progeny (direct method) or whether it isbased on extrapolation back to the first generationfrom a prediction at genetic equilibrium (indirect
melhod). Although the frequency of harmful effects
from induced mutations (from the exposure of a single
generation) would be expected to decrease beyond thefirst generation, owing to negative selection, it should
be kept in mind that some of the genetic effects ofradiation, e.g. aneuploid segregants from certain translocations, or mutations leading to abnormal imprinting
in gametes of first generation offspring, might not
manifest until the second or subsequent generations.

316. The doubling dose (or indirect) method of genetic risk estimation expresses risk in relation to thenatural incidence of mutations and genetic diseases
that are evident at birth in the general population. The
doubling dose is the arnount of radiation necessary to
produce twice as many niutations as would occur
sponta~~eously
in the population in a generation. It is
obtained by dividing the average rate of spontaneousANNM G: IIEREDITARYEFFECTS OF IIADIAT~ON

mutations at a given set of gene loci by the rate ofinduction of mutations at the same set of loci. The
reciprocal of the doubling dose is the relative niutation
risk. A low doubling dose means a high relative niutalion risk, and vice versa. This nlethod is generally
used to estimate risks under equilibrium co~~ditions.
The currently used doubling dose estimate, 1 Sv, forlow-dose-rate or chronic exposures to sparsely ionizing
radiation such as x rays or gamma rays is based primarily on mouse data on autosomal recessive mutations at seven specific loci and is expected to be atleast of the correct order of magnitude. One difficultyof the doubling dose method in estimating the risk of
autosomal dominant and X-linked diseases in man isto specify correctly the mutational component, or thecomponent of a given disorder that is due to genetic
mutation.

317. In the direct method, the estimated ratcs of
induction of domil~aritmutations affecting the skcleton
or causing cataracts in the eye of the mouse are used
to derive estimates of the total risk of dominant genetic disease to the first-generation (F,) progeny of an
exposed human population. Assumptions about the'persistence of mutations in the population, however,
could permit extrapolating first-generation esliniales tolater generations. The direct method and the doublingdose method each has its inherent advantages and disadvantages in using the results of animal cxperiments
to calculate the risks in humans of induction of hereditary disorders caused by radiation. It is thus
recommended that both methods continue to be usedand compared. Caution should be exercised, however,when extrapolating mouse studies to humans: there arenotable differences between mice and humans in disease expression, early development, placentation andtypes of congenital anomalies that are most frequent.
There are also strain differences in rnicc, which areprobably comparable to ethnic differences in humans.

IV.
A.

n7

318. Whilc people who have been exposed to radiation have been shown to suffer direct effects fromexposure, such as increascd cancer rates, the data on
survivors of Uie atomic bon~bingsindicate that acutc
irradiation will1 moderate doses of iol~izingradiation
has a negligible adverse effect on the health of thesubsequent generation. A number of different indicators, such as untoward pregnancy outcome, cancer in the children of exposed parents and mutations
affecting certain protein charackristics, have been used
to infer doubling doses. Several types of analyses ofseven data sets failed to reveal a statisticallysignificant effect of parental radiation for various
indicators. The average combined gonadal dose of
acute ionizing radiation received by the proximally
exposed parents (0.4 Sv) approximates that which inthe past had been estimated to be a genetic doublingdose for mice. The statistical power of these studies issuch that the absence of an effect of parental exposure
to the atomic bombings on any of the indicators
suggests humans may not be as sensitive to the genetic
effects of radiation as has for some years been
projected on the basis of niurine doubling-dose data.

319. The estimate obtained from the studies on theatomic bomb survivors suggests that a doubling dose
estimate for humans of between 1.7 and 2.2 Sv foracute irradiation and 4.0 Sv for chronic exposure,should be used. It also suggests that the genes used in
the specific locus studies in mice may be more radiosensitive than most genes in humans. Studies of populations living in areas of high background radiation, or
exposed to radiation through accidents, support theconclusions from the Japanese studies, i.e. that humans
have little risk of hereditary damage from moderately
low exposures to ionizing radiation, The potential
differe~lcesbetween acutc and chronic exposures andbetween different types of radiation require further
study.

FUTURE PERSPECTIVES

MOLECULAR INVESTIGATIONS

320. S o far, the hereditary effects of radialion havebeen discussed and assessed mainly at the level ofphenotypes. Indced, changes in phenotypes are ofprimary interest to society. There are, however,complex problems of methodology in cstirnatirig such
effects, as discussed in the previous Chapters. Many
uncertainties have to be bridged by assumptions andextrapolations. On the other hand, basic research ingenetics, and especially in human genetics, is concentrating more and more on the structure of genes Ihem-

selves arid their products. To allow using these newtechnologies in testing for radiation effects, newapproaches have been, or are being, developed at thelevels of gene DNA and proteins.

321. In view of Ihe difficulties in assessing mutational
effects at the phenotypic arid gene-product levels, on the
one hand, and recent progress in studying DNA
sequences directly, on Ihe other, it is not surprising thatthe possibility of studying possible radiation errccls
directly in the DNA has bcen explored. A number ofapproaclies have been suggested, including the following:ANNEX G: HEREDITARY EI'IXCIS OF R A D I A ~ O N

nsimplications of the information. The purpose of thesestudics is to anticipate and address implications forindividuals and society in arcas such as healthirisura~iccarid pre~~atal
testing and will develop policy
options, c.g. in areas where there might be conflict of
328. The riiapping a ~ i dsequencirig of I I O I I - ~ I U ~ ~ I I ~ interest, to ensure that the inronnation is used for the
benefit of individuals and society [Ull 1.
genomcs will allow scientists to work with si~riplcr
systems (i.e. smaller genomes) and to nianipulate and330. The Human Genome Project is expected to havc
study the structure and function of mapped gcncs inat least four corollary benefits [WS]:the intact organism, which is cxtrcniely difficult to doin humans. Because many essential genes arc largely
conserved over species boundaries, insights gained(a) it will provide a direct method for analyzing
mutation rates, as well as the effects of particularfrom animal models can onen be applied to the study
mutagens (including radiation), using humanof human genes [C4]. According to researchers whc
DNA. Thus, risk estimates will be far more acsupport the project, the traditional manner of searching
curate than at present, and the various complifor an abnormal gene is unnecessarily coslly andcating factors will be able to be defined andwasteful of the scientist's time; it is, moreover, pracanalysed individually;tically untenable for genetically complex defects suchas Alzheimer's disease, cancer or schizophrenia [C8]. (b) new laboratory technologies will be developed toachieve the goals of the project;
A positional approach (as opposed to a functional
approach) makes it possible to isolate the abnormal(c) new computer technology will be applied toniolecular biology. with a concomitant dcvelopgenes when the structure and function of the gene prornent of new hardware, software and databaseduct are unknown. It was the positional mclhod thatdesigns to support arid facilitate thc massive
led to the cloning of the genes for cystic fibrosis andscale of the u~tdertaking;neurofibromatosis. It has an even greater advantage forpolygenic and multifactorial disordcrs [a].
(d) the identification and cloning of medically andbiologically important genes will, in turn, furnish
scientists with material for research on their329. The long-term goal of the project is to sequence
identity, structure and function for many years to
the entire human genome. The urtdertaking should be
come.
Froni the standpoint of the hereditarycompleted in 15 years [W5].
Because the information
effectsof radiation, it is expected that once thegained from the mapping and sequencing of genes forhumangenome has becn sequenced, a muchhuman disease, as well as for traits such as sex andbetterunderstanding of radiation biology,
intelligence, will havc profound social implications,susceptible
areas of the human genome and the
3%7% of the budgets for most genome projects havetracingofsuspected
damage will be possible.
becn allocated for studying the ethical, legal and social

panels of genetic markers, along with scquc~tcctaggedsites, to be used in positioning a genetic defect, greatly
facilitating the identification of gcncs for spccificdiseascs and malforniations.

