Background Material for the Development of the Food and Drug Administration’s Recommendations on ( hyroid-Blocking with Potassium Iodide), ‘: le, ® ll fe oO ©) fe! ie e < | hiaY 42 1084 LIB tY UNIVERSITY OF CALIFORNIA U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Food and Drug Administration ''BRH PUBLICATIONS Publications of the Bureau of Radiological Health (BRH) are available as paper copies from either the U.S. Government Printing Office (GPO) or the National Technical Information Service as indicated by the GPO or PB prefix, respectively, on the ordering number. Publications are also available in microfiche from NTIS at $3.50 per copy. To receive all BRH reports in microfiche, at $0.85 each, you may establish a deposit account with NTIS and request automatic distribution of "FDA/HFX" reports under the "Selected Research in Microfiche" program. Publications without GPO or PB number are available only from BRH, without charge. 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''HHS Publication FDA 81-8158 Background Material for the Development of the Food and Drug Administration’s Recommendations on _ (Thyroid-Blocking with Potassium Iodide) ) Jerome A. Halperin, M.P.H. Deputy Director Bureau of Drugs e Bernard Shleien, Pharm.D. Assistant Director for Scientific Affairs Bureau of Radiological Health e Shirley E. Kahana, M.D. Medical Officer Bureau of Drugs e James M. Bilstad, M.D. Group Leader for Endocrine Drugs Bureau of Drugs March 1981 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Food and Drug Administration Bureau of Radiological Health ‘Rockville, Maryland 20857 ''NY —/ ee “to ia f=. x / KWL ''IKC6SS [3% Jag, 192 | The Bureau of Radiological Health develops and carries out a national program to«- Bd control unnecessary human exposure to potentially hazardous ionizing and nonionizing /~ Y radiations and to ensure the safe, efficacious use of such radiations. The Bureau publishes the results of its work in scientific journals and in its own technical reports. FOREWORD These reports provide a mechanism for disseminating results of Bureau and contractor projects. They are distributed to Federal, State, and local governments; industry; hospitals; the medical profession; educators; researchers; libraries; professional and trade organiza- tions; the press; and others. The reports are sold by the Government Printing Office and/or the National Technical Information Service. The Bureau also makes its technical reports available to the World Health Organization. Under a memorandum of agreement between WHO and the Department of Health and Human Services, three WHO Collaborating Centers have been established within the Bureau of Radiological Health, FDA: WHO Collaborating Center for Standardization of Protection Against Nonionizing Radiations; WHO Collaborating Center for Training and General Tasks in Radiation Medicine; and WHO Collaborating Center for Nuclear Medicine. Please report errors or omissions to the Bureau. Your comments and requests for further information are also encouraged. John C. se Director Bureau of Radiological Health iii 218073 ''PREFACE By Federal Register notice of October 22, 1980 (45 FR 69905), the Federal Emergency Management Agency (FEMA) outlined the responsibilities of several Federal agencies: concerning emergency response planning guidance that the agencies should provide to State and local authorities. This updated a prior notice published in the Federal Register by the General Services Administration (GSA) on December 24, 1975 (40 FR 59494), on the same subject. GSA responsibility for emergency management was transferred by Executive Order to FEMA. The Department of Health and Human Services (HHS) is responsible for assisting State and local authorities in developing plans for preventing adverse effects from exposure to radiation in the event that radioactivity is released into the environment. These plans are to include the prophylactic use of drugs that would reduce the radiation dose to specific organs from the sudden release into the environment of large quantities of radioactivity that might include several radioactive isotopes of iodine. By Federal Register notice of December 15, 1978 (43 FR 58798), FDA requested submissions of new drug applications for potassium iodide in oral dosage forms for use as a thyroid-blocking agent. This was the first FDA step in meeting the Departmental responsi- bilities as outlined by GSA. Now potassium iodide as a thyroid-blocking agent for use ina radiation emergency is available commercially in both a tablet and a solution form (see 45 FR 11912). FDA is taking another step in meeting HHS responsibilities as outlined by FEMA by publishing proposed recommendations on the use of potassium iodide for the general public. FEMA and the Nuclear Regulatory Commission are charged with the responsibility for issuing recommendations relative to the procurement, storage and distribution of potassium iodide. This report provides background material for the FDA proposed recommendations on thyroid-blocking with potassium iodide. Notice of availability of the proposed recommendations will appear in the Federal Register. This background report presents: 1) the mechanism of action, efficacy, safety and availability of potassium iodide as a thyroid-blocking agent; 2) examples of actual and theoretical nuclear accidents and pathways of exposure which could require thyroid- blocking; 3) a discussion of previous recommendations relative to the use of potassium iodide as a thyroid-blocking agent as well as alternative protective actions; 4) descriptions of populations of special concern; and, 5) problems dealing with the procurement, storage and distribution of the drug. 6h /r Jerome A. Halperin, M.P.H. Deputy Director Bureau of Drugs [Bamec? : Bernard Shleien, Pharm.D. Assistant Director for Scientific Affairs Bureau of Radiological Health iv ''CONTENTS POREWORD »s es eee RR Re we ew ee ee ee PREFACE 4.2264 # © 1 ee ee ee 7. eee we ww ABSTRACT INTRODUCTION ...., Mechanism of Action Efficacy , Safety, iii iiiiiiiiiiiis Availability ee eee See eg e [.e NUCLEAR ACCIDENTS: ACTUAL AND THEORETICAL ...... we % Actual, .... 2... 2... pee ee “6 mee w a i * w # &@ 2 Theoretical .........0.008008806 00408 ecce.e.se oe ew % Pathways of Exposure. ......... Pow ne wh we we we USE OF POTASSIUM IODIDE AS A THYROID-BLOCKING AGENT AND ALTERNATIVE PROTECTIVE ACTIONS ......... ones Introduction’ «© «ee eo ww wee eee ee eke hl NCRP Report No. 55 ....... a ee ee ae ae ee : EPA/NRC Guidance. .......2.064.-. ow we oe wm HS wm Illustrative Example. ....... ee er Alternative Protective Actions -....... oUF eo 2 ee Populations of Special Concern - - - 6 6 se ee ee ew ew we ew ew wee PROCUREMENT, STORAGE AND DISTRIBUTION ---. +2... ee. MONITORING THE EFFECTIVENESS OF POTASSIUM IODIDE DURING AND AFTER A RADIATION ACCIDENT ....