Pathological Effects of Thyroid Irradiation

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PATHOLOGICAL EFFECTS OF THYROID IRIUDIATION A Repor~ to the Federal Radiation Council Division of Medical Sciences National Academy of Sciences - National Research Council

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A special Subcormnittee of the National Acadeuy of Sciences - National Research Council Advisory Committee to the Federal Radiation Council met September 19, 1966 to consider the July, 1962 Report on conclusions reached at this meeting and by subsequent correspondence are presented in this report and are based on information available through November, 1966. The members of the Subcormnittee acted as individuals, not as representatives of their organizations. Shields Warren, Chairman of Subcommittee on Effects of Radiation on the Thyroid This report was approved by the Advisory Committee to the Federal Radiation Council at its meeting on 10 December 1966. Cyril L. Comar, Chairman

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PATHOLOGICAL EFFECTS OF THYROID The constituent groups of the National Academy of Sciences - National Research Council Committees on the Biological Effects of Atomic Radiation, now disbanded, had met periodically since their formation in 1955 to consider various aspects of the general problem. In 1961 a report on Internal / Radioactive Emittersl was issued, which included a discussion of the effects of iodine-131 on the human thyroid gland. A special report on the Pathological Effects of Thyroid Irradiation was issued by the Federal Radiation Council in July, 1962.2 Enough new evidence on the effects of irradiation of the thyroid has come to hand to warrant consideration by the Advisory Committee to the Federal Radiation Council; for this purpose there was established a Subcommittee on the Effects of Radiation on the Thyroid Gland augmented by consultants with special knowledge of the field. Although parts of the available data are unpublished and incomplete, some hve6tigations have reached a point where certain conclusions can be safely drawn. Some of these data come from long-term studies on the effects of medi- ‘ tally indicated irradiations involving the thyroid gland of man. Other data come from long-term animal experiments using either iodine-131.or X-rays as the source of radiation. The human thyroid gland may be exposed to radiation from a variety of sources. Medical and dental requirements can lead to an X-ray exposure, either from a direct beam or as scatter from the irradiation of adjacent areas. Radioactive iodine may be administered for either diagnostic or therapeutic purposes. Substantial quantities of iodine-131 are produced in nuclear fission and may be released to the environment, principally during nuclear testing in the atmosphere or from some types of reactor The most important radionuclide of iodine, iodine-131, has a very short half-life of 8 days which limits the quantities that can gain entrance into the body. Fallout from nuclear detonations or from a nuclear reactor accident may deposit iodine-131, as well as other radionuclides, including very short-lived radioiodines, on vegetation and in water supplies downwind from the point of release. The absorption of idodine-131 by inhalation will be unimportant except possibly in fallout intensities which are intolerable for other reasons or immediately following a reactor accident. Direct absorption through the skin has not been demonstrated to be an %ubl-ication No. 883, “InternalE matters/’ 1961, of the National Academy of 2“Pathological Effects of Thyroid Irradiation,” Federal Radiation Council,

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important mode of entry of radio iodines in fallout. In sources of drink- . ing water for major urban populations the delay between rainfall and consumption usually assures decay of iodine-131 to an insignificant level. In addition dilution and other factors are effective in reducing the fallFresh food becomes, then, the main source of iodine-131 from the environment. For most foods the time delay between harvest and consumption is sufficient to reduce iodine-131 to an insignificant level. This is not generally the case with fresh milk for which the time between production and consumption averages about 3 days in the United States. There is some evidence suggesting that consumption of some locally grown vegetables and produce, even after washing and normal home preparation, could concei~ably contribute to the diet amounts of the order of those from fresh milk. However, there is no question but that fresh milk is by far the major contributor of iodine-131 to the United States population as a whole. Relatively little information is available on the consumption of fresh cow’s milk by people in various age groups. The most detailed study now availabl was completed in 1962 and presents per capita consumption by age and sex.8,5 During the first few months of life, the intake of fresh cm’s milk may be zero for infants who are breast-fed or given formulas based on processed products. From the survey study, the average for children under one year of age was about 0.5 liter per day which was maintained until late in teenage after which a gradual decline occurred. For adult males and femles in the population-at-large averages were 0.35 and 0.25 liters per day respectively. The range extended from persons consuming no milk to a group comprising 1 to 10 percent who consumed more than 1 liter per day. Large individual differences were found at all ages. The thyroid gland is unique in its relation to the metabolism of iodine in either stable or radioactive form. Weighing only about 1 to 2 grams at birth, and 15 to 20 grams in the adult, this gland has a high affinity for iodine. A normal thyroid will absorb and retain 15 to 30 percent of a small quantity of ingested iodine, The exact amount retained will depend, among other things, upon the amount of stable iodine ingested during the “The Transfer of Fallout Radionuclides from Diet to Man,” Chapter 9, in Radioactive Fallout, Soils, Plants, Foods, Man edited by E. B. Fowler, 4Bureau of the Census, Department of Commerce and Division of Radiological Health, Public Health Service, “National Food Consumption Survey: Fresh Whole Milk Consumption in the United States.” Radiological Health Data 5Bureau of the Census, Department of Commerce and Division of Radiological Health, Public Health Service, “Consumption of Selected Food Items in