CONCLUSIONS
331. The present situation in radiation genetic risk
estimation can be summarized as follows: (a) cunellt
risk estimates for Mendelian diseases appear to beconservative and to provide an adequate margin ofsafety in radiation protection; and @) while none of
the methods used for risk cstiniation is free of
uncertainties, in the absence of more reliable methods
it would not be prudent to abandon any of theapproaches or to alter the risk estimates presented in
the UNSCEAR 1986 and 1988 Reports [U2, Ul]. New
data and understanding have served primarily toincrease the complexity of the task of risk estimation.

332 Some relatively reliable data are available on theincidencr: of chromoson~alabemtions and on a few rare
dominant or X-linked conditions (sentinel niutadons) inhutnans. It is, ia principle, possible to determine thebackground sponta~icousincidence of congenital anomalics
at birth in a human population However, to do so requires
a sophisticated logistical network that includes, aniong
other things, a precise definition of end-points. To allow
comparing data fro111various cou~ilriesand different time
periods within the same country, uilemational coordinationis necessary. The Hungarian registry is a good example ofa ~iationalsaccrtirig system.

333. Even with data from such a system at hand, it is
not yet possible to predict an increase in the incidenceof congenital anomalies attributable to a spccific exposure of the gonads to radiation, since such a prediction would require esti~natiagh e mutational cornpo~ientof such all increase. An estimation of this corn-

780

UNSCEAR 1993 UEPOHT

ponent would in turn require much more Ihoroughknowledge of the genetic basis of these anonlalies andthe involvement of environnlental factors.
334. Observations on human populations and experiments with animals are improving risk estimation;
however, both of these methods require considerable
extrapolation: from a very few sentinel mutations to
all genetic disease, and from animal to human. It
must, therefore, be kept firmly in [nilid that both thedirect and the doubling dose method still provide only
rough estimates of risk. Because both methods require
extrapolation and estimation, the terms direct andindirect (or doubling dose) are not entirely accurate. It
might be more appropriate to refer to the two methods
as the absolute method and the relative method, or
perhaps as the first-generation method arid the equilibrium method.

335. The direct and doubling dose methods haveyielded risk estimates that are of a similar order ofmagnitude; because each method has its advantages
and drawbacks, it would seem prudent to continue
using both to derive information that is as complete as
possible. The estimates obtained should be regarded aslower limits, with the caveat that radiation effects on
multifactorial disease, gene regulation and nontraditional forms of inheritance are not well understood and may require different methods of estimation.
336. One purpose of this Annex has been to point out
the difficulties that are inherent in any attempt toquantitatively predict the health hazards to future
generations caused by exposures to ionizing radiation.
Such predictions, based on extrapolations fiom animal
experiments and on the direct observation of exposed
population groups, are possible in genetically simple
and straightfonvard situations, such as for cytogenetically visible chromosomal aberrations or rare dominant and X-linked diseases. For all other groups of
diseases, such an estimate is not yet possible and willprobably remain impossible for some time to come.
The studies on the children of atomic bomb survivors
at Hiroshima and Nagasaki suggest that the adverse
effects on the f i s t generation of progeny Gom a single
moderate radiation dose will probably be only minor.
A more specific statement cannot be made at this time.

337. When considering mutations on the molecularlevel, several points should be kept in mind. The relative frequency of the various molecular changes seenin spontaneous mutation differs from that seen inradiation-induced mutation. It has been noted that most
spontaneous mutations tend to be small point mutations, while a majority of radiation-induced mutations
are larger DNA deletions. The fact that radiation-induced mutations are likely to differ from spontaneous
mutations in the type of mutation produced, Gequency
and sites affected, and in the disease phenotypes pro-

duced, must also be considered and, in fact, expectedin any attempt at risk estimation. It should also be
kept in niind U~atalmost all work done on the effects
of gcrni-cell irradiation on phenotypic damage inprogeny has been done in males; fe~nalegerm cells
may have very differerit susceptibility to differerit
types of induced mutation at different stages,
particularly during in lrtero developmerit of the female.
These points offer convincing arguments that a simple,
direct correlation between the number of mutations
arid the degree of mutation damage would be exceedingly difficult, if not impossible, in both animal andhuman studies.

338. Many newly recognized mechanisms of gene
regulation and genetic disease in humans were notknown by classical geneticists and thus have not been
considered in previous estinlates of genetic risk. They
could, however, be significantly affected by radiation.
Any estimation of risk must understand and consider
these additional potential sources of hereditary disease;
however the current state of knowledge of non-traditional mechanisms such as genomic imprinting andallelic expansion (see Section 1.D) is limited. It may
be assumed that these mechanisms could have transgenerational effects and would not necessarily manifest in the FI or even the F2 generation, but h e r e arefew data with which to quantify risk.

339. From a purely scientific point of view, then, theproblem cannot be defined more precisely at this time,and numerous questions require further examination.
Thus, risk estimates can be made only with great uncertainty. It remains impossible to make any responsible statement on the morbidity of genetic effects in
middle and advanced age in humans, but a preliminary
statement regarding morbidity and mortality in young
age might be attempted. Almost the only empirical
data available for such an estimate are the data onchildren of survivors of the atomic bombings at Hiroshima and Nagasaki, since the extensive experimental
animal work can only approximate effects in humans.
340. The study of children of the atomic bomb survivors has shown that the long-term monitoring of
cerhin risk groups is possible. However, despite arelatively large sample size and exposure to relatively
high radiation doses, the outcome of this study has
been largely negative so far; i.e. it has found little orno convincing evidence that radiation influences theincidence of congenital malformations (or other rnultifactorial conditions). In view of this result, it canhardly be imagined that an even larger risk groupwould lead to positive findings. Studies on populations
living in areas of high natural background radiation invarious parts of the world, such as China, Brazil andsouthern India, have also demonstrated no clear evidence of any genetic risk Gonl exposure to radiation.

ANNW G: HEREDITARY EFFECIS 0
1' IblDIATION

341. The situation for multifactorial diseases, which
include not only congenital dkorders but also disorders
with onset at all ages, is still more difficult. Complex
systems of intertwined genetic polyniorphisnls in
combination with a great variety of mutations leading todisease in human populations are becoming evident tomedical genetic researchers. Esti~natcsof incidence andeven prevalence in a population critically depend on
parameters such as the definition of disease in generaland the delineation of diseases from the range of normal
variability of conditions. Moreover, epidemiologicalresearch has shown that the incidence and prevalel~ceofmany such diseases differ from one population toanother, and even within the same population from one
time period to another, mainly owing to environmental
factors.
342 A serics of recommendations can be formulated toassist future attempts at risk estimation. It is first of allrecommended that studies in both mice and humans ofgenetic damage due to radiation should be carried to themolecular level. Information from the Human Genome
Project will bc especially helpful in this regard. Since it
is now possible to deterniine which chromosonies were
inherited from which parent, it can be determined on amolecular level whether a mutation in a child wasinherited fkom the parent with higher exposure toradiation,
343. However, it is likely to be a long time before thefindings of the Human Genome Project provide
definitive ways of cstirnating genetic risk from radiation.
In the meantime, infomiation is needed on the possibility
that radiation induces mutations that cause specificgenetic disorders with non-traditional inheritance. If it
can be shown that some mechanisms leading toabnormal development differ considerably between miceand humans, experiments must bc designed to indicate
whether such differences are likely to lead to
substantially different radiation risks in the two species.
Taking mouse studies to a molecular level would help tomake this comparison.