- 2.2.1 eee eee SUMMARY « e e e e @ @ ee e e e e e @ @ ° ° oso e e e e @ @ oc e e @ REFERENCES «+ «© « & &B ec ew ee me we ew ee mw oe © eo ew eo e@¢ @¢ ¢ je je e e e e e e © e e © © «© «6 o ee e¢ e e e e e e © © © © © © © © @ « Page iii iv vi OPN rR NDDO 14 14 14 ''ABSTRACT Halperin, J.A., B. Shleien, S.E. Kahana, and J.M. Bilstad. Background Material for the Development of the Food and Drug Administration's Recommendations on Thyroid-Blocking with Potassium Iodide. HHS Publication (FDA) 81-8158 (March 1981). This report provides background material for the development of FDA's recommendations on thyroid-blocking with potassium iodide in the event of a radiation emergency. It presents: 1) the mechanism of action, efficacy, safety and availability of potassium iodide as a thyroid-blocking agent; 2) examples of actual and theoretical nuclear accidents and pathways of exposure which could require thyroid-blocking; 3) a discussion of previous recommendations relative to the use of potassium iodide as a thyroid-blocking agent as well as alternative protective actions; 4) descriptions of populations of special concern; and, 5) problems dealing with the procurement, storage and distribution of the drug. The opinions and statements contained in this report do not necessarily represent the views or the stated policy of the World Health Organization (WHO). vi ''BACKGROUND MATERIAL FOR THE DEVELOPMENT OF THE FOOD AND DRUG ADMINISTRATION'S RECOMMENDATIONS ON THY ROID-BLOCKING WITH POTASSIUM IODIDE INTRODUCTION There is considerable debate about the appropriate role of a thyroid-blocking agent as an element of a public health response to an accidental release of radioiodines from a nuclear power plant. As one step in facilitating the availability of and providing guidance for the use of prophylactic drugs to reduce radiation doses in the event of accidental releases of radioactive materials (1), the Food and Drug Administration (FDA) published a notice in the Federal Register of December 15, 1978, entitled "Potassium Iodide as a Thyroid-Blocking Agent in a Radiation Emergency" (2). This notice requested submission of New Drug Applications (NDAs) for potassium iodide in specific oral dosing forms, announced the availability of labeling guidelines, and declared such preparations to be suitable under specific conditions for marketing as over-the-counter drug products. Prior to publication, the FDA worked closely with the Ad Hoc Committee on Thyroid Blocking of the National Council on Radiation Protection and Measurements (NCRP); the FDA notice closely followed the recommendations of NCRP Report No. 55, "Protection of the Thyroid Gland in the Event of Releases of Radioiodine" (3). The Three Mile Island accident emphasized the need for radiation emergency planning, which should include consideration of the potential use of potassium iodide to reduce the uptake of radioiodines by the thyroid gland, thereby mitigating the possible adverse effects of such exposure. Thyroiditis may occur as an early effect but, since it has been observed only with very large doses of }31], it is unlikely to be a complication of off-site releases (3). Hypothyroidism and thyroid nodules with either benign or malignant characteristics are complications of lower dose exposure and occur later in time. The levels of radiation exposure associated with these abnormalities have recently been reviewed and planning officials are urged to familiarize themselves with the available human data (4,5). Minimizing the risk of such complications is of obvious significance to the public health. Understanding the mechanism of action of potassium iodide is essential to its appropriate use as a radiation protection measure. To be most effective, potassium iodide would have to be administered promptly--either before, simultaneous with, or within 2 hours of the onset of exposure. Also important is an understanding of the rationale for the recommended dosage regimen and the possible side effects. Finally, guidelines for potassium iodide use, including the nature of the radiation hazard, pathways of exposure, population at risk, methods of storage and distribution, alternative or complementary protective actions and possible legal ramifications must be considered. MECHANISM OF ACTION Iodine in the diet reaches the circulation as iodide. The thyroid gland has an active iodide transport system which enables it to concentrate iodide so that the ratio of thyroid to plasma iodide concentrations is usually between 20-to-1 and 50-to-1. The ability to concentrate iodide is not limited to the thyroid gland but is found to a lesser degree in other organs, including the salivary glands, parts of the gastrointestinal tract, mammary glands, and placenta (6). The latter two have special significance for pregnant women and nursing infants. Once in the thyroid, iodide is rapidly incorporated into organic molecules that are synthesized into thyroid hormones and ultimately released into the general circulation. 1 ''There is also an intra-thyroidal cycling of iodide from deiodination of hormone precursor molecules. Iodide so produced is available in the gland for re-organification or it may "leak" from the gland back into the general circulation (7). Estimates of the fractional turnover rate of incorporated iodine from the adult thyroid have varied, but it is generally considered to be about | percent per day; this corresponds to a biological half life of approximately 70 days (8). Although a variety of chemical substances can block the accumulation of radioiodine in the thyroid gland, and hence its conversion to relatively long-lived organic compounds, stable iodide in the form of therapeutic doses of potassium iodide appears to be most suitable for this purpose. A number of factors were considered in choosing potassium iodide over other blocking agents such as propylthiouracil, methimazole, perchlorate, thiocyanate or iodate. These factors included the degree of blocking achieved, the rapidity of onset and duration of the blocking effect, the safety of the blocking agent, and the ease with which the drug could be made available under present FDA regulations. The effectiveness of large doses of stable iodide in reducing the amount of radioactive iodine taken up by the thyroid gland appears to be dependent on two factors: (1) the proportion of radioactive iodine relative to the increased amount of stable iodide in circulating blood is greatly reduced (dilution effect); (2) as the levels of iodide in blood increase, there is an autoregulatory mechanism that limits the rate at which further iodide is accumulated by the gland; the precise nature of this iodide-induced effect has not been established. The suppression of uptake of radioiodine persists for as long as the intake of stable iodide is maintained at adequate levels. The administration of potassium iodide, however, would not significantly reduce the amount of radioiodine already trapped in the gland in hormonal form. Of possible additional benefit is an acute inhibition of organification of iodine observed with excess iodide intake (Wolff-Chaikoff Effect) (9). This phenomenon is, however, usually short-lived in euthyroid individuals. Unlike the inhibitory effect on the transport system, the thyroid escapes from iodide inhibition of organification despite the maintenance of high concentrations of circulating iodide. The usual duration of this effect in humans has not been precisely defined; in rats, escape occurs after about 48 hours. It should be re- emphasized that such an escape would not affect the blocking of uptake of radioiodine by protective doses of potassium iodide. As far as is known, the latter can continue for long periods of time. EFFICACY As noted above, the usefulness of potassium iodide depends on its capacity to block entry of radioiodines; therefore, it is important to review briefly the pattern of a standard 24-hour uptake curve after ingestion of a single bolus of !31I, (Of the various iodine isotopes, 131] is the one of principal concern to the neighboring population. See NCRP Report No. 55 for further information regarding other isotopes and their properties and significance.) Figure | demonstrates that, in normal individuals retaining 10-40 percent of the administered amount of !31], most of the radioiodine is accumulated in the thyroid over a 10- to 12-hour interval; a smaller amount is accumulated over the