3
Health Risks of I-131 Exposure

The major health risks associated with exposure to iodine-131 (I-131) involve the thyroid gland, which concentrates this radionuclide. Assessment of the magnitude of the public-health problem posed by exposure to I-131 estimated by the National Cancer Institute (NCI 1997a) entails understanding

  • The biology of the thyroid gland.

  • The relationship of exposure to ionizing radiation and the occurrence of thyroid cancer.

  • The effect of radiation on the frequency of nonmalignant thyroid disease.

  • Projections of the risk of thyroid cancer through the lifetime of exposed individuals.

  • The estimates of the proportion of cases of I-131 related thyroid cancer that have already occurred.

THYROID GLAND BIOLOGY

The thyroid gland (see Figure 3.1) is a butterfly-shaped, ductless gland astride the trachea on the anterior side of the throat.

The gland usually begins as an endodermal thickening and a pouch in the floor of the pharynx, visible about 3 weeks after conception. Thyroid follicular cells develop in the embryo, and by the 10th week of gestation, iodine is accumulated and colloid is present within the follicles. Thyroxine then becomes detectable and the gland is functional (O'Rahilly and Muller 1992). The thyroid gland is the source of several hormones in which iodine is an important constituent. The thyroid is the only organ in the body that greatly concentrates and retains iodine.



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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications 3 Health Risks of I-131 Exposure The major health risks associated with exposure to iodine-131 (I-131) involve the thyroid gland, which concentrates this radionuclide. Assessment of the magnitude of the public-health problem posed by exposure to I-131 estimated by the National Cancer Institute (NCI 1997a) entails understanding The biology of the thyroid gland. The relationship of exposure to ionizing radiation and the occurrence of thyroid cancer. The effect of radiation on the frequency of nonmalignant thyroid disease. Projections of the risk of thyroid cancer through the lifetime of exposed individuals. The estimates of the proportion of cases of I-131 related thyroid cancer that have already occurred. THYROID GLAND BIOLOGY The thyroid gland (see Figure 3.1) is a butterfly-shaped, ductless gland astride the trachea on the anterior side of the throat. The gland usually begins as an endodermal thickening and a pouch in the floor of the pharynx, visible about 3 weeks after conception. Thyroid follicular cells develop in the embryo, and by the 10th week of gestation, iodine is accumulated and colloid is present within the follicles. Thyroxine then becomes detectable and the gland is functional (O'Rahilly and Muller 1992). The thyroid gland is the source of several hormones in which iodine is an important constituent. The thyroid is the only organ in the body that greatly concentrates and retains iodine.

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications FIGURE 3.1 Anatomical drawing of thyroid location (courtesy of American Cancer Society). Normal Thyroid Physiology Concern about the carcinogenic effects of exposure to radioiodine on the thyroid gland is motivated by three major factors. First, evidence has accumulated that the thyroid gland is uniquely sensitive to the effects of radiation. There is some evidence that measurable increases in thyroid cancer can occur with external doses of radiation as low as 0.1 sievert (Sv) (10 rem). A finite risk at low doses of that magnitude is consistent with risks for other solid cancers reported for the Japanese atomic-bomb survivors (Pierce and others 1996). Second, the cow-milk-man pathway described in the NCI (1997a) report and discussed in Chapter 2 of this report provides a mechanism by which radioiodines in the environment can be greatly concentrated in the human food chain. Finally, because most of the radiation dose is from ingested or inhaled radioiodine, the radiation dose to the thyroid is 500-1,000 times greater than is the largest radiation dose to other organs in the body. For several reasons, persons exposed to I-131 as children are uniquely at risk for carcinogenic effects. First, children drink more milk relative to their body size than do adults. Second, the same amount or a higher fraction of internalized iodine is concentrated in the smaller thyroid glands of children; therefore the radiation dose to the thyroid in children is higher than it is in adults. Finally, studies of children whose thyroid glands were exposed to external radiation suggest a strong inverse relationship between age at exposure and the carcinogenic effects of radiation on the thyroid. Over the age of 15, little increase in thyroid cancers has been observed. Below the age of 15, thyroid cancer increased by a factor of approximately 2 for every 5 years' decrease in age. Not only is the frequency of malignant nodules increased by thyroid irradiation, but benign nodules also occur with greater than usual frequency after irradiation (Wong and others 1996). Stable iodine and its radioactive isotopes are water-soluble and readily absorbed, either from the gastrointestinal tract after ingestion or through the lungs

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications after inhalation. The first step in the synthesis and storage of thyroid hormone involves a mechanism for concentrating iodine from extracellular fluid, variably called the iodine pump, the transport mechanism, the iodide-concentrating mechanism, or the iodine trap. Transport of I- across the thyroid membrane is an energy-dependent process linked to the transport of sodium; this fact led to the concept of an Na+-I- cotransport (symport) system, with an ion gradient generated by Na+-K+ ATPase as the driving force. By this mechanism, the thyroid attains remarkably high concentrations of iodide; concentrations of 30 to 40 times that in blood are usual though values in excess of 400 fold over the level in the bloodstream have been recorded (Taurog 1996). Other tissues in humans contain sodium iodide symporters: the gastric mucosa, salivary glands, mammary glands, choroid plexus, ovaries, placenta, and skin (Smanik and others 1996). Breast tissue, which contains iodine symporters, can therefore pump iodine into breast milk. Once iodine is concentrated in the thyroid follicular cell, it is incorporated into tyrosine molecules that form part of a larger protein, thyroglobulin. Thyroglobulin is the storage form of thyroid hormone that is kept, often for long periods, within the thyroid gland. Once iodine has been incorporated into proteins by the thyroid, the biologic half-life of iodine within the thyroid is typically 80-120 days; non-protein-bound iodine has a biologic half-life of several hours in the body. The long half-life of thyroid iodine results in nearly all of the energy from the I-131 being deposited in the thyroid. The liver inactivates thyroid hormone, breaking it into smaller, biologically inert components that are eventually excreted by the kidney. Thyroid hormone is essential to life. It regulates many metabolic processes, including the rate of cellular oxygen consumption, and it affects the performance of many body systems, including the heart and nervous systems. Breaking down thyroglobulin within the thyroid produces two main forms of thyroid hormone, tetraiodothyronine and triiodothyronine, which are then secreted into the blood. Tetraiodothyronine (thyroxine) is secreted in much greater quantities than is triiodothyronine; it has 4 iodine molecules and a half-life of about 7 days in the circulation. Triiodothyronine, the most potent thyroid hormone, has 3 iodine molecules and a half-life of about 12 hours in serum. Most of the triiodothyronine in the blood comes from conversion of tetraiodothyronine to triiodothyronine by the body. The unique ability of the thyroid gland to concentrate iodine has enabled the effective use of radioiodines in the diagnosis and treatment of thyroid disorders, including an overactive thyroid (Graves disease or toxic multinodular goiter), and differentiated (papillary and follicular) thyroid cancers (Mazzaferri and Jhiang 1994). Given for medical purposes in doses that range from 5 to 200 millicuries (mCi), I-131 efficiently destroys overactive and malignant thyroid tissues. For many years, I-131 was used in very small amounts (50-100 mCi) for diagnostic studies. Typically, these were 24-hour thyroidal radioactive iodine uptake, which is a measurement of the amount of iodine taken up by the thyroid

