UNSCEAR chernobyl.pdf

Excerpt from

UNSCEAR 2001 REPORT

ANNEX

Hereditary effects of radiation

3. Possible genetic effects of radiation exposures resulting from the Chernobyl accident

or from living in the vicinity of a nuclear power plant

(a) Down’s syndrome and congenital abnormalities

(paragraph 362, given below as paragraph 1, and the following):

1. In the UNSCEAR 1993 Report [U4], it was mentioned that the results of Czeizel et al. [C23] had

showed no increase in the prevalence of selected sentinel anomalies (predominantly autosomal

dominant and X-linked diseases of childhood onset and Down's syndrome) in Hungary after the

Chernobyl accident. Sperling et al. [S35], however, reported that in West Berlin, nine months after the

Chernobyl accident (i.e. in January 1987), there was a significant increase in Down's syndrome; a

cluster of 12 cases was found compared with two or three expected. (Note that the term cluster is used

here in an epidemiological sense and not in the sense used in genetics to describe mutations originating

from a single progenitor cell.) After excluding factors that might have explained the increase, including

maternal age distribution, only exposure to radiation after the Chernobyl accident remained. In six of

the seven cases that could be cytogenetically studied, the extra chromosome was found to be of maternal

origin. The occurrence of the above cases coincided with the time of highest radiation exposure (when

the conceptions should have occurred), particularly inhalation of 131 I, prompting the authors to suggest

that exposure to ionizing radiation, especially 131 I, might be the causal factor. This interpretation is open

to doubt, however, in view of the very low radiation doses.

2. In another study carried out in Germany, Burkart et al. [B26] recorded an increase in Down's

syndrome births (10 observed vs. 4.4 expected) in northern Bavaria in December 1986, close in time

to the occurrence of the Down's syndrome cluster in West Berlin. Further analysis revealed that the

increase in northern Bavaria was due mainly to four diagnoses made in the urban areas of Nuremberg,

Fuerth, and Erlangen. Chernobyl radiation exposure could be excluded as the cause, because the areas

had received very little contamination and because the peak occurred in December 1986, one month

before the occurrence of the Down's syndrome cluster in West Berlin.

3. In commenting on the Berlin cluster, Burkart et al. [B26] noted that (a) biological considerations

argue against Chernobyl fallout as a plausible cause of the Berlin cluster; (b) the Chernobyl exposure

cannot have been a common causal factor in northern Bavaria and West Berlin, since the higher rates in

the former area can be traced to a time period shortly before fallout took place; and (c) in the absence of

further clues, the close temporal relationship of the Berlin and the Bavarian clusters should be carefully

analysed to generate hypotheses on a common factor influencing the incidence of Down's syndrome.

UNSCEAR 2001 REPORT

4. De Wals et al. [D26] reported on the results of a survey on the incidence of chromosomal

syndromes (including Down's syndrome) in Europe registered in 19 birth defects registries from January

1986 to March 1987. The study population comprised 764 chromosomal syndrome cases, of which 621

were Down's syndrome cases in 482,193 total births. No evidence for any clustering was found in any

of the registries for the period January to March 1987. Analysis of the frequency rates by month of

conception also did not indicate any increase after May 1986.

5. Little [L30] provided a comprehensive review of studies undertaken in the wake of the Chernobyl

accident with particular reference to those on congenital abnormalities and other adverse reproductive

outcomes. The main points that emerge are the following: (a) an increased frequency of Down's

syndrome in West Berlin in January 1987 and increases in the frequency of neural tube defects in

several small hospital-based series in Turkey are not confirmed in larger and more representative series

in Europe; (b) no clear changes are apparent in the birth prevalence of congenital anomalies in Belarus

or the Ukraine (the republics with the highest exposures), although the data are difficult to interpret

because the methods of acquisition were not described and were not reported in full; (c) the conclusion

that there is no consistent evidence on congenital anomalies applies to other measured outcomes of

pregnancy as well (miscarriages, perinatal mortality and low birth weight, sex ratio shifts, and multiple

births); (d) there is evidence of indirect effects: an increase in induced abortions due to anxieties

created, which is substantial enough to show up as a reduction in the total number of births; (e) no data

are available on the reproductive outcomes of women pregnant at the time of the accident who were

evacuated from the 30-km zone of contamination, of workers on site at the time of the accident, or of

recovery operation workers; and (f) no data are available from several of the countries closest to the

Chernobyl area (see also [B5, G9]).

