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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0286
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 8 4587-4592
Copyright © 2005 by The Endocrine Society

Occupational Exposure to Ionizing Radiation Is Associated with Autoimmune Thyroid Disease

Henry Völzke, André Werner, Henri Wallaschofski, Nele Friedrich, Daniel M. Robinson, Stefan Kindler, Matthias Kraft, Ulrich John and Wolfgang Hoffmann

Institute of Epidemiology and Social Medicine (H.V., A.W., N.F., S.K., U.J.), Medical Department (H.W., D.M.R., M.K.), and Institute for Community Medicine (W.H.), Ernst Moritz Arndt University, D-17487 Greifswald, Germany

Address all correspondence and requests for reprints to: Henry Völzke, M.D., Department of Epidemiology and Social Medicine, Ernst Moritz Arndt University, Walther Rathenau Strasse 48, D-17487 Greifswald, Germany. E-mail: voelzke{at}uni-greifswald.de.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: The thyroid gland is a potential target organ for radiation-related damage.

Objective: The aim of the analysis was to investigate the association between occupational exposure to ionizing radiation and autoimmune thyroid disease (AITD).

Design: Our design was the cross-sectional Study of Health in Pomerania.

Setting: The setting was the general community.

Subjects: Analyses were performed in a population-based sample of 4299 subjects. Among them, 160 persons reported a history of occupational exposure to ionizing radiation.

Main Outcome Measure: AITD was defined as the combined presence of hypoechogenicity in thyroid ultrasound and antithyroxiperoxidase antibodies greater than 200 IU/ml.

Results: Females with occupational exposure to ionizing radiation had more often AITD than nonexposed females (10.0 vs. 3.4%; P < 0.05). This association persisted after adjustment for relevant confounders (odds ratio, 3.46; 95% confidence interval, 1.16–10.31; P < 0.05). In males, there were too few subjects who fulfilled the criteria of AITD, but the association between the exposure to radiation and hypoechogenicity of the thyroid gland barely missed statistical significance (odds ratio, 2.20; 95% confidence interval, 0.92–5.26; P = 0.08). In both females and males, subjects who reported a length of exposure of more than 5 yr exhibited the highest risk of the endpoints.

Conclusions: We conclude that occupational exposure to ionizing radiation is related to the risk of AITD. The usage of thyroid protection shields by radiation workers is strongly recommended.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE THYROID GLAND is a potential target organ for radiation-related damage. Current discussion concerns the association between environmental exposure to irradiation and autoimmune thyroid disease (AITD) (1). Several studies that were performed in children from contaminated areas after the Chernobyl nuclear plant accident demonstrated an increased risk of positive antithyroid antibodies (2, 3, 4) and of AITD diagnosed by ultrasound and fine needle aspiration (5). Moreover, a dose-response relation between radiation exposure and the prevalence of positive antithyroglobulin antibodies was found in some of these studies (2). Likewise, the estimated irradiation dose among Japanese atomic bomb survivors was associated with antibody-positive hypothyroidism (6). However, other studies from Hiroshima and Nagasaki (7, 8, 9) and from areas where nuclear weapons had been tested (10, 11, 12) could not confirm such associations between irradiation and AITD. Reasons for these conflicting results include methodological differences as well as the status of iodine supply in the exposed populations. It has been suggested that iodine deficiency may provoke the individual susceptibility to develop an AITD after irradiation (4).

Although general mortality of radiation workers seems not to be increased (13), thyroid carcinoma is a possible high-dose effect of occupational exposure to ionizing radiation (14). This risk can effectively be prevented by wearing appropriate thyroid protection shields. Experimental dosimetry studies demonstrated that these devices decrease the effective organ dose to the thyroid during cardiac catheterization procedures by a factor of 30 or higher (15). However, in daily practice, thyroid protection shields are frequently not worn by the medical personnel or are even not provided by the hospitals (16). Thus it seems reasonable to assume that the thyroid is relevantly exposed to ionizing radiation among persons who are generally exposed to radiation by occupation. To the best of our knowledge, the risk of AITD in this context has not yet been investigated.

