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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-0498
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 11 4344-4351
Copyright © 2006 by The Endocrine Society

Autoimmune Thyroiditis and Exposure to Iodine 131 in the Ukrainian Cohort Study of Thyroid Cancer and Other Thyroid Diseases after the Chornobyl Accident: Results from the First Screening Cycle (1998–2000)

M. D. Tronko, A. V. Brenner, V. A. Olijnyk, J. Robbins, O. V. Epstein, R. J. McConnell, T. I. Bogdanova, D. J. Fink, I. A. Likhtarev, J. H. Lubin, V. V. Markov, A. C. Bouville, G. M. Terekhova, L. B. Zablotska, V. M. Shpak, A. B. Brill, V. P. Tereshchenko, I. J. Masnyk, E. Ron, M. Hatch and G. R. Howe1

Institute of Endocrinology and Metabolism (M.D.T., V.A.O., O.V.E., T.I.B., V.V.M., G.M.T., V.M.S., V.P.T.), 04114 Kyiv, Ukraine; Scientific Center for Radiation Medicine (I.A.L.), Academy of Medical Sciences, 04050 Kyiv, Ukraine; Division of Cancer Epidemiology and Genetics (A.V.B., J.H.L., A.C.B., I.J.M., E.R., M.H.), National Cancer Institute, and Clinical Endocrinology Branch (J.R.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892-7238; Department of Medicine (R.J.M.), The Thyroid Center, and Department of Pathology (D.J.F.), College of Physicians and Surgeons, and Department of Epidemiology (L.B.Z., G.R.H.), Mailman School of Public Health, Columbia University, New York, New York 10032; and Department of Radiation and Radiological Sciences (A.B.B.), School of Medicine, Vanderbilt University, Nashville, Tennessee 37232

Address all correspondence and requests for reprints to: Alina Brenner, M.D., Ph.D., Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Boulevard, Room 7090, Bethesda, Maryland 20892-7238. E-mail: brennera{at}mail.nih.gov.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Due to the Chornobyl accident, millions were exposed to radioactive isotopes of iodine and some received appreciable iodine 131 (131I) doses. A subsequent increase in thyroid cancer has been largely attributed to this exposure, but evidence concerning autoimmune thyroiditis (AIT) remains inconclusive.

Objective: The objective of the study was to quantify risk of AIT after 131I exposure.

Design/Setting/Participants: Baseline data were collected from the first screening cycle (1998–2000) of a large cohort of radiation-exposed individuals (n = 12,240), residents of contaminated, iodine-deficient territories of Ukraine. Study individuals were under the age of 18 yr on April 26, 1986, and had thyroid radioactivity measurements made shortly after the accident.

Outcomes: AIT was defined a priori based on various combinations of elevated antibodies to thyroid peroxidase (ATPO), TSH, and clinical findings; elevated ATPO were considered to be an indicator of thyroid autoimmunity.

Results: No significant association was found between 131I thyroid dose estimates and AIT, but prevalence of elevated ATPO demonstrated a modest, significant association with 131I that was well described by several concave models. This relationship was apparent in individuals with moderately elevated ATPO and euthyroid, thyroid disease-free individuals.

Conclusions: Twelve to 14 yr after the Chornobyl accident, no radiation-related increase in prevalence of AIT was found in a large cohort study, the first in which 131I thyroid doses were estimated using individual radioactivity measurements. However, a dose-response relationship with ATPO prevalence raises the possibility that clinically important changes may occur over time. Thus, further follow-up and analysis of prospective data in this cohort are necessary.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
AS A RESULT of the accident at the Chornobyl nuclear power plant on April 26, 1986, about 5 million residents of Ukraine, Belarus, and the Russian Federation were exposed to radioactive fallout, with some individuals receiving appreciable exposure (1). Because the fallout included a mix of radioactive isotopes of iodine that naturally concentrate in the thyroid gland (2), of which iodine 131 (131I) was a major contributor (1), and in view of experimental (3, 4) and epidemiological evidence (5, 6, 7, 8) regarding the effects of radiation on the thyroid gland, there was concern that the long-term consequences of 131I exposure might include a dose-related increase in various thyroid diseases. A strong relationship between such exposure and thyroid cancer has been established (9, 10, 11, 12). However, evidence concerning the relationship with thyroid autoimmunity and autoimmune thyroiditis (AIT) remains limited and inconclusive (reviewed in Ref. 13). This may be due in part to the lack of an internationally accepted classification and criteria for AIT (14), imprecise thyroid doses, and the limited sample size of many studies (13). Furthermore, the relation of dietary iodine intake to spontaneous AIT is inconsistent (15), and even less is known about whether the dietary iodine is important for 131I-induced AIT. Nevertheless, because AIT is common and its prevalence increases markedly with age (14), even a weak relationship with 131I exposure could result in a substantial burden among the exposed populations.