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications from the blood and thyroid imaging studies that give some information about the configuration of the thyroid. (This is in contrast to larger doses of I-131, in the range of 10 to 200 mCi, that are given to ablate malignant thyroid tissue or to treat overactive thyroid glands. Large doses of I-131 ordinarily destroy the thyroid gland and thus do not induce thyroid cancer.) In addition to diagnostic and research exposure, children have also experienced therapeutic exposure to I-131 as described below. Thyroid Cancer and Thyroid Nodules Thyroid cancer is usually clinically manifested as a nodule on the gland. Most thyroid nodules are benign. Palpable thyroid nodules, both benign and malignant, increase in frequency with age and are more common among women than they are in men. Although studies vary, perhaps 5 percent of women over the age of 50 and about 1 percent of men over 50 have thyroid nodules that can be felt during physical examination. The prevalence of thyroid nodules detected by ultrasonography is as much as 10-fold greater than the prevalence of palpable thyroid nodules, depending on the population (Tan and Gharib 1997; Ezzat and others 1994). Most thyroid nodules detected by ultrasound are small (<1 cm in diameter) and not palpable, whether or not the population being studied has received thyroid radiation (Schneider and others 1997; Tan and Gharib 1997; Ezzat and others 1994). Larger thyroid nodules (1.5 cm or larger) are more likely to be associated with clinically significant thyroid cancer (Mazzaferri and Jhiang 1994). For several reasons, however, even these large nodules are not always palpable. First, to detect a nodule by palpation, its consistency must be recognizably different from the consistency of the normal thyroid gland. Second, some nodules are in areas that are difficult to palpate, such as on the back surface of the gland or behind the sternum. Third, the thickness of the neck of some patients makes examination of the thyroid difficult. Finally, the examiner's skill and the completeness of the examination will, in part, determine the palpability of the nodule. In one study of 54 individuals who had been exposed to therapeutic head and neck irradiation during childhood for benign conditions, ultrasound detected 157 nodules in 87 percent (47) of the subjects; 52 percent (28) had 40 nodules in all that were 1.0 cm or larger. Of the 11 nodules that were 1.5 cm or larger, palpation detected only 5, or 45 percent (Schneider and others 1997). Other studies of populations not exposed to I-131 have reported better results (Chapter 4). Most thyroid nodules biopsied by fine-needle aspiration (FNA) are benign, even in patients who have a history of head and neck irradiation (Mazzaferri 1993a). The high prevalence of benign thyroid nodules in the general population and among persons with a history of head and neck irradiation increases the risk of false-positive test results. This is discussed in detail in Chapter 4 of this report.

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications Incidence of Clinically Manifest and Occult Disease The two principal malignancies of the thyroid follicle cell are papillary and follicular thyroid cancer. Malignant tumors resulting from exposure to ionizing radiation are almost exclusively papillary cancers (Nikiforov and Gnepp 1994). Those tumors also account for more than 80 percent of the thyroid cancers occurring spontaneously among persons with no known history of thyroid radiation (Mazzaferri 1991). According to American Cancer Society estimates, 17,200 new cases of thyroid cancer will be diagnosed in 1998 in the United States, ranking thyroid cancer 14th in incidence among 35 categories (Figure 3.2). Its incidence varies with gender and age and is highest in women between the ages of 30 and 70 years; the peak incidence reaches 13.2 per 100,000 per year between the ages of 50 and 54 (see Table 3.1). The incidence of thyroid cancer is lower in men. In men, thyroid cancer peaks between the ages of 60 and 70, when its annual incidence is 8.6 per 100,000 (NIH 1997). In the latest Surveillance, Epidemiology, and End Result report (SEER 1998), the average lifetime risk over a 95-year lifespan of being diagnosed with some form of thyroid cancer was 0.66 percent (6.6 per 1,000) for TABLE 3.1 Thyroid Cancer (Invasive) Incidence Rates per 100,000 Persons, 1990+1994, by Age at Diagnosis Age at Diagnosis Total Males Females All ages 4.9 2.8 6.9 0-4 0.0 0.0 0.0 5-9 0.1 0.1 0.1 10-14 0.4 0.3 0.6 15-19 1.4 0.3 2.6 20-24 3.9 1.0 6.8 25-29 5.4 2.3 8.6 30-34 6.8 2.4 11.1 35-39 7.8 3.7 11.8 40-44 7.9 3.7 12.0 45-49 8.5 4.8 12.2 50-54 9.5 5.7 13.2 55-59 9.3 6.1 12.4 60-64 8.6 7.0 10.1 65-69 9.9 7.5 11.8 70-74 9.7 8.6 10.5 75-79 9.5 8.5 10.2 80-84 7.7 6.1 8.6 85+ 7.9 7.2 8.2   SOURCE: (NCI 1997b).

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications FIGURE 3.2 Percent of all cancer cases (data from ACS 1998).

