Late Radiation Effects in Marshall Islanders Exposed to Fallout 28 Years Ago (Radiation Carcinogenesis: Epidemiology and Biological Significance, PP 57-71) (Partial)

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Radiarion Cmcirrogenmti Spidemiow and Biological SigmJkanrz edited by Raven Press, New York 1984 Late Radiation Effects in Marshall Islanders Exposed to Fallout 28 Years Ago Brookhaven National Laboratow, 32 Ivy Lane, Setauket, New York 11733 In 1954, following detonation of a megaton nuclear device at Bikini, an unfortunate accident occurred owing to an unpredicted shift in winds resulting in exposure to radioactive fallout of 250 Marshallese people, 28 American servicemen on atolls to the east, and 23 Japanese fishermen on their fishing vessel. In this presentation, medical findings in the exposed Marshallese noted over the past 28 years will be briefly reviewed with particular emphasis on late effects on the thyroid gland. Details of the accident, evacuation of the people, and medical surveys and tindings can be found elsewhere (10-14,37,55). The exposure of the Marshallese differs from the exposure of the Japanese at Hiroshima and Nagasaki. The Japanese were exposed directly to the detonating bombs, and this resulted in gamma and neutron radiation, and blast and thermal trauma, with considerable early mortality. The Marshallese on the other hand were too far distant from the detonation for any direct effects, and their exposure was due entirely to fallout radiation during the 2 days prior to evacuation. This consisted of penetrating whole-body gamma radiation, irradiation of the skin (principally beta radiation) from fallout deposited on the skin, and internal absorption of radionuclides from ingestion of contaminated food and water. The most serious internal exposure was that to the thyroid from radioiodines, which were relatively abundant in the fallout. Table 1 shows the estimated doses (whole body and thyroid) received by the Marshallese on the three atolls (at approximate dktances from Bikini of 100 miles on Rongelap, 90 to 100 miles on Ailingnae, and 300 miles on Utirik). It should be emphasized that these are only rough dose estimates, since many uncertainties were involved in the dose calculations (13,33). On the basis of the degree of hematological depressions in the different groups, the whole-body gamma dose estimates do not appear to be far out of line. There is much greater uncertainty regarding the thyroid doses, which is unfortunate beeause doseeffect relationships for these findings are of considerable interest. The thyroid

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TABLE 1. Estimated radiation doses in exposed populations Est. thyroid dose (rem) Est. WhOk3-bOdy by age at exposure No. gamma dose “ Includes in utero exposures (3 on Rongelap, 1 on Ailingnae, and 6 on Utirik). doses were due to gamma radiation plus radioiodines. 1 Because of the smaller size of the thyroid gland in children, their exposure from radioiodines was considerably greater. Although the estimated dose in a 3-year-oId Rongelap child was 700 to 1,400 rads, the dose to a l-year-old child was perhaps 2,000 or more rads. These dose estimates unfortunately had to be based on a single pooled 24-hr urine sample from Rongelap people collected 15 days after exposure, with the assumption that the I-13 1 excreted in this sample represented 0.1 ?ZO of the I-131 initially taken in (33). The short-lived radioiodines (I-132,1-133,1135) were not measurable but were estimated to have contributed 2–3 times the dose from I-13 1 to the thyroid. The possible importance of these isotopes will be referred to later. The thyroid doses to the Ailingnae and Utirik groups were arrived at by extrapolation based on relative gamma dose estimates. About 200 Rongelap people who were not on Rongelap at the time of the accident, matched as nearly as possible with the exposed group with respect to age and sex, have been examined regularly for comparison purposes. In addition, during the past decade, about 400 other unexposed Rongelap people in the same age range as the exposed people and about 500 younger Marshallese have had thyroid examinations in order to establish the prevalence of thyroid abnormalities in unexposed Marshallese people. Though some of these “controls” have been exposed to slight residual radiation while living parttime on Rongelap and Utirik, any effects of such low levels of exposure would not be detectable and would not nullify their use for comparative purposes (13). PINDINGS DURING THE FIRST DECADE The early findings in the exposed Rongelap and Ailingnae groups (14) included transient nausea and vomiting, and depression of peripheral blood elements to 1 Reevaluation of early dosimetry, now under way at Brookhaven National Laboratory with additional data that have become available indicates that thyroid dosea maybe higher than previously estimated (39). In thw report the earlier eatimatca shown in Table 1 are used.

