Our results from the first screening in the cohort of Belarusian children and adolescents exposed to radioactive iodine fallout from the Chornobyl accident showed a significant dose–response relationship between 131
I thyroid dose and thyroid cancer, which was linear–exponential across the full range of doses, but consistent with linearity below 5
Gy (EOR/Gy=2.15, 95% CI: 0.81–5.47). There was some indication that men and those exposed at younger ages had larger radiation-associated risks, as measured by EOR/Gy, but they were not statistically significant. Proxy indicators of iodine deficiency enhanced radiation-associated risks of thyroid cancer. Similar effects with higher-point EOR/Gy estimates were observed for pre-screening thyroid cancer cases confirmed through medical records.
A major strength of the study was the individual estimates of 131I thyroid doses based on thyroid radioactivity measurements performed within 2 months after the accident and on questionnaire data collected during screening and before diagnosis. Thus, although based on the prevalence data and cross-sectional by design, our study results were not affected by selection or recall bias. All subjects were screened using a standard protocol and screeners were masked to estimates of radiation dose, thus diminishing potential confounding effects of screening and dose-related differential screening. Our findings were further strengthened by the high FNA and surgery compliance rates (95.8% and 91.0%, respectively) and the review of all cases by international pathology experts. Our estimate of EOR was robust and not affected by exclusion of one follicular carcinoma case, cases with simultaneous follicular adenoma or cases with incidental finding of cancer from analysis (EOR/Gy of 2.15, 2.74 and 2.55, respectively).
The study has several limitations. Because only 11
970 of the 36
739 individuals eligible to participate (32.6%) were screened, a possible non-participation bias is a concern. The major reason for non-participation was the difficulty in locating and tracing eligible subjects. Thus, slightly more than 50% of potential subjects could not be traced, primarily because of the high mobility of this young population in the period between the 1986 Chornobyl accident and the start of screening in 1997, and the limited identifying information in the thyroid activity logs through which eligibility was determined. Among those invited into the study, 73.8% participated, which is similar to other large cohort studies (Szklo, 1998
) and to the participation rate observed in the parallel study in Ukraine (67.5%) (Tronko et al, 2006
). About a quarter of those invited to participate did not come for screening, primarily because they lived far from screening centres. Although mobile teams were organised to screen study subjects who lived in areas distant from the stationary screening centres in Minsk or Gomel, this was not possible for areas in other oblasts with sparse distribution of potential study subjects. These areas were also less contaminated after the accident, which could potentially explain the significant differences in dose distribution among participants and non-participants (43% participated among those with thyroid activity measurements 1
Gy and above vs
31% with measurements of 0.3–1.0
Gy and 26% of those with measurement <0.3
Gy) (Stezhko et al, 2004
). However, since screening procedures were uniformly applied to all subjects, any differences in participation were non-differential and would not bias the EOR/Gy estimates for prevalent cases detected during screening. The dose-dependent participation of self-reported pre-screening cases cannot be excluded and could have resulted in higher EOR/Gy estimates. Furthermore, all statistical analyses were adjusted for effects of other potential risk factors such as age, gender and oblast of residence (proxy for iodine deficiency) to eliminate possible effects of differential selection. The annual screening for individuals less than 18 years of age compared to biennial for those more than 18 years may have resulted in increased diagnosis of thyroid cancers among the former. The difference in risk estimates between the two age groups was sizeable although not statistically significant (EOR/Gy of 5.10 for those screened before age 18 years and 1.62 for older study participants, P
=0.30), but is probably due to higher risks among those exposed at younger ages. Only the central dose estimates were available at the time of analysis and uncertainties in dosimetry have not been taken into account, but their potential impact on the thyroid risk estimates will be evaluated in a later publication.