Therefore, we analyzed the association between occupational exposure to ionizing radiation and the risk of AITD using data of the population-based Study of Health in Pomerania (SHIP) and tested whether such a relation was independent from important confounding factors.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
SHIP is a cross-sectional survey in Western Pomerania, a region in Northeast Germany. This region was a formerly iodine-deficient area with endemic goiter. The prophylactic procedures that were gradually introduced during the 1980s have resulted in a stable and adequate iodine supply in the study area during the past decade. The total population of Western Pomerania selected for SHIP comprised 212,157 inhabitants. A two-stage cluster sampling method was adopted from the World Health Organization MONICA Project, Augsburg, Germany (17) and yielded 12 5-yr age strata (20–79 yr) for both genders, each including 292 individuals. Data collection started in October 1997 and was finished in March 2001. The net sample (without migrated or deceased persons) comprised 6267 eligible subjects, and 4310 (68.8% of eligible subjects) participated (18). All participants gave written informed consent. The study conformed to the principles of the Declaration of Helsinki as reflected by an a priori approval of the Ethics Committee of the University of Greifswald.

Six women and five men had missing results for antithyroperoxidase antibodies (anti-TPO) and were therefore excluded. This resulted in a final study population of 4299 subjects (2187 females) who were available for the present analyses.

Sociodemographic characteristics, medical histories on thyroid disorders, and information on occupation were assessed by computer-aided face-to-face interviews. All persons were questioned whether they had ever been occupationally exposed to ionizing radiation. In case of positive answers, they were further asked to provide more detailed information on the type and the duration of this exposure. School education was categorized into three levels (low, <10 yr; medium, 10 yr; and high, >10 yr, categories based on the Eastern German three-level school system). According to smoking habits, participants were categorized into current, former, and never smokers. Diabetes was defined as self-reported physician diagnosis of diabetes. Previously diagnosed thyroid disorders were present in case of known thyroid disease or if thyroid medication was being taken according to the anatomic, therapeutic, and chemical code H03 (iodine, thyroid hormone replacement, suppression therapy, or thyrostatics).

Nonfasting blood samples were drawn from the cubital vein. Serum anti-TPO were measured by an enzyme immunoassay (VARELISA; Elias Medizintechnik GmbH, Freiburg, Germany). The detection limit of this assay was 1 IU/ml. Serum anti-TPO exceeding a level of 200 IU/ml were considered positive (19). Serum TSH, free T3 (FT3) and free T4 (FT4) levels were measured by immunochemiluminescent procedures [Byk Sangtec Diagnostica GmbH, Frankfurt, Germany (TSH and FT4) and Brahms, Berlin, Germany (LUMItest, FT3)]. All assays of serum thyroid function tests were performed on the LIA-mat analyzer from Byk Sangtec according to the manufacturer’s recommendations. Reference ranges for TSH, FT4, and FT3, which were recently established for the West Pomeranian population were 0.25–2.12 mIU/liter, 8.3–18.9 pmol/liter, and 3.8–7.0 pmol/liter, respectively (20). Subclinical hyperthyroidism was defined as serum TSH level less than 0.1 mIU/liter and FT3 as well as FT4 levels within the reference range. Overt hyperthyroidism was present if the serum TSH level was less than 0.1 mIU/liter and FT3 or FT4 levels were increased. Overt hypothyroidism was defined as elevated serum TSH and decreased FT3 or FT4 levels. Spot urine samples were collected and analyzed for iodine concentration by a photometric procedure (Photometer ECOM 6122; Eppendorf, Hamburg, Germany) (21).

Thyroid ultrasonography was performed with an ultrasound VST-Gateway with a 5-MHz linear array transducer (Diasonics, Santa Clara, CA). The normal thyroid echo pattern was classified as homogeneous. A homogeneous echo pattern with reduced echogenicity was defined as hypoechogenic. AITD was defined as the combined presence of a hypoechogenic thyroid pattern and positive anti-TPO levels. Thyroid volume was calculated as length x width x depth x 0.479 (ml) for each lobe (22). Goiter was defined as a thyroid volume exceeding 18 ml in women and 25 ml in men (23). Nodular changes exceeding 10 mm in diameter were defined as nodules.