Here we report results for the prevalence of AIT and elevated antibodies to thyroid peroxidase (ATPO) in relation to 131I thyroid dose estimates 12–14 yr after exposure using data from the first screening cycle (1998–2000) of a large Ukrainian cohort of subjects (n = 12,240) who reside in an area of mild to moderate iodine deficiency (16) and have individual measurements of thyroid radioactivity taken shortly after the Chornobyl accident (17). We considered multiple AIT outcomes defined a priori based on various combinations of the following criteria: the degree of ATPO and TSH elevation and the presence of ultrasonographic or palpable abnormalities suggestive of AIT. Elevated levels of ATPO in the absence of evidence of thyroid gland abnormality were considered to be an indicator of thyroid autoimmunity rather than diagnostic of AIT.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The cohort

Details of the design of this study, and a parallel study in Belarus, have been published previously (17). In brief, the cohort includes individuals with direct thyroid radioactivity measurements made in May or June 1986 who were under the age of 18 yr on April 26, 1986, and resided in neighboring Chernihiv, Zhytomyr, or Kyiv oblasts or the city of Kyiv, Ukraine, in 1998. An oblast is an administrative subdivision similar in size to a state or province.

The original sampling list included 75,349 individual records stratified on preliminary 131I thyroid dose estimates. All individuals from the highest dose group (1 Gy or more) and a random sample of those from lower-dose groups were selected, resulting in 32,385 potential study participants (17). Among the subjects originally selected, 2,466 (8%) were not eligible and 10,307 (32%) could not be located primarily due to postaccident resettlement or migration. Therefore, we invited 19,612 individuals of whom 6,369 (32%) refused to participate or failed to attend the initial screening and 13,243 individuals (68%) who were screened for the first time between 1998 and 2000. Furthermore, we excluded 40 individuals who were out of the age range, 17 who had missing thyroid dose estimates, and 946 who had a history of thyroid surgery or reported medication with thyroid hormones or presence of thyroid disease before the initial screening examination, resulting in a sample of 12,240 individuals for the current analysis.

The study was reviewed and approved by institutional review boards in Ukraine and the United States, and all subjects signed an informed consent form.

Screening examination

Individuals were screened biennially either by a mobile team or at the Research Institute of Endocrinology and Metabolism in Kyiv. Screening procedures included thyroid palpation and ultrasonographic examination by an ultrasonographer; independent clinical examination and palpation by an endocrinologist; a serum sample; a spot urine sample; and a series of structured questionnaires eliciting information on demographics, medical history, and items relevant to thyroid dose estimation, such as residential history, milk consumption, and iodine prophylaxis in May-June 1986.

Ultrasound examination

The thyroid was examined using a 7.5-MHz linear transducer (Toshiba 240, Tokyo, Japan) with the subject supine and neck extended. Presence of nodules, echostructure, and pattern of echogenicity was recorded. The thyroid volume was calculated based on the volume of an ellipsoid (length x width x depth x 0.479) as described by Brunn et al. (18). The isthmus was taken into account only if its thickness was more than 5 mm.

