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Thyroid Diseases in Atomic Bomb Survivors Exposed in Utero

Departments of Clinical Studies (M.I., K.A., K.N., M.A., A.H., N.S., M.S., S.F., M.Y., R.M.) and Statistics (E.N.), Radiation Effects Research Foundation, Nagasaki 850-0013 and Hiroshima 732-0815, Japan; First Department of Internal Medicine (M.I., T.U., K.E), Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501, Japan; Sasebo Chuo Hospital (T.T.), Nagasaki 857-1195, Japan; and Japan Radioisotope Association (S.N.), Tokyo 113-8941, Japan

Address all correspondence and requests for reprints to: Misa Imaizumi, M.D., Department of Clinical Studies, Radiation Effects Research Foundation, 1-8-6 Nakagawa, Nagasaki 850-0013, Japan. E-mail: misaima{at}rerf.or.jp.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Objective: The objective of the study was to evaluate the association of thyroid disease with radiation dose in atomic bomb survivors exposed in utero.

Design: This was a cross-sectional study.

Setting: The study was conducted in atomic bomb survivors in Hiroshima and Nagasaki, Japan.

Participants: Participants included 328 atomic bomb survivors exposed in utero (mean age 55.2 yr, 162 males) who participated in the thyroid study at the Radiation Effects Research Foundation. Examinations were conducted between March 2000 and February 2003.

Main Outcome Measures: The relationships of various thyroid conditions to atomic bomb radiation dose were measured.

Results: Among the 319 participants excluding nine participants whose exposure radiation dose was not estimated, the mean maternal uterine radiation dose was 0.256 Gy. We observed no significant dose-response relationship for the prevalence of solid thyroid nodules (odds ratio at 1 Gy, 2.78; 95% confidence interval 0.50–11.80, P = 0.22), but the risk estimate was similar to the estimate for childhood exposures. The prevalence of cysts and autoimmune thyroid diseases was not associated with radiation dose (P > 0.30). We could not evaluate the dose response for malignant tumors or benign nodules due to the small number of cases.

Conclusions: We did not observe a statistically significant linear dose response to radiation for thyroid nodules or autoimmune thyroid diseases 55–58 yr after participants’ in utero exposure. However, the risk estimate for solid thyroid nodules was similar for those exposed in utero and those exposed in childhood. Because the study had limited statistical power to detect moderately sized effects, further studies are needed for a definitive conclusion.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The long-term health effects of intrauterine exposure to ionizing radiation have garnered public interest but have not been fully evaluated. Several reports exist regarding association between childhood cancer and intrauterine exposure to ionizing radiation (1, 2, 3, 4). Only one investigation has examined the relationship between in utero radiation exposure and risk of cancer in adulthood. In that study of atomic bomb survivors, the overall cancer incidence among subjects 5–39 yr old (1950–1984) varied with their in utero radiation dose (excess relative risk per Gy, 2.77), but the risk was not evident 5 yr later [excess odds ratio (EOR) < 0] (5, 6). Site-specific disorders other than cancer have rarely been assessed in people exposed to radiation in utero. Radiation-related microcephaly and mental retardation were demonstrated in Japanese atomic bomb survivors exposed between 8 and 25 wk gestational age (7, 8), and radiation-related reduced height was seen, irrespective of gestational age at the time of the bombing (9).

Previous studies have reported that risk for thyroid cancer and thyroid nodules increases sharply with radiation dose and that the effect is greater when the exposed age is younger (10, 11, 12, 13, 14). Risk for thyroid diseases after in utero exposure, however, has rarely been investigated (15). In our recent thyroid screening study of 4091 Hiroshima and Nagasaki atomic bomb survivors, we found a significant linear dose-response relationship for the prevalence of all solid nodules and for malignant and benign thyroid nodules but not for autoimmune thyroid diseases in the postnatally exposed people (16). The dose responses were more pronounced in those exposed at younger ages (16). In the present study, we assessed the in utero-exposed group in this cohort 55–58 yr after their A-bomb exposure.