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications women and 0.27 percent (2.7 per 1,000) for men. By way of comparison, the lifetime risks for women of developing invasive in situ breast cancer or invasive in situ colon cancer are 14.2 percent and 6 percent, respectively. For men, the lifetime risks of developing prostate or lung cancer are 18.8 percent and 8.4 percent, respectively. The lifetime risk of dying from some form of thyroid cancer was 0.07 percent for women and 0.04 percent for men. These figures compare to 3.46 percent and 2.53 percent lifetime risks of dying, respectively, from breast cancer and colon/rectal cancer for women and 3.64 percent and 2.57 percent for prostate and colon/rectal cancer for men. The risk of dying of thyroid cancer in countries with efficient medical care systems is low. The long-term mortality rates for papillary thyroid carcinoma are less than 10 percent at 30 years after diagnosis (Mazzaferri and Jhiang 1994). The American Cancer Society estimates that 1,200 people will die from thyroid cancer in 1998, accounting for about 0.2 percent of all cancer deaths. Unlike its incidence, which has been rising, the mortality rates for thyroid cancer have been falling. Between 1973 and 1994, the mortality rates for thyroid cancer dropped more than 23 percent, both for people younger than 65 years and for people older than 65 at the time of diagnosis (NIH 1997). See Figure 3.3. Between 1973 and 1992, the incidence of thyroid cancer rose almost 28 percent (p < 0.05)—a change that has been observed in persons both under and over the age of 65 at the time of diagnosis. In the SEER reports, 14 of 23 cancer sites showed increasing incidence during this period; only 4 of the 14, including thyroid cancer, showed decreasing mortality. The contrast between the incidence and mortality trends has been attributed to more sophisticated detection technologies (ultrasound for nodules and FNA biopsy for cancer) and more complete diagnostic reporting (Wang and Crapo 1997). A large number of thyroid cancers are small, occult tumors that are usually not detected during a person's lifetime and that rarely progress to cause problems. Clinically silent tumors are generally papillary microcancers smaller than 1.0 cm in diameter. They may be found unexpectedly during surgery for benign thyroid disease, at autopsy, or by FNA biopsy of a nodule discovered by ultrasonography. Their prevalence varies according to the geographic location and possibly ethnicity, the type of tumor, and the intensity of the pathologic examination (Moosa and Mazzaferri 1997). In autopsy studies of persons who died without known thyroid disease, the prevalence of occult thyroid cancer ranges from 5 to 13 percent among studies in the continental United States and 6 to 36 percent among studies in Europe (Moosa and Mazzaferri 1997; Thorvaldsson and others 1992; Harach and others 1985). Occult cancer is found in all age groups but is more frequent after the age of 40; there is no gender difference in frequency. Thus, there is good reason to suspect many healthy people harbor tiny thyroid cancers that will never harm them. The problem of microcancers is not unique to the thyroid gland. Similar tumors are found even more commonly in the breast and prostate. The introduction

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications FIGURE 3.3 Percent of all cancer mortality (data from ACS 1998).

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications of sophisticated diagnostic tests has resulted in the discovery of many microcancers that are unlikely to harm the patient. A major challenge for medical research is to differentiate clinically significant microcancers from those that will never harm the patient. Failure to make this differentiation will result in some patients undergoing treatment for harmless diseases and others imprudently having their diseases ignored. Research cited in Chapter 4 suggests that people want to factor information about these usually nonprogressing cancers into their decisions about cancer screening and treatment. Thyroid Cancer in Persons (All Ages) Not Exposed to Radiation Most clinically apparent papillary thyroid cancers are first manifested as one or several palpable thyroid nodules, discovered in about half the cases by the patient (Mazzaferri 1993a). They are otherwise usually asymptomatic, although a small proportion of highly invasive tumors are very symptomatic. At the time of diagnosis, the primary tumor is typically 2.0-2.5 cm, but can range from a few millimeters to more than 5 cm in diameter. With routine study of permanent histologic sections, about 20 percent of papillary cancers are multiple tumors thought to represent intrathyroidal metastases, but with meticulous study more small tumors (up to 80 percent in some studies) are usually apparent within the gland (Mazzaferri 1991). Some 5-10 percent of the primary tumors that occur without known exposure to radiation invade the thyroid capsule, growing directly into surrounding tissues, thus increasing both the morbidity and the mortality of papillary carcer (Mazzaferri and Jhiang 1994; Emerick and others 1993). The most commonly invaded structures are the neck muscles and vessels, recurrent laryngeal nerves, larynx, pharynx, and esophagus—but tumors can extend into the spinal cord and brachial plexus. At the time papillary cancer is diagnosed, about 40 percent of adult patients have metastases to regional lymph nodes and about 5 percent have distant metastases, usually to the lung (Mazzaferri 1991). Mortality rates for adults with papillary thyroid cancer are generally less than 10 percent over several decades after initial therapy (Mazzaferri 1993b). Cancer-specific mortality rates in adults with papillary cancer are about 5 percent at 10 years and slightly less than 10 percent at 20-30 years after treatment; the 5-year survival rate is only about 50 percent for patients with distant metastases (Dinneen and others 1995; Mazzaferri and Jhiang 1994; Mazzaferri 1991; Hay 1990). As is characteristic of many cancers and other diseases, cancer-specific mortality rates are progressively higher for patients over age 40 (Figure 3.4) and among persons with more advanced tumor stages at the time of diagnosis. Thyroid Cancer in Children Not Exposed to Radiation Thyroid cancer that occurs spontaneously has somewhat different features in