781

to cancer. More animal experiments are also needed todetermine the risk of nondisjunction, Robertsoniantranslocations, autosomal recessive mutations nianifestingin subsequerit generations and the role of radiation in
upsetting r~ontraditiol~al mecllanisrns of disease
inheritance, such as genoniic imprinting and transposable
elements.
346. Several obvious gaps in knowledge exist regarding
the induction of doniinant phenotypic damage. Until suchdamage is measured in offspring following the irradiationof oocytcs (probably mature arid maturing oocytes inmice), the direct method can be applied to women only
by assuming that the relationship between the sexes is
the same as predicted from specific-locus results.
Estimates are needed for the phenotypic damage that
results when both males and females are exposed tohigh-LET radiation.
347. Additional experiments using different strains ofniice or olher small experimental mammals could
indicate the extent to which genetic background
determines the overall level of induced doniinant genetic
damage. It would also be usehl to determine the extent
of induced phenotypic damage following several
successive generations of radiation exposure. Such rcsults
could validate the assumptions used in extrapolatingfrom the first-generation direct estimate to later
generations.

348. It is known that Mendelian diseases in mammals
can be induced by radiation. It seems likely that risk
estimation can become more precise as more humangenes arc sequenced, mutation spectra analysed andmechanisms uruavelled. It is therefore essential thatscientists making genetic risk estimates keep abreast of
progress in molecular biology.
349. New mouse in vivo lest systems should bedesigned, including tests for dominant mutations, whichtake into account the homologies between the human andmouse genomes. Molecular studies with somatic cell
mutations, both spontaneous and induced, will extend theknowledge of mutation spectra and mechanisms.

344. In addition, a formal protocol should be established
for follow-up studies on heritable effects in the event ofaccidents involving ionizing ndiation; such i~~vcstigatio~w 350. In well-studied experimental systems, mostradiation-induced mutations are recessive and are due to
may yield a great deal of information on human genetic
DNA deletions. If human germ cell responses arerisk that could not be obtained in any other way.
similar. such mutatio~~swill accumulate in the gene pool.
345. Additional information is needed on the inductio~~ Given the very low levels of inbreeding in present-day
human populations, homozygosity for induced recessivesof phenotypic damage observed in the progeny of
may occur only rarely. Thus it would be useful to have
irradiated experimental mammals. It would be useful toassessments, instead, of the overall adverse health effects
have data on body systems other than those involving
in heterozygote carriers of induced recessive mulations.
skeletal and cataract mutations. It would be especiallyIn humans, a useful starting poult would he to compare
valuable if data could be developed that would, in somethe health of nornial individuals with that of obligate
straightforward way, permit estimates of Ihe risk ofheterozygotes for known recessive mutations.
inducing dominant mutations that affect predispositions

UNSCEAR 1993 REPORT

782

Tnhle 1
Incidence or gencllc or pnrllr~llygenetic diseases having serious henllll consqucnccs before lhc uge or 25 years a(031
R a e p a million lirv birrhc

Caregory

Pcrcenlage of rotd binhs

P.r( A: Serious discmn with known genclic acliology
Daninan~Rccusivc
X-linked(3hromtamal
Mullifadorial
Genetic unknown

1,395
1,655
532
1,845
46.583
1.164

Tual

0.14
0.17
0.05
0.18
4.64
0.12
5.32

53.175
P a d B: Serious congenital u~lurnulicr

All magenital a n m a l i a (ICDA codes 740-759)
Congenital a n o m a l i ~uith genetic aetiology (included in Par1 A above)

52,SOS2b,581

5.26
266

P m C: Serious genetic dheases and congenital anon in lit^
Dirordcrs in Pari A (above) and -genital

anomalies m% induded

79.392

7.94

Based m the British Cdumtilr Hcallh Surveillance R c e j s y in a study d 1,169,873 births f r m 1952 lo 1983.

Table 2
Examples of molecular mechnnlsms that cause spontaneous deletions and duplications

is71
ilfechanism

ErMtplc

Rcplicadon dippage in tandem rcpcats

Some ha-globin structural variants
Some mutadons in f a a a VII and facta IX genes

Unequal hcmologaus recanbinaticm-related gcna

M a t alpha-rhalahsemias, anomalous trichromacy

Unequal hanologocn rmmbinatim between Alu repeals

Some alpha-globin gene ddclicms
Lowdmsity lipoprotein rcccptor gene dclctims and duplicatimr
Fabry dismc. steroid sulphalase deficiency

Nmhandogoor, rccanhnation with one brca@oint in a near Alu repeals

Somc delelions in alpha, beta and umplcx thalasrunias
lipprorein lipase deficiency

Uncqual dnn chranarid exchange

Some dystrophin gcne duplications

Gene convurim involdng a functional gene and a pseudogene

21-hydroxylase ddrciency (adrenal hyperplasia)

Table 3
Gcnclic risk eslln~nteslor scrlous e ( T i ~ t sin huninns rroiti 0.01 Gy or low-LET rndinlion
Tmn~tipplici~lionof Ule direct niethnd lo ti~ouscdnlri
fipecrad frequency in the f i s t xmrration(Number ppa million live b i r t h )Bprir of mimarc

From u p a r u r c of d w :From a p a r u r r of fcmnlu:

10-20
5-10

0-9 '
05

15-30

014

Phmotypic changes in miceliving 3 weeks a Imgcr
dying baweeu birth and 3 weeks d agc

Tdnl. each scx

15-44

Total, b a h sexes"

h e r atirnatcbased on induccd cataracts; rnultipliraticm factor 36.6. The dsm, collcdcd at hgh dosc rat-

have been carected bawd on specificlocus results.

Based m many experiments m the amcwnt of induced dcath and on two cxpcriments that indicate that part of total c w u n i n g after hinh.
Data unavailaMe. Estimate assumed t o be 44% d rcsult with irradiated malcs, an uppcr bound suggested by specific-lms cxpaimmts. B c w r a c o f qualitatived i f f c r m c a in mutations bclwcen males and females, there is additional uncertainty in this risk ehtirnale.
Indudes risks for all types &inheritance, including transl-lions.
unbalanced products d r c c i p r w l ~ n n s l o c ~ t i o andn r rccipr-l
dominant mutations.

translmtions h a t act like

Table 4
Esliniates of mlnirnal gametic doubling dascs from nnnlysis of end-points of genetic cKecls
in survivors of the atomic bombings[Njl

Gcnctic effect

Ohsovcd
foldbockpwnd
incidence

Untoward
pregnancy outcome

0.0502

FI mortality

0.0458tIsrimnrad
wnrionolconuiburion
ro bockgroundincidence "O.(X)174.0027

Murruiondcomponent

Regrssion
pnromercrsb

3.4-5.4

6: 0.0026:0.0028

3.5-5.7

p: 0.00076rO.0015
a: 0.063a.001

"

99%

95%

90%

0.14-0.23

0.18-0.29

0.21-0.33

0.51-0.63

0.66-1.10

0.61-1.32(%)

a: 0.039:0.0058

0.0016-0.0026

Doubling dare (SL~1% ofof l o w conf&ce

El cancer

0.00120.00002-0.00005

2.0-4.0~:-0.00006zO.W026
a: 0.0010~0.00033

0.04-0.07

O.OS-0.l I

0.07-0.15

Scxchrornohane ancuploids

0.00300.0030100

p: O.OocW4rO.00oC9
a: 0.0025rO.00043

1.U

1.60

1.91

~ o cei n d i n g for prdcins

O.aOM)13

0.000013

100

p:-0.00o01?0.M)001
a: 0.00001r0.00001

0.99

227

7.41

Per diploid locus.
Equal to mulntional mnlributioo divided by o t s a v e d total tackground incidence (x 100 f a 5).
The douMing dose is qua1 to alp (equinlent to the reciprocal of the excesr relat~verisk per sirvcrt). 'Ihc rmn~maldouMing d m c is the rcnprocal d : p/a+ the normal derivate at the desired probability level t i m u the square rmt of the variance d P/uObserved zygotic mutation rates.

