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ADDENDUM TO RECOMMENDATION 4: MEDICAL The Advisory Committee's charter requires that we consider the issue of notice to experimental subjects of potential health risk and the need for medical If required to protect the health pf individuals who were subjects of a human radiation experiment, or their descendants, the Advisory Committee may recommend to the Human Radiation Interagency Working Group that an agency notify particular subjects of an experiment, or their descendants, of any potential health risk or the need for medical The basic intent of this provision is not directed at subjects who have already died, or at subjects who have already become ill and been treated. It is Primarily aimed at asymptomatic subjects who remain at significant risk for the development of radiation-induced cancers. Because at least two and as many as five decades have passed since the experiments took place, most of those who may eventually develop cancer as a result of the experiment will already have developed symptoms and sought treatment. However, some subjects may still be at risk and thus arguably might benefit from medical follow-up. The initial consideration in deciding whether to implement a program of active notification and medical follow-up is the identification of populations of subjects who have been put at significant risk for the development of radiogenic cancers. The magnitude and focus of these risk estimates are driven by the specific organs placed at highest risk from the particular radiation exposure (for example, thyroid being the organ at greatest risk in the iodine 131 experiments, testes in the Oregon and Washington prisoner experiments, and the brain for the nasopharyngeal radium experiments). Risk estimates are calculated for each target organ according to a number of assumptions that may include adjustments for variables such as age at exposure, sex, or type of radiation (isotope VS. external beam) and are generally expressed in terms of excess cancer incidence/mortality for a given population over a specified period at a specified The Advisory Committee adopted 'an excess site-specific cancer mortality (death) greater than 1 case in 1,000 (lifetime) as a criterion for determining that a subject had been placed at increased risk, However, because of the substantial passage of time since the initial exposure, the criteria for consideration of active notification were set at 1/1,000 future or remaining lifetime risk and an excess
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relative risk of greater than 10 percent (organ specific). This level of risk was arbitrarily chosen by the Advisory Committee. When compared with the normal risk of developing cancer (220out of 1,OOO), this level of risk is small. The Advisory Committee chose this small remaining lifetime risk as a reasonable initial criterion to decide if a more in-depth analysis of the effectiveness of screening and intervention was needed. lifetime risk for radiogenic cancer mortality, a second criterion must be satisfied before a government-fbnded medical follow-up program is recommended, namely whether the exposed individuals would likely benefit from a program of early detection or early treatment of the malignancy. Effective screening procedures for the detection of an early-stage cancer exist only for a limited number of cancer sites. Moreover, the lack of specificity of all diagnostic screening tests results in a significant number of "false positives" (a positive test result in an individual who in truth is not affected), resulting in unnecessary and potentially hazardous medical procedures that may cause health problems in and of themselves. On the other hand, most diagnostic tests are also imperfectly sensitive, meaning that some individuals who actually have the disease will be falsely reassured that they are cancer free and may thereby delay seeking attention when it becomes symptomatic. To this end the Advisory Committee has adopted the following criteria for assessing the value of screening, preventive, or therapeutic measures for exposed subjects of biomedical experiments:20 Once a population has been determined to have an increased remaining 1. The condition must have a significant effect on the quality or length of life. 2. The condition must have an asymptomatic period during which it can be detected by available 3. These screening methods must have high sensitivity and specificity. 4. Treatment in the asymptomatic phase must yield a therapeutic result supeiior to that obtained by delaying treatment until symptoms appear. 5 . The medical benefits of screening and early treatment must outweigh any detrimental medical effects or risks. These criteria were applied to each exposed population at significant risk for development of a malignancy and evaluated according to the organ(s) at risk
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fiom radiation exposure. In each case, the conditions enumerated above must be satisfied before specific medical follow-up would be recommended. chapters 7 and 9. To summarize, the Advisory Committee found no experiments involving iodine 131 administration to children that met our 1/1,000 criterion for remaining lifetime risk of dying of cancer; even in the most highly exposed individuals, risks were estimated to be 1/2,000 (remaining lifetime risk). In addition, the U.S. Preventive Services (USPS)Task Force concluded that "routine screening for thyroid disorders is otherwise not warranted in asymptomatic adults or children." Although it has been suggested that people placed at risk for development of thyroid carcinoma following high-dose external irradiation to the upper body may benefit fiom regular physical examination of the thyroid, there are no data to support a similar risk or benefit for those who have been exposed to diagnostic or therapeutic doses of