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications FIGURE 3.4 Incidence and cancer-specific mortality rates for thyroid carcinoma. Drawn from the data published by Kosary CL et al. 1995. SEER Cancer Statistic Review, 1973-1992: Tables and Graphs. National Cancer Institute. NIH Pub. No. 96-2789, Bethesda, MD. young children than it has in adults. In children, it is almost always papillary and usually is at a more advanced stage at the time of diagnosis. Papillary cancer in children more frequently invades beyond the thyroid capsule, and it metastasizes to regional lymph nodes in almost all cases (Hung 1994; Robbins 1994; De Keyser and Van 1985). For example, in a study of 98 children with differentiated thyroid cancer (Travagli and others 1995), lymph node involvement was seen in 88 percent of children at the time of diagnosis, and invasion of the thyroid capsule had occurred in 59 percent. Distant metastases also are more frequent in children than they are in adults with differentiated thyroid cancer. In some series, up to 20 percent of children have distant metastases at the time of diagnosis (about 4 times the rate that occurs in adults) and another 10-20 percent of children develop them during the course of the disease (Harness and others 1992; Schlumberger and others 1987; Goepfert and others 1984). In fact, distant metastases are most frequently observed in the youngest patients, especially those who are younger than 7 at initial treatment. There is a high recurrence rate in children after initial surgical removal of tumors. Despite the aggressiveness of thyroid cancer in children, the long-term mortality rate is only about 2.5 percent, so survival is thus much better for children than it is for adults (Figure 3.2) (Robbins 1994). Because death from recurrent disease can occur many years later, however, the prognosis evolves over

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications decades. Moreover, the statistics are somewhat misleading. In the study of Travagli and others (1995), although relatively few deaths occurred in children, the standardized mortality rate (SMR) was 6.4; however, 95 percent confidence intervals (CIs) were not reported, and a few deaths might result in an unrealistically high SMR. Ret Proto-Oncogene and Papillary Thyroid Cancer Our understanding of the molecular genetics of thyroid cancer has grown substantially in recent years (Fagin 1994b; 1994a; Farid and others 1994). Of particular interest in patients with papillary thyroid carcinoma, and especially in children who have been irradiated, are the genes on chromosomes 10 and 17 involved in paracentric inversions or translocations that result in the activation of the tyrosine kinase domain of the ret proto-oncogene. This is the most common event in papillary thyroid cancers occurring naturally (PTC1) and among those in children after the Chernobyl accident (PTC3). Normally, ret is not expressed in thyroid follicular cells and its promoter is thus inactive. In papillary thyroid cancer, but not in other thyroid neoplasms, the tyrosine kinase domain of ret is turned on and activated by a paracentric inversion on chromosome 10 involving ret and another gene, H4, producing PTC1 (papillary thyroid cancer 1) (Grieco and others 1990). Two other genes are similarly rearranged with ret: RI, which codes for a subunit of the receptor-associated Gs protein that forms PTC2 (Santoro and others 1994), and ELE1, to form PTC3 or PTC4 (Fugazzola and others 1996; Klugbauer and others 1996; Jhiang and others 1994). Ret proto-oncogenes have been detected in 11-59 percent of naturally occurring human papillary thyroid cancers, depending on the means of detection and the population studied (Williams and Tronko 1996). The most common rearrangement among patients with sporadic tumors is PTC1 (Jhiang and Mazzaferri 1994), while PTC3 is the most common in children from the area around Chernobyl who developed thyroid cancer. RADIATION AND THYROID CANCER Thyroid Cancer from External Radiation Exposure Studies evaluating the risk of thyroid cancer from radiation exposure have credence insofar as they use reasonably accurate dosimetry (calculation of radiation doses to the thyroid), have substantial numbers of persons in the dose range of interest (for this population, low to moderate doses), have a reasonably long follow-up period, and have a high follow-up rate. The statistical power and precision of such studies, which are important in weighing the study results, are positively related to the number of thyroid cancers observed and to the mean dose. Summary results of the seven principal cohort studies of thyroid cancer incidence

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications Uncertainty also applies both to the assumption of constancy of ERR and to the assumption of additivity of multiple exposures. This committee notes that natural background doses over the 10-year period of testing would present to each person in the United States an average dose that was approximately half of the average dose from the weapons testing (2 rad or 0.02 Gy). The amount of natural background radiation varies geographically, such that, in some areas, the 10-year average could have been lower or higher by 0.01 Gy (1 rad), when radon exposures are ignored, bringing the average dose to 0.03 Gy (3 rad) or 0.04 Gy (4 rad) to the thyroid over the 10 years of testing. Some areas would have been lower and some higher in the calculated fallout dose ranges. It would be informative, therefore, to determine how background radiation would alter total dose, and hence risk, to persons over this 10-year period. Calculations could be done to compare the total doses using the actual background dose for each county to add to the total estimated dose to the average individual in each county, but this would require substantial effort. Analyses of the risk of thyroid cancer after exposure to ionizing radiation such as those analyzed by Ron and colleagues essentially assume similarity in naturally occurring and radiation related thyroid cancers. Although this chapter has cited histologic evidence suggesting that the differences in thyroid cancers in children exposed from the Chernobyl accident, there are no data yet relevant to effects in adults exposed as children to the I-131 levels associated with the Nevada weapons tests. Given some of the issues noted above, the committee suggests that DHHS consider some additional analyses to evaluate further the estimated confidence intervals for the risk projections and to improve understanding of the sensitivity of the projections to changes in key assumptions. Such analyses might include (1) use of alternative dose-response models, (2) choice of different average population doses, (3) use of a model of excess relative risk that declines as a function of years since exposure, and (4) exclusion of the tinea capitis study from the Ron analysis. As indicated above, there are few data to show a statistically significant carcinogenic effect of radiation to an organ or whole body below a dose of 0.1 Gy (10 rad). Epidemiologic studies, which might be helpful, are complicated when estimated doses are low. For example, very large samples are needed to demonstrate an effect. Results of some epidemiologic analyses of the possible effects of I-131 fallout from the Nevada weapons tests are discussed below. Epidemiologic Analyses Using Cancer Registries Neither the NCI (1997a) report nor the analyses provided by Land (Appendix B, this report) consider whether there is any epidemiologic evidence of increases in thyroid cancer from exposure to Nevada Test Site fallout. Data from various tumor registries around the country could be useful in reducing the uncertainty in the estimate of the collective excess of thyroid cancer cases. In particular,