Statistical analysis

All statistical analyses were performed with SAS software, version 9.1 (SAS Inc., Cary, NC). Data on quantitative characteristics are expressed as 25th, 50th, and 75th percentiles (PROC UNIVARIATE). Data on qualitative characteristics are expressed as percent values or absolute numbers as indicated (PROC FREQ). The study population was grouped according to the presence and absence of occupational exposure to ionizing radiation. Comparisons between groups were made using the Mann-Whitney U (continuous data, PROC NPAR1WAY) and the {chi}2 test (nominal data, PROC FREQ). Bivariate comparisons between exposed and nonexposed subjects with respect to AITD were done by a two-sided Fisher’s exact test. Because there are relevant gender differences with respect to the exposure as well as the endpoint (females are less likely to be occupationally exposed to ionizing radiation but have a higher risk of AITD compared with men), sex-stratified multivariable analyses were carried out. Logistic regression analyses were run to identify an independent association between occupational exposure to ionizing radiation and AITD (PROC LOGISTIC). Regression models were fitted including all variables as main factors. A sequence of backward regression analyses was performed to reduce the number of potential confounders to a basic set. Only those variables remained in the model if its exclusion from the model led to at least a 10% change in the coefficient of interest. In the final models, a sequence of backward and forward stepwise regression analyses incorporated two-way interaction effects between the exposure variable of interest and all other variables into the model (24). The decision to maintain an interaction in the model was made based on the likelihood ratio (consistent P value of <0.1). Sensitivity analyses were performed by using different definitions of the exposure and the confounding as well as the dependent variables. The odds ratios (OR) and the corresponding 95% confidence intervals (CI) are given. A value of P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
One hundred and sixty subjects (120 males, 40 females) reported a previous history of occupational exposure to ionizing radiation. Ninety-three of them (58.1%) had worked at a nuclear power plant; the rest were either medical or laboratory workers. The proportion of subjects who were employed at a nuclear power plant was higher in males than in females (70.0 vs. 22.5%; P < 0.05). The median duration of the exposure was 5 yr (minimum 1 yr, maximum 30 yr). In the youngest decade of 20- to 29-yr-old persons, 92.3% reported a duration of the exposure of 5 yr or less, whereas in the older decades of more than 40 yr there were 44.1–61.1% of subjects who were exposed over a period of more than 5 yr. Persons with occupational exposure to ionizing radiation were more often of male gender, of higher education, less often never smokers but more often former smokers than persons who had never been exposed to occupational radiation (Table 1Go). Both groups were similar with respect to age, parity, and history of diabetes (Table 1Go). Likewise, thyroid-related characteristics were similarly distributed between both groups (Table 2Go). No subject had a prior history of thyroid carcinoma.


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  		TABLE 1. Sociodemographic characteristics and data of risk behavior among subjects with and without a history of occupational exposure to ionizing radiation

 

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  		TABLE 2. Thyroid-related characteristics among subjects with and without a history of occupational exposure to ionizing radiation

 
In females, however, descriptive statistics revealed an increased risk of AITD among females who were exposed to occupational radiation. Proportions of AITD in exposed and nonexposed women were 10.0% (4 of 40) and 3.4% (72 of 2146), respectively (Fisher’s exact test P < 0.05). This association persisted after adjustment for age and other important confounding risk factors for AITD (Table 3Go). Besides the occupational exposure to ionizing radiation, multivariable analyses revealed a low school education and a previously diagnosed thyroid disorder as independent correlates to AITD in the female subpopulation (Table 4Go). With respect to age, the highest risk of AITD was observed in 30- to 39-yr-old women. Smoking status, diabetes, parity, and urine iodine concentrations did not meet the criteria for confounding (namely, that inclusion in the model led to ≥10% change in the coefficient of interest) and were thus excluded from the final analyses. There was no two-way interaction between the exposure and any of the confounder variables that were included in the final model. Sensitivity analyses including different categorizations of age, urine iodine concentration, and parity did not affect the main result of an association between occupational exposure to ionizing radiation and AITD among women. Moreover, different definitions of the endpoint that were used in the full model revealed rising OR for the relation of interest when the dependent variable consisted of the combination of both a hypoechogenic thyroid pattern in ultrasound and increasing anti-TPO levels (Fig. 1Go). Additional analyses were performed by including the duration of the exposure as a different exposure variable in the full model. These analyses revealed a dose-response relation between the duration of the exposure and the risk of AITD among women. Compared with nonexposed, subjects with an exposure of 5 yr or less had a slightly higher risk (OR, 1.59; 95% CI, 0.20–12.4; P = 0.66) and subjects with an exposure of more than 5 yr the highest risk of AITD (OR, 5.72, 95% CI, 1.55–21.10; P < 0.05). Finally, the kind of occupational exposure to radiation was also considered. Women who worked at a nuclear power plant and female medical and laboratory workers exhibited a similar mean risk estimate of AITD (OR, 3.44; 95% CI, 0.40–29.44; and OR, 3.47; 95% CI, 0.99–12.13) as the nonexposed women, but only the latter relation bordered statistical significance (P = 0.05).