UNSCEAR 1993 REPORT

784

I

Tehie 5
Incidence of gcnellc d i s e ~ s eand risk estimates in humans from 0.01 Gy or low-LET radiation from applicationor the Indircct method

lncidcnrc
per m i l l i a lib+ b i r t h

Effccr rrf 0.01 Gy per g o ~ c r a i o n
prr million live bir~hr

Gcnctir dircare
UNSCFAR [ l l l j

UNSCEAR

BUR V

lull

Ic1l

Firs

BEIR V [CI]gcnerorwn

Secondgcnonlion

Equilibriwn

IS

13

100

Auloromal dominantClinically scvc~c
a i n i a l l y mild
X-linked

10,000Autoromal r m i v c

2500

Zm

0.05

0.05

Ovomolmal
S u u d u r ~ lanomalia
Numcriul momaliu

400
3,400

600

24

1

3.800

Coagcnital .nomaliu

60,00020.000-30,000

Mullifadorid discares
I l m di-c
Gnur
Sdeded Mhn

600.MX)FLs

EQuilibrium

gcnernrion

2500
7. 500

5-20
1-15

25
75

400

el

d

IS

<I

Vay dow i n a c u c44

Vcry little i n a u s c

<1

<1

10

10-100NU estimatedN u estimatedN u eat~mnted
NU estimatedN a estimated

609m
30Qm

T d

17

14

I

120

Table 6
Estimates of gametlc doubling doses for acute, high-dme irradialion or spern~atogoniaderived Crom
specific-locus, speclflc-phenotype systems in the mouse[N'l

SLslemOrigin of wcaral d u

Rcfcrcncc

Doubling datc
(GY)

Dluo summarized in

Calcdoral by

Rurrdl s e w - l a u s

101 x C3H

0.44

[FJ,
S12]

[N7)

Daninnnt viriMes

Varicus

0.16

IL61

[La]

Daninmt a l a r a a

1011'1 x QWEl

1-57

[nl

P I

S k d d rnalfmrtiolu

101

0.26

[Ell

1'4

tiiuocompatibility loci

CS7B 1/6M

A.60

lB1l

IS11

DBA
QIUI~CH x 101m
DBA C ~ I I

0.51
0.80. 1 . n

Is*]

P-4

4.00

1~91

IB~I

Vari cur

0.11

IN71

[h"l

3.89

II-81

IN7]

Rccucivc I d h d r

Lea encoding for p r u a n s
Rccurivc viribler

QIl/llell

x 101/)1

lul

In11

.

A N N F X G: HEREDITARY EI.'bTCTS O F R A D I A T I O N

785

Ttihle 7

Correction I n c t o r s u s e d w i t h the d l r c r t method Ir, o l ) h l n c s l l n i t ~ t aof r i s k or d o r r r l ~ i t ~ gn cl n c l l c d l s c r ~ s eIn h u t n a n s
IS61
.Qcp

Corrccrion procedure

Rcrulr37 + 2646
Divide (IA) by 600
Multiply (1B) by 111.9 and 1/3

1.4 l(rL
2 3 10''4.0 1(r6

Multiply ( 1 0 by 10
Divide (ID) by 2

40 lo420 lodQwnriry a corrccrion focror

SkrlcCnl mutations

1A
In
IC
ID
1E

Mutatim frquency (1 + 5 Gy; 2 4 4 f r a d i m a t i o ~y rays)
Mutntim rate (per 0.01 Gy)
C o n d i o n for dose fractimation and dose-rate &ech 'Exuapdadon f r a n rktlcul effects to d l dominants@roportiondity -&ionfactor)Gnection for severity*

Risk of duninant genetic discaw to the lirst-generation progeny
p a 0.01 Gy of paternal cxpmure
Cab&
2A
2U

X
3A
38
3C
4A
4B
4C

5
6

'

mubtionr

Mutatim frequency (4.55 + 4.55 Gy: 24-h fractimatim; y rays)
Mutatim rate (per 0.01 Gy)
Correction for dme Ciaaimation and d m - r a l e &CN 'Mutaticn f r q u m c y (5.34 Gy a a d e 7 n y r )Mutatim rate (per 0.01 Gy)
Correction for dose-rate cffecl
Mutatim frequency (6 Gy, acute y rays)
Mutatim rate (pcr 0.01 Gy)
Concction for dme-ratc e n d
Average of (ZC), (3C)and (4C) u u g h t d by the number of mLtantr
Exrrapdation hmr dominnnt cataracts to all dominants
Risk d daninant genetic disease to the first-gmaation progeny
pcr 0.01 Gy cf paternal cxpsure*

20 1046 + 5.231
by 910
Divide (U)Multiply (2B) by 111.2 and Y3
3 + 19212
Divide (3A) by 534
Multiply (30) by ll3
3 + 11.095
Divide (4A) by 600
Multiply (48) by lf3

Multiply (5) by 36.8

1.15 lo3
1.26 lo4
3.5 1(r70.29 lw3
5.5 l(r7
1.8 l(r70.27 10.'
4.5 l U 7
1.5 l U 7
2 6 l(r7-10 lo4-10 104

1 h c ccrrsaion f a d a s arc bkxd on specific-locus cxpcrimcntr arricd out at Oak Ridge.
B a r d on the McKusick catalogue d autosanal phcndypcr. 1975 editica [M7]; at that time, it was estimated that atout 74 out d 328 clinically important
autororml d o m i w t ~ a d i t i m inr man i n v d w d cne or m a c parts d t h e &aon (about 20%); h w e v a , since &dad d e f w arc m a e easily dia@&anlhac d o h u a p n syrtcmr. the uuc f i p e was assumed to be about 10%.
The uxrcction fa dore-&aaionatim effects (U1.2) is b a d on u n w r c a t specific-locur rtudiu in Ncuhaberg.
b r e d on h e MdCusick catalogue d autoromal phcnaypu, 1978 edition [ M I ; at that time, it was estimated that 20 out d 736 of all known and provm
dominant mutations (27%) were a s s d a t e d with m e or another form of calaraa in man; recent analpis by Favor [R],bared on the McKudck catalogue d
autoromd p h ~ y p c a 1966.
edition [M7], showr that t h a c numbers are. respectively. 28 and 1.17t i s . 2 4 % of known dominant mutations arc ascodaledwith cataradr. 'Ihe multiplicatioa f a a a is therefore 41.