next 12-hour period. Hence, an important factor in obtaining satisfactory blocking of peak radioiodine uptake is the temporal relation of stable iodide administration to radioiodine exposure. This has been investigated by performing 24-hour radioactive iodine uptakes, varying both doses of potassium iodide and time intervals between administration and exposure (10). When doses approximating 100 mg of stable iodide (equivalent to 130 mg of potassium iodide) have been given just prior to or simultaneous with an oral tracer dose of '31I, a 90 percent or greater reduction in peak thyroid accumulation of }31] has been observed. (For example, if the unblocked 24-hour uptake of 131] were normally 20 percent of the administered dose, then the uptake would be expected to be 2 percent or less with such a prior or simultaneous administration of potassium iodide.) A substantial benefit (e.g., a 2 '' FREQUENCY OF 24 HOUR UPTAKES 15 > FREQUENC ° Oo wo 0 10 20 30 40 50 UPTAKE ,% rN aS THYROIDAL |] UPTAKE, % Or +——t t t +——+ +——+ + + + O 24 6 8 10 l2 14 16 I8 20 22 24 HOURS AFTER I ADMINISTRATION Figure l. Thyroidal 131] .uptake in 62 euthyroid volunteers administered sodium iodide 131] and their frequency distribution (from reference 10). ''block of 50 percent) is attainable only during the first 3 to 4 hours after acute exposure, lf initial administration is delayed beyond this, the usefulness of potassium iodide will be limited and little benefit can be expected after 10 to 12 hours for a single exposure. For more prolonged radioiodine exposure, potassium iodide will, of course, be useful at any time during the exposure as it will reduce further accumulation. A smaller dose, 50 mg iodide (65 mg of potassium iodide), can be used in infants under | year of age. The range and mean 24-hour 1317 uptake in the normal adult U.S. population was reported in early 1970 publications to be significantly lower than that illustrated here, most likely reflecting the effect of an increase in dietary iodine. A more recent assessment in one metropolitan area has indicated a trend toward higher uptakes (mean 20.5 percent +61 percent) in association with a marked decrease in the iodine content of bread as a source of dietary iodine (11). It is probable that geographical variations in mean 24-hour **?1 uptakes exist based on regional differences in dietary iodine content from bread or other sources. Despite such variations in the numerical value of the mean 24-hour 1317 uptake in the normal population, the pattern of accumulation of 1317 is similar, so that conclusions regarding the temporal relationship of exposure to the efficacy of potassium iodide as a blocking agent are still valid. Such variations would obviously affect the calculation of the radiation dose received by the gland from any given exposure and for any degree of block. The onset of blocking with an oral dose of 100 mg of stable iodide is readily demonstrated within 30 minutes of administration (12). The decay of the blocking effect after iodide administration is relatively slow; single daily doses of 130 mg of potassium iodide should be adequate to maintain effective blocking. Repeated daily administration is necessary not only for chronic exposure but also for a period ot time after acute exposure in order to allow for renal excretion of circulating radioiodine. Renal clearance of iodide, usually in the range of 30 to 50 ml of serum/min, is closely related to glomerular filtration and is little affected by the iodide load (8,13). Most radioiodine not taken up by the thyroid gland after a single oral bolus of 1311 is excreted in the urine over the subsequent 48-hour period (14). Thus, the minimum duration of potassium iodide administration should be 3 days even if there is no continuing exposure. It is unlikely that administration would be required beyond 10 days in view of the availability of other countermeasures (e.g., interruption of contaminated milk supplies, evacuation). However, should extraordinary circumstances prevail and significant radioiodine contamination still be present, continued use of potassium iodide would be required. SAFETY The incidence of significant adverse reactions from short-term administration of potassium iodide in daily doses of 65 or 130 mg is unknown but is expected to be low. Potassium iodide in large doses (300-1200 mg daily) and on a long-term basis has been widely used for years in the management of bronchial asthma and other pulmonary disorders. Doses of 100 mg or more have been employed for prolonged periods in children (15). Individual reports of complications of iodide administration in the medical literature for the most part do not identify the size of the patient population taking iodides from which the cases have been drawn. While under-reporting undoubtedly exists, the number of reports of adverse reactions from potassium iodide received by the FDA has been low. (The 160 adverse reactions to potassium iodide received by the Division of Drug Experience of the FDA from 1969 to 1980 were reviewed. Particular attention was paid to identifying those reported as having occurred in the group less than 10 years of age; none were noted, In 19 of these reports the age was unknown.) Furthermore, the occurrence of most side effects and toxicities appears to be proportional to the dose and duration of therapy. Known allergy to iodide would appear to be the only contraindication to its use in a radiation emergency. The adverse reactions can be grouped into thyroid and non-thyroid effects (16). The non- thyroid side effects include skin rashes, swelling of the parotid glands ("iodide mumps"), and 4 ''a collection of symptoms referred to as iodism; these symptoms include metallic taste, burning mouth and throat, sore teeth and gums, rashes, symptoms of a head cold, gastric upset and diarrhea. Systemic hypersensitivity reactions (allergic-like) may also occur with, for example, fever, joint pains, and edema of various tissues. Discontinuing iodide, instituting supportive or specific medical therapy, and evacuation may be necessary depending upon the nature and severity of the observed adverse reactions. It would obviously be desirable to be able to identify particular members of the population who might be at greater risk of exhibiting a sensitivity reaction to potassium iodide. That iodide and iodine administration in patients rarely have been associated with sensitivity reactions was noted in a recent publication in which four patients with hypocomplementemic vasculitis associated with either chronic idiopathic urticaria or systemic lupus erythematosis were reported as exhibiting sensitivity to potassium iodide at doses of 500 mg daily on 5 of 11 days or 1000 mg as a single challenge (17). It was suggested that patients with similar clinical features might also be sensitive to the drug. The sensitivity reactions were non-fatal in outcome and varied from an exacerbation of urticaria to systemic manifestations. Patients with this uncommon disorder should preferentially be evacuated, However, if potassium iodide administration is unavoidable, such patients should be hospitalized where they could be monitored closely. Complications of iodide administration involving the thyroid gland include hyper- thyroidism, hypothyroidism and iodide goiter. Goiter may also occur in infants born to mothers who have taken large doses of potassium iodide for prolonged periods of time during pregnancy (18). However, for the recommended dosage and duration of administration, the incidence of such changes in thyroid function in the general population should be very low. Physicians should nevertheless be prepared to recognize and manage such conditions, most of which are readily reversible by cessation of potassium iodide administration. Persons using potassium iodide as a thyroid-blocking agent in a radiation accident should be familiar with the possible side effects. Labeling guidelines which include such information in readily understandable form are available (2,19). Even though the occurrence of significant side effects is not anticipated with any degree of frequency, public awareness should result in their early recognition, prompt treatment and, hence, minimal risk. AVAILABILITY In the Federal Register notice of December 15, 1978 (2) the FDA requested submission of New Drug Applications (NDAs) for potassium iodide in oral form for use as a thyroid- blocking agent in a radiation emergency. The Agency waived the requirements for submission of full reports of toxicology studies in animals and clinical studies in humans stating that the requirements were met by citing the scientific literature. Potassium iodide was declared to be suitable as an over-the-counter drug if specific conditions were met: these include special labeling to accompany the immediate container, and use as a thyroid- blocking agent in a radiation emergency only upon the direction of responsible State or local public health officials. The availability of a labeling guideline for potassium iodide for use as a thyroid-blocking agent in a radiation emergency also was announced. Notice of a oe of this labeling guideline was published in the Federal Register of August 17, 1979 19), Dose-specific tablet and liquid forms of potassium iodide were included in the request for submission of NDAs. At the time of the Three Mile Island accident, no such applications had been received. To meet the possible emergency need, FDA arranged for the manufacture of a supply of Potassium Iodide Solution USP and delivery to Harrisburg, Pennsylvania, where the drug was stockpiled in a State-owned warehouse. None of the drug was distributed to local centers; however, Pennsylvania officials did have a plan (20,21) for distributing supplies of the drug accompanied by patient information sheets printed by FDA. This plan would have been put into effect if a decision had been made to employ the drug. ''Subsequent to the Three Mile Island accident, the FDA received and approved New Drug Applications for scored 130 mg tablets of potassium iodide and for Potassium Iodide Solution USP in a calibrated light-resistant dropper system delivering 21 mg of potassium iodide per drop. Public health officials and nuclear utility operators must now determine whether potassium iodide has a role in their emergency preparedness plans and, if so, must acquire adequate supplies and locate them in accordance with established plans for their distribution and use. NUCLEAR ACCIDENTS: ACTUAL AND THEORETICAL ACTUAL In addition to the accident at Three Mile Island there have been four accidental releases of iodine-131 to the environment from nuclear facilities over the past 2 decades. Table | provides estimates of the magnitude of these releases and the resultant thyroid doses. During the Three Mile Island accident the total amount of radioiodine released to the environment was estimated to be 13 to 17 Ci (22). There was no report of thyroid doses via the inhalation pathway; the maximum dose to an infant thyroid via milk was estimated to be 0.005 rem, far below the level at which any protective action is needed (23) . THEORETICAL A sudden release from an operating nuclear power plant of large quantities of gaseous fission products (including several radioisotopes of iodine) could result from a loss-of- coolant accident due to a melting of the fuel cladding. The potential off-site absorbed doses to the thyroid may be estimated on the basis of a given set of reactor, meteorological and topographic conditions. These dose estimates can vary widely, depending on the assumptions chosen. Illustrations of two such calculations are presented in NCRP Report No. 55. In the "conservative" model it is presumed that the releases of radioiodine from the fuel are large and engineered safeguards are not fully operable, whereas in the "realistic" Table 1. Accidental releases of iodine-131 to the environment from nuclear facilities Estimated maximum off- Magnitude of iodine-131 site dose to thyroid Event Year release (Ci) (rem*) Windscale(2*) 1957 20 ,000 16 §i.<117*)2*) 1961 10 in first 16 hours; total 0.035 of 80 over next 30 days Hanford (27) 1963 60 0.03 Savannah River (28) 1964 94 in first few days; 1.2 total of 153 in 26 days *Doses for iodine-131 to the thyroid, for the purposes of this paper, are expressed _in rems or rads interchangeably. The two are essentially equal for iodine-131. The doses listed in this table have been calculated for a child's thyroid (2-5 grams in weight). The corresponding adult thyroid dose at Windscale is estimated at 9.5 rem. In no case was a thyroid-blocking agent used, although milk was dumped during: the Windscale incident if the thyroid dose to children was projected to be in excess of 20 rem. ''mode] it is assumed that all events and processes take place as designed and engineered. (See Appendix B of NCRP Report No. 55 for further definition of the assumptions involved, including reactor power level, primary containment leak rate, years of reactor operation, filter efficiencies and meteorological conditions.) Table 2 is a reproduction of the resultant calculated doses, in rads for the conservative model and in millirads for the realistic model. While the values are highly qualified and do not relate to any particular reactor and its site, the table is included for the purpose of illustrating the orders of magnitude that might obtain under a given set of conditions. It will also be employed later in the paper to show how such projections, when calculated for a specific accident, can be used to define the area within which the use of potassium iodide might be an appropriate protective measure. It is the burden of the reactor operator to maintain the capacity for rapid generation of such projections as are appropriate to the particular facility, and to take into consideration varying conditions that can influence the nature, quantity and environmental distribution of an accidental release. In the event of a radiation emergency, nuclear utility operators are also responsible for the immediate communication of such information to designated public health officials. Thyroid dose estimates for a loss-of-coolant accident without emergency core cooling and with a breach of the reactor containment were not included in NCRP 55. A recent estimate for such an unlikely accident in which very large quantities of radioiodines are released suggests that 10-60 percent of the children exposed within 200 miles downwind from the reactor could eventually develop thyroid nodules (29). The detailed assumptions upon which this projection was made were not given. PATHWAYS OF EXPOSURE The primary route of exposure to radioiodines, when airborne radioiodines are being released, is inhalation of contaminated air. Uptake of radioiodines over subsequent days to weeks occurs primarily via the pathway from pasture to cow to milk to human. The total human dose from the milk pathway can even exceed the inhalation dose by substantial amounts if large dairy farming areas are contaminated. However, other protective action measures are available, such as the use of uncontaminated feed and diversion or confiscation of contaminated milk, which could mitigate further exposure through the ingestion pathway. The primary radiation protection measure for airborne radioiodine is avoidance of exposure by remaining inside buildings, by use of respiratory protective equipment, or by evacuation from the area. The use of potassium iodide in the recommended dosage regimen may be considered in addition to these measures if exposure has occurred or if there is risk of exposure. When used in conjunction with evacuation, potassium iodide should be continued until the evacuees reach a "safe" area and adequate time has elapsed for renal excretion of circulating radioiodines. USE OF POTASSIUM IODIDE AS A THYROID-BLOCKING AGENT AND ALTERNATIVE PROTECTIVE ACTIONS INTRODUCTION Definitive Federal guidelines for the use of potassium iodide as a thyroid-blocking agent are not as yet available nor is it the purpose of this background document to propose them. Rather, recommendations on potassium iodide use and alternative protective actions recommended by the NCRP, the Environmental Protection Agency, and the Nuclear Regulatory Commission will be summarized (30,31). (In the Radiobiology Forum of 1970, the question of iodide prophylaxis was addressed (32). It is the authors' understanding that the British have considered potassium iodate as well as potassium iodide for this purpose. The 7 a ee . x ee SS ae ''Table 2. Estimates of total thyroid absorbed doses from 1317135) for a postulated loss-of-coolant accident Time after release (hours) Distance (miles) 2 8 24 96 720 Dose* Conservative estimate (rads) Pressurized water reactor 0.5 110 230 280 320 350 1 50 110 120 140 150 2 21 45 51 55 58 5 6.3 14 15 16 17 10 2.6 5.6 6.2 6.6 6.7 20 1.2 2.9 2.8 209 3.0 30 0.8 1.6 1.8 1.9 1.9 40 0.6 LZ 1.2 1.4 1.4 50 0.4 1.0 1.0 1.1 1.1 Boiling water reactor 0.5 210 790 1100 1500 1700 1 100 370 460 580 660 Z 42 150 180 230 250 5 13 47 54 65 71 10 Dud 19 22 26 28 20 243 8.7 9.9 13 13 30 lao 5.6 6.3 72 7.7 40 Ld 4.2 4.7 5.3 Swit 50 0.9 3.3 3.7 4.2 4.5 Realistic estimate (millirads) Pressurized water reactor 0.5 110 210 490 810 1100 1 22 100 200 300 400 2 22 4] 73 110 140 5 6.7 12 20 28 36 10 2.8 5.1 8.3 12 15 20 1.2 2.3 3.6 4.9 6.1 30 0.8 1.5 2.3 3.0 3.7 40 0.6 Led 1,7 2.2 2.6 50 0.5 0.9 1.3 1.7 21 Boiling water reactor 0.5 0.21 Lek 5.1 17 29 1 0.0 0.55 1.8 5.4 962 2 0.04 0.22 0.66 1.9 3.2 5 0.01 0.06 0.18 0.49 0.79 10 0.005 0.03 0.07 0.19 0.30 20 0.002 0.01 0.03 0.08 0.12 30 0.001 0.008 0.02 0.05 0.07 40 0.001 0.006 0.01 0.03 0.05 50 0.001 0.005 0.008 0.02 0.04 *Contributions to the total absorbed dose in the first few days fro om the various radioiodine nuclides a apgiomimarely, 3 as follows: 60 percent Be ‘; 30 percent 7h. 10 percent a al I, and oon The contribution at later times is almost all due to I because of the more rapid decay of the other iodines. The absorbed dose to the whole body due to external radiation from the plume is generally less than the total absorbed thyroid dose by about one or two orders of magnitude. ''presently available approved preparations, recommended dosage regimen, and criteria for use are not known by the authors.) Finally, for the purpose of illustration, this document will examine the practical impact of these differing views should they be adopted by responsible public health officials in a given radiation emergency. Each State has the public health responsibility for formulating guidance and decision- making rules to define when the public would be given potassium iodide and instructed to use it. Such guidance was not available in Pennsylvania during the Three Mile Island emergency. The Department of Health, Education and Welfare recommended to the Governor of Pennsylvania that persons on Three Mile Island begin taking potassium iodide and that persons within a radius of about 10 miles of the reactor site be given bottles of the drug for potential use. The Pennsylvania Secretary of Health declined to accept that advice, stating that by the time the HEW recommendation reached the State the acute phases 5 we emergency had passed and prophylactic use of potassium iodide was not necessary 20). In preparing guidance and decision-making rules, State agencies and local officials should be cognizant of their duty to warn citizens of the nature of the radiation hazard and of the potential adverse effects of potassium iodide. In those instances where the States will administer or direct the administration of the drug to its citizens, States may be subject to the same kinds of liability as exist in public immunization programs (33,34), States should assure that citizens are provided with, and are encouraged to read, the patient information leaflet before they receive a dose of the drug. NCRP REPORT NO. 55 NCRP Report No. 55 recommends that a blocking agent be considered if initial estimates at the facility project total absorbed doses of 10-30 rads or more to the thyroid. When such doses are anticipated, the NCRP recommends the blocking agent be administered immediately to employees at the facility and to other support personnel coming to or working near the facility. For the general population residing outside the plant boundaries, if the anticipated thyroid absorbed dose is less than 10 rads, the NCRP states it may be preferable to consider instructing people to remain indoors and await further instructions. If the estimates of the total thyroid absorbed dose to the population exceed 10 rads, the NCRP recommends that use of a blocking agent be considered. The report goes on to state that because of the substantially reduced effectiveness of the blocking agent after exposure to the radioiodines has commenced, and because reliable radiation monitoring data may not be available promptly, the decision to administer the potassium iodide should be based upon a pre-established emergency response plan. EPA/NRC GUIDANCE The EPA Protective Action Guides call for evacuation and controlled access as protective actions when the projected total accumulated thyroid doses are estimated at 5- 25 rem for the general population. The EPA Guides call for protective actions for emergency workers at a projected thyroid dose of 125 rem. The use of potassium iodide is not specifically noted as an appropriate protective action for the general population. A joint NRC/EPA report on the planning basis for radiological emergency response plans (NUREG0396) recommends that planning for evacuation should extend to 10 miles, based on plume exposures with the highest assumed fission product release and adverse meteorological conditions (31). ''ILLUSTRATIVE EXAMPLE The circumstances in which potassium iodide might be considered following a nuclear facility accident will be reviewed. For illustrative purposes only, the authors assume: (1) that exposure occurs via the inhalation pathway promptly after release of radioiodines; (2) that the level of anticipated exposure in the first 24 hours after release is such that thyroid blocking is determined to be an appropriate protective measure; (3) that potassium iodide will be employed as a thyroid-blocking agent when the average projected thyroid absorbed dose to the general population is 10 rem or greater; and (4) that the assumptions for estimating total thyroid absorbed doses are the same as those for the models illustrated in NCRP Report No. 55. Using the "realistic" and "conservative" accident values from Table 2, one finds that the use of a blocking agent would never be required for "realistic" estimate accidents, as it is highly unlikely that any person living outside the boundary of the nuclear facility would receive a total accumulated dose to the thyroid in excess of 10 rem from such an accident. For "conservative" estimate accidents, persons living within about 2 miles of a boiling water reactor (BWR) or about | mile of a pressurized water reactor (PWR) boundary would be at risk of receiving considerable whole body exposure. This estimate is based on the assumption that whole body doses would generally be about one or two orders of magnitude below the thyroid dose. In a 24-hour period, and at a distance of 2 miles from a BWR, the estimated thyroid dose is 180 rads under the "conservative" assumption; the corresponding PWR dose is 120 rads at a distance of | mile. If one assumes a difference of one to two orders of magnitude between thyroid and whole body doses, and considers EPA's Protective Action Guides which recommend protective action at whole body doses between | and 5 rem, then evacuation is appropriate (30). As previously stated, when evacuation cannot be accomplished prior to exposure, there may be a need to consider the use of potassium iodide in those persons being evacuated. Persons living beyond about 5 miles from a PWR and 20 miles from a BWR would be unlikely to receive an estimated thyroid dose in excess of 10 rem. Thus, based on the aforementioned assumptions, for those people living between | and 5 miles from a PWR and between 2 and 20 miles from a BWR (i.e., beyond the immediate evacuation area but within the zone where thyroid doses are estimated to be 10 rem or greater), blocking the uptake of radioiodines by the thyroid gland with potassium iodide would be an appropriate protective measure, For accidents that result in loss of coolant and breach of containment, the dispersion of radioiodines may affect a much greater area and persons at significantly greater distances may be at risk of thyroid doses of 10 rems or greater. State radiation control agencies or nuclear utilities desiring to consider such accidents in the development of emergency response plans should refer to the safety analysis reports of the individual reactor facilities for guidance in calculating the potential release characteristics and the resultant areas and populations that could be affected. In this example, potassium iodide for thyroid blocking is considered to be a proper response for a portion of the population involved in a nuclear emergency for whom the projected radiation dose to the thyroid is 10 rem or greater. Public health agencies must determine the "action level" at which they will advise the general public to start taking the drug. The 10-rem level is arbitrary, although it is consistent with NCRP 55. It is based upon an assumption that on a population basis the risk of potential adverse effects from a 10- rem radiation dose to the thyroid exceeds the risk of any adverse effects that might be encountered as a result of administering potassium iodide in daily doses of 65 mg to individuals under | year of age or 130 mg to the remainder of the population for a period of several days. As the radiation doses decrease below 10 rem, the relative risks of the potential adverse effects of the radiation and of the drug become less clear. 10 ''ALTERNATIVE PROTECTIVE ACTIONS If public health authorities choose to evacuate people within a larger downwind distance from the facility, and if those people are moved promptly, the use of potassium iodide may not be necessary. Evacuation is a more effective method of reducing (or eliminating) thyroid exposure and may be a more desirable protective measure, especially for the population at greater risk from such exposure (i.e., infants, children, and pregnant women) and when the population density in the area is low enough to make evacuation a reasonable option. When evacuation is neither feasible nor deemed necessary, the risk of radiation exposure can be reduced by eliminating possible sources of !*!] exposure via ingestion. This can be accomplished in large part by interruption of the milk pathway through diversion or confiscation of contaminated milk or milk products. Barrier type protective measures (e.g., staying indoors) or use of respiratory protective devices should also be considered. POPULATIONS OF SPECIAL CONCERN Planning officials should be cognizant that certain members of the general population may be at increased risk in the event of exposure to radioiodine: The Pregnant Woman The pregnant woman herself is at risk in addition to the special concern for the developing fetus. Pregnancy is often accompanied by some degree of thyroid enlargement and increased 131] uptake, which potentially increases the risk to the maternal thyroid (35). Consideration of possible effects on the fetus has prompted a recommendation that therapeutic doses of potassium iodide not be used as an expectorant in pregnant women (18). Pregnancy, however, is not regarded as a contraindication to the proper use of potassium iodide in relatively low doses over a short period of time as a thyroid blocking agent in the event of a nuclear accident. The Fetus Iodide reaches the fetal circulation via the placenta which, in some species and probably in man, appears to have an active transport system similar to that of the thyroid (6,36). The fetal thyroid is capable of trapping iodine at approximately 12 weeks of gestation; thereafter the uptake of iodine increases with gestational age. Using animal and human data, estimates of the human fetal thyroid radioiodine burden for a given acute exposure reveal that the dose to the fetal thyroid gland during the second half of gestation derived from either maternal ingestion or inhalation may exceed that of the adult (37). In addition, the immature gland may possess greater sensitivity for radiation-induced neoplasia (38,39). When prophylactic administration of potassium iodide is employed in the mother, it should be effective simultaneously in reducing both maternal and fetal thyroid exposure to radioiodine. The fetus, together with the premature neonate, may also be more vulnerable to certain adverse effects of stable iodide, namely, the induction of goiter and/or hypothyroidism (40,41). There have been reports of goiters in the infants of asthmatic mothers who took therapeutic doses of potassium iodide for prolonged periods during pregnancy (18). As noted above, this has led to warnings concerning the use of large doses of potassium iodide as an expectorant in pregnant women. However, sizeable goiters have not been common and would not be anticipated to occur frequently with the dosage regimen recommended for use in thyroid blocking during a radiation emergency. LL ''The Neonate Estimating the radioiodine burden of the thyroid of the neonate is complex. First, the radioactive iodine uptake of the neonatal thyroid has been reported to be significantly elevated during the first few days of life compared to levels in the infant and adult (42). When expressed as uptake per gram of thyroid tissue, this difference is further magnified. The nursing neonate is also at risk of increased exposure via the oral route because of the concentration of radioiodine in the mammary gland and its secretion in milk. On the other hand, the biological half life of organically incorporated radioiodine may be shorter in the neonate than in the adult; this would reduce the duration of exposure of thyroid tissue to accumulated radioiodine (37,42,43) . Moreover, estimates of exposure from inhalation of radioiodine must be adjusted to reflect relative respiratory intake (44). Finally, the net estimate of thyroid exposure must be evaluated in the perspective of an immature gland with the potential for greater radiosensitivity. Use of suitable safe milk substitutes and confinement in the protective environment of a hospital or home (or evacuation) should therefore be considered. In making a decision whether or not to use potassium iodide under these circumstances one must weigh the possible risks from its use against the hazard from exposure to radioiodine. Human experience with large doses of iodide in this age group is limited. Neonatal hyperthyroidism, where iodide has been recommended for use therapeutically in doses of 8 to 16 mg administered at 8-hour intervals, is an uncommon disorder (45). The published case reports do not provide adequate information from which firm conclusions can be drawn concerning the potential side effects of iodide in this dosing range, particularly for the thyroid side effects that might occur in a normal neonate. Recent reports of transient hypothyroidism in newborns associated with the repetitive use of iodine containing topical antimicrobial solutions suggest an underlying susceptibility to the inhibitory effect of stable iodide on thyroid hormone synthesis (46,47). However, no alteration in thyroid function was observed in neonates in another study employing such a topical preparation despite the presence of elevated plasma iodine levels; the authors nevertheless recommended caution in regard to repeated prolonged periods of application (48). These observations have prompted concern about the appropriate use of potassium iodide as a thyroid-blocking agent in the neonatal population. Although the reported changes appear to be reversible, a brief period of hypothyroidism during this critical stage of development is not necessarily without long- term effects. Given the present preliminary stage of information, no alteration in the recommended dosage regimen appears to be indicated, particularly in view of the potential higher risk for the adverse effects of radioiodine of this same age group. Meanwhile, it is reassuring that, while it is the youngest segment of the newborn population who might be most susceptible to exposure to either radioactive or stable iodine, it is this group that would likely be in hospitals where proper medical supervision would be available. The Infant and Young Child The infant and young child, by comparison with adults, are population groups at greater risk in regard to the possible adverse effects of exposure to radioiodines. Throughout infancy and childhood, while the radioactive iodine uptake as conventionally measured is similar to that of the adult, the uptake expressed per gram of thyroid tissue remains significantly elevated. Thus, for an equivalent exposure there is a greater concentration of radioiodine on a per unit thyroid weight basis, i.e., since the thyroid of infants and young children is smaller but picks up the same proportional amount of radioiodine, the radiation dose for a given exposure is an inverse function of thyroid size. Second, exposure of the infant and child may even exceed that of the adult because of the dietary reliance on fresh milk with resultant significant potential for '*'I intake via the oral route. Finally, the glands of infants and young children are still immature and therefore probably continue to possess greater sensitivity for radiation-induced neoplasia as compared to the mature glands of adults (4,5). These reasons all point to the consideration of all available countermeasures based on potential exposure to this particular age group in the population. Appropriate countermeasures include the use of uncontaminated milk or safe milk substitutes to reduce 12 ''oral exposure; sheltering, evacuation, and/or the use of stable iodide should be considered for protection against inhaled radioiodines. Reports of iodide-induced goiter and skin disorders (particularly in adolescents) have resulted in the adoption of a more conservative attitude by pediatricians toward the use of therapeutic doses of potassium iodide in asthma (18). However, consideration of both the risks involved in the event of a nuclear emergency, and the lower-dose shorter-term regimen, provides support for the relative safety of using potassium iodide in a radiation accident. PROCUREMENT, STORAGE AND DISTRIBUTION Acquiring adequate supplies of potassium iodide raises the issue of who should supply or pay for the drug. While the FDA provided the drug during the Three Mile Island emergency, it will not provide the drug in the future. The authors are unaware of plans by other Federal agencies to provide the drug. State agencies may choose to purchase supplies and stockpile them. Both of these options require expenditure of public funds. A third option would have the utilities which operate the nuclear power plants purchase the drug and provide it to State health agencies for stockpiling. The utilities could be required to purchase and provide the drug to State agencies as a condition of the Federal construction or operating licenses or any of the licenses or permits they must obtain from the State government before construction or operation may begin. Based on the need for rapid administration of potassium iodide for full utilization of its thyroid-blocking potential, storage and distribution of potassium iodide in tablet or solution form are of particular concern, A further confounding problem is that supplies of potassium iodide tablets and solution currently approved for marketing bear 2-year expirations. Stockpiles will therefore have to be replaced, thus adding to the logistic and economic concerns. Further studies of product stability currently underway may result in approval of longer expiration dates on future lots of the products. Presently, little definitive planning is evident for making the drug available promptly to potentially exposed persons. The NCRP suggests stockpiling supplies of potassium iodide tablets in distribution centers including fire houses, police stations, hospitals, clinics, factories, office buildings, municipal buildings, schools, physicians' and dentists! offices, pharmacies, and the nuclear facility itself. The problem, however, is not solely storage but also distribution, It is difficult to discern how the drug can be made available to persons in the "high risk" area soon enough to allow for effective thyroid blocking unless each household is provided in advance with a supply sufficient for all residents of the household. The need to consider predistribution may extend even beyond such an area, depending upon the radiation guidelines established for the use of potassium iodide. A recent news article noted that a draft report prepared for the Council on Environ- mental Quality (CEQ) suggests that a supply of potassium iodide be fastened to electric meters (49), a notion originally suggested in 1973 (50). While predistribution has the obvious advantage of putting the drug into the hands of the public before the onset of 131] exposure, there are equally obvious potential problems, e.g., persons may move and take the drug with them, bottles or packages may be lost or broken, and outdated supplies may not have been replaced. Fastening packages to. electric meters poses other problems such as common meters in multifamily dwellings, meters on the outside of private houses exposed to the elements, multiple meters in public areas of apartment houses within reach of children, and even possible damage to the meter and electrical system by individuals trying to hurriedly secure tablets if they are stored inside the glass covers. Thus, this particular proposal would appear to present too many disadvantages to be considered seriously. 13 ''MONITORING THE EFFECTIVENESS OF POTASSIUM IODIDE DURING AND AFTER A RADIATION ACCIDENT A detailed discussion of monitoring is beyond the scope of this presentation. However, it is important to emphasize that plans for monitoring the effectiveness of thyroid blocking, including long-term clinical followup for radiation damage as well as an assessment of any complications of potassium iodide administration, should be part of any planning program. NCRP Report No. 55 discusses both early and later complications of thyroid and whole body exposure. Regarding the possible side effects of potassium iodide administration, the importance of monitoring thyroid function in the neonatal period (particularly for premature newborns) has already been noted. In addition, following the emergency it would seem prudent to reassess thyroid function in patients with pre-existent thyroid disease. SUMMARY The use of potassium iodide as an agent to reduce the uptake of radioiodine in the event of accidental releases of radioiodines from a nuclear power plant is a public health countermeasure for which substantial planning is required. Although this drug is recognized by the Food and Drug Administration as safe and effective as a thyroid-blocking agent in a radiation emergency under specified conditions, the decision as to when and in whom it should be used remains with responsible State and local public health officials. For the most effective utilization, pre-planning on a State, local or regional level is required that considers details of: 1!) anticipated absorbed radiation doses to the thyroid that would trigger the use of the drug and a specified procedure for estimating or determining these doses; 2) rapid distribution plans so that potentially affected population groups could begin taking the drug shortly before exposure begins, or as soon as possible after its onset; 3) supplies of the drug adequate for up to 10 days' administration; 4) a mechanism for informing the public of the need for, and timing of, taking the drug; and (5) alternative and/or supplementary actions. The availability of potassium iodide provides a protective action to be considered with other safety measures in a radiation emergency. It is not the only action by which anticipated thyroid doses can be avoided, nor is it necessarily the best one. However, under certain conditions it provides an element of needed flexibility. 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Thyroidal radioiodine uptake rate measurement in infants. Am J Dis Child 103:738-49 (1962). Bryant, P.M. Derivations of working limits for continuous release rates of !2°1 to atmosphere. Health Phys 19:6l1-6 (1970). Kereiakes, J.G., R.A. Seltzer, B. Blackburn, and E.L. Saenger. Radionuclide doses to infants and children: A plea for a standard child. Health Phys 11:999-1004 (1965). Fisher, D.A. Hyperthyroidism, pediatric aspects. In: The Thyroid, 4th edition, S.C. Werner and S.H. Ingbar, Eds., p. 806. Harper and Row, New York (1978). Leger, F.A., F. Kiesgen, J.P. Fournet, et al. High incidence of post-natal iodine- induced hypothyroidism in premature neonates. Ann Endocrinol 39:40A (1978). Chabrolle, J.B. and A. Rossier. Goiter and hypothyroidism in the newborn after cutaneous absorption of iodine. Arch Dis Child 53:495-8 (1978). Pyati, S.P. et al. Absorption of iodine in the neonate following topical use of povidone iodine. J Pediatr 91:825-8 (1977). Carter, L.J. Nationwide protection from iodine-131 urged. Science 206:201-4 (1979). Report of the Clinch Valley Study, May 15 - June 2, 1972. J.A. Auxier and R.O. Chester, Eds. Publication No. ORNL-4835. Oak Ridge National Laboratory, Oak Ridge, Tenn. (January 1973). *U.S. GOVERNMENT PRINTING OFFICE: 1981-0-341-177/31 17 ''''FDA 80-8107 FDA 80-8108 FDA 80-8109 FDA 80-8110 FDA 80-8111 FDA 80-8113 FDA 80-8116 FDA 80-8117 FDA 80-8118 FDA 80-8119 FDA 80-8120 FDA 80-8121 FDA 80-8122 FDA 80-8124 FDA 80-8125 FDA 80-8126 FDA 80-8128 FDA 80-8129 FDA 80-8130 FDA 80-8131 FDA 80-8135 FDA 81-8027 FDA 81-8033 FDA 81-8034 FDA 81-8070 FDA 81-8136 FDA 81-8139 FDA 81-8141 FDA 81-8146 FDA 81-8147 Quantitative Analysis of the Reduction in Organ Dose in Diagnostic Radiology by Means of Entrance Exposure Guidelines (GPO 017-015-00164-4, $1.75) (PB 80- 174956, mf only). Positive Beam Limitation Effectiveness Evaluation (GPO 017-015-00163-6, $2.00) (PB 80-166937, mf only). . Proceedings of a Workshop on Thermal Physiology (PB 80-187867, $9.50). Quality Assurance Programs for Diagnostic Radiology Facilities (GPO 017-015- 00166-1, $2.50) (PB 80-183338, mf only). Get the Picture on Dental X Rays (brochure). Sourcebook - Medical Radiation Materials for Patients (GPO 017-015-00178-4, $2.00). Chest X-Ray Screening Practices: An Annotated Bibliography (GPO 017-015- 00167-9, $3.50) (PB 80-183890, mf only). X Radiation and the Human Fetus - A Bibliography (PB 80-157712, $20.00). A Word of Caution on Tanning Booths (brochure). Measurements of Emission Levels During Microwave and Shortwave Diathermy Treatments (GPO 017-015-00168-7, $1.75) (PB 80-194772, mf only). Microwave Oven Radiation (brochure) (supersedes FDA 79-8058). Laser Light Shows Safety - Who's Responsible? (brochure). Microwave Hazard Instruments: An Evaluation of the Narda 8100, Holaday HI- 1500, and Simpson 380M (PB 80-227820, $6.50). Optimization of Chest Radiography - Proceedings of a Symposium Held in Madison, Wisconsin, April 30-May 2, 1979 (GPO 017-015-00176-8, $7.50) (PB 30- 208317, mf only). Research Into the Biological Effects of Ionizing Radiation in The Bureau of Radiological Health (GPO 017-015-00172-5, $4.00) (PB 80-217268, mf only). Symposium on Biological Effects, Imaging Techniques, and Dosimetry of Ionizing Radiations (July 1980) (GPO 017-015-001 95-0, $8.00) (PB 81-112351, mf only). The Selection of Patients for X-ray Examinations: The Pelvimetry Examination (GPO 017-015-00174-1, $2.00) (PB 81-113490, mf only). ‘ean Genetic Damage from Diagnostic X Irradiation: A Review (PB 81-101743, 6.50). Nationwide Survey of Cobalt-60 Teletherapy: Final Report (PB 81-101784, $9.50). Vignettes of Early Radiation Workers: A Videotape Series (flyer). Hazards from Broken Mercury Vapor and Metal Halide Lamps (Notice of Alert) (pamphlet). Directory of Personnel Responsible for Radiological Health Programs (supersedes FDA 80-8027, March 1980). Bureau of Radiological Health Publications Index (supersedes FDA 79-8033) (PB 81- 156192, $18.50). Report of State and Local Radiological Health Programs, Fiscal Year 1979. Bureau of Radiological Health Publications Subject Index (supersedes FDA 80- 8070, May 1980) (PB 81-149478, $5.00). Optical Radiation Emissions from Selected Sources: Part I - Quartz Halogen and Fluorescent Lamps (GPO 017-015-00177-6, $6.50) (PB 81-139693, mf only). Quality Assurance in Diagnostic Ultrasound - A Manual for the Clinical User (GPO 017-015-00179-2, $4.00) (PB 81-139727, mf only). Quality Assurance in Diagnostic Radiology and Nuclear Medicine - The Obvious Decision (PB 81-164477, $14.00). Radiographic Film Processing Quality Assurance: (GPO 017-015-00180-6. $4.00). Quality Assurance in Diagnostic Radiology: Implementation. A Self-Teaching Workbook A Guide for State Program ''U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Food and Drug Administration Bureau of Radiological Health Rockville, Maryland 20857 OFFICIAL BUSINES _ADDRESS CORRECTION REQUESTED ~ Return this sheet to above address, if you do NOT wish to receive this material [ | or if change of address is needed! | (indi- cate change, including ZIP code). FDA fee YEARS PIONEERS IN CONSUMER PROTECTION AN EQUAL OPPORTUNITY EMPLOYER THIRD CLASS BULK RATE Postage Fees Paid PHS PERMIT G29 SpIpoy UINIsseIOg HIM BUTYOO[G-PlosAY], UO suOIepUsWWODSY s.UOneNSIUTUpY ''GENERAL LIBRARY - U.C. BERKELEY BOO0s82hbbh ''''