A recently published parallel study in Ukraine (Tronko et al, 2006
) observed a higher mean thyroid dose (0.78 vs
Gy). In both studies those younger at the time of exposure tended to have higher risks per unit of dose, whereas the effects of gender were in opposite directions. The estimate of risk among those with doses less than 5
Gy in Ukraine (EOR/Gy=7.35, 95% CI: 2.23–53.11) was much closer in magnitude to the risk estimate for pre-screening cases in our study than to the estimate based on screening-detected cases. This may be due to the heightened awareness in the medical community in Belarus of the potential risk of thyroid cancer among children exposed to the fallout, especially from the heavily contaminated areas in Gomel oblast, and widespread ultrasound screening campaigns in the first 5–10 years after the accident (Ito et al, 1997
; Astakhova et al, 1998
). We observed that half of pre-screening cases were among those exposed younger than 5 years old compared with a third among screening cases, and the mean dose of pre-screening cases was significantly higher compared with screening cases (1.77 vs
Gy) but somewhat lower compared to the Ukrainian screening cases (2.00
Gy), supporting the possibility of early detection of cases among those exposed at younger ages from heavily contaminated areas. Only 14 pre-screening cases were reported in the Ukrainian cohort of similar size during the same period of observation and no risk analyses were reported (Tronko et al, 2006
Several studies have investigated risk of Chornobyl-related thyroid cancer among persons exposed as children or adolescents. Case–control studies from the Bryansk oblast of the Russian Federation (Davis et al, 2004
; Kopecky et al, 2006
) reported significantly increased risk of thyroid cancer with no variation by gender or age of exposure. A case–control study of thyroid cancer diagnosed in 1987–1992 in children from Belarus (Astakhova et al, 1998
) found increased risks with dose only among children exposed in Gomel oblast, but in a later study of cases diagnosed in 1992–1998 (Cardis et al, 2005
) no differences by oblast were observed. Cardis et al
reported an OR at 1
Gy of 4.9, 95% CI: 2.2–7.5 from a linear-quadratic model over the entire dose range, with evidence of non-linearity at doses above 1.5–2.0. Absence of individual dose estimates and possible underascertainment of thyroid cancer cases from the Cancer Registry of Belarus could be responsible for observed differences in risk estimates with our study (OR at 1 Gy=3.68 from the linear–exponential model).
Our estimates of risk were somewhat lower than those reported from the study of the survivors of atomic bombings in Japan where risk at age 30 was ERR/Gy=5.35 among those exposed younger than 10 and ERR/Gy=4.28 among those exposed between 10 and 19 years old (Preston et al, 2007
), and much lower compared to the estimate from the pooled analysis of risks after X-ray and γ
-irradiation (ERR/Gy=7.7, 95% CI: 2.1–28.7) (Ron et al, 1995
). Our CIs overlap suggesting compatibility of findings. In studies of external irradiation of the thyroid gland, younger age at exposure was significantly associated with increased risk and the evidence for gender was suggestive although not uniform across studies.
Iodine deficiency is thought to increase radioiodine uptake by the thyroid gland and to modify thyroid function after radiation exposure (Robbins et al, 2001
). Two studies reported an inverse association between iodine deficiency, defined by low urinary iodine excretion levels (Shakhtarin et al, 2003
) or levels of stable iodine in soil in areas of residence at the time of accident (Cardis et al, 2005
), and increased risk of radiation-associated thyroid cancer. In the parallel Ukrainian study, place of residence and current iodine excretion did not modify the risk of thyroid cancer (Tronko et al, 2006
) or the risk of benign follicular adenoma (Zablotska et al, 2008
). The areas of the northern Ukraine where the study was conducted have more severe iodine insufficiency than the study areas in Belarus, where at the time of screening two-thirds of study participants were iodine deficient with urine levels <100μ
(). We used four proxy indicators to describe past iodine deficiency and observed that history of diffuse goiter, and diffuse goiter and thyroid volume enlargement diagnosed during screening were significant modifiers of cancer risk. Study participants exposed in Gomel oblast had higher risks compared to subjects from other oblasts (P
=0.07) and the difference in risk estimates was even more pronounced and significant in the combined analysis of pre-screening and prevalent cases (P
=0.04). This could be an indication of more severe past iodine deficiency in Gomel oblast. Although the prevalence of goiter at the time of screening in our study was comparable across oblasts, several reports (Kholodova and Fedorova, 1992
; Gerasimov, 1993
; Gembicki et al, 1997
) have suggested that iodine deficiency in Gomel oblast around the time of the accident was high and described concerted governmental efforts of iodine supplementation in Gomel 5–10 years after the accident (VanMiddlesworth, 2002
We did not observe any differences in risk by the size of tumour. To evaluate the effect of referral of smaller nodules sonographically suspicious for malignancy for biopsy, we analysed size of nodule referred for FNA among non-incidental cases (5–10 vs
mm) and estimated an EOR/Gy of 3.43 (95% CI: not estimated to 464) for the group of smaller nodules (N
=20 cases) and 1.85 (95% CI: 0.79–4.01) for the larger nodules (N
>0.50; not shown). The clinical importance of small screening-detected cancers is not well understood and we could not evaluate it in this study based on the first round of screening.
Our findings indicate that in a cohort of children and adolescents from Belarus exposed to the fallout from the Chornobyl accident, thyroid cancer is associated with exposure to 131I. Future analyses of incident thyroid cancers identified during additional two screening cycles (2001–2007) should shed light on the clinical importance of screening-detected tumours and age at exposure and time trends effects.