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications analysis of registry data allows for the comparison of thyroid cancer incidence between birth cohorts within the same general locality. The NRC panel had access to three such analyses—one undertaken by the committee, one for the state of Idaho, and one prepared by NCI analysts. In addition, it reviewed the Utah study (Kerber and others 1993) cited earlier in this chapter. That study, which was published in the Journal of the American Medical Association, found more thyroid cancers that would be expected for a nonexposed population and produced a risk coefficient of 7.9 per Gy, almost the same value as calculated by Ron (7.7 per Gy). To get an idea of the power of epidemiologic studies, consider the use of tumor incidence data from registries reporting (as do the current SEER data) all thyroid cases occurring over the years 1973–1992. Note that, according to Land's analysis, there is a population of 17.6 × 106 who were 0-4 years in 1952, and thus were 21-44 between 1973 and 1992. Persons who were 0-4 years old in 1963 were born during the era of underground testing, and thus may be considered to have been largely unexposed. Their attained ages over the same 1973-1992 period will range from 10 to 33 years. Thus, we may compare, for example, the rates of thyroid cancer incidence among persons aged 25-29 between these two birth cohorts. The average age of the earlier birth cohort over the time of atmospheric testing (1951–1958) is approximately 3.5 years. From Table 3.4, this corresponds to an average thyroid dose of approximately 0.067 Gy (6.7 rad), which, in turn, corresponds to an estimated excess risk of thyroid cancer of approximately 1.43 for this cohort compared with the later, unexposed birth cohort. Assuming that the rate of thyroid cancer in the unexposed cohort is 4.5 per 100,000 person-years (SEER data), to have sufficient statistical power (90 percent) to detect such an excess incidence, the monitoring system would have to have covered approximately 617,000 people in each of the birth cohorts. This would yield an expected 199 cases of thyroid cancer in the exposed cohort and 139 in the unexposed cohort. If we use a risk factor 4.3 times smaller than median value of 7.7 per Gy (which gives the lower end of Land's CI), then approximately 9.9 million persons would have had to have been monitored from each birth cohort to have the same power to detect a 10 percent increase. The SEER registries cover about 10 percent of the entire U.S. population, or about 1.8 million persons from the 1948–1952 birth cohort born. Potentially, then SEER registry data could help assess whether past incidence in these birth cohorts is consistent with the higher part of the estimated range of excess risk provided by Land. For this report, the committee examined thyroid cancer incidence rates by birth cohort using SEER data. It also reviewed an analysis of Idaho registry data and another analysis of SEER data (Gilbert and others, in press for the Journal of the National Cancer Institute ) that used incidence data from 1973–1994 and thyroid cancer mortality data from the 48 contiguous states from 1957 to 1994. The approach of Gilbert and colleagues was to relate county-level geographic variation in thyroid cancer incidence and mortality with the NCI's county-by-county

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications estimates of thyroid dose. This committee took a different approach. It compared "exposed" versus "unexposed" birth cohorts for differences in thyroid cancer rates. The analyses of Gilbert and colleagues are performed within each birth-cohort separately, so that no specific comparison of "unexposed" versus "exposed'' birth cohorts is given. The two approaches—variation by birth cohort in SEER and in Idaho, and variation by geographical region in SEER and in the mortality data—are complementary, but each is subject to certain limitations. For example, the Idaho analysis is limited because of the small population of the state, which, in turn, limits the numbers of thyroid cancers to relatively small numbers. The birth cohort approach to the SEER data ignores the geographical variation in estimated dose. Also, the interpretation of results may be complicated by external factors such as secular trends in thyroid incidence and by exposure to I-131 from other sources such as the Pacific or Siberian nuclear tests, which continued beyond the time of above ground testing at the NTS. The analysis of Gilbert and colleagues avoids the latter complexity, but introduces other, perhaps more important problems, because county level doses are known with far less certainty than are the average doses for the birth cohorts. Moreover, the analysis of Gilbert and colleagues is much more affected by the results of migration from county to county either at the time of exposure or in later life. Publicly available thyroid cancer incidence data from 9 tumor registries that make up the SEER program are tabulated in Table 3.5 for the two birth cohorts described above, for the attained ages of 25-29 years, by region (far west and the rest of the country). The far-western registries are in San Francisco-Oakland, Hawaii, and Seattle; the other, not-far-western registries are in Connecticut, Detroit, Iowa, New Mexico, Utah, and Atlanta. The far-western areas were much less exposed to Nevada Test Site fallout than was the rest of the country, so their incidence data are tabulated separately, although considerable migration from eastern to western areas can be assumed to have taken place. For the registries outside the far west, there is some evidence of about a 10 percent excess of thyroid cancers in the exposed birth cohort, but the estimate is not statistically significant. An evident excess for males in the far-western registries is unexpected, but the numbers of cases, 38 and 28, on which this observation is based are not large. Given the NCI dose estimates, such excess cases are not likely to be attributable to exposure to Nevada Test Site fallout. Comparisons of thyroid cancer rates in an earlier birth cohort, 1938-1942, with rates among the 1948-1952 birth cohort also are of interest (Table 3.6). The 1938-1942 birth cohort was aged 9-20 during 1951-1958. According to Table 3.4, the estimated excess risk of thyroid cancer would have ranged from 5 to 15 percent for this cohort, compared with more than 40 percent for the 1948-1952 cohort. SEER data allow us to compare rates of cancer at ages 35-39 for these two cohorts (Table 3.6). Again, about a 10 percent excess risk for the 1948-1952 birth cohort is seen in the non-far-western registries, but this is not statistically significant. The data from the far-western registries are not consistent between males