	Subjects and Methods

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Subjects

The Adult Health Study (AHS) is a clinical program established in 1958 by the Radiation Effects Research Foundation (RERF), formerly the Atomic Bomb Casualty Commission, comprising Hiroshima and Nagasaki atomic bomb survivors. The AHS biennial health examinations have generated clinical information that complements death and tumor registry data. A detailed description of the program has been published elsewhere (17, 18). In 1978 individuals exposed in utero (n = 1021) were added to the AHS cohort. Those subjects were born between the day after the bombing (which took place in 1945 on August 6 in Hiroshima and August 9 in Nagasaki) and April 30, 1946. The participants in the present study were drawn from that cohort. Of the 974 in utero-exposed AHS cohort members who were alive in March 2000, 374 visited RERF for health examination between then and February 2003. At the time of the examination, we informed them about the thyroid screening study; 328 (87.7%) agreed to participate and completed the thyroid examination (mean age 55.2 yr; 162 males, Fig. 1).

View larger version (18K): [in this window] [in a new window]   FIG. 1. Flow chart showing in utero cohort members and the selection of study participants. *, Suspended contact between potential study subjects and RERF.

Estimated dose and age at exposure

As a surrogate fetal thyroid dose, we used the maternal uterine radiation dose estimated by dosimetry system 2002 (DS02) (19). We based days of pregnancy at the time of the bombing (ATB) on the inferred first day of the last menstrual period and calculated it as follows: days of pregnancy ATB = 280 – (days between August 6 or 9, 1945, and the date of birth), in which the mean duration of pregnancy is taken to be 280 d. To obtain gestational week (postovulatory age in weeks), we subtracted 14 d from the days of pregnancy ATB and converted age in days to age in weeks by dividing by 7, i.e. gestational week = (days of pregnancy ATB – 14)/7. Conceptuses exposed in the first trimester were born (earlier dates refer to Hiroshima, later dates to Nagasaki) between February 7 or 10, 1946, and April 30, 1946, corresponding to 0–12 wk after ovulation. Those exposed in the second trimester were born between November 7 or 10, 1945, and February 6 or 9, 1946, corresponding to 12–24 wk after ovulation. Those exposed in the third trimester were born between August 6 or 9, 1945, and November 6 or 9, 1945, corresponding to 25 or more weeks after ovulation. For the comparison group exposed in childhood, we used all 437 people (189 men) whose age at exposure was 0–5 yr (mean ± SD, 2.6 ± 1.6 yr) with estimated thyroid radiation doses in the previously investigated cohort members (16); the mean thyroid radiation dose for those exposed to at least 0.005 Gy was 0.921 Gy (0.006–4.040 Gy). Among them, 277 were exposed in Hiroshima and 160 in Nagasaki.

Clinical examination and laboratory methods

Participants visited RERF’s Hiroshima and Nagasaki Laboratories for clinical examination. Details about clinical examinations and laboratory methods were previously described (16). In brief, a trained nurse with a questionnaire recorded information on current and past thyroid disease and thyroid medications. A blood sample was drawn to measure concentrations of free T₄, TSH, antithyroid peroxidase (TPO) antibody (Ab), and antithyroglobulin (Tg) Ab. Free T₄ and TSH levels were determined with a Lumipulse 1200 analyzer (FUJIREBIO Inc., Tokyo, Japan) using the immunometric technique based on chemiluminescence. Lyphochek Immunoassay TMJ Control (Bio-Rad Laboratories, Hercules, CA) was used for quality control at every measurement, and the internal reference range of our institute was used. TPO Ab and Tg Ab were measured by ELISA (MESACUP-2 test anti-TPO and MESACUP-2 test anti-Tg, respectively; Medical & Biological Laboratories Co., Ltd., Nagoya, Japan), and the concentration of 10 IU/ml or greater was defined as positive from instructions of the respective commercial kits. All participants underwent thyroid ultrasonography (Yokogawa GE LOGIQ 500; Hiroshima, Japan; ALOKA SSD 2000; Nagasaki, Japan) to detect solid nodules and cysts by certified ultrasonographers. All the recorded films were reviewed for diagnosis by radiologists. The ultrasonographers were initially trained for ensuring uniformity of ultrasound procedures. The films of 140 randomly selected subjects among the participants were reviewed by radiologists other than those making the initial diagnoses for diagnostic standardization between Hiroshima and Nagasaki during the examination period. Agreement among them was 98.5%.