786

UNSCEAR 1993 REPORTGlossary
allelean alternative form of a gcnc at a givcn locus. Being diploid organisms, humans may
have two alleles at a given locus, i.e. a normal and a mutant allele. Abbreviation or
allelomorph

allclic association

the association of two allcles at distinct lod beyond chance expectation. Normally aconsequence of d o s e linkagc: loci within a mcgabasc usually show somc allclic
association

allelic disorders

disorders. which may bephcnotypically different, that an: due to mutations in the samegene

a h repetitive sequence

repetitive scquena: found about 500,000 timcs in human gcnomc. The sequence
contains a recognition site for the restriction enzyme Alul and is around 300 base painin length.

amplification

an increase in the number of copies of a particular DNA fragment. Can occur undernatural circumstances, e.g. amplification of a repcat sequence, as in fragile-X syndrome,or during laboratory prooedures such as doning or polymerase chain reaction

ancuploida chromosome number that is not an exact multiple of the haploid number; anindividual with an ancuploid chromosome number. Usually rcfcrs to an absence(monosomy) or an extra copy (kisomy) of a single chromosome

annealing

see hybridization

anticipation

phenomenon in which the severity of a genctic condition appears to become more
severe and/or arise at an earlier age with subsequent generations

antisense strand (of DNA)the non-coding strand of the DNA doublc helix that serves as the template, for mRNA
synthesis

association

the oaurrence of an allele with a disease more often than chance should allow

autmmeany chromosome other than a sex chromosome. Men have 22 pain of autosomes andan X- and a Y-chromosome: women have the same autosome pairs and two
Xchromosames. In the Paris convention, written 46XY and 46XX

bacteriophagesee phage. Bacterial virus used as a vcctor for cloning segments of DNA

band

a chromosomal segment defined by distinct staining. Both lighter and darker segments
are called bands and are numbered from the centromere outwards, with smaller bands
classified by a second number. Bands 11, 12, 13, 21, 22, 31 could be a continuous
series.

base pair (bp)in the DNA double helix, a purine and pyrimidine base on each strand that intcract witheach other through hydrogen bonding. Thc number of base pairs is often used a s ameasure of the length of a DNA segment, e.g. 500 bp.

basesequence
bladom ere

the order of nudmtide bases in a DNA molecule. Length is usually defined in basepain.
one of the cells produced by deavage of a fertilized ovum, forming the blastoderm

breakpointrefers to sites of breakage when chromosomes break (and rccombinc)carrieran unafleded individual who is hctemzygous at a particular locus for a normal gene
and an abnormal gene which, although it may be detectable by laboratory tests, is not
expressed phenotypically. Variously uscd to covcr both permanent non-expression inrecessives and X-linked recessives and temporary nonexpression in dominants (e.g.
Iluntington's chorea). More recently used to dcscribe unalfccted individuals who carry
unstable or dynamic mulations that can expand and cause a genetic condition in
offspring
complementary DNA. The synthetic DNA equivalent of messenger RNA (mRNA) witha sequence complementary to the DNA strand from which i t is derived

cDNA

cDNA librarya collcdion of doncs containing inserls of ovcrlnpping cDNA fragments representing
expressed sequences (mRNA). cDNA libraries differ from one tissue or cell type toanother.

ANNEX G: IIEREDITARY EFFECTS OF RADIATION

787

the unit of genetic distancc defined as the length of a segment of chromosome which
has a 1% chance of recombining at meiosis. See also recombination percentage.
rquivaient segments of chromosomes usually recombine more frequently at oogenesis
than at spermatogenesis. Because even numbers of recombinant events between two
strands cancel out, the recombination pcrcenlage is always less than the genetic distanceand can never exceed 50%. The percentage recombination and the genetic distance in
ccntimorgans are very similar when linkage is close (i.e. less than 10%).
the part of the chromosome by which it is moved at e l l division and which separatesi t into two arms, appearing as a distinct "waist" on microscopy. Point of spindle
attachment to the chromosome during meiosis and mitosischimaeraan organism compounded from hvo or more zygotes. A mosaic is formed from variant
e l l s derived from the same zygote.

chiasmathe crossing of chromatid strands of homologous chromosomes during meiosis

chorionic villus sampling

procedure used to oblain fetal cells for prenatal diagnosis; involves biopsy of theplacental membranes. Now usually done transabdominally from 8 weeks of pregnancy
during mitosis each chromosome replicates into two D N A strands called chromatids. At
meiosis ~ecombinationis due to chiasmah bctween non-identical pairs of chromatids.

chromatin

the composite of DNA and proteins that comprises chromosomes

chromosome

thread-like, deep-staining bodies situated in the nucleus. They are composed of DNA
and protein and carry the genetic information.

cis

on the same chromosome, usually quite close. The opposite of trans, which relates tothe other,homologue. Cis effects are due to physical action between segments of thesame DNA strand; trans effeds are due to diffusion. Historically implies on the same
chromosome. In molecular biology refers to an effect on a gene directed by thesequence of that gene or very close to it on the same chrornosome (in contrast to transeffects, which are produced by other factors, such as the transcription factors encodedby other genes). The terms are commonly used to describe factors that influence gene
expression.

cleavage

mitotic segmentation of the fertilized ovum, the size of the zygote remaining unchanged
and the cleavage cells, or blastomeres, becoming smaller and smaller with each divisionclone

a group of individual organisms or cells derived from a single individual by asexual
reproduction

cloning

production of genetically identical cells (clones) from a single ancestral ell;cloning
is utilized in molecular biology to propagate single or discrete DNA fragments ofinterest.

coding sequence

those parts of the gene from which the genetic code is "translated" into amino acidsequences of a protein

co-domimnt

when both alleles are expressed in the heterozygote

wdon

a group of three adjacent nucleotides that codes for particular amino adds or for the
initiation or termination of the amino acid chain

w d o n usage

given the degeneracy of the genetic code, refers to the preference of codons used tospeafy particular amino acids. Often differs among species and among differcnt genes
and proteinscomplementary

two nucleotide sequences are complementary when they can form a perfect double helix
because they have a mirror-image relationshipcompound heterozygore

an individual who has different mutant alleles at a given locus

congeniral

existing at, and usually beforc, birth; referring to conditions present at birth, regardlessof their causation
relationship by descent from a common ancestor. a consanguineous mating is between
individuals who have one or more common ancestors. As all individuals have common
ancestors it is usually restricted to couples with a common pair of grandparents, e.g.
first cousins.

788

wnsensus sequenceconserved sequence
contiguous gene syndrome

contig map
cosmidcoupling

crossing-overDNA marker

UNSCFAR 1993 R!2PORT

a minimum nudcotide sequcnce found 10 be common (although not necessarily
identical) in different genes and in genes frorn different organisms that is associatedwith a specific function. Examples include binding sites for transcription factors andsplicing machinery.
base sequence in a DNA molecule (or an nmino acid sequence in a protein) that hasremained essentially unchanged throughoul evolution
syndrome due to abnormalities of two or more genes that map next to each other ona chromosome; most often caused by a deletion that involves several contiguous genes
genetic map showing the order of (contiguous) DNA fragments in the genome
a cloning vector derived from a natural bacterial parasite capable of accommodating up
to 40 Kb of DNA (see plasmid)
whcn alleles frorn hvo loci are known to bc on the same chromosome; the opposite ofrepulsion. Also, all alleics derived frorn one parent
the exchange of segment of a chromosome in meiosis. Small chromosomes usually havea single chiasma, so that of the four chromosomes entering gamete. two are hybrid andtwo unchanged, e.g. if the parental chromosomes are ABCDE and abule, the gametes
could be ABCDE, ABcde, abCDE and abcde. The middle two are recombinant
chromosomes with a crossover between loci B and C.
deoxyribonucleic acid. The long double-stranded molecule whose sequence of the four
possible nucleotide bases provides the genetic information. The strands are held
together by hydrogen bonds between nitrogenous bases that constitute the code: adenine(A) and thymine (T) which pair with each other, and guanine (G) and cytosine (C),which pair with each other.
a DNA sequence variation that is easily dctedable; examples include restriction
fragment length polymorphisms and dinucleotide and trinucleotide repeat
polymorphisms.

DNA methylotion

attachment of methyl groups to DNA, most commonly at cytosine residues. May be
involved in regulation of gene expression

DNA polymerase

enzyme responsible for replication of DNA

DNA sequence

the relative order of base pairs

degeneracy(of the genetic code) different codons code for the same amino aciddeletionloss of a portion of a gene or chromosome; a type of mutation; a synonym of
deficiency

diploidcontaining two chromosome sets. The normal condition of mast human cells except
gametes: megakaryocytes, Purkinje cells and a few others have multiple sets.

dizygotic

twins derived from two distinct zygotesdomaina discrete portion of a protein (and corresponding segment of gene) with its ownfunction. A protein may have several different domains and the same domain may befound in different proteins.
a trait that is expressed in the heterozygote, sometimes only late in life
mutations that produce an abnormal clinical phenotype (disorder or trait) whcn present
in the heterozygous state

domimnt negalivc mutations

heterozygous mutations in whidr the produd of the mutant allele interferes with thefunction of the product normal allele

doubling dosethe dose of radiation hat, under a given set of conditions, will lead to an overallmutation frequency that is double the spontaneous frequency
a DNA sequence is written from the left, or 5', direction or to the right. or 3' direction.
Downstream refers to the 3' direction. i.e. the stop codon for a gene is downstram (3')
of the coding sequences of that gene.

dysmorphology

study of abnormalities of morphologic development

electroplroresis

an analytical method used to separate nuclcic acid, peptidc or protein fragments bascd
on size and charge of the molecule; typically smaller fragments lravcl furtber throughthe media (gel) in which separation is carried out.

ANNFX G: HEREDITARY EFFECTS 01:RhDIAIlON

789

enchromatin

darkly stained chromatin

en1:ancers

DNA squenccs that increase transcription of a nearby gene; they can act in either
may bc eitl~er5' or 3' to the gene or within an intron.
the chromatin that is thought to conlain active or potentially active genes. Light (vs.
dark) bands on G-bandinga region of a gene containing a coding sequence. Most genes have several exons
separated by introns, which are usually longer.

erpressivity

the extent to which a genetic defect is expressed

Fl, F2 etc.

the firs1 (F1) or second (F2) generation of progeny of a mating

founder effecta genetic effect due to the establishment of a new population by a few original founders
who carry only a small fraction of the total genetic variation of the original population,with the consequena: that some mutant alleles may reach unusually high frequencies
in the new population. [Examples: the 2,000 Dutch settlers in South Africa in the 17thand 18th centuries, who did not marry outside the small ethnic group, eventually giving
rise to a population of about 3 million. Frequency of familial hypercholesterolemia (FH)
heterozygotcs: 1/85 to 1/100 and 95% of mutations accounted for by only three alleles.
Likewise, the current population of French Canadians of 5.8 million descznded from
7,000 French settlers between 1608 and 1763. One familial hypercholesterolemia
mutation accounts for about 60% of the heterozygotes in this group.]

frameshifr mutation

a mutation that alters the normal triplet reading frame so that codons downstream fromthe mutation are out of register and not read properly

fragile site

gap or defect noted in the continuity of a chromosome when stained, e.g. fragile-X site.
Many are apparent only when cells are cultured under special conditions.

gametemature reproductive cell (sperm or ovum); contains a haploid set of chromosomes (23for humans)gene

the unit responsible for transmitting an inherited character, the region of DNA thatspecifies the synthesis of a protein

gene targeting

artificial modification of a gene in a specific and directed fashion. Typically refers to
substituting one DNA sequence for another to inactivate a gene or introduce or correcta mutation in a gene

genetic locus

a specific position or location in the genome

genetic fingerprinta pattern of restriction fragments detected by probes that recognizes alleles at highly
polymorphic loci; this is effectively unique to all individuals except identical twins.

genetic marker

an allele used in following the inheritance pattern of loci in cell lines, pedigrees orpopulations

genetic distancethe functional distance between two loci defined through recombination; it is measured
in centimorgans; for small values ( 4 0 % ) it is approximately equal to the recombination
percentage.

genetic dr$ithe tendency for variations to occur in the genetic composition of small isolated
inbreeding populations by chance. Such populations become genetically different fromthe original population from which they were derived.

genomethe complete genetic composition of an individual's chromosome; the complete set ofgenes characteristic of a species

genome DNA

DNA from a genome containing all coding (exon) and noncoding (intron and other)sequences, in contrast to cDNA, which contains only coding sequences

genomic librarya collection of clones containing DNA inserts of overlapping DNA fragments
representing the entire genome of an organism

genotype

the alleles present in an individual at a locus or loci under consideration

germ cellsee gamete

germ-line mosaicism

presence of two or more cell lines in the gonadal cells. lmplies risk of transmission of
mutations present in the gonads to offspringgonadal mosaicism
haploidsee germ-line mosaicism
containing one chromosome set as found in gametcs nfter meiosis. The normal
condition for gametes. The human haploid ~iumbcris 23, half the diploid number of 46.
the condition of cells with respect to genes whcn only one set is present, as for genes
on the X-chromosome in the mnlc

heterochrornatin
hetero,ysde
histones

chromatin composed of repetitive DNh; stains as dark (versus light) bands in
G-bandingan individual with two different alleles at a particular locus (adj. hcterozygous)
proteins assodated with DNA in chron~osomcs

homeobar domaina short DNAsequence common to a group of DNA binding proteins involved in patternformation in early embryogenesis

homologies

similarities found in DNA or protein scqucnccs whcn individuals of the same ordifferent species arc comparedhomologous

matched. The other of a pair of chromosomes

homologous chromosomes

chromosomes containing the same linear gcne sequences. In a normal mating, 1 of apair of homologous chromosomes is derived from each parent. Humans normally have
22 pairs of homologous chromosomes and 2 X-chromosomes or 1 X- and1 Y-chromosome.

homologous recombination

substitution of a segment of DNA by anothcr that is identical (homologous) or nearlyso. Occurs naturally during meiotic recombination; also used in the laboratory for genetargeting to modify the sequence of a genehousekeeping genes

genes that encode proteim neocssary for basic cellular functions. They are expressedin virtually all cells.

human gene therapy

insertion of normal DNA directly into cells to correct a gcnetic defecthybridization (annealing)

the artificial conjunction of two complementary DNA strands, one of which usually
carries a radioadive marker. Also used for the production of cells containing
chromosomes from more than one species

imprinting

phenomenon in which an allele at a given locus is altered or inadivated depending onwhether it is inherited from the mother or (he father. Implies a functional difference ingenetic information depending on whclhcr i t is inherited from the father or the motherin situ hybridization

use of a nucleic acid probe to dctcd the presence of a DNA sequence in chromosome
spreads or in interphase nuclei or of an RNA sequence in cells. It is used to map genesequenm to chromosomal sites and to detect gene expression.

insertin molecular genetics, refen to DNA sequence of interest that has been inserted into
a cloning vector such as a plasmid or badcriophage

insertion

type of mutation in which a DNA sequence of variable length is inserted into a genedisrupting the normal structure of that gene

intron (intervening sequences)the DNA sequences that interrupt the proteincoding sequences of a gene. The regionof a gene that separates exons or coding sequences. They are removed during
processing of mRNA. Introns may contain sequences involved in regulating expressionof a gene.

kYo?vpethe chromosome set; the number, size and shape of the chromosomes of a somatic cell
may be displayed diagrammatically as an idiogram.

kilobase (kb)a thousand baxs. A common unit for specifying the size of gcnes and physicaldistances along a DNA region

library

collection of dones in which overlapping genomic or cDNA fragments have been
inserted into a particular cloning vcdor

linkagethe non-independent meiotic segregation of alleles at different IOU, which is usually
because the loci concerned are all on the same chromosome, and only separable byrecombination. Linked loci are within measurable genetic distance of one another on
the same chromosome, or arc members of the same linkage group, e.g. on the same
chromosome. Distant loci on the same chromosome may show independent segregationand now show linkage. They are then described as syntonic.