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications and females; males show 32 percent fewer thyroid cancer cases in the 1948-1952 cohort, and females show a 23 percent increase. Because differences in thyroid cancer incidence in the western registries are less apt to be due to I-131 exposure from the Nevada Test Site than are differences in the other registries, they suggest some difficulties in attributing differences in the non-far-western cohorts to I-131. Appendix D provides a detailed examination of the thyroid cancer rates in Idaho by birth cohort and county for the period 1970-1996. While several Idaho counties showed elevated rates of thyroid cancer, they did not correlate very closely with estimated thyroid dose. The birth cohort born from 1948 to 1958 showed a 5 percent excess of incident cases compared to earlier and later cohorts, but this increase was not significant with the 95 percent confidence interval as the excess among the counties ranges from -7 to +18 percent. Within the most sensitive of the three birth cohorts examined in the Idaho analysis, there was little evidence of association with county or the county-specific estimate of thyroid dose; however the power to detect a dose response, within the relatively small population of Idaho, is quite low. The analysis of Gilbert and colleagues relates geographic variation in thyroid cancer incidence and mortality rates in counties from the 48 contiguous states to the NCI estimates of average dose within each county. Overall that analysis finds negative nonsignificant excess risk due to I-131 exposure. However, when the analysis is restricted to those subjects exposed in infancy (age <1 y), a positive association between dose and risk is marginally significant for both thyroid cancer incidence (p = 0.11) and mortality (p = 0.054). The findings for that very narrow age group (<1 y at exposure), however, contrast with those in the group aged 1-5 years at exposure, for which dose responses were estimated to be negative despite the fact that subjects aged 1-5 years ought to be nearly as radiosensitive as the infants (based on findings from the external radiation studies). When the analyses of Gilbert and colleagues were restricted to subjects who were aged 0-4 at any time during 1950-1954 (i.e. those born between 1950-59), a significant association between I-131 exposure and thyroid cancer mortality (ERR per Gy = 12.0, p = 0.005) was detected. No other birth cohort (including those born between 1955 and 1964) showed positive risk estimates for mortality based on the county level dose estimates. Moreover there was no increase in incidence detected in the 1950-1959 birth cohort (ERR per Gy = 0.3, p = 0.66) The fact that mortality but not incidence showed a dose response in this birth cohort is puzzling. There were almost 3 times as many incident cases as thyroid cancer deaths (12,657 vs. 4,602), which would imply that the power to detect increases in risk should be far greater in the thyroid cancer incidence data than in the mortality data. The impression left by these three studies—birth cohort comparisons of incidence in Idaho, birth cohort comparisons in SEER, and the study of Gilbert and colleagues using geographical variation in SEER incidence and thyroid cancer mortality—is that there is little evidence of widespread increases in risk related to

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications TABLE 3.5 SEER Thyroid Cancer Incidence Data. Comparisons of Thyroid Cancer Rates at Ages 25-29 Between Birth Cohorts Born in 1948-1952 (Exposed) and 1959-1963 (Relatively Unexposed) Birth Cohort Number of 25-29 Year Olds Number of Thyroid Cancers Approximate Rate per 100,000 Person-Years Percentage Excess in Birth Cohort p-Value for Excess Far western registries 1948-1952 (Monitored in 1977) Males 317,724 38 2.39 65.6 0.10 Females 310,404 136 8.76 8.1 0.50 1959-1963 (Monitored in 1988) Males 387,623 28 1.44 —   Females 367,614 149 8.11 —   Other registries 1948-1952 (Monitored in 1977) Males 590,102 52 1.76 9.8 0.63 Females 601,506 257 8.55 9.9 0.28 1959-1963 (Monitored in 1988) Males 673,052 54 1.60 —   Females 683,896 266 7.78 —   the pattern of exposure of I-131 as described in the NCI report. They suggest that the numbers of excess cases of thyroid cancer due to I-131 exposure from the Nevada weapons tests are likely to be in the lower part of the range estimated in the Land memo. Furthermore, the estimate of only a 10 percent increase in risk between the exposed and nonexposed birth cohorts as detected in SEER, lies in the lower portion of the range of excess cases that was estimated by Land. Translating the 10 percent increase in risk for these cohorts to excess lifetime risk (using the linear constant excess relative risk model) amounts to approximately 11,300 excess cases (using an RBE of 0.6). The range of uncertainty attached to this estimate, however, is itself large, so that the use of registry data beyond what is currently available in SEER is important to pursue and will allow more detailed comparisons of age-specific rates of thyroid cancer. Some registries, such as the one in Connecticut, predate the SEER data years by a considerable margin. This discussion has emphasized the uncertainties inherent in using the NCI (NCI 1997a) report to determine the likely number of excess thyroid cancer cases caused by exposure of the American public to I-131 fallout from the Nevada Test Site. Nevertheless, based on the other data reviewed in this chapter, the committee finds it reasonable to conclude that some excess cases of thyroid cancer have occurred and will continue to occur as a result of the Nevada weapons tests.

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications TABLE 3.6 SEER Thyroid Cancer Incidence Data. Comparisons of Thyroid Cancer Rates at Age 35-39 Between Birth Cohorts Born in 1938-1942 (Relatively Unexposed) and 1948-1952 (Exposed) Birth Cohort Number of 35-39 Year Olds Number of Thyroid Cancers Approximate Rate per 100,00 Person-Years Percentage Excess in Birth Cohort p-Value for Excess Far western registries 1938-1942 (Monitored in 1977) Males 209,307 52 4.97 —   Females 203,509 95 9.34 —   1948-1952 (Monitored in 1988) Males 350,438 59 3.37 -32.2 0.05 Females 344,993 198 11.48 22.9 0.09 Eastern registries 1938-1942 (Monitored in 1977) Males 388,265 59 3.04 —   Females 407,757 182 8.97 —   1948-1952 (Monitored in 1988) Males 584,760 102 3.49 14.8 0.4 Females 605,706 294 9.71 8.2 0.4 Estimate of the Number of Cases of Thyroid Cancer that Have Already Been Manifested The population at excess risk of thyroid cancer from I-131 due to fallout from weapons testing at the Nevada Test Site consists of people born between approximately 1940 and 1957. These individuals are now in their early 40's to late 50's in age, and are more than 40 years past their initial exposures. Reported follow-up of the groups considered by Ron and colleagues (1995) is as yet insufficient to be certain that childhood exposure to thyroid radiation results in continued risk for the remainder of one's lifetime (that is, beyond 40 years from time of exposure). Assuming a constancy of excess relative risk obtains, then the distribution of excess thyroid cases would mirror the age specific rates of this cancer. Table 3.7 gives the fraction of thyroid cancer risk manifested by ages 40-60 for males, females, and the sexes combined, with the computations based upon the incidence rates published by SEER. It should be noted that when the sexes are combined the expected values are closer to those for females than for males because females have a higher background risk of thyroid cancer. Since the birth cohort most at risk is presently between the ages of 45 and 50 years, a reasonable estimate of the fraction of excess cases that have already occurred is about 45 percent. This calculation, as

