## Abstract

Background The Chernobyl nuclear accident of 1986 released large quantities of radioactive material causing widespread contamination. In the Ukraine alone, more than 4 million people were exposed to radiation. The exact health consequences of this exposure are still being assessed.

Methods To ascertain the effect of in utero radiation exposure and the development of leukaemia, a review was undertaken of leukaemia sub-types occurring among children born in the year of the accident (1986) and followed 10 years post-exposure. A comparison was made of leukaemia cumulative incidence rates among children from both an exposed and unexposed oblast.

Results Rate ratios (RR) for the all cell types grouping of leukaemia revealed that rates in the exposed Oblast were significantly elevated for females, males and both genders combined. Rates of acute lymphoblastic leukaemia (ALL) were dramatically elevated for males and to a lesser extent for females. For both genders combined, the RR for ALL was more than three times greater in the exposed compared to the unexposed region.

Conclusion Study results suggest that the increased risk of leukaemia and acute leukaemia among those children born in 1986 and resident in radioactively contaminated territories may be associated with exposure to radiation resulting from the Chernobyl accident.

The Chernobyl radiation accident is undoubtedly the greatest environmental catastrophe in the history of mankind. Vast areas of Europe were contaminated by radioactive fallout. In the Ukraine alone it is estimated that more than 4 million people were exposed to radiation.1 While this accident happened over a decade ago (26 April 1986), it will be several more decades before the exact health consequences are known.

Cancers of the thyroid and leukaemia have been found to be associated with radiation exposure. Those thought to be at greater risk of untoward health consequences from exposure are people under the age of 20, particularly those exposed in the first decade of life.24 Data from both the Hiroshima and Nagasaki (Japan) atomic bombing and also from follow-up studies of nuclear tests in Utah (USA) indicate that the maximum health effects occur during the first 12 years after exposure.3,4 We assessed acute leukaemia cases occurring among children who were in utero at the time of exposure to determine to what degree, if any, these events were associated with the Chernobyl accident. This paper presents data on acute leukaemia occurring in such children in two regions of the Ukraine; one presumed to have received radioactive contamination (Zhitomir) and one presumed to have been unaffected (Poltava).

## Methods

The Zhitomir and Poltava regions were selected on the basis of radio-dosimetry studies conducted by the Research Center for Radiation Medicine of the Academy of Medical Sciences of the Ukraine. Zhitomir is situated to the east of the Chernobyl nuclear power plant (Figure 1) and is rich in mineral resources. It comprises 29 900 km2 and has a total population of 1 507 000. Exposure of the Zhitomir population during the 10 post-exposure years reached 11.15 thousands person Sv.1 Poltava is situated on the left bank of the river Dnipro, hundreds of kilometres southwest of the Chernobyl nuclear power plant. It covers an area of 28 800 km2 and has a population of 1 771 000. The control population in Poltava was unaffected by radiation contamination from Chernobyl.

Children born in the year of the Chernobyl accident (1986) and living within these regions comprised the study populations. The 1986 birth cohort in Zhitomir was 24 231 and in Poltava it was 23 567. The case group included children born in Zhitomir during the year of the Chernobyl accident (1986) and diagnosed with leukaemia 1986–1996.

Cases of leukaemia were identified through an exhaustive manual search of records contained at the regional hospitals and oncological centre archives, as well as the register of children's cancer-haematological pathology of the Institute of Haematology of Ministry for Health Protection of Ukraine. Record-based histopathological confirmation of disease status was available for all cases included in these analyses. Acute leukaemia diagnoses were further confirmed by an international group of expert haematologists who reviewed the original slides as part of a larger case-control study. The same methodology of case ascertainment was employed in both oblasts to avoid bias. Moreover, members of the Leukaemia Diagnostic Working Group were blinded to child's place of birth. We are thus confident that all leukaemia cases were identified and assigned the correct diagnosis.

Data on annual average population numbers within the regions were obtained from the Ministry of Statistics of Ukraine. Cumulative effective radiation doses for the study populations are those accumulated between 1986 and 1996 and were calculated using the methodical approach described by Likhtariov.5 Exposures to a variety of sources were considered in the calculations of the annual average effective radiation dose. These included: external gamma-radiation from both the radioactive cloud (at the early stage of accident) and radioactive fallout on the ground; and internal radiation from radioisotopes of caesium (134Cs, 137Cs), strontium (89Sr, 90Sr) and also transuranium elements (238–240Pu, 241Am) transmitted via food consumption and inhalation. The accumulated collective radiation dose during 11 post-catastrophe years is sum-total of annual collective effective radiation dose for each year of observation.