Serum assays

ATPO, TSH, and thyroglobulin (Tg) were measured in serum samples (available for 99% of the cohort) with LUMitest immunochemiluminescence assays (BRAHMS Diagnostica GMBH, Heningsdorf, Germany) using a Bertholdt 953 luminometer (Pforzheim, Germany). All assays were conducted according to the manufacturer’s instructions. Measurements of antibodies to Tg began later in the first screening cycle and were available for only 27% of the entire cohort. Similarly, measurements of serum-free T4 were performed only if TSH was outside the reference range; these were not available for the cohort as a whole.

The analytical sensitivity of the assay for ATPO antibodies was 16.7 U/ml; the intraassay coefficient of variation (CV) at 84 and 375 U/ml were 8.1 and 6.5%, respectively, and the interassay CVs were 11.4 and 7.7%, respectively. Based on evaluation of reference limits in a reference sample from our cohort, an elevation of ATPO above 60 U/ml, consistent with BRAHMS, was considered positive or elevated.

The analytical sensitivity of the assay for TSH was 0.008 mIU/liter; the intraassay CVs at 0.03 and 2.0 mIU/liter were 3.0 and 2.2%, respectively, and the interassay CVs were 10.9 and 2.8%, respectively. Based on evaluation of reference limits in a reference sample from our cohort, reference limits of TSH were set between 0.3 and 4.0 mIU/liter. Because initial measurements of serum TSH (n = 272) were performed using an alternative assay, we excluded these from the analysis.

The analytical sensitivity of the assay for Tg was 0.02 ng/ml. The Tg assay allows for a recovery test to evaluate whether interference with antibodies to Tg may occur. However, not all relevant interfering effects could be detected, and the usefulness of the recovery test is questionable (19, 20). The intraassay and interassay CVs at 5 ng/ml were 2.2 and 4.6%, respectively. According to the manufacturer, reference limits of Tg measurements were between 2 and 70 ng/ml.

Iodine determination

Iodine assay and findings have been described elsewhere (16). Urinary iodine content was measured using the Sandell-Kolthoff reaction as described by Dunn et al. (21) and expressed in micrograms per liter. The analytic sensitivity of the assay was 6 µg/liter.

Outcome definitions

We first analyzed prevalence of elevated ATPO (Table 1Go, definition 1), the most commonly reported outcome (13, 22, 44), considered to be an indicator of thyroid autoimmunity but not an independent indicator of AIT. We further considered AIT defined a priori based on a combination of laboratory, ultrasonographic, and palpable findings indicative of thyroid gland abnormality (definition 2). It consisted of two types of cases: type I, which had to meet at least two major criteria conveying higher confidence in their diagnoses, and type II, which had to meet one major and at least one minor criterion or at least two minor criteria conveying lower confidence in the diagnosis. Finally, to compare our results with those of other reports, we separately analyzed antibody-positive ultrasonographic changes (definition 3) (23) and antibody-positive hypothyroidism (definition 4) (22, 24, 44) that are nested in both definitions 1 and 2.


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  		TABLE 1. Outcome definitions: Ukrainian cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident, 1998–2000

 
Dosimetry

Detailed dosimetric methods have been published elsewhere (17, 25). Briefly, individual 131I thyroid doses and their uncertainties were estimated from the combination of thyroid radioactivity measurements, data on dietary and lifestyle habits, and environmental transfer models using a Monte Carlo procedure with 1000 realizations per individual (25). The distribution of 1000 individual 131I dose estimates is close to lognormal with geometric SD ranging from 1.6 to 5.0 for most of the cohort members (25). For the current analysis, we used the arithmetic mean of 1000 individual 131I dose estimates. The arithmetic and geometric means of the individual 131I arithmetic means in the cohort were 0.79 and 0.26 Gy, respectively (26). Although at present only 131I dose estimates are available for all study participants, this accounts for about 90% of the total thyroid dose for most individuals (17). The remainder represents other isotopes of iodine and internal and external exposure to isotopes of cesium (17, 25).

Statistical analysis

We estimated the odds ratios (ORs) and computed 95% confidence intervals (CIs) using logistic regression as implemented in the GMBO module of EPICURE (27). The adjustment variables were outcome specific (shown in the table footnotes) and included gender, age and calendar year at first examination, study oblast, serum TSH, Tg, thyroid volume, family history of thyroid disease, season of blood collection, fasting before blood collection, storage time of serum samples, thyroid consistency, thyroid echostructure and echogenicity, presence of nodules, and current smoking status. Urinary iodine concentration was not significantly associated with any outcomes after adjustment for other important factors and therefore was not retained in the models.