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preceding few days or weeks. Iodine not absorbed by the thyroid will be rapidly excreted, primarily in the urine. Thu6, in a short time after a single intake, the gland will contain the highest concentration of the . iodine remaining in the body. Because of its great avidity for radioiodine the thyroid will receive the largest radiation dose, particularly if the form is iodine-131: The radiation dose delivered to other tis8uee will be, at most, a few percent of that received by the thyroid gland. A concentration of 1 pc of iodine-131 per gram of thyroid tissue will produce a time-integrated 7 About 10 percentdose of about 113 rads,6 ranging from 90 to 130 rads, of this dose will be received in the first 24 hours, probably over 25 percent in the first 2 days. When the thyroid is included in the beam from an external radiation source, such as an X-ray tube, a considerable amount of surrounding tissue will necessarily receive doses equal to or even greater than that received by the gland itself. Differences i+ growth rate and histology of the thyroid from birth through early childhood have led some to believe that the infant thyroid is more vulnerable than that of the adult to injury from ionizing radiation. In addition to differences in size and proportion of proliferating , cells of the thyroid in infants, children, and adults, there may be significant alterations in absorption, metabolic turnover, and cell sensitivity with advancing age. Any of these factors might affect the amount of biological damage resulting from a given radiation dose. Neither the relative importance nor the aggregate effect of these variables is kn~, 1. Direct Effects of Iodine-131 It has been pointed out that iodine-131 entering the body is promptly and selectively concentrated in the thyroid gland, or is excreted. The direct radiobiological effects are thus confined to the gland itself. The principal effects, which have been observed only after high doses of radioactive iodine, include a decrease in the metabolic activity of the gland, and at still higher doses, an atrophy of epithelial cells, and the appearance of numbers of atypical cells. These changes in function and structure are seen only after doses of thousands of rads. Thyroid cancer is an uncottunonresult, described with certainty to date only in animals. 6Report of the International Commission on Radiological Units and Measurements (ICRU), 1959. National Bureau of Standards Handbook 78, 7Silver S.: Radioactive Isotopes in Medicine and Biology. Lea and Febiger, Philadelphia, 2nd cd., 1962, page 117.

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2. Indirect Effects Mediated Through the Endocrine System The thyroid gland is one of the several endocrine-organs of the body whose activity is interdependent upon and responsive to disturbance in the functions of other members of the system. For example, when thyroid function is 6uppre6Sed, there is characteristically an increased production by the pituitary gland of a hormone that stimulates the cells of the thyroid. This mechanism is the basis of an hypothesis that has been advanced to explain the production of thyroid cancer by agents whose primary effect is to impair thyroid function. The resulting over-stimulation of unimpaired or slightly damaged cells by pituitary hormone is presumed to first induce hy-perplasia or other effects which may then occasionally progress to true neoplasia, In the case of human beings irradiated as infants or children, the incidence of thyroid neoplasms rises sharply during puberty and adolescence. The high requirement for thyroid function during this period of life presumably plays a powerful secondary role in inducing neoplastic transformation of the irradiated gland. The Incidence of radiation-induced thyroid disease in this group appears to fall off after age 20 to 25 years. 3. Other Indirect Effects in Cancer Induction In the last report of this group, it was stated that the probability of developing thyroid cancer after irradiation iS influenced by factors other than endocrine effects or the direct action of radiation absorbed in the thyroid gland itself. The reasons for this statement were twofold: first, the apparent absence of a dose response in thyroid cancer in persons treated with a wide range of dosage; and, second, the remarkable variation in thyroid cancer incidence in selected groups of children who received comparable doses of X-rays to the thyroid but different doses to tissues other than thyroid. In the past four years, the data on which these conclusions were based have been reconsidered in the light of new estimates of thyroid doses in these cases under study. The radiation dose to the thyroid depends strongly upon the exact location of the gland with respect to the primary beam, as well as upon the air dose. By estimating thyroid dose using reasonable assumptions as to beam port placement, it is possible to show a strong dose response for radiation-induced thyroid neoplasms. Furthermore, the remarkable variation in incidence of thyroid cancer in selected groups of persons who received comparable air doses of X-rays can be explained by the variation in thyroid dose resulting from variations of the geometrical relations to the primiry beam. Although possibility that irradiation of other tissues uxay have influenced tumor induction cannot be excluded, it is not necessary to invoke hypothesis to explain the obsenations. In various diagnostic procedures such as radiography of