Incidence rates (P) for the period of observation (1986–1996) were calculated according to the formula 2:6

$P\ =\ i/{\Sigma}n_{(t)}\ {\cdot}\ 100\ 000$

where: P is the incidence rate level from 1986 to 1996 (per 100 000 person-years); i is the incidence of acute leukaemia occurring among children born in 1986 and living in the observed territories for the period from 1986 to 1996; and Σn(t) is the sum of annual population (children born in 1986) in observed regions for the period from 1986 to 1996.

Cumulative incidence rates (CI) for the period were calculated according to the formula:

$CI\ =\ {\Sigma}i_{j}/{\Sigma}n_{ij}$

where: CI is the cumulative incidence rate; ij is the incidence of acute leukaemia for each year in the observed period; and nj is the number of children born in 1986 living in the given territory for each year of observation.

$Relative\ risk\ of\ disease\ was\ calculated\ as:\ R\ =\ CI_{1}/CI_{2}$

where: R is the relative risk of leukaemia; CI1 is the cumulative incidence rate of acute leukaemia in the given year of observed period among children born in 1986 and living in the contaminated territories of the Zhitomir region; and CI2 is the cumulative incidence rate of acute leukaemia in the given year of observed period among children born in 1986 and living in the control territories of the Poltava region.

The 95% confidence intervals for incidence rate ratios (RR) were calculated as described by Rothman.7

## Results

Between 1986 and 1996 a total of 21 cases of leukaemia were observed in Zhitomir occurring among children born during 1986. A total of eight cases were observed in the largely uncontaminated Poltava region. The majority of leukaemias, as would be expected in this age group, were acute lymphoblastic leukaemias (ALL). These accounted for 13 (62%) of the leukaemias in Zhitomir and 4 (50%) of those in Poltava.

According to our estimates the collective effective exposure dose for the studied population, accumulated to 1996 is around 107 man-Sv. More than 80% of that dose was accumulated during the first 5 years after the accident. Individual effective exposure dose in the studied population is estimated in the range of 0.1 and 200 mSv.

## Discussion

Results from this study demonstrate a difference in incidence rates of all leukaemias combined and for ALL between a region with Chernobyl-related radiation contamination and a region without such exposure. While this study is ecological in nature, the results are highly suggestive of a radiation effect on children born in the year of the Chernobyl accident. A number of studies have been conducted to study possible associations of exposure to Chernobyl and childhood leukaemia. Results, for a variety of reasons, have been somewhat equivocal but some have yielded results similar to ours. An observed increase in leukaemia cases in Belarus was reported for the 7-year period following the Chernobyl accident.8 Rates were 1.2 times higher after the accident compared to the pre-accident period among the population living in territories with a level of radioactive pollution exceeding 555 kBq per m2. This study also was ecological in nature and exposure was based on that of the territory's population and did not take into account age-sex distribution and estimation of individual radiation doses.

The temporal trends from time of exposure to diagnosis of leukaemia observed in our study correlate well with data reported from Hiroshima and Nagasaki, and the US.3,4,9 The Life Span Study sample of the Radiation Effects Research Foundation for Hiroshima and Nagasaki observed an increased risk of leukaemia 1 to 3 years after the bombings with peak occurrence 6 to 7 years from exposure.3 In addition, younger age at time of exposure was associated with greater risk of leukaemia. Our results are remarkably similar with peak rates of leukaemia occurring in 1991 with attenuation thereafter. However, these data alone are not all that remarkable and may be partially explained by the natural history of ALL which is known to peak in early childhood and then decline by age 10. What is remarkable is the consistent difference between regions with Zhitomir demonstrating higher rates (overall RR = 3.4).

Stevens et al. in their study of leukaemia and radioactive fallout from the Nevada test site observed a significant association for acute leukaemias among those individuals age 20 or younger at time of exposure.4 However, in further subgroup analyses no association was observed for individuals exposed in utero or during the first year of life. Conversely, Petridou reported that in utero exposure to ionizing radiation from Chernobyl resulted in more than a twofold risk of leukaemia in exposed compared to unexposed children.10 Akiba et al. reported increased infant mortality from leukaemia among children resident in areas with high background radiation (1.7–2.0 mSev/year).11 However, this study was based on only three deaths and there is some question as to the comparability of their reference population. Michaelis et al. 12 attempted to replicate Petridou's study using data from western Germany, but after completing detailed time-trend analyses failed to observe any effect of radiation from Chernobyl on childhood leukaemia. Petridou13 speculated that this lack of replication might be due to non-differential exposure misclassification, sparsity of data and questionable correspondence between environmental measurements and personal exposures. Hjalmars et al.14 reported no significant increase in the incidence of acute childhood leukaemias in Sweden after the Chernobyl accident. Sali et al.15 report results of a series of studies carried out in the exposed populations of Europe. They too report no observed increases in childhood leukaemia that may be attributed to Chernobyl. It is difficult to assimilate these various reports into one meaningful summary given that it is sometimes difficult to discern the validity of individual reports owing to differences in cancer registration systems, means of case ascertainment and very real differences in Chernobyl-related exposures across countries. Moreover all of these studies, including our own, are descriptive and as such subject to the ecologic fallacy. Darby and Roman16 point out some of the challenges in the conduct of leukaemia studies in general and international comparisons resulting from Chernobyl in particular.