The primary models fitted to evaluate the relationship with continuous 131I dose estimates included linear in dose OR(d) = 1 + {gamma} * d, linear-quadratic OR(d) = 1 + {gamma} * d + {delta} * d2, and linear-exponential OR(d) = 1 + {gamma} * d * exp{delta} * d excess OR models (LEOR), where EOR = OR – 1. These models are nested in a more general family of models OR(d) = 1 + ({gamma} * d + {delta} * d2) * exp–({xi}d +.{zeta}d2) known to fit most radiation data and effects, particularly resulting from DNA damage (28). In addition, we fitted log-linear OR(d) = exp({gamma} * d) and power OR(d) = d{gamma} models in dose for comparison with the LEOR models because convergence problems are sometimes encountered in fitting LEOR models, particularly when interaction terms are included. In all the equations, d denotes an estimate of 131I thyroid dose, and {gamma}, {delta}, {xi}, and {zeta} are estimated parameters for various terms of 131I dose. Within each family of models, we started with the simplest model and moved to a more complex model only if the inclusion of a higher term significantly improved the model fit. The statistical significance of model parameters, test of trend, and comparison in fit among the models was evaluated with likelihood ratio {chi}2 tests with degrees of freedom (df) equal to the difference in number of parameters in comparison models. The tests of nonlinearity in dose-response relationship were carried out using score tests of the null hypotheses {delta} = 0 or {delta} = 0 and {xi} = 0 or {zeta} = 0. All statistical tests were two sided and considered significant for P ≤ 0.05. For descriptive purposes, analyses of ORs in seven distinct categories of 131I thyroid dose estimates are presented. These categories were chosen to assure an even distribution of the limited number of AIT cases in males.

To test interaction or departure from the constant risk model, we fitted the best dose-response model with main effects only and compared its deviance with a model that also included dose-response parameters within J categories of the background factor of interest (gender, age at exposure, urinary iodine). Because the dose-response relationship for ATPO prevalence did not vary by the factor of interest when either a power or linear-exponential relationship was assumed, we present only the results of interaction tests based on the power models. A significant P value at J-1 df indicates that the effect of dose on outcome of interest was not homogeneous across levels of the factor under consideration.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Twelve percent (n = 1456) of the analysis cohort had ATPO levels above 60 U/ml. ORs for prevalence of elevated ATPO adjusted for the relevant background factors were heterogeneous and significantly increased in all but one dose category (Table 2Go). Based on the LEOR model, we found a significant linear trend under 0.9 Gy (P = 0.04, df = 1). Over the entire range of 131I dose estimates, there was a significant concave trend consistent with a power (P = 0.001, df = 1) or linear-exponential relationship (P = 0.01, df = 2). Under 2 Gy, the two fitted curves followed each other closely, whereas at higher doses the power model tended to plateau and linear-exponential curved downward (Fig. 1Go). However, both of these curvilinear models described the data equally well.


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  		TABLE 2. Association between prevalent autoimmune thyroid outcomes and 131I thyroid dose estimates: Ukrainian cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident, 1998–2000

 

Figure 1
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  		FIG. 1. Association between prevalence of ATPO and 131I thyroid dose estimates: Ukrainian cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident, 1998–2000. Power dose-response model was plotted as OR = dose0.08 and linear-exponential model plotted as OR = 1 + 0.67 * dose * exp(–0.63 * dose); both curves were adjusted to pass through the lowest 131I dose category. {blacksquare}, Category-specific ORs; solid lines, power model; broken lines, linear-exponential model; lines and dashes, OR = 1.

 
To evaluate whether a significant dose-response relationship was evident in individuals with higher levels of ATPO, believed to be more predictive of AIT (14), we evaluated the dose-response separately by levels of ATPO elevation (Table 3Go). We found a significant relationship with 131I for the prevalence of moderately elevated ATPO levels but not for the prevalence of highly elevated ATPO levels (Table 3Go), although the difference in dose response between high and moderate ATPO levels was not significant (P = 0.57, df = 6).