When abnormalities of thyroid function were detected (see Diagnostic criteria), patients were referred to the Hiroshima University Hospital or the Nagasaki University Hospital for further examination. Ultrasound-guided fine needle aspiration biopsy was performed in participants with solid nodules 1 cm or greater in diameter.

Two physicians specializing in thyroid diseases (M.I. and T.U.) made their diagnoses while unaware of radiation doses.

Diagnostic criteria

Diagnostic criteria were previously described (16). In brief, participants with nodules 1 cm or greater in diameter, or a prior history of thyroid nodule surgery and histological confirmation, were classified as having thyroid nodules. Thyroid nodules were divided into solid nodules and cysts, and solid nodules were evaluated by cytological or histological examination. A cystic nodule with a solid component was classified as a solid nodule.

Participants were classified as positive for antithyroid antibodies if their serum concentration of TPO Ab or Tg Ab was 10 IU/ml or greater. Participants were classified as having hypothyroidism if their serum concentration of TSH was 4.0 mIU/liter or greater and their free T₄ levels were less than 0.71 ng/dl (9.1 pmol/liter) or they were receiving thyroid hormone replacement therapy because of low thyroid hormone levels. Hypothyroidism after ablation with radioiodine therapy, external thyroid radiation therapy, thyroid surgery, or use of antithyroid drugs was not treated as hypothyroidism.

Participants with serum TSH levels less than 0.41 mIU/liter and free T₄ levels greater than 1.52 ng/dl (19.6 pmol/liter), or those with confirmed medical histories of hyperthyroidism, were classified as having hyperthyroidism. Among hyperthyroid patients, those with a history of Graves’ disease or those with a positive TSH receptor antibody test, thyroid stimulating antibody test, or thyroid scintigraphy were considered to have Graves’ disease.

Statistical analysis

We used a linear logistic regression model for thyroid disease prevalence p with main effects,

where City and Sex indicate Nagasaki and female, GW = (gestational week – 10)/10, D is maternal uterine DS02(19) radiation dose (grays), and β’s are regression parameters. Because the frequency of the various thyroid disease cases is low and inclusion of the two-variable interaction results in a failure in fitting, we used the main effect model for analysis. The odds ratio (OR) adjusted by city, sex, and gestational week was exp(β₄) at 1 Gy. We used the DS02 radiation dose with an assigned relative biological effectiveness of 10 for neutrons, which is the sum of the maternal uterine gamma dose and 10 times the maternal uterine neutron dose. We adjusted the maternal gamma and neutron uterine doses for a 35% dose error and truncated it at 4 Gy (20, 21).

To compare radiation effects on solid thyroid nodules for the 319 subjects with known in utero exposures and the 437 subjects exposed at 0–5 yr of age, we analyzed each group separately and combined the analyses, applying a linear logistic model and a linear excess OR model (16). In the separate analyses, to maintain the consistency of analytical procedures between the two groups, we adjusted dose-response parameter estimates by sex and city but not by gestational week or age ATB. In the combined analysis, we included the following variables in the background model of both linear logistic and linear EOR models: city, sex, in utero indicator, and sex by in utero indicator interaction. In the combined analysis, we estimated the dose-effect parameter and tested the dose by in utero indicator interaction to ascertain between-group differences in dose effect. We selected the linear logistic and linear EOR models with the Akaike information criterion (AIC) (22) in which AIC is defined as deviance plus 2 times the number of parameters in the model. We used the GMBO program in Epicure version 2 to obtain maximum likelihood estimates of the parameters (23). We based all tests, and the 95% confidence bands, on likelihood ratio statistics.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Table 1 shows characteristics of the study subjects in Hiroshima and Nagasaki. Table 2 shows number of participants classified by maternal uterine radiation dose and trimester at exposure. Among those exposed to known doses of at least 0.005 Gy, the mean dose was 0.256 Gy (range 0.022–1.789 Gy) with the 155 males receiving 0.287 Gy (0.028–1.789 Gy) and the 164 females receiving 0.227 Gy (0.022–1.046 Gy). The radiation dose distribution was highly skewed, with the majority of the participants in the low dose range and only 18 exposed to 0.5 Gy or more.

