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BRIEF REPORT |
Programs in Epidemiology (T.E.H., S.D., L.O.) and Cancer Prevention (K.J.K.), Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98195; Division of Endocrinology and Metabolism (T.E.H.), University of Washington School of Medicine, Seattle, Washington 98195; and Departments of Epidemiology (S.D.) and Biostatistics (K.J.K.), University of Washington School of Public Health and Community Medicine, Seattle, Washington 98195
Address all correspondence and requests for reprints to: Dr. Thomas Hamilton, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, M4-A830, P.O. Box 19024, Seattle, Washington 98109-1024. E-mail: tehamilton{at}aol.com.
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Abstract |
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Objective: The objective of this study was to determine whether exposure to 131I from the Hanford Nuclear Site during 1944–1957 increased the risk of hyperparathyroidism among people living in the area.
Design: The Hanford Thyroid Disease Study was conducted as a retrospective cohort study.
Setting: The study setting was the general community in Washington State.
Participants: The participants were 5199 persons born to mothers with usual residence in one of seven counties in eastern Washington State, randomly selected from birth records for the years 1940–1946.
Intervention: Of the 5199 selected, 3440 underwent a Hanford Thyroid Disease Study clinical evaluation, including an evaluation for hyperparathyroidism. Individual thyroid radiation dose, which could be estimated for 3191 study participants, ranged from 0.0029–2823 mGy (mean, 174 mGy).
Main Outcome Measure: Hyperparathyroidism was the main outcome measure.
Results: Of 3440 evaluable participants, we confirmed 12 cases of primary hyperparathyroidism (0.35%). We found no evidence that the cumulative incidence of hyperparathyroidism increased with increasing radiation dose.
Conclusion: In summary, this study shows no evidence that 131I, received at young ages and at the doses and exposure conditions experienced by this cohort, increased the risk of primary hyperparathyroidism. However, the effects of different doses and conditions of exposure to 131I on the risk of hyperparathyroidism remain to be defined.
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Introduction |
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Among Japanese atomic bomb survivors, the prevalence of hyperparathyroidism was found to increase with an age-dependent linear dose-response, with higher risk among persons who were younger at the time of exposure (4). Similarly, in a group of 444 persons treated with x-rays (0.6–45.7 Gy) for tuberculous cervical adenitis (5), a dose-response was observed, and the overall incidence of hyperparathyroidism was 14%.
In contrast to the considerable evidence that external 
-radiation exposure increases the risk of hyperparathyroidism, there is much less evidence for the effect of exposure to radioactive iodine. Animal studies indicate that parathyroid hyperplasia or adenomas develop sooner and more frequently in rats given 131I than in control animals (6, 7). In a retrospective study, Bondeson et al. (8) reported 600 consecutive cases of primary hyperparathyroidism, including 10 with documentation of previous 131I treatment given for Graves’ disease or ablation of thyroid remnants. These results, although inconclusive, suggested that 131I exposure may increase the risk of developing primary hyperparathyroidism.
Significant environmental exposure to 131I occurred as a result of plutonium production for atomic weapons at the Hanford Nuclear Reservation in Washington State from 1944–1957. During this period, approximately 740,000 Ci (2.73 x 1016 Bq) 131I was released into the atmosphere (9, 10). The Hanford Thyroid Disease Study (HTDS) investigated whether persons exposed as children to Hanford 131I were at increased risk of developing thyroid disease. Because of the potential for 131I absorbed in thyroid follicular cells to irradiate adjacent parathyroid cells, we also investigated whether such persons were at increased risk of developing primary hyperparathyroidism.
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Subjects and Methods |
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Study methods have been described previously (11). Briefly, 5199 individuals born during 1940–1946 to mothers who lived in counties either close to or distant from the Hanford nuclear site were randomly selected. The cohort included individuals with a wide range of doses who were infants or young children during peak years of 131I emissions from Hanford (1945–1949). Efforts were made to trace all cohort members to their current residences. All living cohort members who could be contacted were invited to participate in the study. All participants gave written informed consent for all study procedures in accordance with federal and institutional guidelines.
Clinical evaluation
Study participants were interviewed regarding previous thyroid and parathyroid disease, had a thyroid ultrasound scan, underwent thyroid physical examination, and had blood drawn. Medical records were sought to document previous diagnoses of parathyroid disease.
Serum calcium (8.4–10.2 mg/dl) was measured to screen for hyperparathyroidism. Participants with a level above 10.2 mg/dl were recontacted to repeat the calcium and measure serum albumin, phosphate, and intact PTH by immunoradiometric assay (Nichols Institute, Inc., San Juan Capistrano, CA; normal, 10–65 pg/ml). Primary hyperparathyroidism was defined as an elevated PTH and hypercalcemia (initial or retest value) based on the HTDS evaluation or documented from previous medical records.
Participants with primary hyperparathyroidism were advised to see their primary physician for recommendations and treatment. Permission was requested to obtain subsequent medical, surgical, and pathology records if the participant underwent parathyroid surgery resulting from an HTDS recommendation for additional evaluation.