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  		TABLE 3. Association between prevalence of elevated ATPO and 131I thyroid dose estimates according to level of ATPO elevation: Ukrainian cohort study of thyroid cancer and other thyroid diseases following the Chornobyl accident, 1998–2000

 
To address potential confounding from the occurrence of multiple thyroid disorders, we limited analysis of ATPO prevalence to euthyroid, thyroid disease-free individuals (n = 8688) and results were similar (Fig. 2Go).


Figure 2
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  		FIG. 2. Association between prevalence of ATPO and 131I thyroid dose estimates in euthyroid thyroid disease-free individuals: Ukrainian cohort study of thyroid cancer and other thyroid diseases after the Chornobyl accident, 1998–2000. Power dose-response model plotted as OR = dose0.11, linear-exponential model plotted as OR = 1 + 0.48 * dose * exp(–0.29 * dose); both curves were adjusted to pass through the lowest 131I dose category. {blacksquare}, Category-specific ORs; solid lines, power model; broken lines, linear-exponential model; lines and dashes, OR = 1.

 
Assuming a power relationship between prevalence of elevated ATPO and 131I, no effect modification by gender (P = 0.58, df = 1), age at exposure (P = 0.64, df = 1), or urinary iodine (P = 0.33, df = 3) was apparent.

In the analysis cohort, 196 individuals met definition 2 of AIT. Because there were no meaningful differences between type I (n = 34) and type II (n = 162) AIT cases for the adjustment factors or thyroid dose (not shown), we present the results for all AIT cases combined (Table 2Go). As expected, among minimally exposed individuals (<0.14 Gy, Table 2Go), females were about five times more likely to have AIT than males. There was no evidence of monotonic trend in the adjusted ORs across seven dose categories or significant trend based on a variety of continuous models (Table 2Go). The pattern of ORs with dose varied significantly by gender (P < 0.03, df = 6), with males appearing to have higher radiation risks for the same 131I dose (Table 2Go). In both genders, there was a suggestion of a nonlinear trend (data not shown). However, due to the lack of statistical power, it was not possible to determine which model provided the best fit. No evidence of variation in dose-response by age at exposure (P = 0.62, df = 6) or urinary iodine (P = 0.28, df = 6) was found.

Because the number of cases with antibody-positive hypoechoic changes was small (n = 36), we do not present these data. The analysis based on alternative categorization of 131I dose estimates, as well as on several continuous models, revealed little evidence of a significant dose-response relationship with antibody-positive hypoechoic changes (not shown) or antibody-positive hypothyroidism (Table 2Go). There was no significant effect modification of the dose-response by gender (definition 3: P = 0.76 df = 1; definition 4: P = 0.31, df = 6), age at exposure (definition 3: P = 0.74, df = 1; definition 4: P = 0.87, df = 6), or urinary iodine (definition 3: P = 0.27, df = 1; definition 4: P = 0.93, df = 6), although for antibody-positive hypoechoic changes, the male vs. female differences in dose response could not be meaningfully evaluated because 30 of 36 cases were females.

Table 4Go summarizes the geometric means of urinary iodine concentration according to levels of serum Tg and TSH. As expected, urinary iodine concentration was significantly higher at lower levels of serum Tg or TSH, although the decrease in urinary iodine with increasing TSH levels was not monotone.


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  		TABLE 4. Concentration of urinary iodine according to levels of serum Tg and TSH: Ukrainian cohort study of thyroid cancer and other thyroid diseases following the Chornobyl accident, 1998–2000

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The current study is the first to evaluate the relationship between individual 131I thyroid dose estimates and AIT in a large, well-established cohort of individuals exposed to radioactive fallout from the Chornobyl accident during childhood while residing in an area of mild to moderate iodine deficiency (16, 17). A unique feature of this study is the availability of thyroid radioactivity measurements made shortly after the accident (17, 25). The entire cohort is screened biennially for a range of thyroid diseases, making feasible an evaluation of subclinical and clinical autoimmune thyroid outcomes. Because there is a uniform screening protocol, potential confounding by dose is not an issue.