6. Siffel et al. [S34] studied the occurrence of sentinel anomalies (also including congenital

abnormalities and Down's syndrome) in children (n=26,893) born within a 20-km radius of the Paks

nuclear power plant in Hungary. Comparisons of the frequencies of sentinel anomalies, congenital

abnormalities, unidentified multiple congenital abnormalities, and Down's syndrome before and after

the operation of the power plant revealed no significant differences. It was concluded that the slightly

elevated radiation background (0.2

1954, and data on

doses and medical documents of the families were available. The authors found indications for a

possible increase in pre-reproductive mortality of the children of exposed mothers.

(b) Mutations in human minisatellite loci

7. Background. As discussed in paragraph 52, a significant fraction of the eukaryotic (including

the human) genome is composed of repetitive-sequence DNA. Much of this DNA has been grouped into

various families based on sequence, organization, and size [S92]. In some of these families, variations

in sequence and/or in the number of repeat units occur within and between species. One class of the

repetitive DNA elements, simple tandem repeats, is characterized by a motif of short oligonucleotide

core sequences reiterated in tandem arrays. These elements have been variously called minisatellites

[J15], midisatellites [N17], and microsatellites [L34]. This repetitive DNA has been found to occur at

many highly polymorphic (hypervariable) loci dispersed throughout the genome. The exceptionally high

levels of polymorphic variation at these loci are due to variation in the number of tandem repeat cores.

Family studies have demonstrated that simple tandem repeat loci are inherited in a co-dominant

Mendelian fashion [K42] (see Jeffreys et al. [J5] for a recent review.)

0.4 µSv a 1 ) attributable to the operation of the power plant did not

affect germinal and somatic mutation rates. Izhevsky et al. [I9], carried out a retrospective study on the

pregnancy outcomes and pre-reproductive mortality of children of workers of the Mayak nuclear power

plant. The workers were occupationally exposed to gamma radiation during 1948

HEREDITARY EFFECTS OF RADIATION

8. The diversity of alleles at both human and mouse minisatellite loci is a result of mutation rates

that are orders of magnitude higher than those of most protein-coding genes (e.g. [J5, J16, K42, K43,

S63]). The principal advantage of these high mutation rates is that significant changes can be detected

with smaller sample sizes. There is evidence to suggest that in somatic cells, the new length alleles may

arise by mitotic recombination or unequal sister chromatid exchange; replication slippage does not

appear to be a dominant process [J5, W22]. Analysis of minisatellite mutations in sperm suggests that

they may arise by gene-conversion-like events, the reasonable candidate stage being meiosis [J5]. Worth

noting here is that minisatellite variations very rarely have phenotypic effects (e.g. trinucleotide repeat

expansions; see Table 8).

9. Radiation-induced minisatellite mutations. Dubrova et al. [D19] studied germ-line minisatellite

mutations among children born between February and September 1994 to parents who were

continuously resident in heavily polluted areas of the Mogilev region of Belarus after the Chernobyl

accident. Blood samples were collected from 79 families (father, mother, and child) for DNA analysis.

The control sample consisted of 105 non-irradiated Caucasian families from the United Kingdom, sex-

matched to the offspring of the exposed group. DNA fingerprints were produced from all families by

using the multi-locus minisatellite probe 33.15 and two hypervariable single-locus probes, MS1 and

MS31. Additionally, most families were profiled with the minisatellite probes MS32 and CEB1. For

the Mogilev families, the level of 137 Cs surface contamination was used as a dose measure, i.e. families

were divided according to the median 137 Cs contamination levels into those inhabiting less contaminated

areas (<250 kBq m 2 ) and more contaminated areas (>250 kBq m 2 ).

10. The important findings are that (a) the frequency of minisatellite mutations is about twice as high

in the children of the exposed families as in controls, and (b) the mutation frequencies show a

correlation with the level of caesium contamination as demarcated above. The authors suggested that

these findings are consistent with radiation induction of germ-line mutations but also noted that other

non-radioactive contaminants from Chernobyl, such as heavy metals, could be responsible for the

observed, apparently dose-dependent increase in the mutation rate.

11. In a subsequent extension of the above study, Dubrova et al. [D29] recruited 48 additional

families from the affected region and used five additional minisatellite probes, including the multi-locus

probe 33.6 and four hypervariable single-locus probes. These additional data confirmed the twofold

higher mutation rate in children of exposed parents than in those of non-exposed. The spectra of

mutations seen in the unexposed and exposed groups were indistinguishable, suggesting that the

increased mutation frequency observed over multiple loci arise indirectly by some mechanism that

enhances spontaneous minisatellite mutations. Obviously, further work is needed to clarify the structural

basis of radiation-induced minisatellite mutations.

12. It has been argued [N19] that the use of control families from the United Kingdom introduces a

significant confounding factor as well as possible ethnic/genetic differences from the population of

Belarus. Secondly, the families in the United Kingdom may have experienced different patterns of

environmental exposure to potentially mutagenic industrial and agricultural chemicals that might have

contributed germ-line variation. Thirdly, it is not clear from the surface contamination maps of the

region why control families receiving insignificant radiation doses were not obtained or why a second

set of controls of children conceived prior to the accident could not be identified. Fourth, the trend in

mutation frequency with likely dose received is also dependent on the division of families into just two

groups on the basis of radiocaesium contamination; an analysis of trends based on individual

assessment of contamination would be more revealing. Finally, from the data presented, it would seem

that the germ-line doses in the whole region remain sufficiently uncertain to question the true

significance of a less than twofold difference in mutation frequency between the two groups.

UNSCEAR 2001 REPORT

13. In a pilot feasibility study carried out on the children of survivors of the atomic bombings in

Japan, Kodaira et al. [K44] (see also Neel [N18] for a commentary) screened 64 children from 50

exposed families and 60 from 50 control families for mutations at six minisatellite loci using the

following probes: Pc-1, λTM-18, ChdTC-15, pλg3, λMS-1, and CEB-1. The cell lines chosen for this

study were from the most heavily exposed parents, whose average parental combined gonadal

equivalent dose was 1.9 Sv. A total of 28 mutations were found, but these were at the pλg3, λMS-1, and

CEB-1 loci (there were no mutations at the other three loci). Twenty-two of these were in controls (of

1,098 alleles tested, i.e. 2%), six in the children derived from the irradiated gametes (among 390 alleles,

i.e. 1.5%). Thus, there was no significant difference in mutation frequencies. Since they used different

loci from Dubrova et al., the authors suggested that the use of the DNA fingerprint probes 33.16 and

33.15 may be worthwhile in studies of the children of survivors of the atomic bombings. However, the

subsequent preliminary results of Kodaira and Satoh [K50] and Satoh and Kodaira [S44] using the

above two probes showed no significant difference in mutation frequencies between the children of the

exposed parents and the control children.

4. Summary

14. Two studies of the genetic effects of radiation in humans have recently been published. One of

them involved the offspring of survivors of cancer who had received chemo- and/or radiotherapy

treatments and the other involved females who had been exposed to radiation (from beta particles,

gamma rays, and x rays) during infancy for the treatment of haemangiomas. Neither of these found

significant effects attributable to parental exposure to chemical agents and/or radiation.

15. The results of studies of minisatellite mutations in the children of those exposed in areas

contaminated by the Chernobyl accident and in the children of those exposed to the atomic bombings

in Japan are not consistent: in children from Chernobyl areas, the mutation frequencies were increased,

while in the Japanese children, there were no such increases. It should be noted that the control children

for the Chernobyl study were from the United Kingdom.

16. The search for genetic effects associated with Chernobyl exposures in Belarus or Ukraine, which

had the highest contamination, and in a number of European countries provide no unambiguous

evidence for an increase in the frequencies of one or more of the following: Down's syndrome,

congenital anomalies, miscarriages, perinatal mortality, etc.

(The full text of the UNSCEAR 2001 Report will be available on the internet shortly)

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