View larger version (10K): [in this window] [in a new window]   FIG. 2. Radiation dose response for solid nodules. The curve displays the OR from a linear logistic regression model. The points are dose category-specific ORs with 95% confidence intervals, plotted at the mean radiation dose of the study population within each category. The dose categories shown on the plots represent less than 0.005, 0.005–0.499, 0.500–0.999, and 1.000 Gy or greater. No significant dose response was observed.

Table 6 shows the ORs of all solid nodules for in utero and childhood exposures. In linear logistic model, the ORs at 1 Gy were similar for both groups, but whereas there was a statistically significant dose-response effect for those exposed in childhood (P < 0.001), there was not one for those exposed in utero (P = 0.20). When we performed a combined analysis of both types of exposure according to the previous published analytical method (24) to determine whether there were differences in risk estimates between the in utero- and childhood-exposed groups, we observed a significant dose effect (P < 0.001) for solid nodules but no interaction of dose by the in utero indicator (P = 0.97), suggesting that there was no statistical significant difference in OR for thyroid solid nodules between childhood exposure and in utero exposure. We further evaluated the association between the prevalence of solid nodules and maternal uterine radiation dose by the linear EOR model (the same model we used in our previous thyroid study among postnatally exposed survivors) (16) because it is better suited to these analyses than the linear logistic model in terms of the AIC. The EOR model yielded similar results (Table 6).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

The Utah Fallout Study suggested that the fetal thyroid is not sensitive to radiation-induced neoplastic change (15). No data on this subject are available from Chernobyl (25). In beagles, experimental irradiation during prenatal development does not increase risk for neoplastic thyroid disease or hypothyroidism, whereas irradiation at 2 and 70 d postnatally increased risk for thyroid follicular cell neoplasia (26). In the present study, whereas we did not observe a statistically significant association between prevalence of thyroid nodules and radiation dose in survivors exposed in utero, we did observe one in survivors exposed during early childhood. Our finding of no significant dose-response relationship for autoimmune thyroid disease in the in utero-exposed subjects is similar to our previous for survivors exposed in childhood (16). These results are consistent with the findings of the Utah Fallout Study (15) and the beagle study (26). Moreover, the frequency of chromosomal translocations in peripheral lymphocytes in 40-yr-old survivors exposed in utero did not increase with radiation dose (27). Animal studies also have not demonstrated high radiosensitivity in fetuses (28, 29, 30, 31). The reason for that is uncertain. It may be that radiation does not induce chromosome damage in fetal cells or that radiation-induced damage does not persist, as has been shown for mouse lymphocytes and bone marrow cells (32).

It is possible, however, that we failed to detect a significant relationship between thyroid disease and radiation dose in the present study because of the limited size of the cohort and the relatively low doses they received. The OR estimates and 95% confidence intervals provide an indication of the magnitude of possible effects, and in the present study, the 95% upper confidence boundary of the OR for thyroid solid nodules (OR at 1 Gy, 2.78, 95% CI 0.50 to 11.80) cannot rule out the possibility of a large increase in the prevalence of thyroid solid nodules among survivors exposed in utero. In the combined analysis of intrauterine exposure and childhood exposure, a significant dose effect was observed in thyroid solid nodules, and there was no significant interaction of dose by the in utero indicator. The latter finding indicates that there was no statistically significant difference in OR for thyroid solid nodules between childhood exposure and in utero exposure. Because the risk estimates were similar for in utero and postnatal exposure (Table 6), it would be prudent to assume that in utero exposure confers a risk of thyroid nodules. A recent report showing the higher proliferative rate of fetal thyroid cells compared with childhood thyroid cells (33) supports the possibility that the fetal thyroid is radiosensitive, but we could not reach a definitive conclusion in this study. Assuming the same dose distribution and using a 5% two-sided test, a sample size three times larger than the current sample size would be required to reach a definitive conclusion.