We emphasize findings concerning a priori-defined AIT because this warrants continued surveillance and/or treatment. Due to the lack of internationally accepted classification and criteria of AIT (14), we considered multiple outcomes. After controlling for a variety of confounders, none of the clinical outcomes (definitions 2–4, Table 1Go) was significantly associated with 131I thyroid dose estimates. The absence of association for antibody-positive hypothyroidism is consistent with the study of individuals exposed to 131I from the Hanford nuclear site during childhood (44) and the recent study of Hiroshima and Nagasaki atomic bomb survivors (22) but not an earlier study of Nagasaki atomic bomb survivors (24), which reported a significant linear-quadratic relationship between prevalence of antibody-positive hypothyroidism and individual thyroid doses. The absence of association for antibody-positive hypoechoic changes on ultrasound in our study contrasts with a population-based study of health in Pomerania (23), which found a significant association for this outcome with self-reported history of occupational exposure to ionizing radiation. Such inconsistent results from studies with similarly defined autoimmune thyroid outcomes could be attributed to the unique circumstances of population exposure including different types of radiation or mix of radionuclides, dose rates, age at exposure, or time since exposure if radiation risk varies by these factors. Unfortunately, the most relevant comparison with the results of other studies conducted in populations exposed to the Chornobyl fallout during childhood is hampered because these either did not state the AIT criteria explicitly or relied solely on measurements of antithyroid antibodies or did not have individual doses.

Because we used data from the first screening examination conducted 12–14 yr after the accident, variation in risk by time since exposure could not be properly addressed. Unlike studies of thyroid cancer and external irradiation during childhood (7), there was little evidence of variation in risk of AIT by age at exposure, although in our cohort, age at exposure could not be separated from the attained age. We found significant effect modification of the dose response by gender for the main AIT outcome but not for antibody-positive hypothyroidism or antibody-positive hypoechoic changes. Although males appeared to have higher risks with 131I, in both genders, there was a suggestion of nonlinear trend. It is well known that prevalence of thyroid disease, particularly of autoimmune origin, is higher in females (29, 30), and our findings in minimally exposed individuals are in agreement. Females are also more prone to any autoimmune disease (31). Therefore, an apparent radiation-related increase in males is difficult to explain, and acquisition of additional cases from subsequent screenings should increase our ability to provide more details. Until then, gender differences in dose response, although intriguing, warrant cautious interpretation.

Evidence concerning the relationship between AIT and low levels of stable iodine intake is inconsistent (15). Previously we (16) reported that 30% of the study cohort was mildly and 42% was moderately iodine deficient as determined by measurements of iodine content in spot urine samples. Similar to studies from areas of comparable iodine deficiency using estimated 24-h values of iodine excretion (32, 33, 34), urinary iodine concentration in the study cohort was significantly higher at lower levels of serum Tg and TSH. More importantly, we found no evidence that urinary iodine was associated with background prevalence of AIT or that the dose response with AIT varied by urinary iodine after adjustment for other covariates, including Tg and TSH.

We considered an elevation of ATPO to be an indicator of a thyroid autoimmunity phenomenon rather than an independent indicator of AIT. There was a modest significant association between prevalence of ATPO and 131I thyroid dose estimates. Our finding is consistent with several post-Chornobyl studies (35, 36, 37, 38, 39, 40), although these are generally difficult to interpret due to design issues, limited sample size, lack of individual dose estimates, or proper adjustment. We are the first to report that after adjustment for the relevant factors, association between prevalence of elevated ATPO and 131I thyroid dose estimates was not consistent with linearity over the entire range of doses or less than 10 Gy, was well described by power or linear-exponential function, did not vary by age at exposure, gender, or urinary iodine, persisted in euthyroid, thyroid disease-free individuals and individuals with moderately elevated ATPO, implying that this association was not due to comorbidity with other thyroid diseases or AIT.