iodine 131.2' The Advisory Committee recognizes that in addition to the very small risk of a fatal thyroid cancer, individuals exposed as children to iodine 131 also have a larger risk of a nonfatal thyroid cancer or benign tumor, a lifetime risk that in many of the experiments we considered exceeded 1/1,000 and in a few individuals exceeded 1/100. We recognize that such conditions may require medical treatment and may be associated with considerable anxiety and discomfort. After considerable discussion, however, the Committee concluded that notification was not warranted for the purpose of detecting such conditions early, on several grounds. First, the prognosis for such conditions under standard clinical care is excellent, and there is no evidence that early detection improves the outcome. Second, even among the subgroup of about 200 children exposed to this level of risk, the number of excess cancers expected is less than one, whereas the normal prevalence in an unexposed population is about 20 to 30 percent. Third, many thyroid cancers that are detectable by screening may have no clinical significance. Finally, the most effective means of screening for thyroid cancer remains palpation, which has low sensitivity and low specificity. For the prisoners subjected to testicular irradiation, the Advisory Committee estimates that even the most heavily exposed individual (600 rad to the testicles) would have a risk of only 0.4/1,000t2of developing a fatal cancer, which does not attain our stated criterion. Furthermore, the USPS Task Force has concluded that "there is insufficient evidence of clinical benefit or harm to recommend for or against routine screening of asymptomatic men [other than those with a history of cryptorchidism, orchiopexy, or testicular atrophy] for testicular cancer."23 These considerations lead the Advisory Committee to recommend against any program of active notification of these subjects. However, subjects who voluntarily request medical check-up or counseling should have such provided in a standard clinical setting. Advisory Committee has estimated that the lifetime risk of tumors to the central Details of the Advisory Committee's risk calculations can be found in For the children who received nasopharyngeal radium treatments, the
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nervous system (brain), head, and neck regions is approximately 4.35/1,000 and the excess relative risk is about 62 percent, both with considerable uncertain tie^.^^ Although these experiments were conducted in the 1940s and much of the risk has probably already been expressed, it is still possible that the future risk is greater than or equal to our arbitrary 1/1,000 risk criterion, However, at greatest risk are the brain, and head and neck tissues, for which there is neither an accepted nor recommended screening procedure.2s Thus, while the subjects in these experiments meet the Advisory Committee's arbitrary 1/1,000 criterion for consideration for notification and medical follow-up (criterion 1 in Recommendation 4, above), the utility of such a program has not been demonstrated, so criterion 2 of Recommendation 4 is not satisfied. Adult military personnel who participated in trials of this procedure received significantly lower radiation exposures, did not attain our arbitrary 1/1,000 criterion for risk, and would similarly fail to meet the criteria in guideline 2. Therefore, the Advisory Committee does not recommend notification and medical follow-up of children or adults in this group of experiments. The Advisory Committee's charter also requires that we consider the need for notification of descendants of experimental subjects for purposes of health protection. The rationale for considering notification in this instance derived from the assumption that the offspring of former subjects might be at risk for disease or disability as a consequence of inherited mutations resulting fiom their parent's previous radiation exposure. The weight of evidence suggests that the risk of heritable genetic effects fiom the radiation exposures in the experiments we reviewed is very small, although it is possible that some offspring of exposed individuak might carry mutations that were caused by radiation.26 Moreover, in most medical experiments involving external sources of radiation, efforts are made to shield the gonads (ovariedtestes) as much as possible. With the exception of the testicular irradiation experiments, where subjects agreed to undergo vasectomy to prevent transmission of any mutations that might have occurred, experiments involving external irradiation are likely to have produced relatively small gonadal doses, as would those experiments involving tracers. Even therapeutic studies involving internal radionuclides would generally involve only modest gonadal doses. Thus, in the vast majority of experiments, it is likely that the risk of radiation-induced mutations is small in relation to natural rates. In addition to cancer and genetic effects, there are only a small number of well-established effects of radiation, including severe mental retardation among those exposed in utero (particularly between eight and fifteen weeks of gestation), sterility, cataracts, and hypothyroidism. Unlike cancer and genetic effects, however, these other endpoints appear to be "deterministic" effects that appear only after high doses that are unlikely to have been received by subjects in the experiments under consideration for notification. The Advisory Committee heard extensive public testimony about a range of other conditions that those testifying thought might be related to radiation exposures. However, the Advisory
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Committee believes that a program of active notification must be grounded on curredly accepted scientific evidence concerning the conditions that are likely to be caused by radiation.