We found a significant linear dose–response relationship between low to moderate 131I doses to the thyroid and prevalence of subclinical hypothyroidism among individuals who were children or adolescents at the time of the Chornobyl accident and underwent an in-depth thyroid examination 12–14 years later. After controlling for a variety of potential confounders, the overall estimated EOR per gray was 0.10 (95% CI, 0.03 to 0.21). EOR per gray was higher in individuals with ATPO levels ≤ 60 U/mL compared with those with ATPO > 60 U/mL.
We do not believe that the results of our study could be attributed to selection bias, even though we screened 40.9% of those selected from the file of thyroid activity measurements, representing 67.5% of those invited to participate, because distribution of measured thyroid radioactivity was similar among participants (n
= 13,243) and nonparticipants (n
= 19,142) (Stezhko et al. 2004
). Further, we adjusted our analyses for a variety of possible confounders and effect modifiers to avoid any potential effects of differential distribution of such variables among participants and non-participants. Additional exclusion of individuals with self-reported history of thyroid disease or intake of thyroid hormones before the first screening is unlikely to have introduced bias because the results of analyses including and excluding these individuals were similar.
We did not take into account the impact of uncertainties in dose estimates in our analysis aimed at providing initial evidence on the relationship between prevalent hypothyroidism and environmental 131
I exposure. We previously reported that uncertainties in estimates of the individual 131
I thyroid doses were approximately lognormally distributed, with geometric standard deviations ranging from 1.6 to 5.0 and a median of 1.7 (Likhtarev et al. 2003
). These uncertainties are comparable with, and in most cases smaller than, those reported in other studies of environmental 131
I exposure (Davis et al. 2004
; Lyon et al. 2006
), primarily because all the participants had individual thyroid radioactivity measurements taken shortly after the accident. Two sources of uncertainty in thyroid dose estimates in our study, accounting for > 95% of overall uncertainty, were thyroid mass of the subject at the time of the measurement and measured radioactivity in thyroid (Likhtarev et al. 2003
). Because the error for thyroid mass is likely to be a mixture of classical and Berkson error, and the error for direct thyroid measurement is largely classical, our study should have a mixed error structure. Using data from a study of thyroid disease in relation to radiation fallout from the Nevada test site, Mallick et al. (2002)
showed that accounting for measurement error, based on a mixture error model, resulted in radiation risk estimates that were higher than unadjusted estimates, but < 100% higher when all error was assumed to be classical. Based on these results, it seems reasonable to assume that the true radiation risk for hypothyroidism is likely to be higher than what we report here, although with greater uncertainty.
It is well known that high thyroid doses received during therapeutic external irradiation of the head and neck for childhood cancer (ranging from 30 to 70 Gy) and from 131
I radiotherapy for Graves disease (typically ≥ 50 Gy) result in direct killing of thyroid cells and lead to subsequent development of structural and/or functional abnormalities of the thyroid, with primary hypothyroidism being the most common thyroid dysfunction (Cooper 2005
; Hancock et al. 1995
; Jereczek-Fossa et al. 2004
). By contrast, data concerning risk of hypothyroidism after diagnostic 131
I administration and environmental exposure due to nuclear weapons tests and releases from nuclear reactors have been limited and inconsistent (Davis et al. 2004
; Larsen et al. 1982
; Lyon et al. 2006
; Takahashi et al. 1999
Our finding of increased prevalence of subclinical hypothyroidism after 131
I exposure is in agreement with earlier observations (Larsen et al. 1982
) but not later ones (Takahashi et al. 1999
) in Marshall Islanders exposed to 131
I at doses from 1.35 to 3.35 Gy as a consequence of nuclear weapons testing. The latter negative finding for the Marshallese is consistent with the results of the Hanford Thyroid Disease Study, which 50 years after exposures from the Hanford nuclear facility (Washington State, USA) found no association between hypothyroidism, based on various outcome definitions, and 131
I dose estimates [mean (median) thyroid dose, 0.20 (0.10) Gy] (Davis et al. 2004
). Reevaluation of thyroid disease risk in relation to exposure from the Nevada nuclear test site suggested that risk of AIT with hypothyroidism may increase with thyroid dose (p
= 0.18), but this finding was based on only 35 cases (Lyon et al. 2006
). The data from atomic bomb survivors exposed to external high-dose-rate gamma irradiation in a range from 0 to 4 Gy are also inconsistent (Imaizumi et al. 2006
; Nagataki et al. 1994
). Although in an earlier study a significant bell-shaped dose–response curve for antibody-positive hypothyroidism was reported (Nagataki et al. 1994
), it was not confirmed in a later study (Imaizumi et al. 2006
). Inconsistent findings in all these studies may reflect the unique circumstances of population exposure, including different types of radiation or mix of radionuclides, dose rates, age at exposure, or time since exposure, assuming that radiation risk for hypothyroidism varies by these factors.
The observed association between the prevalence of subclinical hypothyroidism and 131I dose in our study, although highly significant (p = 0.003), is small, with an estimated 0.10 EOR/Gy. Nevertheless, this association appears to be robust and unlikely to be attributable to confounding because adjustment for a variety of important factors had no meaningful effect on the estimate. We found little evidence of a departure of the dose response from linearity based on several alternative models. When we excluded from the analysis individuals with doses ≥ 2 Gy, the EOR per gray, although not statistically significant, did not change materially (EOR/Gy = 0.15), supporting linearity of the dose response even at lower dose levels. If the true relationship between hypothyroidism prevalence and 131I thyroid dose is close to what we observed, most previous studies would have had low statistical power to detect a relationship.
The relationship among serum ATPO, 131
I, and risk of hypothyroidism in our study was complex. When included in the same model simultaneously, the associations of risk with 131
I and ATPO were comparable with the respective associations when these factors were included individually. This observation does not support the idea that the radiation-related increase in prevalence of subclinical hypothyroidism could be attributed to the radiation-related increase in prevalence of ATPO that we reported previously (Tronko et al. 2006a
). In fact, we found a significant interaction between 131
I and ATPO level in the prevalence of subclinical hypothyroidism, suggesting that the effects of 131
I and ATPO were not statistically independent. Specifically, individuals with ATPO ≤ 60 U/mL had a stronger dose–response relationship than did individuals with ATPO > 60 U/mL. Today, little is known about biological and clinical consequences of low doses of 131
I on the thyroid gland and whether they cause sufficient direct or indirect thyroid damage that could result in subclinical hypothyroidism. It has been hypothesized that the 131
I-related increase, at least for ATPO antibodies, may be transitory (Agate et al. 2008
). Given the fact that our analysis is cross-sectional in nature and that findings from clinical studies concerning the role of antibodies in the development of hypothyroidism after 131
I therapy are conflicting (Ceccarelli et al. 2005
; Chiovato et al. 1998
; Mariotti et al. 1986
), prospective data are needed to characterize the dynamic of radiation-related risk of hypothyroidism and to confirm its relation with ATPO.
In summary, this is the first study to find a significant relationship between prevalence of hypothyroidism and individual 131I thyroid doses due to environmental exposure. The radiation effect was small, a 10% increase per gray, and was largely limited to subclinical hypothyroidism. Additional data from prospective studies is required to enhance our understanding of the long-term consequences of 131I exposure on thyroid function and to clarify what role antithyroid antibodies have in this process.