We should also take into account differences in radiosensitivity at different stages of fetal development. Radiation exposure 8–25 wk after ovulation, for example, is associated with mental retardation due to microcephalus (7, 8). In mice, in utero radiation causes a slight increase in liver and skin tumors in the late uterine stage but persistent growth retardation in the middle uterine stage (28). Thus, it is reasonable to think that radiosensitivity of the thyroid depends on the developmental stage of the thyroid at the time of exposure. The main anlage of the thyroid gland develops as a median endodermal downgrowth from the tongue and can be seen in the human embryo before the end of the third week. The thyroid gland begins to become functional at about the 12th week of gestation (34). The proliferative rate of thyroid cells (as determined by the expression of nuclear factor Ki-67) is highest at 11–20 wk of gestation (33), which suggests that the fetal thyroid gland is most radiosensitive during the early stages of gestation. That we observed no interaction of radiation dose by gestational week was probably due to the small number of participants, as previously discussed. A possible association between radiation and gestational stage in thyroid cancer may be revealed in the incidence and mortality follow-up study of the larger in utero cohort (n = 3289) (24), but even that study sample may be too small to uncover anything but a large effect.

Another limitation is that we used maternal uterine radiation dose as a surrogate fetal thyroid dose because actual fetal organ doses are not available. Atomic bomb radiation causes whole-body external radiation exposure unlike thyroid-specific internal exposure by radioactive iodine. It has been reported that there is little difference between the fetal absorbed dose and the estimated maternal uterine absorbed dose (35). Thus, it is reasonable to use maternal uterine dose instead of fetal organ dose to evaluate the effects of atomic bomb radiation in utero by adjusting for gestational week in this study as was done in the previous studies (5, 6, 7, 8, 9, 24). However, fetal organ dose may be overestimated, particularly in the first half of pregnancy when more fluid surrounds the fetus (35). Therefore, it is possible that the radiation dose-response curves (Fig. 2) of this study are shifted to the right, leading to underestimation of the radiation effects on thyroid nodules.

We could not evaluate the radiation-dose response for thyroid cancer because of the small number of cases, especially lack of male cases. Because epidemiological studies have demonstrated a strong association between benign thyroid nodules and thyroid cancer risk, (36, 37, 38, 39, 40), the relationship between solid thyroid nodule and radiation dose may be a useful for predicting radiation effects on thyroid cancer. Radiation effects on thyroid cancer might be observed in in utero-exposed people if the case number were to increase substantially. This is suggested because when all solid thyroid nodules including malignant tumor and benign nodules were combined, the aggregate number was positively associated with radiation dose, although statistical significance was still not achieved (Fig. 2). Regardless, it may be difficult to prove this association in a future follow-up study due to the small size of this cohort.

In conclusion, we found no statistically significant effects on the prevalence of thyroid nodules or autoimmune thyroid diseases among A-bomb survivors exposed in utero, and the risk estimates for solid thyroid nodules were similar for those exposed in utero and those exposed in childhood. Our study population is unique: there is no other study that has investigated middle-aged adults who, while in utero, received relatively accurate estimated doses of A-bomb radiation. Our findings provide useful information of direct relevance to current public concerns about thyroid condition exposed to ionizing radiation in utero. It is possible, however, that effects were there but undetected in our small study sample. Definitive conclusions must await further studies.

	Acknowledgments

 
We thank the people working on the Hiroshima and Nagasaki tumor and tissue registries. We also thank Drs. Roy E. Shore and Thomas M. Seed for reviewing the manuscript, Shinichiro Ichimaru for data preparation, and Kaoru Yoshida for general assistance.

	Footnotes

 
This work was supported by the RERF (Research Protocol 2-99), Hiroshima and Nagasaki, Japan, a private, nonprofit foundation funded by the Japanese Ministry of Health, Labor, and Welfare, and the U.S. Department of Energy, with the latter funding provided through the National Academy of Sciences.

Disclosure Statement: The authors have nothing to disclose.

First Published Online March 4, 2008

Abbreviations: Ab, Antibody; AHS, Adult Health Study; AIC, Akaike information criterion; ATB, at the time of the bombing; CI, confidence interval; DS02, dosimetry system 2002; EOR, excess odds ratio; OR, odds ratio; RERF, Radiation Effects Research Foundation; Tg, thyroglobulin; TPO, thyroid peroxidase.

Received January 7, 2008.

Accepted February 26, 2008.

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Top Abstract Introduction Subjects and Methods Results Discussion References

 

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