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cervical spine, or larynx and fluoroscope of the larynx or esophagus, the thyroid gland may be exposed to a fraction of a roentgen up to several roentgens. These are frequent procedures, and to date no examples of cancer of the thyroid have been attributed to such exposures. However, systematic effort to determine such a relationship has not been made to In radiation treatment of hyperthyroidism, the thyroid gland ~Y be exposed to doses of several thousand roentgens. This procedure has been carried out on thousands of patients, and carcinoma of the thyroid is an extremely rare complication. Another practice, no longer in common use, is to trea”t supposedly enlarged thymus glands in infants and children by exposing the upper chest and neck to doses of 100 r to 600 r or more of X-ray. When large treatment ports, particularly those placed posteriorly, were used, the thyroid gland often received the full depth dose from the primary X-ray beam. Similar exposures of the thyroid may result from X-ray treatment of enlarged cervical lymph nodes or skin diseases. Subsequent studies of these patients, both retrospective and prospective, by several authors, have disclosed a small but significant incidence of thyroid cancer in excess of the expected rate as determined by comparison with control groups of siblings. This indicates that the thyroid gland in children is susceptible to cancer induction by radiation at relatively high doses. Evidence at low doses The use of iodine-131 was introduced into clinical medicine about 25 years ago, and for 15 years it has been widely used in a variety of diagnostic procedures. Most of these diagnostic procedures utilize between 5 to 100 microcuries of iodine-131, and most of the retained dose concentrates in the thyroid. No cases of thyroid cancer induction have been reported in the patients who have undergone these procedures. _i#-” The principal uses of iodine-131 are in the treatment of hyperthyroidism and in the management of some cases of thyroid cancer. tions were acting on tissues already cancerous. There is little evidence8 at hand that any of the treatments for hyperthyroidism has produced a thyroid cancer, although doses have ranged from a few thousand rads upward. Ablative doses would in effect rule out the possibility of tumor induction. 8Staffurth, J. S.: Thyroid Cancer After 131-1 Therapy for Thyrotoxicosis.

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From this and other evidence, it appears that iodine-131 is consid- . erably less effective than comparable doses of externally applied X-rays in producing thyroid cancer.. The magnitude of this difference cannot be stated since not-a single confirmed case ascribable to iodine-131 is known. . In making a comparison it must be kept in mind that X-rays are ordinarily delivered at a high dose rate in a single sitting or in a few divided doses; - and the thyroid as well as the blood vessels supplying it and the adjoining tissues are uniformly exposed. In addition the age of the patients treated and their clinical conditions are rarely the same in the two types of treatment. If the radiation were administered at the same low dose rate for both iodine-131 and X-ray, the ostensible difference qight not be as great. 1In a reactor accident, radioactive iodine was released to the environment , and control measures were instituted to prevent human thyroid doses from exceeding 20 rads. No increase in the incidence of thyroid neoplasia in this area has been reported, but it must be remembered that the complete effects of this episode will not be known for many years. 7. ‘Total Radiation Doses in Childhood Cancer of the Thyroid Although thyroid cancer occurs in children who are not lmown to have been exposed to artificially produced radiation, some history of X-ray ex- ‘ posure has been obtained by several workers in well over half the cases in which careful inquiry has been made. The X-ray doses received by …