The major limitation of the present study is that it is ecological. While reliable estimates of presumed exposures are available for the regions included, individual burdens through internal and external exposures are not considered. Therefore, while our results may support an association of perinatal exposure to ionizing radiation and increased risk of leukaemia, other factors may be at work.

What other ecological factors could influence leukaemia risk among people living in radioactively contaminated territories? One could imagine that other industrial exposures via pollution may have had some effect. However, in the years immediately after 1986 many industrial enterprises have reduced or even ceased operation due to a series of economic crises which still exist at present. Another bias could occur if there was significant out-migration of exposed individuals (i.e. those presumably with greater risk of ALL). However, this might have differentially increased the rates of ALL in the unexposed oblast and thus reduced the magnitude of the difference that we observed. At the very least, our observations might therefore be a conservative estimate of the effect.

In summary, study results suggest that the increased risk of acute leukaemia among those children born in 1986 and resident in radioactively contaminated territories may be associated with exposure to ionizing radiation resulting from the Chernobyl accident. The increase in rates of acute leukaemia was primarily due to the lymphoblastic cell type. This effect was more evident among males than females. The observed pattern of acute leukaemia occurrence from 1986 to 1996 is similar to findings from the A-bomb survivors' study and that of residents downwind from nuclear test sites in US. Finally, while risk of acute leukaemia among the exposed population was distributed non-uniformly during the 11 years after the Chernobyl accident, perhaps due to sample size and relative rarity of the event, the peak risks were predictably noted approximately 3 to 6 years post-accident.

Table 1

Cumulative incidence rate ratios by acute leukaemia cell type, sex and region (1986–1996)

Region
Zhitomir Poltava
Acute leukaemia cell type Sex No. of cases Cumulative incidence rate No. of cases Cumulative incidence rate Rate ratio 95% confidence intervals
Incidence rate per 100 000 person-years.
Lymphoblastic Female 4.0 1.8 2.2 0.3–4.3
Male 6.2 1.5 4.1 1.2–14.0
Both 13 5.1 1.5 3.4 1.1–10.4
Myeloblastic Female 1.6 0.9 1.8 0.2–19.9
Male 2.3 0.7 3.3 0.3–31.5
Both 2.0 0.7 2.9 0.614.7
Monoblastic Female 0.0 0.0 0.0
Male 0.8 0.7 1.1 0.2–7.8
Both 0.4 0.4 1.0 0.1–7.1
Undifferentiated Female 0.8 0.0 0.0
Male 0.8 0.7 1.1 0.2–8.2
Both 0.8 0.4 2.0 0.2–31.8
All leukaemia cell types Female 6.3 2.8 2.3 0.6–8.6
Male 13 10.1 3.7 2.7 1.6–4.7
Both 21 8,2 3.0 2.7 1.9–3.8
Region
Zhitomir Poltava
Acute leukaemia cell type Sex No. of cases Cumulative incidence rate No. of cases Cumulative incidence rate Rate ratio 95% confidence intervals
Incidence rate per 100 000 person-years.
Lymphoblastic Female 4.0 1.8 2.2 0.3–4.3
Male 6.2 1.5 4.1 1.2–14.0
Both 13 5.1 1.5 3.4 1.1–10.4
Myeloblastic Female 1.6 0.9 1.8 0.2–19.9
Male 2.3 0.7 3.3 0.3–31.5
Both 2.0 0.7 2.9 0.614.7
Monoblastic Female 0.0 0.0 0.0
Male 0.8 0.7 1.1 0.2–7.8
Both 0.4 0.4 1.0 0.1–7.1
Undifferentiated Female 0.8 0.0 0.0
Male 0.8 0.7 1.1 0.2–8.2
Both 0.8 0.4 2.0 0.2–31.8
All leukaemia cell types Female 6.3 2.8 2.3 0.6–8.6
Male 13 10.1 3.7 2.7 1.6–4.7
Both 21 8,2 3.0 2.7 1.9–3.8
Table 2