Our finding of an association between prevalence of elevated ATPO and thyroid dose raises questions about its underlying biological mechanism and clinical importance. Little is known about the effects of low doses of 131I on the thyroid gland (41), especially whether these may cause sufficient thyroid damage and expose the existing or transformed antigenic determinants of thyroid cells to the immune system. It has been hypothesized that the production of antibodies to the same thyroid damage may vary, reflecting individual responsiveness of the immune system that may not be strictly a dose-dependent, particularly linear, phenomenon (13). In agreement with this, the results of our study are not consistent with linearity, although our own a priori hypothesis was a linear relationship. With respect to clinical importance of ATPO elevation, it should be kept in mind that whereas elevated levels of antithyroid antibodies and high levels, in particular, are a hallmark of AIT (14), mild elevation of antibodies can occur in other nonautoimmune thyroid diseases and in about 10% of healthy individuals (14, 42). An elevation of antithyroid antibodies alone does not require immediate intervention but is known to be associated with higher risk of progression to hypothyroidism (2–4% per year) (43). Thus, it is possible that a dose-response relationship with ATPO prevalence may precede and/or promote the occurrence of AIT in the future. Alternatively, such an association may reflect prior thyroid damage and be transitory, not necessarily resulting in AIT. In fact, a study of individuals exposed to 131I from the Hanford nuclear site 40 yr after exposure found no association between prevalence of antithyroid antibodies and individual 131I dose estimates (44). However, to answer with confidence which of these possibilities is true, further follow-up and analysis of prospective data from the subsequent screening cycles in this cohort are necessary.

When interpreting the results of our study, several limitations should be considered. Of the eligible and traced individuals, 68% participated. However, the dose distribution based on preliminary 131I thyroid dose estimates was similar between all the potential study individuals and the participants so it is unlikely that losses related to inability to locate or refusal resulted in a selection bias (17). Similarly, exclusion of 946 individuals with self-reported history of thyroid disease before the first screening, intake of thyroid hormones, or thyroid surgery carried out to assure the same diagnostic and screening practices or presence of thyroid tissue did not appear to introduce bias because the results of analyses including and excluding these individuals, among whom there were 183 cases with elevated ATPO and 68 cases with AIT, were comparable (not shown). It is unlikely that the reported association is due to confounding because in all the analyses, we adjusted for a variety of potential confounding factors, including Tg, and this had no meaningful effect on parameters of dose response. The impact of uncertainty in dose estimates was not taken into account. This is a complex process and its potential impact on risk estimates will be considered later.

In summary, no significant relationship between 131I thyroid dose estimates based on individual measurements of radioactivity and prevalence of AIT 12–14 yr after the Chornobyl accident was observed in this large cohort of individuals exposed to radioactive fallout during childhood and residing in an area of mild to moderate iodine deficiency. In contrast, prevalence of elevated ATPO demonstrated a modest, significant association with 131I that was well described by the power or linear-exponential function. This relationship was apparent in individuals with moderately elevated ATPO and euthyroid, thyroid disease-free individuals. There were differences in dose response for AIT by gender that, although intriguing, warrant cautious interpretation. Further follow-up and analysis of prospective data from this cohort will be important to provide more detail about the long-term consequences of 131I exposure in relation to AIT.


   Acknowledgments
 
The study team is grateful to the Louise Hamilton Kyiv Data Management Center of the University of Illinois at Chicago, supported in part by the U.S. National Institutes of Health Fogarty International Center, and its head, Oleksandr Zvinchuk, for excellent assistance with cohort database support and data management.


   Footnotes
 
This work was supported by the Intramural Research Program of the U.S. National Cancer Institute, National Institutes of Health, Department of Health and Human Services, and the Department of Energy. The U.S. Nuclear Regulatory Commission provided the initial funds for purchase of equipment.

First Published Online August 15, 2006

1 Deceased. Back

Abbreviations: AIT, Autoimmune thyroiditis; ATPO, antibodies to thyroid peroxidase; CI, confidence interval; CV, coefficient of variation; LEOR, linear excess OR; OR, odds ratio; Tg, thyroglobulin.

Received March 6, 2006.

Accepted August 9, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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