ANNEX G: HEREDITARY EFFECTS OF MDIATTON

79 1

linkage disequilibriumx e allelic association

locus

the position on a chromosome. Usually that of a gene, hut may refer to a DNA marker

lod scorea statistical method used to determine if a set of linkage data indicates two loci arelinked or unlinked. A lod (log of odds ratio) score of +3 (1,000:l odds) is commonly
acccptcd to indicate that linkage exists, and a score of -2 (100:l odds against) excludes
linkage.
the proccss of determining the location of a gene by either direct observation or family
study

mapping

markera detectable physical location on a chromosome. It can be a restriction enzyme cutting
site, a gene, or a di- or trinucleotide repeat polymorphism whose presence andinheritance can be monitored.

maternal inheritanceinheritance pattern displayed by mitochondrial genes that are propagated from one
generation to the nexl through the mothers; the mitochondria of the zygote comesalmost entirely from the ovum.

megabase ( M b )one million base pairs of DNA sequence roughly equal to 1 cM of genetic distance

Mendelianmeiosisa trait obeying Mendel's first law of independent segregation of the alleles at the same
locus conveyed by each parent
h e type of cell division that occurs during gamete formation and results in the halvingof the diploid somatic number of chromosomes so that each gamete is haploid andcontains one of each chromosome pair. These post-meiotic chromosomes are usually
partly paternal and partly maternal in origin.

messenger RNA (mRNA)

processed RNA that serves as a template for protein synthesis or for synthesis of cDNA

microsatellite

highly polymorphic DNA marker comprised of mononucieotides, dinucleotides,
trinucleotides or tetranucleotides that are repeated in tandem arrays and distributed
throughout the genomes. The best studies are the C A (alternatively GT) dinuclmtide
repeats. They are used for genetic mapping.
highly polymorphic DNA markers comprised of a variable number of tandem repeatsthat tend to cluster near the telomeric ends of chromosomes. The repeats often containa repeat of 10 nucleotides. They are used for genetic mapping.

missense mutation

mutation that causes one amino acid to be substituted for anothermitochondria1 (mt) D N A

DNA distinct from nuclear DNA in that it is mostly unique sequence DNA and codesfor proteins that reside in mitodondria

mitosisthe type of cell division that occurs in somatic cells

monogenic

a synonym of Mendelian, i.e. governed by only one genemonozygotic

twins derived from a single zygotemorphogenesis

evolution and development of form, as the development of the shape of a particularorgan or part of the bodymosaicisman individual with substantial proportions of two or more cell lines derived from asingle zygote
threedimensional structure of gene product (protein) with known or implied function,i.e. DNA binding, traverse membrane etc. Often inferred from cDNA sequencemotif

refers to the type of inheritance determined by many factors including both genes andthe environment. If these are assumed additive, estimates of heritability may be made.
In Mendelian and infective disorders a single factor will have a deciding role inmanifestation, although not necessarily in severity or the potential for prevention ortreatment. See also polygenic
a permanent and heritable change in genetic material (includes point mutations,deletions and changes in number or structure of chromosomes)
mutation frequency

number of mutations observed divided by number of progeny or cells examined

non-di.sjunction

failure of two members of a chromosome pair to disjoin (separate) during cell divisionnonsense mutation

mutation that changes a codon for an amino acid to a termination or stop codon andleads to premature termination of translation

792

UNSCMR 19B REPORT

nucleosome

the basic structural unit of chrorniilin, in which DNA is wrappd around a core ofhistone molecules

nucleotide

a purine or pyrimidine base to which a sugar (ribose or dcoxyribox) and 1, 2 or 3
phosphate groups arc attachedmrcleusthc organelle in eukaryolic cells that contains the gcnclic matcrial

oligonucleo~ide

a short p i m of DNA, typically 5-50 nuclcotidc.

oncogenea gene, one or more forms of which is associated with cancer. Many oncogenes are
involved, dircctly or indirectly, in controlling the ratc of e l l growth.

open reading framea stretch of DNA following an irlitiation codon that docs not conlain a stop codon.
Open reading frames in a nuclcotidc sequence suggest an exon and thcrcforc a gene.

Paris convention

the notation system in which the karyotype is defined by the number of chromosomes
followed by the sex chromosomes and information, if any, on an abnormality, e.g.
46XY,47XliY (+21); 45x0;47XXY. The position on a chromosome is defined by p
and q (petit and queue) for the short and long arm and thcn by numbers defining bands
and sub-bands, which are numbercd outwards from the ccntromere. Usually therc are
2-4 major bands and 2-5 minor bands, the term band covcring both deeply and lightly
staining segments.

pedigreea diagrammatic representation of a family history

penetrance

the frequency of expression of a trait or genotypc. The proportion of individuals
observed to show a particular phenotypic effect of a mulint gene compared with thenumber expected on the basis of Mendelian inhcrihnce
a virus that infects bacteria and is a useful cloning vector for medium size pieces ofDNA between 5 and 25 kb

phenocopy

an environmenlally induced mimic of a genetic disorderphenotypethe appearana: (physical, biochcniical and physiological) of an individual that resultsfrom the interaction of cnvironmcnt and genotype. Often used to define theconsequences of a particular mutation

physical map

a map of physical landmarks on a DNA fragment or chromosome measured in basepain. Landmarks indude restriction endocnucleose recognition sites, DNA sequenceand chromosomal bands.
extrachromosomal small circular DNA moleculc capable of autonomous replication
within a bacterium. Commonly used as a cloning vector for small pieces of DNA,
typically 50-5,000 bases

p l y A RNA

RNA transcript that contains a tail of p l y A residues at its 3' end; implies that an
RNA sequence is mRNA. The p l y A residues serve as stop signals to terminatetranscription.

polyomines

compounds with many amino groups that are associated in the cell with nucleic acids

polygenic

inheritance determined by many genes at differcnt loci, each with small additive effects.
A simple example is height within either sex. See also multifactorial

polymerase

see DNA polymerase, RNA plymcrase

polymerase chain reaction (PCR)a method to amplify a DNA sequence using a heat-stable polymerase and two sets ofprimers that define the sequence to bc amplified. Several variations have beendeveloped for speafic needs. May be combined with rcvcrse transcription of mRNA
to cDNA to amplify an mRNA, so-called RT-PCR
the occurrence in a population of two or more gcnctically determined forms in such
frequencies that the rarest of them could not bc maintained by mutation alone. Used invarious distinct senses. especially in KFLl's where i t is used to imply altcrnative forms.
Usually implies commonest allele is less than 99% so that over 2% of individuals areheterozygous.

polyploidan abnormal chromosomal complement that exceeds the diploid numbcr and is an exact
multiple of the haploid number

ANNEX G: HEREDITARY EFFECTS Or: R4DIATlON

793

positional cloning

strategy for identifying and cloning a gene based on its location in the genome ratherlhan on the biologic function of its product. Usually involves linking the gene locus ofinterest to one that has already been mappcd

pre-mutationa permanent and heritable change in a gene that does not have phenotypic consequences(does not cause disease) but predisposes to a "full" mutation that may

primary transcript

the initial RNA transcript of a gene, before p r o w s i n g to mRN& it contains introns aswell as cxonr.