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  		TABLE 3. AITD in females with and without a history of occupational exposure to ionizing radiation

 

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  		TABLE 4. Additional risk factors for AITD in females

 


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  		FIG. 1. The relation between different definitions of the exposure variable and the risk of AITD in females, with increasing OR for AITD by using hypoechogenicity in ultrasound alone or the combination of hypoechogenic thyroid pattern and varying definitions of increased anti-TPO titers according to percentiles. The 75th, 80th, 85th, 90th, and 95th percentiles of the anti-TPO distribution were 14.6 mIU/ml, 33.0 mIU/ml, 52.4 mIU/ml, 117.3 mIU/ml, and 365.0 mIU/ml, respectively. Data are OR ({blacksquare}) and 95% CI.

 
Among the 120 males who were occupationally exposed to ionizing radiation, there was no subject who met the initial criteria of AITD because of the low number of male subjects with positive anti-TPO levels. Even when using the combination of hypoechogenicity and the 75th percentile of the anti-TPO distribution (2.6 IU/ml) as the definition of AITD, no male with a history of occupational exposure to radiation fulfilled these criteria. Therefore, logistic regression analyses using a combined endpoint could not be performed. However, the proportion of males with a hypoechogenic thyroid pattern in ultrasound was slightly higher among the exposed than the nonexposed [seven of 120 (5.8%) vs. 64 of 1992 (3.2%); Fisher’s exact test P = 0.12). In the final regression model, the association between occupational exposure to ionizing radiation and hypoechogenicity barely missed statistical significance (OR, 2.20; 95% CI, 0.92–5.26; P = 0.08). Besides age, a previous thyroid disorder (OR, 14.8; 95% CI, 8.2–27.0; P < 0.05) and urine iodine concentrations greater than 100 µg/liter (OR, 3.10; 95% CI, 1.49–6.46; P < 0.05) were related to a hypoechogenic thyroid pattern in males. In the male subpopulation, smoking and diabetes mellitus did not meet the criteria of confounding and were thus excluded from the final model. No two-way interaction was found to be statistically significant in the final model. To investigate a dose-response relation, the history of occupational exposure to radiation was replaced by the duration of the exposure in the final model. Although males with a length of occupational exposure to radiation of 5 yr or less had a similar risk of reduced echogenicity in thyroid ultrasound compared with nonexposed (OR, 1.03; 95% CI, 0.23–4.64; P = 0.97), this risk was increased among men who reported a duration of the exposure of more than 5 yr (OR, 3.48; 95% CI, 1.25–9.69; P < 0.05). With regard to the type of radiation, the risk of AITD could not be calculated for men who reported an exposure through working as medical or laboratory personnel, because there was no subject with a hypoechogenic thyroid gland in this group. For workers of a nuclear power plant, the risk was increased (OR, 3.20; 95% CI, 1.30–7.90; P < 0.05).


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
We report an independent association between occupational exposure to ionizing radiation and the risk of AITD among females. In addition, a dose-effect relation between the duration of the exposure and AITD was demonstrated. Among males, such associations were weakened and were obtained only by using a hypoechogenic thyroid pattern in ultrasound as the dependent variable. To the best of our knowledge, this is the first study that investigated the potential risk of occupational exposure to ionizing radiation with respect to AITD.