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications TABLE 3.7 Fraction of Expected Thyroid Cancer Cases Occurring by a Given Age. Age (years) Females (%) Males (%) Sexes combined (%) 40 33 20 30 45 42 27 38 50 52 35 48 55 61 45 57 60 69 54 65 are all of the risk calculations in this report, is strongly dependent upon the assumption of a constant excess relative risk throughout a lifetime after early childhood exposure to thyroid radiation. If the excess relative risk declines with attained age, the fraction of cases expressed to date would obviously be different, but in the absence of evidence of such a decline, the committee believes the number, 45 percent, is reasonable as said. Clearly, this value has important implications with regard to the steps that might be invoked to diminish the as yet unmanifested public health consequences of the exposures to I-131. CONCLUSIONS Exposure to I-131 as a by-product of nuclear reactions can cause thyroid cancer as shown conclusively by the 1986 nuclear accident in Chernobyl, which resulted in high level exposure for many people. The NCI dose reconstruction model indicates that the level of exposure to I-131 was sufficient to cause and continue to cause excess cases of thyroid cancer. Because of uncertainty about the doses and the estimates of cancer risk, the number of excess cases of thyroid cancer is impossible to predict except within a wide range. Epidemiological analyses of past thyroid cancer incidence and mortality rates provide little evidence of widespread increases in thyroid cancer risk related to the pattern of exposure to I-131 described in the NCI report. They suggest that any increase in the number of thyroid cancer cases is likely to be in the lower part of the ranges estimated by NCI. The epidemiological analyses are, however, subject to considerable limitations and uncertainties. Given the uncertainties in both the dose reconstruction model and the epidemiological analyses, further epidemiological analyses will be necessary to clarify the extent to which the Nevada tests increased the incidence of thyroid cancer. Pending these studies, it is prudent for DHHS to plan its responses as if excess cases of thyroid cancer have occurred. Individual-specific estimates of the probability of developing thyroid cancer from exposure to fallout from the Nevada testing program are uncertain to a greater degree than the dose estimates because of the additional uncertainty, in

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications particular, about the cancer-causing effect of low doses of I-131. Nonetheless, the committee concluded that the Nevada weapons-testing program resulted in I-131 exposure that has increased the usual risk of thyroid cancer for some members of the population, mainly those who were very young and drank milk from a backyard cow or, in particular, a backyard goat. The program of public information discussed in Chapter 5 will inform people about their possible exposure and the risk of thyroid cancer. ADDENDUM 3: UNDERSTANDING RADIATION RISK FACTORS AND INDIVIDUAL RISK Radiation cancer risk factors can be expressed in a variety of forms including Relative Risk (RR) and Excess Relative Risk (ERR). Values of these factors have been discussed in the text and appear in Table 3.4 but both are complex mathematical concepts. These factors can be used to derive a more useful figure for an individual exposed to radiation: that being the chance that the person will develop cancer in his or her remaining lifetime following a radiation exposure. This section is intended to elucidate the interpretation and use of these factors for that purpose. Before proceeding with detailed explanations, it must be noted that there is considerable uncertainty associated with the cancer risk factors as derived from epidemiological studies. Thus, the risk1 of contracting cancer that one might determine from a calculation should be understood to be only an estimate and the true value of their risk may be several times higher or lower.2 In addition, the biological response to radiation exposure is different for every individual. Thus, some individuals will be more susceptible to radiation damage and its effects and others less so. Factors influencing individual sensitivity are presently not sufficiently well understood to be accounted for in individual risk calculations. One useful expression of risk is the Percentage Lifetime Risk. Lifetime Risk expresses the chance of contracting a cancer within a lifetime (85+ years for a 1   In this discussion, the words risk, chance, probability, and likelihood can be assumed to have the same meaning. 2   For the mathematically inclined reader: The extent of this uncertainty will be a combination of the uncertainty in the dose estimate and the uncertainty in the cancer risk factor derived from epidemiological studies. The uncertainty in the dose estimate will vary with location, with higher uncertainties in those western states nearer to the Nevada Test Site (a factor of 6 to 20 either side of the estimated geometric mean dose) and lower uncertainties in the eastern United States (a factor of 3 to 10 either side of the estimated geometric mean dose). The uncertainty in the cancer risk factor has been estimated to be approximately a factor of 3.6 on either side of the central estimate (the central estimate of risk is an Excess Relative Risk of 7.7 per gray [Gy]). The overall uncertainty in the Percentage Lifetime Risk estimate for an individual is large and could be 5 to 30 times depending on location of residence at the time of exposure. This means that the true Percentage Lifetime Risk could be much smaller (by 5 to 30 times) or much larger (by 5 to 30 times).

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications newborn) or within the remainder of life following a radiation exposure. Because all types of cancers can occur in the absence of radiation, there is a background incidence rate even when no exposure has taken place. Thus, the Percentage Lifetime Risk is never zero, even in the absence of radiation exposure above that from natural background radiation.3 In the case of thyroid cancer, about 0.25 percent of males (1 in 400) and 0.65 percent of females (1 in 153) will have the disease within his or her lifetime for reasons unrelated to radiation exposure (above that from natural background radiation). Thus, without any radiation exposure above that from natural background radiation, the Percentage Lifetime Risk for males and females is 0.25 and 0.65, respectively (see line 6 of Table 3.4). The chance of a single person developing a disease is a difficult concept for most people to understand because one either contracts the disease or does not. Lifetime Risk can perhaps be better explained by defining it to express the number of people out of each 100 similar people that would develop the disease. The same numerical value of Percentage Lifetime Risk can apply equally well to the chance for an individual to develop cancer, or to the proportion of people out of each 100 that will develop cancer. The interpretation used is largely a matter of individual preference. In the case of thyroid cancer caused by radiation, adults of 20 years of age and greater at time of exposure are considered to be at negligible risk. Thus, their Lifetime Risk (see column 6 of Table 3.4) is equal to the background incidence of this disease in an unexposed American population (0.25 percent males, 0.65 percent females). The Percentage Lifetime Risk from the Nevada Tests for other age cohorts is shown in Table 3.4 based on the average radiation dose noted in column 3 as computed by NCI. The Percentage Lifetime Risk is, in general, higher for larger radiation doses, higher when exposure occurs at younger ages, and higher for females compared to males at the same age and the same radiation dose. In Table 3.4, adults over 20 years of age (last line of the table) can serve as a reference group to which other age cohorts are compared. Using that simple idea, a Relative Risk figure (see column 6 of Table 3.4) can be calculated, which simply expresses a multiple of the risk to an unexposed person or the adult. In Table 3.4 for example, the Relative Risk for individuals of age 15-19 years at time of exposure is 1.01 or 1 percent higher than the adult groups for the same average dose as the adults received. This small increase in the Relative Risk does not significantly affect Lifetime Risk which is about 0.25 percent, the same as for older peers. As mentioned earlier, the Relative Risk increases with increasing dose but is also greater for younger ages of exposure. That effect can also be seen in Table 3.4, which gives higher Relative Risks (always in relation to the adult cohort) for the younger groups who also had higher average doses from the Nevada tests. Higher Relative Risks result in proportionally higher Percentage Lifetime Risks. 3   The thyroid gland would receive on average about 0.001 Sv annually from natural ionizing radiation in the environment.

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications For example, those less than 1 year of age at exposure (who received on average 10.3 rad) have a Relative Risk of 1.67. This is the same as saying the risk is 1.67 times the risk of adults (who received an average dose of 1.8 rad). Consequently the Percentage Lifetime Risk for the less than 1 year old group is 1.67 times that of adults, equal to 0.42 percent (males) or 1.07 percent (females). In lieu of presenting further mathematical detail necessary to manipulate the risk factors, it appears more useful to further discuss only the Percentage Lifetime Risk. This value may be obtained directly from Table 3.4 if certain assumptions can be made. Specifically, the table presents the Percentage Lifetime Risks for individuals who received a radiation dose equal to the average for his or her age cohort as estimated by NCI. Column 5 of Table 3.4 gives those risk values given the assumptions used. The highest risk for a male is 0.42 percent, which is for an exposure of about 10 rad at one year of age. The highest risk for a female would be 1.1 percent.4 The risk of 0.42 percent (male) or 1.1 percent (females) equates to about 1 in 240 males of his age cohort or 1 in 92 females developing thyroid cancer sometime in her life if lived to age 85+. The disease rates computed above for a 10 rad exposure to a 1 year old are 67 percent higher than the background incidence, which is 1 in 400 males or 1 in 173 females developing thyroid cancer sometime in his or her life. By way of comparison, women have about a 1 in 8 Lifetime Risk to age 85 of being diagnosed with breast cancer and men about a 1 in 5 Lifetime Risk of being diagnosed with prostate cancer. For the Lifetime Risks presented in Table 3.4 to be applicable to any individual, that person must have received the national average dose for his or her age cohort. For a person to determine the dose with any confidence would require extensive calculations, even then the uncertainty would be great. For those individuals highly concerned about their individual risks, determining relevant doses specifically for themselves is a difficult undertaking. At present, there are few alternatives to completing complex calculations though an alternative method is suggested in Addendum 5. One method for a person to estimate his or her personal risk would begin with obtaining an estimate of the individual total dose (from all tests) from the NCI Web site. That process is difficult and the concerns expressed in this report about the uncertainty of calculated doses should be borne in mind. Under the assumption that the computed dose accurately represents the exposure of the individual, one's Percentage Lifetime Risk could then be estimated by the following steps: Obtain the Percentage Lifetime Risk from Table 3.4 for the age cohort. 4   For females, the Percentage Lifetime Risk is estimated to be 2.6 times greater than males at any dose.

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Exposure of the American People to Iodine-131 from Nevada Nuclear-Bomb Tests: Review of the National Cancer Institute Report and Public Health Implications Subtract 0.25 (males) or 0.65 (females) (the Lifetime Risk for the adult group) from the value found in step 1. Calculate the ratio of the one's dose estimate to the average dose for the age cohort. Multiply this ratio by the value from step 2 above. Add the adult value for Percentage Lifetime Risk (0.25 for males or 0.65 for females) to the number from step 4 above. The number calculated by the above five steps would be an estimate of one's individual Percentage Lifetime Risk. It could be interpreted as the percent chance of developing thyroid cancer during their lifetime to 85+ years of age, or the proportion of 100 people who would develop the disease. For example, if the person was less than 1 year old at time of exposure and his or her individual dose estimate was about 50 rad, he or she would calculate a Percentage Lifetime Risk of about 1.1 (males) or 2.9 (females), meaning that the chance of developing thyroid cancer by age 85 would be about 1 percent (males) or 3 percent (females). Equivalently, for this 50 rad dose, it would mean that 1 of every 100 males or 1 of every 35 females like themselves would contract the disease because of the radiation exposure. Relatively few individuals likely received doses as high as 50 rad, thus relatively few persons would have chances of developing thyroid cancer this great.5 Two final points are worthy of note in this discussion of risk estimates. First, for those who are diagnosed with radiation related thyroid cancer, the prognosis, as previously discussed, is good. Second, the individuals that are diagnosed with thyroid cancer can have a relatively high probability that the disease was caused by radiation exposure even if the likelihood that they would get the disease was low. For example, the probability that a cancer is a result of radiation exposure (this probability is termed "probability of causation" or PC) (NIH 1985) can be calculated as [Relative Risk - 1]/[Relative Risk].6 Thus, for the child having received an actual dose of 10.3 rad (see Table 3.4), the PC would equal (1.67 - 1)/1.67 = 0.40. This corresponds to a 40 percent chance the cancer was a result of radiation exposure. This can be compared with a chance of only 0.42 percent (male) or 1.07 percent (female) that they would have developed the disease during their lives following a 10.3 rad exposure at 1 year of age. The PC becomes increasingly higher for larger radiation doses. 5   The primary exception would be individuals who routinely drank goats' milk. NCI estimated the number of such individuals in the United States who were in childhood at time of exposure to have been about 20,000. These persons could have received doses greater than 100 rad at many locations. 6   There are alternate ways to write this equation, all are equivalent: PC = (RR - 1)/RR = ERR/RR = ERR/(1 + ERR).