Radiation dose estimation
As described more fully previously (12, 13), the Hanford Environmental Dose Reconstruction project’s computer program CIDER (14) was used to estimate the thyroid radiation doses from Hanford’s 131I received by individual participants from December 1944 through 1957. Because CIDER estimates doses accumulated during the time that a person lived within the Hanford Environmental Dose Reconstruction study area, doses could only be estimated for 3191 participants, designated in-area participants. The remaining out of area participants were included in the study, but could not be included in the primary dose-response analyses, because the CIDER program could not estimate their thyroid doses (n = 249). Dose-determining characteristics, such as places and times of residence and quantities and sources of foods and milk consumed, were recorded in computer-assisted telephone interviews (CATIs) of mothers or others with knowledge of the participant’s life during 1944–1957 whenever possible. Otherwise, doses were based on the participant’s self-reported residence history and default dietary data incorporated into CIDER.
CIDER only estimates doses to thyroid glands, not to parathyroid glands. Only about 10% of the dose from 131I is from -irradiation, for which thyroid and parathyroid doses are approximately equal; the remaining 90% of the dose is from ß-irradiation. The dose to the parathyroid glands from ß-irradiation (with exposure path <2 mm) is likely to be less than the dose to thyroid cells adjacent to the parathyroid glands. By using estimated thyroid, rather than parathyroid, dose in analyses of radiation dose responses, we effectively assumed that the two doses are (nearly) proportional. This is, in effect, a rescaling of the exposure variable from parathyroid dose D to thyroid dose K x D, where K is the unknown constant of proportionality and has no effect on the statistical significance of associations between outcomes and exposure.
Statistical methods
The primary analysis of the relationship between cumulative incidence of hyperparathyroidism and estimated thyroid dose from Hanford 131I was based on sex-stratified linear dose-response models. The sex-specific background rates and the dose-response coefficient were estimated by the method of maximum likelihood. The likelihood ratio test was used to test the significance of the dose response, and because the alternative hypothesis of interest was that risk increased with dose, statistical significance was represented by one-sided P values. The 95% confidence intervals were adjusted for the simultaneous estimation of background rates and dose coefficients using the Bonferroni technique.
Additional analyses assessed the impact of using alternative dose-response models (logistic and linear-quadratic) or characterizations of exposure to Hanford 131I (using doses based on default data rather than individual responses, categorizing participants by their mother’s usual place of residence, and excluding participants who might have an exceptionally strong influence on the estimated dose response, i.e. those with the highest doses).
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Results |
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). Among the 11 participants with hyperparathyroidism based on the HTDS evaluation, serum calcium ranged from 10.3–11.9 mg/dl, and PTH ranged from 70–180 pg/ml. Seven of these 11 cases subsequently underwent parathyroidectomy and provided medical records; five had confirmation of parathyroid adenoma, and no parathyroid tissue was identified in two. One additional participant with probable hyperparathyroidism who did not meet our strict diagnostic criteria (hypercalcemia with high normal PTH) was not included in the primary analyses, but was included in an additional analysis, with no change in results.
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). None of the additional analyses significantly altered these results.
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Discussion |
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Perhaps the most important reason for the lack of a radiation dose response in this cohort is that the actual doses to the parathyroid glands were probably much lower than those to the thyroid (mean, 174 mGy). Because 90% of the 131I dose is ß-irradiation with short exposure distances, and there is no uptake of 131I in parathyroid tissue, the parathyroid doses will be significantly less than the dose to the thyroid. Although nearly all parathyroid cells will be exposed to the small -radiation component from 131I, some parathyroid tissue may not receive any ß-irradiation. Reported doses in studies of persons exposed to external beam radiation (to both thyroid and parathyroid) range from 400–45,000 mGy (2, 3, 4, 5). Another factor that could explain the lack of a significant dose-response is that external beam radiation is delivered at high dose rates, whereas the doses received from Hanford 131I were protracted over months or years.
Several studies have reported primary hyperparathyroidism in unselected populations (15, 16, 17, 18). A prevalence of 0.21–0.6% (15, 16, 17) was found in studies that, like the HTDS, required elevated PTH and hypercalcemia as criteria for hyperparathyroidism. Studies of unselected populations using less restrictive diagnostic criteria, either hypercalcemia and high normal PTH levels or high normal calcium levels and elevated PTH levels, show a slightly higher prevalence of 1–3% (19, 20). The HTDS cumulative incidence rate of 0.35% for hyperparathyroidism is consistent with these studies, suggesting that it is unlikely that diagnoses of hyperparathyroidism were missed, or that the prevalence of hyperparathyroidism was generally increased in the HTDS cohort.
In summary, no evidence was found that exposure to 131I from Hanford increased the risk of hyperparathyroidism. These results are consistent with the hypothesis that if 131I exposure poses a risk for primary hyperparathyroidism, it probably occurs at thyroid doses higher than those experienced by the HTDS cohort. Although it is well established that external -radiation increases the risk of hyperparathyroidism, the results of this study indicate that 131I as a potential cause of hyperparathyroidism is still in question.
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Acknowledgments |
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Footnotes |
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First Published Online October 4, 2005
Abbreviations: CATI, Computer-assisted telephone interview; HTDS, Hanford Thyroid Disease Study.
Received May 16, 2005.
Accepted September 27, 2005.
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