There is an important difference between the present findings and results from studies that were performed after the Chernobyl nuclear plant accident (2, 3, 4, 5) or after atomic bombing (6). In the latter circumstances, exposed individuals inhaled radioactive 131I fallout that was accumulated in the thyroid gland. The pathogenesis of the resulting AITD shares similarities with the pathogenesis of Graves’ disease that may occur after 131I therapy of multinodular goiter (25). In the present context, however, most of the females and a considerable proportion of males who reported a previous exposure to ionizing radiation worked as laboratory or medical personnel. They were likely exposed predominantly to external irradiation with a similar probability to workers of nuclear power plants in the absence of a severe nuclear accident. This external radiation might also be sufficient to expose thyroidal antigens to the immune system and thus induce autoimmunity by stimulation of dendritic cells (26).

The present data obtained gender differences in the relation between occupational exposure to ionizing radiation and AITD. By using a specific a priori definition of AITD as a combined endpoint of ultrasound characteristics and increased anti-TPO levels, such a relation was present only among females. An important explanation for the lack of such an association among males was the generally low frequency of increased anti-TPO levels in the male subpopulation, which corresponds to a number of other studies (19, 27). Other explanations of these differences are gender-specific effects of radiation on the thyroid gland that have also been demonstrated after the Chernobyl accident (3) and different types of exposure to radiation (high proportion of males and low proportion of females who had worked at a nuclear power plant). Although the inclusion of high anti-TPO levels in the definition of AITD was useful in the female subpopulation, the present data might indicate that anti-TPO levels are less suitable to describe the radiation-related risk of AITD among males compared with the finding of a hypoechogenic pattern in thyroid ultrasound. In general, the specificity of anti-TPO levels to predict AITD-related thyroid dysfunction is currently debated (27, 28, 29).

From our data, we can only speculate about the nature of AITD as a potential radiation effect. Although additional studies are clearly indicated to assess the mechanisms and whether a specific type of radiation exposure is responsible for AITD, radiation protection practice should adopt the precautionary principle. Thus, damage of the thyroid gland by external radiation can effectively be reduced by using thyroid protection shields and additional protection devices (15, 30). As to the results of the present study, the use of thyroid protection shields by radiation workers to prevent AITD should be recommended.

The strengths of the present study are the large population investigated and the specific definition of AITD for which both ultrasound characteristics and laboratory data were used in the female subpopulation. Limitations include the relatively low number of exposed persons and the lack of detailed information on lifetime radiation exposure. However, the risk estimation for the association between the exposure to radiation and AITD was precise, consistent over a number of sensitivity analyses, and not seriously affected by different categorizations of confounding risk factors. We were also able to demonstrate a dose-dependent relation between the duration of the exposure and AITD among both females and males. Because the dose rate that exposed people may have varied, the duration of occupational exposure to radiation is only a proxy of the cumulative radiation dose and cannot fully substitute a more accurately measured individual exposure in additional studies. Although a cross-sectional study like the present is generally not suitable to establish causal relations, the latter points and the given biological plausibility may indicate such causality. Additional case-control studies are, however, needed to confirm the present findings, and cohort studies should be designed to investigate possible causal relations and the effect size of the exposure to radiation on the risk of AITD. Furthermore, studies should be performed to evaluate the usefulness of thyroid ultrasound screening in radiation workers to detect asymptomatic AITD and to prevent hypothyroidism.

We conclude that occupational exposure to ionizing radiation is related to the risk of AITD. Although confirmation of a causal relation is pending, the use of thyroid protection shields by radiation workers is strongly recommended based on the precautionary principle.


   Footnotes
 
This work is part of the Community Medicine Research (CMR) net of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grant ZZ9603), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania, Germany.

The CMR encompasses several research projects that share data from the population-based SHIP (http://www.medizin.uni-greifswald.de/cm).

First Published Online May 10, 2005

Abbreviations: AITD, Autoimmune thyroid disease; anti-TPO, antithyroperoxidase antibodies; CI, confidence interval; FT3, free T3; FT4, free T4; OR, odds ratio; SHIP, Study of Health in Pomerania.

Received February 9, 2005.

Accepted May 3, 2005.


   References
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 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals