Dosimetry Interpretation and Risk Assessment Associated with the I-131 Thyroid Studies of Individuals at the Wrentham and Fernald Schools (1954 - 1965) Members of State School Thyroid Studies S.J. Adelstein, M.D., Ph.D.* Leonard Bushnell, M.D. Frank P. Castronova, Jr., Ph.D.* Margaret Dale, J.D. J. Anthony Parket, M.D.* Richard Pharo, M.D. Edward W. Webster, Ph.D.* *Members of the Dosimetry and Risk Assessment Subcommittee Report date June 13, 1994 18 SUMMARY AND DISCUSSION The radiation dose (expressed in rems) after receiving radioactive iodine (I-131) is dependent on 3 factors: - the amount of radioactivity administered (microcuries); - the fraction of the radioactivity which is taken up by the thyroid gland; - the age of the person receiving the radioactivity. The age factor is very important since the weight (size) of the thyroid gland in grams is much smaller in young children than in adults, and, therefore, the amount of radioactivity in one gram of thyroid tissue (which determines the radiation dose) is much higher in young children. For example, in a 1-year old child the thyroid weight is about 2 grams compared with 20 grams in the average adult, leading to a radiation does about 10 times greater in the child compared with an adult concentrating the same amount of I-131 in their thyroid. But in a 10-year old child the radiation dose would only be about two times greater than in the adult because their thyroid glands are closer in size to those in adults. In this report the thyroid gland radiation dose and also the dose to the remainder of the body have been calculated for each person who received I-131 in the 4 studies reviewed, taking account of their age, the size of the thyroid gland, the gland uptake of I-131, and the amount of I-131 administered. The risk of developing thyroid cancer later in life as a consequence of the radiation dose the thyroid gland received is dependent on 4 factors: - the amount of radiation dose to the thyroid gland; - the age of the person receiving the dose; - the time (years) that has elapsed after the dose; - the gender of the person. For the same thyroid dose (rems) children, particularly young children have a greater risk for developing thyroid cancer than adults. In this report the risk has been calculated employing higher risks per rem for children than for adults, with the risks progressively decreasing for ages 1-5,5-10,10-20, and grater than 20. The risk for a person living for 60 years after the radiation dose is assumed to be about twice that for a person living for 30 years. For the same radiation dose females have about twice the risk of males. The risks for groups of persons in each age group are given in Appendix C for each of the four experiments. They are presented as the number of thyroid cancer cases induced by radiation in a group of 1,000 exposed persons (assumed to be 50% male and 50% female) during the period of 50 years following the administration of I-131. From comparison of column 7 (thyroid cancer incidence) and column 11 (cancer incidence elsewhere in the body), it is evident that the risk of thyroid cancer is about 10 times greater than the risk of all other types of cancer including leukemia. The largest thyroid cancer risk in any of the child groups is a 1% chance (that is, 10 chances in 1,000 persons). 19 CONCLUSIONS Dr. Lyon and the Harvard Medical School team have arrived at similar overall conclusions. Dr. Lyon in his report has deduced the total thyroid cancer risk to be 0.55 extra cases among the 116 exposed children at the Wrentham School aged 1 to 15 years. For the 21 children at the Fernald School aged 1 to 18+ years he deduced 0.20 extra cases. From Appendix C in our report we deduce the thyroid cancer risk in the 116 Wrentham children to be 0.1 extra cases. In the 23 (not 21) Fernald subjects we deduce 0.027 extra cases. WE agree with dr. Lyon that the expected number of extra thyroid cancer cases among the total of 137 subjects in the two schools is likely to be less than one. We also agree that the number of expected cases if there had been no irradiation would most probably also be less than one (that is, about 0.5 cases). We believe that Dr. Lyons' higher estimates of radiation- induced cases are mainly due to his evident "worst case" assumptions that all the children received "the maximum dose before age 1" and that all the children would live to age 74. Employing these assumptions and the risk value adopted by Dr. Lyon, we have derived 0.30 extra thyroid cancer cases at Wrentham, derived as follows: 0.00000084/rem/year x 44 rems x 69 years x 116 persons = 0.295 Dr. Lyon must have assumed a dose greater than 44 rems. Our calculation of 0.1 extra cases employs ages 1 to 18+ at exposure and a life expectancy of 50 years after exposure. Our highest risk, for children aged 1 to 5 years, was similar to that of Dr. Lyon, viz. 1.0/million/rem/year vs. 0.84/million/rem/year. 20 Dosimetry Interpretation and Risk Assessment Associated with the I-131 Thyroid Studies of Individuals at the Wrentham and Fernald Schools (1954 - 1965) Article Discussed #1:Benda, et.al., Thyroid Function in Myotonia Dystrophica, Am J Med Sci, 228,668, 1954 #2:Kurland, et.al., Radioisotope Study of Thyroid Function in 21 Mongoloid Subjects Including Observation in 7 Parents, J Clin Endocrinol, 23, 552, 1957 #3:Saxena, et.al., Minimal Dosages if Iodide Required to Suppress Uptake of Iodine-131 by the Normal Thyroid, Science, 138, 430, 1962 #4:Saxena, et.al., Thyroid Function in Mongolism, J Pedi, 67, 363, 1965 Background The use of I-131 labeled potassium or sodium iodide (known as I- 131 unless otherwise indicated) as an radioactive tracer for thyroid function was quickly accepted by the medical community. This is apparent from the numerous published reports pertaining to thyroid function beginning with the earliest animal studies in 1930's. Concomitant with its use at that time was the challenge to accurately determine the quantity of I-131 within the thyroid gland. This was a direct function of the accounting equipment available as well as the suitability of the radioiodine solution. Both of the latter parameters were quite elementary relative to current standards. However, with I-131 the rapidity of thyroidal accumulation could be demonstrated noninvasively with a simple Geiger counter. It became evident that determination of radioiodine uptake had important diagnostic applications. The published articles listed about pertain to thyroid function determinations in several groups of subjects, primarily children, at the fernald and Wrentham Schools. In normals, the organ receiving the highest radiation dose after I-131 administration is the thyroid gland. This would be a 21 (ILLEGIBLE) function of the % uptake value and would much smaller when the thyroid gland is nonfuctioning. All the subjects studied had functions thyroid glands with a range of % uptake values. The average normal I-131 thyroid uptake @ 24 hours is approximately 25%. Dosimetry Parameters The Thyroid gland is the primary tissue irradiated after I-131 administration. The relative small size of this organ, especially in children, crates a high concentration condition which directly effects radiation dose. Other organs receive a lesser radiation dose. The primary radiation risk includes the possibility of either cancerous or benign thyroid neoplasms and secondarily, cancer to other organs. Thyroid cancer is easily treatable. The incidence risk is therefore greater than the mortality risk by a factor of 10. The whole body risk can be expressed in terms of effective dose (E) which is the sum of the products of individual organs corrected for their radiosensitivity factors. Since the thyroid gland dominates this value (99% of total) it can be excluded when calculating the effective dose (see example in Appendix A). A similar situation exists with annual natural background radiation where the lung contribution due to radon is 66.7% of 300 mrem or 200mrem. The latter value could be expressed as annual natural background radiation minus the contribution from radon inhalation if the lung risk was being determined separately. Current thyroid uptake studies are performed at Children's Hospital and Massachusetts General Hospital with a radioiodine called I-123. It has a shorter half life than I-131, 13 hours vs. 8.08 days, and provides a reduced thyroid radiation dose. This radionuclide became available during the 1970's. The children's thyroid dose for I-123 is approximately 1 rad. Patient Studies Reference #1 above The myotonia dystrophica patients consisted of 6 males who received 54 microCi's of I-131 each for the purpose of determining thyroid function. The latter values ranged from 15.7% to 42.1% with an average of 29.4%. The ages of the subjects were not provided. However, adults were assumed because the daily urine output was collected in two 1 liter jars and the patients "body build" is mentioned as a source of error when determining % uptake. The thyroid dose average 84.6 rads (44.1 - 116.3 rads) with a concomitant effective dose of 4.23 rem (2.26- 6.06 rem). 22 The average effective dose minus the thyroid contribution is 0.042 rem. Reference #2 above Twenty one subjects with Down syndrome, as well as 7 parents, received 70 and 100 microCi's of I-131 respectively. The age range of the Down syndrome group was between 5 and 27 years old with 4 individual ages not provided. The thyroid dose was highest for the 5 year old (511.8 rads), intermediate for the 13- 16 year old group (139.2 rads) and lowest for those greater than 17 years of age (105.4 rads). the effective doses, not corrected of the thyroid, are 25.6, 7.0 and 5.3 rem respectively. When corrected of the thyroid contribution the effective doses are reduced to 1% of these values. The adult parent grouped averaged 165.2 rad thyroid dose, 8.25 rem effective dose and 0.0825 rem effective dose when corrected for the thyroid contribution. Two children (assumed to be 15 years old) were also injected with 100 microCi's I-131 labeled thyroid hormone (thyroxin). This label behaves differently the I-131 sodium iodide with the lower large in testing receiving the highest dose (0.518 rad) and the effective dose equaling 0.192 rem. Reference #3 above Sixty three children were studied as part of an experiment involving the suppression of I-131 thyroid uptake after nonradioactive iodide administration. The children were a variety of ages; 1-3 yo (N=20, 4-6 yo (N=24) and 9-11 yo (N=19). Wile receiving 300 micrograms of stable iodide each received 1 microCi of I-131 every 2 weeks on 8 different occasions. The % thyroid uptake values varied considerably during this time period from 5 to 24%. The average thyroid dose was 44 rem with an effective does of 2.2 rem and a thyroid corrected effective does of 0.022 rem. If the 5 and 10 year old children are analyzed in a similar fashion their thyroid dose is 30.3 and 14.0 rem, the effective doses are 1.5 and 0.7 rem and, when thyroid corrected, 0.015 and 0.007 rem. Reference #4 above This investigation used similar methodology as the Science paper (#3 above) where 1 microCi of I-131 was administered to 53 children with Down syndrome and 51 others with mental retardation of another etiology. All subjects were less than 16 years of age 23 with a range of 1 to 15 years old with an uptake range of 10.7 to 50.2%. Since individual uptake data were not available the dosimetry was determined for 1 and 15 years old for both percentage uptakes: 1 yo thyroid dose range equals 5 to 24.9 rem, effective dose equals 0.25 to 1.25 rem and effective dose minus thyroid contribution equals 0.0025 to 0.0125 rem; the 15 yo values are 0,8 - 4.1 rem thyroid dose, 0.04 - 0.205 rem effective dose and when corrected for the thyroid, 0.0004 -0.00205 rem. Risk Estimates The risk resulting from I-131 radiation exposure is primarily that associated with thyroid cancer incidence and mortality. Thyroid cancer is a relative rare disease, causing approximately 1000 deaths annually. The overall age adjusted incidence is 3.0 per 100,000 with over 90% survival for radiation induced thyroid cancer. This means that the incidence is much larger than the mortality from thyroid cancer. Not all thyroid cancer is radiation induced. The latent period from radiation exposure to clinical development of thyroid cancer "ILLEGIBLE" usually presenting itself 5 to 30 years after exposure. Several modifying factors associated with the risk of radiation induced thyroid cancer. External radiation is 3 times as effective as I- 131, children (< 18 year old) are much more radiosensitive than adults, and this is approximately twice as common in females as in males, with the incidence increasing with age. Lastly, risk factors for those of Jewish ancestry appears to be 2-8 times higher than for non-Jewish populations. The risk estimates for the present investigations are summarized in Appendix B (Estimates) and Appendix C (Summary Table). These risks estimates are for thyroid cancer incidence, thyroid cancer mortality, and all non-thyroid cancer mortality. 24 APPENDIX A Worksheet for Calculation of Effective Dose Radiopharmaceuticals Based on ICRP-60, 1991) Radiopharmaceuticals: I-131 Sodium Iodide/100 microCi dose Study: Example calculation for adult with a 25% thyroid uptake Organ Weighting Dose Equivalent factor rad/mCi (mRem/100 microCi) Gonads 0.20 0.129 2.58 Red Bond Marrow 0.12 0.259 3.12 LLI 0.12 0.152 1.82 Lung 0.12 0.266 3.19 Stomach 0.12 1.702 20.40 Bladder Wall 0.05 1.700 8.52 Breast 0.05 0.204 1.02 Liver 0.05 0.129 0.649 Kidneys 0.05 0.215 1.07 Thyroid 0.05 1332.000 6,660.0 Pancreas 0.05 0.196 0.982 Bone Surface 0.01 0.226 0.226 ULI 0.05 0.218 1.09 Si 0.05 1.700 8.52 Total E = 6713.2 mrem % thyroid = [6660.0/6713.2] x 102 = 99.2% E-thyroid = 53.2 mrem 25 APPENDIX B SUMMARY OF RISK ESTIMATES USED IN THIS REPORT A. Thyroid cancer (incidence) Age in years 0-5 5-10 10-20 >20 Absolute risk/10PYGy 1 0.5 0.25 0.07 Lifetime* risk/million/rad 40 20 10 2.8 es. Multiply by 1.33 for females and 0.67 for males. For mortality divide by 10. *Lifetime is for 45 years after administration including 5- year latent period. B. Other cancer (incidence) Age in years 5 15 25 35 45 55 65 75 M, Lifetime risk/million/rem 983 881 709 436 462 475 371 199 F, Lifetime risk/million/rem 1258 1223 944 497 501 490 379 213 For mortality divide by 1.54 for males and 2.0 for females. 26 APPENDIX C RADIATION RISK ESTIMATES I-131 Studies FOR REFERENCE SEE (6bb73) 27 HOW WAS CONSENT SOUGHT? In the report on the Calcium and Iron studies, a significant finding was the lack of disclosure of the key fact that radioactive materials were used as a part of the study. The lack of this key information was seen to be not only evidence for the failure to have gotten informed consent, but also to suggest that it had been a conscious act of hiding the use of radioactive materials. The letters that were sent out in both of the thyroid studies at Fernald (Studies No. 1 and 2) were found in the archival records and are duplicated in the Appendix of this report, as they were in the earlier report. This was done to meet the need for "full and accurate disclosure of all facts found" as set forth in the first report. In the nutritional studies that used radioactive Iron tracers, permission letters were sent out in 1946. These letters were no found. The archival records that were fond that related to the Iron studies included only correspondence from the researchers at MIT to the Superintendent at Fernald outlining the understanding of the benefits and risks of the radioactive materials that would be used at that time, and correspondence that indicated permission was granted for this study by the existing state and federal agencies that oversaw research at Fernald during that era. The nutritional studies that used radioactive Calcium tracers sent out their permission letters in 1953. These letters were found. They did not mention radioactive materials would be used as a part of the study. This led to an assumption that this fact was not mentioned in the earlier study's permission letters either. The letters found for the thyroid studies that involved the use of radioactive iodine at Fernald were written in 1951 (for the thyroid studies in persons with Myotonia Dystrophica) and in 1953 (for the thyroid studies in persons with Down syndrome). The dates of the letters clearly overlap for the time periods that included the Calcium and Thyroid studies. The letters for the two studies at Fernald that used radioactive iodine clearly and specifically note the use of radioactive materials and the use of a geiger counter to conduct the test. This leads to the revised speculation that it may be that the decision whether to put that information in the letters to the parents falls more under the broader issues from that time frame that were later noted as portraying the "paternalistic" and authoritative role physicians worked from. They used this type of decision making with all person in deciding what would or would not be disclosed to them within their medical treatment jurisdiction. This widespread personal decision making by physicians was the foundation for the movement of the 1960s that led to the development of informed consent as we understand it and define it today. The term "informed consent" was created in 1972 and federal laws of protection passed in that same year (please see the original report for further discussion on "informed consent"). 28 The permission letter from Study No. 1 (1951) offered the assurance that the "dose of this iodide is approved and absolutely safe" and "the same study is carried out routinely in any large hospital in this country on patients suffering from thyroid disease". [Note: research for this current report showed that the use of 131I as the tracer material of choice for diagnostic thyroid uptake studies continued until the development of 123I in the 1970s. However, some areas of the United States as well as other countries still use 131I in certain situations today for diagnostic and therapeutic uses]. The permission letters from Study No. 2 in 1951 and 1953 stated "the use of this agent is not connected with any harmful effect, and it is used in many routine examinations for thyroid function in first class hospitals of the United States. The examinations are made in connection with the Massachusetts Institute of Technology, and the dosages used are approved by highest authority". For the parents, the letter graphically states that "the test is not connected with any hardship, and consists entirely of drinking a small glass of water with 131I and sitting in a chair for half an hour while the thyroid function is observed through Geiger counters." Study No. 2's letters included a request for payment of the lab tests which, at that time, were $10.00 per PBI test. The majority of letters returned by the parents giving permission also held explanations why they could not afford to help with the cost of the tests. The cost of the tests for those subjects whose parents could not pay was absorbed by Fernald. For Studies No 3&4, which were conducted at the Wrentham School, no consent or research records of any kind have been found. All researchers were contacted and areas for potential storage searched to no avail. 29 MYOTONIA DYSTROPHICA STUDY - STUDY NO. 1 June 5, 1951 Mrs. Massachusetts Dear Mrs. We are writing this letter relative to your brother, . As you may know, he suffers from a chronic disease entitled myotonia dystrophica. Up to the present time this disease is very poorly understood. We are very much interested in developing better diagnostic and therapeutic measures to help patients like , and we are now ready to initiate a study pertaining to the thyroid function in patients with this disease. this study is to be carried out in connection with the Massachusetts Institute of Technology, and consists of blood and other examinations following administration of isotopic iodide. the dose of this iodide is approved and is absolutely safe. The same study is carried out routinely in any large hospital in this country on patients suffering from thyroid disease. In fact, our own study will be conducted partly at the Massachusetts General Hospital. This procedure will not cause any inconvenience or discomfort to and may be quite helpful in contributing to our knowledge of this little known disease. Before proceeding with such a study it will be necessary for us to have your permission to carry it out. We have, therefore, prepared a certificate below. If you are willing to give us permission to conduct the study on , would you please complete and sign the permission and return the entire letter by mail immediately as we expect to begin by June 15, 1951? Very truly your, Malcolm J. Farrell, M.D. Superintendent This is to state that I give my permission for the participation of , in the project mentioned above. Signature Relationship Witnessed by: 30 THE COMMONWEALTH OF MASSACHUSETTS DEPARTMENT OF MENTAL HEALTH MALCOLM J. FARRELL, M.D. SUPERINTENDENT WALTER E. FERNALD STATE SCHOOL BOX C, WAVERLEY 78. MASS November 19, 1951 Date Dear Mrs. Our research in mongolism; which has been under way for fifteen years, has provided more and more evidence as to the definite causes and anomalies in this condition. Based on extensive experience over a period of fifteen years on almost one thousand patients, we feel that we are able to extend the research into the field of clinical investigation. We would like to test the endocrine functions of the different glands, especially the pituitary, thyroid and adrenals. Several tests are necessary which are not harmful to the patient but which involve very complicated biochemical and physical examinations which are connected with extensive expenses. We would like to ask your permission for a blood test on your child, involving the use of a very small amount of radioactive iodide. The use of this agent is not connected with any harmful effect, and it is used in many routine examinations for thyroid function in first class hospitals of the United States. The examination are made in connection with the Massachusetts Institute of Technology, and the dosages used are approved by highest authority. We would also like to ask whether you may be willing to pay for the protein-iodide determinations which are made at the Massachusetts General Hospital and for which we are charged $10 per test. If you would support these studies, which may eventually result in a much more effective therapy of mongolism, by contributing any sum of money to a special research fund, we would greatly appreciate such a gift. The fund will be used entirely for research in mongolism, and will help to pay for tests of patients whose parents are not able to pay the expense. In case you would like to contribute, please make a check payable to the Walter E. Fernald State School Special Research Fund and please give written permission for making the necessary tests, including the use of radioactive iodide. Sincerely yours, Clemens E. Benda, M.D. Clinical Director Approved: Malcolm J. Farrell, M.D. Superintendent 31 January 23, 1953 Dear Mrs. WE informed you in November that we had stared investigations on a group of children. The preliminary examinations already shows hat we are on the way to finding some significant anomalies, and these finds may eventually enable us to treat these children according to their needs. The Thyroid Laboratory of the Beth Israel Hospital is willing and anxious to do a study of the thyroid function in those other who have given birth to a child with the condition under investigation. If you will be good enough to contact us on or before Wednesday, January 28th, we will make arrangements for you to go two mornings to the Thyroid Laboratory at the Beth Israel Hospital. Such an examination should also be of considerable interest to you. The test is not connected with any hardship, and consists entirely of drinking a small glass of water with I131 and sitting in a chair for half an hour while the thyroid function is observed through Geiger Counters. We will deeply appreciate your cooperation in this very important matter. Sincerely yours, Clemens E. Benda, M.D. Director of Research and Clinical Psychiatry Approved: Malcolm J. Farrell, M.D. Superintendent CEH/dfg 32 FINDINGS AND RECOMMENDATIONS These findings are supplemental to the general and overall findings of the original Task Force and its report of April, 1994. 1.Eight experts have calculated that any increased potential for a thyroid cancer is less than a single case for the total population of the subjects of these studies. Further it is their opinion that even if a case were to be found, the relationship to the studies would be impossible to determine. However, just a preventive examination was recommended din the Calcium and Iron studies, it is recommended that an assessment examination be provided for all identified or potential subjects in all of the Thyroid studies. This shall include a specific examination of the thyroid. 2. All positively identified subjects should now be contacted per the instructions outlined in the "Contact with Subjects Subcommittee" Report as included in the original report. 3. The lack of archival records for the two studies at the Wrentham School has prevented the positive identification of those subjects. The criteria set forth in the published articles on these studies has allowed the pool of potential subjects to be reduced to 300 names. From within this pool, a set of highly likely subjects has been identified. However, follow-up and contact shall be done with all of the potential subjects. 4. As in the original recommendation, if the subjects (or potential subjects) are not eligible for existing medical assistance, the Commonwealth shall identify a means for this medical assessment to be done.