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about half normal levels, but without definite clinical signs or mortality and requiring no specific therapy. tintarnination of the skin resulted in widespread “beta bums” and epilation. These lesions healed and hair regrew normally within several months. These findings were not seen in people exposed on Utirik and were present in the servicemen to a lesser extent. It is noteworthy that no . early effects of the internal absorption of radioiodines or other radionuclides were noted. Indeed, nearly a decade passed before effects of thyroid exposure could be documented. During the subsequent years, prior to the development of thyroid abnormalities, there were few findings that could be related to radiation effects (10-13). The general health of the exposed people appeared to be about the same as that of the unexposed people. Vital statistics suggested that mortality and fertility rates were about the same. During the first 4 years, there appeared to be an increase in miscarriages and stillbirths in the exposed Rongelap women, but this observation was uncertain in view of the small numbers involved. Genetic studies and examinations of the newborn have not revealed any detectable abnormalities that might be related to radiation exposure. A slight increase in chromosomal aberrations in lymphocytes was noted in the exposed Rongelap people. Neoplasia (including a fatal leukemia) and thyroid abnormalities are discussed A number of benign tumors have been detected in both exposed and unexposed people in the normal range of expectancy (13). It is noteworthy that in spite of widespread beta bums of the skin, no chronic radiation dermatitis or skin cancers have appeared, and only a minimum amount of scarring and pigmentation can be seen. A number of benign nevi were seen in the healed areas of neck lesions in several women, but these have not increased in recent years. Two cases of pituitary adenomas have occurred. One was a nonfunctioning adenoma in a 40-year-old exposed Rongelap woman that developed several years after removal of a thyroid carcinoma. The patient responded well to x-ray therapy. The second adenoma was a prolactin-secreting tumor recently discovered in a 27-year-old exposed Utirik woman who is now undergoing treatment. In neither case was there evidence that hypothyroidism was a promoting factor, . as has been reported (38,58). Neither does it seem likely that radiation exposure was the etiological agent, since pituitary adenoma,s have not been reported in recent reviews to be radiation induced (52). Except for thyroid carcinomas, the documentation of possible radiation-associated malignancies in the Marshallese has been subject to uncertainties owing to the infrequency of autopsies or reporting of final diagnoses and unsatisfactory statistics on malignancies in the Marshallese people. A number of deaths in older women were thought to be due to cancer of the female genital tract,

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60 FALLOUT EFFECTSMARSHALL ISLANDERS which is not reported to be radiation induced in the exposed Japanese people (5). One death from cancer of the stomach in a Rongelap man exposed to 175 rads gamma radiation may have been related to his exposure. Acute myelogenous leukemia developed in a 19-year-old Rongelap male who was exposed to 175 rads of gamma radiation at 1 year of age (12) and had a subtotal thyroidectomy for removal of benign nodules at age 13. He was treated for leukemia at the National Cancer Institute but responded poorly and died 6 months later. Retrospective studies of his hemograms indicated that he had had a relative neutropenia compared with other exposed and unexposed peers over a number of years prior to his death. It has been clearly demonstrated that the most widespread late effects of fallout exposure in the Marshallese have been related to radiation hjury to the thyroid gland. With the development of thyroid hypofunction and benign and malignant nodules in the Rongelap population in the 2nd decade after exposure, extensive thyroid studies by thyroid experts have been earned out in both exposed and unexposed Marshallese.2 A number of tests of thyroid function have been carried out by methods previously published (35,36). Serum samples have been analyzed for thyroxine roid stimulating hormone (TSH). Stimulation tests with thyrotropin-releasing hormone and TSH and tests for iodine uptake, scans, etc., were done on patients hospitalized for surgery. In view of improved radioimmunoassay and other techniques, retrospective analyses were done on stored frozen serum samples taken in earlier years. The first indication of functional impairment of the thyroid was the observation, toward the end of the Ist decade, of growth retardation in some of the exposed Rongelap children. Numerous data have been collected on statural growth and osseous maturation in the exposed and control children over the years (13,54,55). In 1964 it was noted that two boys exposed at 1 year of age were stunted in growth and became myxedematous, and a number of other children exposed at less than 10 years of age had a slight degree of growth retardation. This was particularly true of the Rongelap boys exposed at less 2 Some of the physicians who have been more actively involved in the thyroid examinations Houston); and D. D. Becker (Cornell Medical Center, New York).

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than 5 years of age. Retrospective analyses of the frozen serum samples revealed that many of the children, prior to thyroid surgery, had elevated TSH levels and in some cases reduced Tt levels, though except for the two myxedematous boys, the hypofunction was not severe enough to be clinically evident. In 1965 Tt (synthroid) treatment was instituted in exposed Rongelap and Ailingnae populations with the objectives of retarding thyroid nodule formation and enhancing growth and development in growth-retarded children. It was given to surgical cases only in the Utirik and control populations. Results of this treatment will be discussed below. In view of the early hypofunction of the thyroid noted in the children, the groups tested for hypofunction have included, in addition to the exposed Rongelap-Ailingnae groups, the exposed Utirik people and many unexposed people. On the basis of control studies in the unexposed Marshallese, an increase in TSH level to >6 pU/ml on at least two occasions was considered positive evidence of hypofunction and ievels between 3 and 6 @J/mi were considered suggestive evidence. In some of the exposed children, the evaluation was based on only one available presurgical sample (13,37). These are very sensitive criteria and represent subclinical or “biochemical” hypofunction. In addition to TSH analyses, results of stimulation tests with TSH and TRH were used in many cases to confirm the findings. Table 2 summarizes these findings. The most marked TSH elevations were noted in the Rongelap people exposed at less than 10 years of age, who had received the highest thyroid doses. Only two of these had clinical hypothyroidism, and most of the others subsequently Est. Positive gestive a The levels in the exposed groups have not been corrected for control levels, since the correction would be small. Includes presurgical data.

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62 FALLOUT EFFECTSMARSHALL ISLANDERS had surgery for removal of thyroid nodules. More recently a number of surviving adults, who received considerably less exposure, without detectable thyroid abnormalities, have shown modest increases in TSH levels. Since many in this group were over 50 years of age, tests of thyroid function were done in older unexposed people, and the results indicated that this finding was not due to In 1964 benign thyroid nodules were removed from three teenage Rongelap girls in the exposed group. Since then benign and malignant nodules have developed in the exposed Rongelap and Ailingnae groups, and more recently to a lesser extent in the exposed Utirik group. A number of such nodules have been noted in the unexposed comparison populations. Table 3 summarizes these findings. The six children exposed at 1 year of age, who had the highest doses, are compared with other children less than 10 years old and with people more than 10 years old at exposure. A total of 46 exposed Marshallese (29 in the Rongelap-Ailingnae group and 17 in the Utirik group) have developed thyroid nodules, and 42 of these have had them removed. Of 600 people in the age-matched unexposed population, 35 had nodules and 14 have had surgery. Table 3 shows the greater development of thyroid nodules in the higher-dose Rongelap-Ailingnae group than in the lower-dose Utirik or matched control group. The greater prevalence in the younger members of the Rongelap group with the larger doses is in contrast to Total nodules Carcinoma Group Est. thyroid a Prevalence has not been corrected for control levels. The carcinoma prevalence is probably low, since all unoperated nodule cases were considered benign for this table. Occult carcinomas were not included as carcinomas.

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the greater prevalence in the older ones among the unexposed people. The usual predominance of nodules in females was observed. Noteworthy was the . development of benign nodules in two of three Rongelap men exposed in utero. In one, exposed at 22 weeks gestation, the thyroid was probably sufficiently functional to incriminate radioiodine transferred from the mother. In the other case, however, exposed at about 12 weeks gestation, the thyroid was probably not functional and perhaps the gamma exposure may have been responsible. Histopathologic diagnoses of Marshallese thyroid lesions have been furnished over the years by a number of pathologists.s These are summarized in TaMost of the benign nodules were “adenomatous nodules,” that is, did not fulfill the criteria of true neoplasms (44). These nodules were frequently multiple. The carcinomas were all of the papillaxy type, which are considered to behave in a clinically more benign fashion than follicular carcinoma or more undifferentiated types (1,23,45). The occult papillary carcinomas (“occult sclerosing carcinoma”) (28, 35) were found in association with adenomatous nodules. They were not listed in the malignant category in view of their generally recognized benign nature (21,23,27,5 1,61). No specific type of histologic lesion was noted in the exposed people, though histologic and cytologic changes associated with radiation injury, such as interstitial fibrosis, lymphocytic thyroiditis, and oxyphylic changes (25,53) were observed in some of the exposed individuals. TABLE 4. Histopatho/og/c diagnoses of thyroid nodules (up to 1982) No. with surgery Atypical adenoma or Occult papillary carcinoma No diagnostic lesion “ Includes unmatched younger Marshallese. ~ Includes more than one diagnosis in some cases.

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Since most of the carcinomas in the Marshallese were in the younger age group and were of the papillary type without distant metastasis, the clinical prognosis for these individuals is excellent (8,26,61). EFFECTIVENESS OFT. TREATMENT Evaluation of the prophylactic effectiveness of T, treatment in preventing development of thyroid nodules has been complicated by difficulties in maintaining a strict treatment regimen. Lack of compliance with the regimen …