primershort polynudwtide chain that anneals to a nucleic acid template and promotes copyingof the template from the primer site

probanda synonym of propositus or proposita. The affected individual who brings the family
to medical attention

probe

single-stranded DNA or RNA molecule of specific base sequence, labelled either
radioactively or by other means, that is used to detect a complementary base sequenceby hybridization. A labelled fragment of DNA (usually labelled with a radioactive
isotope) used to identify a complementary sequence

promotera sequence on a gene that is upstream (5') to coding sequences to which RNA
polymerase binds and initiates transcription of a geneproteina large molecule composed of one or more chains of amino acids in a specificsequence; the sequence is determined by the sequences of nucleotides in the genecoding for the protein. Proteins are required for the structure, function and regulationof the body's cells, tissues and organs, and each protein has unique functions. Examples
arc hormones, enzymes and antibodies.

pseudogene

sequence of DNA that is very similar to a normal gene but has been altered slightly sothat it is not expressedRNAribonucleic acid, the nuclcic acid found mainly in cytoplasm. Messenger RNA (mRNA)transfers genetic information from the nucleus to the ribosomes in the cytoplasm andacts as a template for the synthesis o l polypeptides; transfer RNA (tRNA) transfers
activated amino acids from the cytoplasm to messenger RNA; ribosomal RNA (rRNA)
is a component of the ribosomes that function as the site of polypeptide synthesis.

reading frame

register in which translation machinery reads the genetic triplicate code

recessivea trait that is expressed in individuals who are homozygous for a particular allele

recessive mutations

mutations that produce an abnormal clinical phenotype when present in the homozygous
or hemizygous state. I.letcrozygosity for the mutation, i.e. carrier state, may often be
detected in persons whose clinical phenotype is normal.

recombimnt DNA

DNA that is artificially transferred from the genome of one organism to that of anotherrecombinant DNA molecules

DNA molecules of different origins that are combined and manipulated in thelaboratory

recombinant DNA technologies

laboratory procedures used to manipulate DNA [ragmen&, e.g. cut, modify and ligate,
and introduce them into an organism so that their number can be amplified as theorganism replicates, i.e. cloning

recom bimt ion

the formation of a new combinations of linked genes by crossing-over between theirloci during meiosis

recombination percentage

equivalent segmenL~ usually recombine more frequently at oogenesis than at
spermatogenesis. Because even numbers of cut-and-join events between two strands
cancel out, the recombination percentage, often termed thela, is always less than thegenetic distance and can never exceed 50%. They are almost the same at less than 10%which is just over 10 cM.

repulsion

when specific alleles at two different loci are derived from different parents. The
opposi le of coupling

restriction enzyme

baclerialderived enzyme that recognizes a specific, short nucleotide sequence and cuts
DNA at that site

restriction fragments

DNA fragments that result from digestion of DNA with restriction enzymes

UNSCUR 1993 REPORT

restriction endonuclease
restriction map

a group of enzymes each of which clcavcs DNA at spCcific base sequences (recognitionsite)
a map of a DNA sequence with rcstriction enzyme recognition sitcs serving as
landmarks

restriction sire

shortened term for rcstriclion cndonuclcnse recognition scquence

retrovirus

ItNA viruses that encode the cnzyrne reverse transcriplase so that their RNA can betranscribed into DNA in the host cell; modificd retroviruses are used as vectors to
introduce gcncs (or portions thcrcoo of interest into cukaryotic cells.

reverse transcriptase

an enzyme that catalyses the synthesis of DNA from an RNA template (and thus canalso make cDNA from mRNA)
restriction fragment length polymorphism. I h c occurrence of two or more allelcs in a
population differing in the lengths of fragments produccd by a restriction endonuclease

RFIP
RNA polymerase

enzyme that synthesizes (transcribes) RNA from a DNA template

RNr\ splicing

p r o m s by which intmns are removed from primary RNA transcripts, leaving only
cxons that encode the amino acid scquence of a protein

segregation

separation of allclcs at meiosis
determination o i the order of nuclcotidcs in a DNA or RNA fragment, or the order ofamino adds in a protein
electrophoretic technique by which nucleotidc size differences a s little as a single basepair can be discerned

sequencing
sequencing gel analysis

sequence-tagged sites (STSs)

short sequences of genornic DNA for which the base sequence is known. Polymerase
chain readion can be used to amplify the known sequences, which can serve as
physical landmarks for mapping.

s u chromosome

the chromosomes that primarily govern sex determination (XX in women and XY in
men). The other chromosomes arc autosomes.

somatic cells

all cells in the body except gametes and their precursors

somatic cell hybrid

a hybrid cell line derived from [usion of cells from different sources. I-lumanlrodent
hybrids containing a small amount of human genetic material, such as a single
chromasome, are used in human gene mapping.

somatic mosaicism

the presence of two or more cell lines in somatic (non-germinal) cells

Sourhem blotting

a technique, developed by E.M. Southern in 1975, for transferring DNA to a backing
sheet prior to hybridization. Northern and Western blots are non-eponymous variations
relating to RNA and prolein analyses. DNA is fractionated by electrophoresis, transferred to a membrane (blotted) and detected by a complementary labelled probe thathybridizes to the DNA, revealing information about its identity, size and abundance.

splicing

removal of introns during the p r m s ~ i n gof mRNA
one of the three codons (UAG, UAA or UGA) that cause termination of protein
synthesis
loci on the same chromosome which may or may not be within range of detection
through axegegation

stop codon

tandem repeat sequences

multiple copies of the same base sequence on a chromosome. When the number of
repeats varies in the population, they are useful as DNA markers.

relomeresrcfers to the ends of chromosornes that contain characteristic repetitive DNAsequences

termination codon

see stop codontransfer of a DNA fragment into prokaryotic or eukaryotic cells

transfectiontrans(a) historically implies on a different chromosome; (b) in molecular biology, refers toan effect on a gcne caused by a factor distinct from the sequence of that gcne, incontrast 10 cis cfleas. which are encoded in the sequence of thc gene. Cis and trans arecommonly used to describe factors that influence gcne expression. On different
chromasomes. usually quite close. The opposite of cistranscn'pr

refen to an mRNA molecule that encodes a protcin

transcription

the synthesis of an RNA molecule (tran~cn'pt)from a DNA template in the acll nucleus
catalped by RNA polymerase

site within a gcne wherc transcription of KNA begins
containing foreign DNA. For example, transgenic mice contain foreign DNA scqucnms
in addition to the complete mousc gcnome
assembly of amino acids into peptides baxd on information enoodcd in mRNA, i.c.
mRNA scquence of hases is translated into scqucncc of amino acids in a pcptidc or
protcin. Occur;on ribosomestranslocation

thc lnnsicr of genetic material from one chromosome to another non-homologous
chromosome, usually through a reciprocal cvcnt at meiosis

frisomythe slate of having three homologous chromosomes instead of the usual pair. as intrisomy 21 (Down's syndrome)

rriploida cell with three times the haploid number of chromosomes, i.e. three copies of all
chromwomc types

uniparental disomy

situation in which an individual has two homologous chromosomes (or chromosomal
segments) from one parent and nonc from the other. May be heterodisomy if both
chromosomes from the single parent arc present orisodisomy if two copics of the same
parcntal chromosomc arc present

unique sequence DNA

non-rcpctitivc DNA that potentially codes for mRNA and protein

ups;reama DNA sequence is written from the left, or 5', direction to the right, or 3' direction.
Upstrcam refers to the 5' direction, i.e. regulatory elements of a gene are typicallylocated upstream (5') of the coding xquenccs of that gene.
the vehicle into which DNA is inserted prior to cloning in bacteria. Includes plasmids,
phage and cosmids
the random turning off of all the genes on onc of the X-chromosomes in somatic cells
during early embryonic devclopmc,nt
genes carried on the Xchromosomc. The term sex-linked should only be used on thc
vcry rare occasions both X- and Y-chromosomes arc involved.
the diploid cell resulting from the union of the haploid male (sperm) and female (ovum)
gamcles

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