6
Research Needs

Thyroid cancer is one of the better studied malignancies associated with exposure to ionizing radiation, but there are still many gaps and shortcomings in the data currently available. These deficiencies impinge on our ability to estimate risk appropriately, to delineate those factors that modify risk (such as age at exposure), to understand the biologic processes that underlie the occurrence of and prognosis for radiation-related thyroid cancer, to distinguish between those thyroid nodules that ultimately will be harmful to the patient from those that are not, and to communicate to members of the public and health care professionals the risk that results from exposure to ionizing radiation. The Committee on Exposure of the American People to I-131 from Nevada Atomic-Bomb Tests has examined the more salient of these needs and sets out below a series of recommendations for research. These recommendations are by no means exhaustive, but they attempt to address the more pressing issues the U.S. Department of Health and Human Services (DHHS) must confront. For convenience, these recommendations and their rationales are set out under four rubrics: epidemiology, the biology of radiation-related thyroid cancer, clinical practice, and risk communication.

Though this committee does not believe that further research into understanding all of the impacts of global fallout on the continental United States will make an important contribution to current public health, there are those that might desire a more complete understanding of this matter. Presently, sufficient information does not exist to easily evaluate the possible increase in disease rates in the United States due to exposure of the public to fallout of other radionuclides from U.S. tests or global fallout from tests conducted in other countries. For such an evaluation, further reconstruction of deposition records, transfer of radionuclides in the environment, and calculations to support various exposure scenarios



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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 6 Research Needs Thyroid cancer is one of the better studied malignancies associated with exposure to ionizing radiation, but there are still many gaps and shortcomings in the data currently available. These deficiencies impinge on our ability to estimate risk appropriately, to delineate those factors that modify risk (such as age at exposure), to understand the biologic processes that underlie the occurrence of and prognosis for radiation-related thyroid cancer, to distinguish between those thyroid nodules that ultimately will be harmful to the patient from those that are not, and to communicate to members of the public and health care professionals the risk that results from exposure to ionizing radiation. The Committee on Exposure of the American People to I-131 from Nevada Atomic-Bomb Tests has examined the more salient of these needs and sets out below a series of recommendations for research. These recommendations are by no means exhaustive, but they attempt to address the more pressing issues the U.S. Department of Health and Human Services (DHHS) must confront. For convenience, these recommendations and their rationales are set out under four rubrics: epidemiology, the biology of radiation-related thyroid cancer, clinical practice, and risk communication. Though this committee does not believe that further research into understanding all of the impacts of global fallout on the continental United States will make an important contribution to current public health, there are those that might desire a more complete understanding of this matter. Presently, sufficient information does not exist to easily evaluate the possible increase in disease rates in the United States due to exposure of the public to fallout of other radionuclides from U.S. tests or global fallout from tests conducted in other countries. For such an evaluation, further reconstruction of deposition records, transfer of radionuclides in the environment, and calculations to support various exposure scenarios

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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 would be needed. Such an effort would easily be on the scale or greater of that which NCI accomplished in support of its 1997 report. This ought to only be considered as a research recommendation if the government or public believes attaining a fuller understanding of nuclear testing to be an issue that supercedes other more basic health issues. EPIDEMIOLOGY The report of the National Cancer Institute (NCI 1997a), together with the presentation material provided by Charles Land (Appendix B, this report), gives a theoretical basis for positing that nuclear-weapons testing at the Nevada Test Site led to exposures to the thyroid that resulted in significant excess risk of thyroid disease for some members of the population of the United States, depending on age, geography, and individual consumption and source of milk. As indicated in Land's analyses, and as further discussed in Chapters 2 and 3 of this report, there are still important uncertainties in the assessment of the size of the exposures and their influence on thyroid cancer risk. No epidemiologic evidence was presented either in the NCI (1997a) report or in concomitant releases of information that thyroid cancer risk differs significantly by birth cohort, geography, or behavior as a consequence of the iodine-131 fallout from weapons testing. It would be premature in this committee's view to initiate changes in medical practice based solely on the theoretical calculations unless there is also empirical evidence of an increased risk. Accordingly, a comprehensive study of past incidence of thyroid disease—using the full range of resources from existing tumor registries, including but not restricted to those associated with the Surveillance, Epidemiology, and End Results (SEER) program—is clearly important and essential to more realistic risk estimates. Such studies have the statistical power to detect increases in risk of the size predicted by Land, by birth cohort, and possibly by geography. Studies of current incidence (case-control studies) are feasible and would be useful in evaluating whether behavioral factors such as milk consumption in the 1950s are indeed related to individual risk. For example, a study of 500-1,000 cases matched to an equal number of controls would have good statistical power to detect increases due to behavioral factors (milk consumption), of 50 percent or more. Such a difference in risk would correspond to a difference of 0.08 Gy in dose using the Ron and others (1995) risk estimates for those exposed as very young children. The most heavily exposed birth cohort (persons exposed between the ages of 0 and 4 in 1952) consists of approximately 18 million people. At an average current rate of thyroid cancer of 11 per 100,000 person-years (assuming a 40 percent increased risk due to exposure), this entire cohort would produce about 2,000 cases of thyroid cancer in a year. Case-control studies, however, are likely to be subject to recall biases—especially given the degree of publicity the release of the NCI report received. Nevertheless, case-control studies would appear to be the only reasonable way of empirically relating behavior to risk.