Cumulative incidence rates per 100 000, rate ratios (95% confidence intervals) for leukaemia all types and acute lymphoblastic leukaemia by region and time, sexes combined

1987–1991 1992–1996 Rate ratio
Leukaemia, all types
Zhitomir 11.2 4.4 2.6 (0.9–7.3)
Poltava 5.7 0.8 7.1 (0.9–58.0)
Rate ratio 1.9 (0.8–4.8) 5.5 (0.6–47)
Acute lymphoblastic leukaemia
Zhitomir 8.6 1.8 4.8 (1.1–22.6)
Poltava 3.3 0.0 –
Rate ratio 2.6 (0.8–8.3) –
1987–1991 1992–1996 Rate ratio
Leukaemia, all types
Zhitomir 11.2 4.4 2.6 (0.9–7.3)
Poltava 5.7 0.8 7.1 (0.9–58.0)
Rate ratio 1.9 (0.8–4.8) 5.5 (0.6–47)
Acute lymphoblastic leukaemia
Zhitomir 8.6 1.8 4.8 (1.1–22.6)
Poltava 3.3 0.0 –
Rate ratio 2.6 (0.8–8.3) –
Figure 1

Map showing oblasts under study in relation to Chernobyl nuclear power plant (NPP)

Figure 1

Map showing oblasts under study in relation to Chernobyl nuclear power plant (NPP)

Figure 2

Cumulative incidence rate for acute lymphoblastic leukaemias, genders combined in Zhitomir and Poltava regions

Figure 2

Cumulative incidence rate for acute lymphoblastic leukaemias, genders combined in Zhitomir and Poltava regions

Figure 3

Cumulative incidence rate for leukaemias and genders combined in Zhitomir and Poltara regions

Figure 3

Cumulative incidence rate for leukaemias and genders combined in Zhitomir and Poltara regions

## References

1
Ten Years After the Accident at the Chernobyl NPP //National Report of Ukraine, 1996. Kyiv: Ìinchernobyl, 1996.
2
International Commission on Radiological Protection. Radiation Protection 1990: Recommendations of the International Commission on Radiological Protection (ICRP). Publication 60. New York: Pergamon Press, 1991 (in Russian).
3
Shimizu Y, Schull J, Kato H. Cancer risk among atomic bomb survivors.
JAMA

1990
;
264
:
601
–04.
4
Stevens W, Thomas DC, Lyon JL et al. Leukemia in Utah and radioactive fallout from the Nevada test site. Case-control study.
JAMA

1990
;
264
:
585
–91.
5
Likhtariov IA et al. Retrospective prognosis for doses of population exposure and general 1997 dosimetry determination for the settlements of Ukraine affected by radioactive contamination as a result of the accident at ChNPP. Generalized data for 1986–1997. Issue 7. RCRM AMSU (in Ukrainian).
6
Breslow NE, Day NE. Statistical Methods in Cancer Research. Vol. 1. The Analysis of Case-Control Studies. Lyon: IARC, 1994, pp.129–36.
7
Rothman KJ. Modern Epidemiology. Boston: Little, Brown and Co., 1986.
8
Konoplya EF, Rolevich IV (eds). The Chernobyl Accident Consequences in the Republic of Belarus. National Report. Minsk, 1996, pp.45–46.
9
Yashimoto Y. Cancer risk among children of atomic bomb survivors.
JAMA

1990
;
264
:
595
–600.
10
Petridou E, Trichopoulos D, Dessypris N et al. Infant leukemia after in utero exposure to radiation from Chernobyl.
Nature

1996
;
382
:
352
–53.
11
Akiba S, Quanfu S, Zufan T et al. Infant leukemia mortality among the residents in high-background radiation areas in Guangdong, China. In: Wei L, Sughara T, Tao Z (eds). High Levels of Natural Radiation. Amsterdam: Elsevier Science, 1977.
12
Michaelis J, Kaletsch U, Burkart W, Grosche B. Infant leukemia after the Chernobyl accident.
Nature

1997
;
387
:
246
.
13
Petridou E, Trichopoulos D, Dessypris N et al. Response to Michaelis et al.
Nature

1997
;
387
:
246
.
14
Hjalmars U, Kulldorff M, Gustafsson G. Risk of acute childhood leukemia in Sweden after the Chernobyl reactor accident.
BMJ

1994
;
309
:
154
–57.
15
Sali D, Cardis E, Sztanyik L et al. Cancer consequences of the Chernobyl accident in Europe outside the former USSR: a review.
Int J Cancer

1996
;
67
:
343
–52.
16
Darby SC, Roman E. Links in childhood leukemia.
Nature

1996
;
382
:
303
–04.