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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 Therefore, this committee recommends that NCI consider the feasibility of such studies carefully, with attention given in study design and analysis to minimizing or controlling recall biases to the extent possible. The need for more epidemiologic data on the effects of exposure of young people to I-131 is acute. Weapons testing took place in several other parts of the world, in some cases with even greater fission yields than in Nevada. The NCI's dose reconstruction for Nevada is by far the most comprehensive for such situations to date, and it reveals the great range at which doses to the thyroid gland of public health significance can apply to specific groups in the population. Although the likelihood of a resumption of atmospheric testing is remote, accidents to nuclear facilities also can release substantial quantities of I-131, as demonstrated in 1986 by the Chernobyl reactor accident. The dramatic and early increase in cancer of the thyroid among individuals exposed in childhood after this accident was clearly visible because of the very low spontaneous incidence of the disease. As the exposed population ages and as spontaneous incidence rates increase, the task of identifying the proportion of thyroid disease attributable to I-131 exposure will become increasingly difficult. Nevertheless, the Chernobyl experience provides a unique opportunity to learn for the future and gain further information relevant to the public-health consequences of the Nevada testing. A recent editorial (Baverstock 1998) drew attention to the need for a coherent international response to ensure that the opportunity to learn from this experience is not lost. And in this regard, this committee urges continued support of the collaborative study involving NCI and the Ukrainian Research Center for Radiation Medicine of thyroid cancer among Ukrainian children exposed to the Chernobyl accident. BIOLOGY OF RADIATION-INDUCED THYROID CANCER Several questions of significance remain with respect to the biology of radiation-induced thyroid cancer. The first and most important is that of the relative biological effectiveness (RBE) of I-131 compared with external exposure. There is a discrepancy between previously held thoughts on the RBE of I-131 and the data from Chernobyl, which suggest an RBE closer to 1. Experimental studies have demonstrated no difference in effectiveness between x-rays and I-131 (Lee and others 1982). It is appropriate to consider performing further experimental studies to address the question of x-ray versus I-131 RBE more compellingly. A second question is that of whether there is any difference between the biologic behavior of radiation-induced versus spontaneous thyroid cancer. Some reports suggest that radiation-induced lesions are more aggressive and malignant, but it is not clear how well-founded these reports are. Further studies of the relative malignancy of radiation-related and spontaneous thyroid neoplasms will be important in understanding the true risk for exposed populations. Recent evidence provided by Jhiang and others (1996) shows that ret /PTC1

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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 (papillary thyroid cancer 1) is a genetic event leading by itself to the development of thyroid carcinoma in transgenic mice, an observation that has been confirmed (Santoro and others 1996). Those observations provide strong evidence for the role of ret rearrangements in the development of papillary thyroid cancer, which should be considered in recommendations for future research in patients exposed to radiation from atomic weapons fallout. Moreover, such research could have an important bearing on the nature of the dose-response relationship for thyroid cancer. If, for example, the ret oncogene is commonly activated by a paracentric inversion, a two-hit chromosomal phenomenon, this would suggest a probable linear-quadratic dose-response relationship because paracentric inversions become more likely at higher doses where two hits increase in frequency. CLINICAL PRACTICE As set forth in Chapter 3, the introduction of sophisticated diagnostic tests, such as ultrasonography, has resulted in the discovery of many microcancers that are unlikely to harm the patient. A major challenge for medical research is to differentiate those microcancers that are clinically significant 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 having their diseases ignored imprudently. This problem of microcancers is not unique to the thyroid gland; they are found even more commonly in the breast and prostate. The committee therefore recommends support of clinical studies designed to achieve a better means of differentiating between potentially harmful and harmless microcancers. RISK COMMUNICATION Studies of how to communicate risk appropriately are far more meager than are studies of the risks themselves. Agencies and policy makers historically have been more willing to acknowledge the role of expertise in questions about scientific process than in questions about communication. Thus, the communication advice offered in this document is grounded in fewer studies than are the deliberations about the risk of thyroid cancer or the process and prognosis of that disease. DHHS would be well served by efforts to understand better how individuals make judgments about risk situations and, more specifically, how they use information to do so. Particularly relevant to the thyroid cancer situation are the following questions: What analytical skills do individuals bring to information about frequency and magnitude of risk?

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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 How can communicators offer explanations of risk concepts and processes that convey the intended meanings? How do individuals make decisions about whom they trust when seeking information about risks? How should risks be communicated so that affected audiences are likely to interpret the information offered as being personally relevant? When an information source has lost its credibility, how does that source legitimately regain trust? Given the significant uncertainties surrounding I-131 exposure and cancer risk, the committee suggests that DHHS consider research to develop a better understanding of how people perceive the benefits and harms of cancer screening and how those perceptions are affected by different ways of presenting quantitative information and different ways of structuring clinician-patient communication. In addition to studies not specific to thyroid cancer or radiation-exposed populations, the evaluation component of the Agency for Toxic Substances and Disease Registry (ATSDR) medical-monitoring program might consider the feasibility of a controlled study to compare different information formats or different counseling strategies for patients who come in for testing. As envisaged, the ATSDR medical-monitoring program is not likely to produce useful information about mortality effects of screening for thyroid cancer because people who are screened would be self-selected, and high long-term survival rates can be expected without screening. The program's reports on positive and negative screening results and subsequent follow-up tests, procedures, and findings should still be tracked. In considering its research priorities, DHHS might also consider an outside evaluation of patient experience and perceptions of harms and other benefits of the ATSDR program, although it is not clear that the results could be generalized.