Late Effects of Radioactive Iodine in Fallout Combined Clinical Staff Conference at the National Institutes of Health

704470

Reprinted froni .-~ss.\Ls OF ISTERNAL~IEDICI~E, 1.01. GG, So. 6, June, 1967 Printed in U. S. A.

Moderator: JACOB ROBBINS, M.D., Bethesda, Maryland. Discussants: JOSEPH E. RALL,M.D., PH.D., Bethesda, Maryland, and ROBERTA. CONARD, M.D., Upton, New York Late Effects of Radioactive Iodine in Fallout Combined Clinical Staff Conference at the National Institutes of Health

Moderator: JACOB ROBBINS,M.D., Bethesda, A4arylan.d. Discussants: JOSEPH E. RALL,M.D., PH.D., Bethesda, fMaryland, and ROBERTA. CONAUD,M.D., Upton, New York

R. JACOB ROBBINS:During the nuclear Dr. Conard will describe the findings as D explosion testing in the Pacific Islands they have developed over the ensuing 12 in 1954, a combination of circumstances led years. He was a member of the original ex- to the accidental exposure of a group of pedition dispatched by the Atomic Energy Marshall Islanders, as well as some U. S. Commission and the U. S. Navy and thus Navy personnel and the crew of a Japanese can give us a firsthand report of the initial fishing vessel, the Lucky Dragon, to a radiation effects. The major emphasis of rather unusual sort of fallout. In addition this Confeience, however, will be on the to body surface irradiatioll that led to skin late effects that have become evident only burns and general body irradiation from in the last several years. These observations the surroundings that led to acute radiation highlight a subject that is currently of con- sickness, contamination of food and drink siderable theoletical and practical impor- with radioactive isotopes of iodine pro- tance-the effects of radiation on the thy- duced pathological alterations of the thyroid roid gland. gland. Largely through the perseverance of The Conference will be opened by Dr. Dr. Robert A. Conard of the Brookhaven Joseph E. Kall, Diiector of Jntramural Re- National Laboratory, the Marshall Jsland- search, National Institute of Arthritis and ers, both exposed and unexposed, have been Metabolic Diseases, who has participated the subjects of thorough, repetitive exami- in several ol the previous expeditions to nations by teams of observers sent by the the ,Marshall Islands and who just returned Atomic Energy Commission. with Dr. Conard a few weeks ago from the latest visit. Dr. Rall will discuss the general Received March 27, 1967; accepted for publica- problem of radioactive iodine in fallout tion March 31, 1967. This is an edited transcription of a combined fioin nuclear explosions. clinical staff conference at the Clinical Center, Be- thesda, Md., by the National Institute of Arthritis RADIOACTIVEIODINE IN FALLOUTFROM and Metabolic Discases, National Institutes of NUCLEAREXPLOSIONS Health, Public Health Service, U. S. Depaitment of Health, Education, and Welfare. DR. JOSEPH E. RALL:The heat generated Requests for reprints should be addressed to by a moderate-sized fission explosion gen- Jacob Robbins, M.D., Chief, Clinical Endocrinology erally results in a temperature of the order Branch, National Institute of Arthritis and Meta- bolic Diseases, Bldg. 10, Rm. 8-N-315, National In- of 10 million IC. The complexity of the stitutes of Health, lkthesda, Md. 20014. probleiiis associated with fallout generated 1214 Volume 66, No. 6 LATE EFFECTS OF RADIOACTIVE IODINE IN FALLOUT 1215 June 1961

by such an explosion and its widespread distribution has caused a series of high- energy discussions, and some times I think the temperature achieved by these discussions has approximated that of the cloud itself. I will make a few general remarks about four different aspects of fallout from nuclear explosions. The first concerns explosive nuclear devices; the second, radioactive products from these devices; the third, local factors influencing the distribution of these products; and finally, the biological modu- lation of the fallout products.

Nuclear explosive devices are of two I I I I types, the first being the fission reaction 70 94 118 142 I66 that generally involves ?a5U, Z33U, or plu- MASS NUMBER tonium. The fission produces an enormous FIGURE1. Yield of various isotopes from nuclear re- variety of radioisotopes. There are also fu- actions involving mU and "'Pu. sion explosions, and the Bikini explosion that we are presently discussing was a fu- may decrease, and finally there may be a sion explosion. However, all the fusion ex- relatively smooth curve. In general, how- plosions have to be triggered by a fission- ever, fission produces an abundance of iso- type explosion in order to achieve the topes with mass around 136 and mass around necessary temperature required for fusion, 91. Just why fission occurs asymmetri- which is of the order of 10 to 100 million IC. c;illy is a matter of some interest I will not The fusion explosions are of two types: discuss. 11 might be noted that most of the They are either the deuterium-tritium fusion radioactive isotopes of iodine have a mass that produces helium plus neutrons and between 131 and 135 and hence are major energy, or the deuterium-deuterium explo- fission pi-oclucls. sion that produces either helium or tritium, There is an additional point of interest, and neutrons or, in the case of tritium, a namely, neutron excess. 235U (a common fis- proton, plus energy. The points to remem- sionable material), for example, has 92 pro- ber are [I] fusion explosions are impossible tons in the nucleus and 143 neutrons. If without fission so that there are always this were to undergo fission directly and fission products, and [Z] fusion added to symmetrically, it would produce palladium. fission gives an enormous increase in the There is an extensive series of palladium number of neutrons present, and this has an isotopes, and the most abundant of the effect on the distribution of the radioactive stable ones is loePd, which has exactly half decay products. the number of protons of uranium. But As far as the products themselves are since it has a mass of 106, it has GO neu- concerned, there is an interesting distribu- trons. Therefore, if there were symmetrical tion curve (Figure 1). There are peaks at fission of ?S5U, one would obtain 2 atoms about 136 mass units and at about 94 mass of palladium and an excess of 23 neutrons. units for the fission of 23W. There is a This implies that in a fission explosion slightly different curve for fission of ZSgPu there is an enormous neutron flux in the and 235U.If the fission occurs in the pres- explosive device that irradiates the fis- ence of very high-energy neutrons the peaks sion products, the container, and anything

1004231 Annals of 1216 NATlONAI. INSTITUTES OF HEALTH CLIKICAL STAFF Internal Medicine

around it, producing a variety of isotopes. significant only in relatively short-term fall- Most of these isotopes are radioactive and out because of its 8-day half-life, and for they decay, frequently in a very compli- many years it was not considered to be a cated way. The average number of isotopes serious hazard. 1321 has about 4.5y0 yield; in a chain before any given fission fragment it has a 2.5-hr half-life, so it is only im- reaches a stable isotope is through six dif- portant in very short-term fallout. has ferent daughter generations. a substantial yield, 6y0, and a 21-hr half- There are a number of isotopes of major life, so it is of some importance over the biological importance. First, there are two course of perhaps a week. 1331is another induced isotopes that should be considered. radioisotope of iodine; this has a 6.7-hr 14C is a trivial fission product, but because half-life and is important only for a few of the intense neutron source there is a days. nitrogen-neutron reaction giving 14C. It was There are some other isotopes from fis- estimated several years ago that at that time sion explosions that must be considered. the amount of l4C in the atmosphere was One is I37Cs, which still can be detected roughly 70% greater than before thc first in most exposed individuals in the Marsha11 atomic explosion. Islands. It is also a potential problem be- 24Nais another isotope that is largely an cause of rclatively long-term storage in induced isotope, and it is of particular im- muscle. Cesium is further worrisome in portance in nnderwater blasts or blasts that meat eaters such as Eskimos who eat cari- are at all close to seawater because of the bou. There is cerium, which has almost a sodium in the ocean. Under these condi- 2-yr half-life and a substantial fission yield, tions, a substantial amount of z4Na, which and finally barium. has a 14-hr half-life, can be forniccl, and The amounts of these isotopes formed are in short-term fallout this can be oE some perfectly enormous. Just one example: Ex- importance. plosion of a megaton bomb of the fission Therc arc thee or four other isotopes type produces enough radioactivity so that that are of importance for several reasons. if it is evenly distributed over 1,000 square 80Sr, lor exanipk, has a 5.3% fission yield; miles it will give in 1 hr a close rate of the that is, of 100 atoms of uranium, 5.3 atonis order of 1,000 rads/hr. Hence, a 30-min ex- (if normalized for mass) end up as "Sr, so posure to this amount of radiation would, this is n significant fission product. It a1.m in general, be lethal. This is for a I-mega- has a 28-pr half-life so that it will persist ton bomb, but you may recall that the for a long time. Finally, it localizes in bone Russians cxplodecl a 100-megaton bomb a so that it can be of importancc biologically. few years ago. The explosion to which the The iodine isotopes are clearly of inipr- Marsliallese were exposed was of the order tance. Let me give a few numbers to illus- of 15 megatons. trate variations in fission yield with the type The lifetime of these fission products is of device and the magnitude of release of vel y complicated because there are literally radioactive iodine. For *3*U and high- hundreds of isotopes formed, all of different energy neutrons as the explosive device, half-lives. There is, however, an empirical there is a 4.'igl, yield of 1311. With 2"5U fis- "rule oT 7" that states that at any given sion the yield is 3y0, and for ?35Uwith the for the first 8 or 10 days the amount thermal neutrons it is 2.9%, so that clcpelid- of radioactivity remaining after a fission ing on the device there can be a fairly sub- explosion decreases by a factor of 10 after stantial difference in the amount of prodtic- 7 hr, by a factor of 102 at 72 hr, and by a tion of any given isotope; but in each case factor of 103 at 75 hr. Therefore, if at 1 hr 1311 is an important product. 1311 is clearIy there are 100 units of radioactivity, at 7 hr

1004238 Volume 66, KO. 6 LATE EFFECTS OF RADIOACTIVE IODINE IN FALLOUT June 1967 I217

there are 10 units, and at 7 times 7 (49 hr), humans who consume milk concentrate 1 unit. about one third of the radioiodine that A word has to be said about local factors they ingest in their own thyroids. Iodine in involved, because these have played a major the human thyroid remains in the gland role in the Marshallese explosion. In gen- a long time; in a normal individual iodine eral, one can differentiate underwater ex- in the thyi-oid has a half-life of 60 days. plosions, underground explosions, surface One additional factor is the problem of the explosions, lowaltitude, and high-altitude child versus tlie adult. A 1-year-old child, explosions. One critical factor is whether for example, has a 1-g thyroid; an adult the fireball created by the explosion touches has a 20-g thyroid. The proportional up- the earth or the ocean. If it does, it can take in both is the same, so that the child volatilize as much as 100,000 tons of earth, has roughly 20 times as much radioiodine water, and debris; and this large mass of deposited per gram of thyroid tissue as an material produces two effects on fallout. adul t . First, the volatilized material is subjected We can rather briefly conclude and point to neutron radiation so that large amounts out that fallout depends on a variety of of induced isotopes are produced, and sec- circumstances. It depends on the nuclear ondly, as the mass of volatilized material device exploded. It depends on where it is expands and cools, it condenses and pro- exploded so that it can give close-in fallout, duces particles lai-ge enough to settle to the medium trophospheric fallout, or long- ground. In tlie Marshall Islands after the range stratospheric fallout. The problems explosion, there was so much of this ma- associated with fallout depend on the kind terial that large white particles drifting of isotopes involved. In the case of iodine down from the sky gave the appearance of it is complicated by biological concentra- a snowfall. This is close-in fallout, and it tion through cattle arid through humans, occurs from 10 to 100 miles from the point :ind there is every reason to expect that it of detonation. It results from an injection tould be a serious consequence of fallout. of large amounts of inaterial into the tro- DR. ~~OBBINS:Ordinarily we leave discus- phosphere (the atmosphere from ground sion until the end, but we are going to level to 10 miles). Stratospheric injection, sliift emphasis somewhat here, so if anyone which is into tlie earth's atmosphere more in the audience has any questions on the than 10 miles from tlie ground, results in technical matters that Dr. Rall has brought a much more general fallout because of the up, we could have some questions now. much slower settling of debris that has ;I DR. JAN WOLFF:Is there a chemical se- half-time of some years. In general, this lection at the moment of fission favoring type of injection occurs with high-level ex- one element of a given mass over another plosions, and the fallout is worldwide in (if the same mass? distribution. DR. RALL:In general, there is no chemi- The biological consequences of radio- cal fractionation or preference in the pro- active fallout are complicated by several duction of fission products. The final result, factors. If radioiodine falls out on pasture, however, depends on whether isotopes of a cows grazing there can consume relatively given mass are stable and how long- or large amounts of anything deposited on the short-lived they may be if they are radio- grasses. In addition, the iodine is concen- active. trated in the milk 10 to 40 times the levcl DR. PHILIPPEV. CARDON:You said that in blood; hence, the radioiodine in milk there was a yield of 2.50/, for 1311 in a ther- has been concentrated considerably over nionuclear explosion. If there is a ground that deposited on the ground. Finally, tlie ljurst does that go up substzntially?

1004239 Annals, of 121s NATIONAL INSI’ITUTES OF HEALTH CLINICAL STAFF Internal Xedicine

DR. RALL:For iodine I do not think it RADIOIODINE FALLOUTAND ITS EFFECTSIN makes much difference because there is not THE MARSHALLISLANDS much tellurium or iodine occurring natu- DR. ROBERTA. CONARD:Before I go into rally. The main factor would be just an a discussion of the late effects of radiation enormous amount of material on which it residling from this accident, I would like can condense and be deposited rapidly. For to review very briefly the accident itself elements like sodium with great natural and some of the acute early effects that oc- abundance and that can be produced by curred in the Marshallese people. A large neutrons of var>iiig energies, it does make thermonuclear device was detonated on the a big difference. Bikini Island on March 1, 1954, As Dr. Rall DR. RO~~LHNS:If there are 110 further pointed out, this bomb exploded close to questions we will go on with the second the surface of the earth so that the fireball part of our discussion and hear something touched the earth and the ocean drawing up about the events ;is they occurred in the trenientlous amounts of particulate material Marshall Islands. I ani happy to introduce into (lie cloud, and this material became to you Dr. Robert A. Conard, Senior Scien- mixed with the radioactive fission products. tist at the Brookhaven National Labora- This radioactive material, because it was tory, UpLon, N. 1’. Dr. Conard was a mem- heavier, €ell froin the cloud in a downwind ber of the Naval Medical Research Institute directioii, contaminating several inhabited in Bethesda in 1954 and was one of the key atolls to the east. Figure 2 show a rough members of the team that was formed hur- map of the Marshall Islands and the area riedly to cope wirh the unfortunate occur- involved in the fallout. On Rongelap Is- rence in the Pacific Islands. In the years land, 100 miles from Bikini, the fallout re- since then Dr. Collard has organized annual sembled a light snow and actually coated expeditions to the Islands and thus was on the ground and the trees and became de- the scene when the late effects of the rndi;c- posited 011 the skin and on the hair of the tion became 1x1 ani fes t. people. T-he fallout was less dense the fur-

. 5001 _-- ..zqor . ..- - -1 .

MARSHALL ISLANDS 0 0

MAJURO Q D FICU& 2. Map of fallout area, Marshall Islands, March 1954. Volume 66, KO.6 LATE EFFECTS OF RADIOACTIVE IODINE IN EALLOUT June 1967 1219

TABLE1. Summary of Fallout Effects

Group* Composition Fallout 1:stimated Extent of Skin Observed Gamma Lesions Dose

rads Rongelap 64 Marshallese Heavy (snow-like) 175 Iktensive Ailinginae 18 Marshallese Moderate (mist-like) 69 Less extensive Rongerik 2s Americans Moderate (mist-like) 7s Slight Utirik 157 Marshallese Sone 11 No skin lesions or epilation

* Also exposed were 23 Japanese fishermen who received a sublethal close

ther east it occurred. There were 64 men, They were evacuated by ship and planes women, and children on Rongelap who re- I! days after the accident to the Island of ceived an estimated close of 175 rads of Ktvajalein, which at that time was a large whole-body gamma i.atliation. They also naval base to the south. We, as members suffered extensive skin irradiation from fall- of a special naval medical team, arrived on out deposit on their bodies and some in- the scene about 8 days later and carried out ternal absorption of radioactive materials. extensive examinations on these people for There were IS other Rongelap people on the follorving 3 months. At the end of that a fishing expedition at an adjacent atoll time the Utirik people, who showed no (Ailinginae), 20 inilcs to the south, and they serious eIEects from their exposure, were re- received less fallout, luitli an estimated turned to their home island, which was whole-body dose of 6'3 rads, less extensive considered sale for liabitation. But since irradiation of the skin, and less internal the island of Rongelap was too radioactive absorption of radioactive materials. Therc the people 01 this island, who had sustained were 28 American scrvicemen on Rongerik more scrions cxposure ellects, had to be Island, still further to the east, who re- inoxfed to a temporary village some 150 ceived a moderate amount of fallout with miles to the south whew they lived for 3 very slight skin burns. These men were years. The Rongerik servicemen were re- aware of the fallout dangers and took turned to their duty stations after these

proper precautions such as staying indoors exam ii la t ion s , and taking showers to remove radioacti1.e material from their bodies. The last group, the people of Utirik Island, 157 men, , women, and children. saw no fallout at all, and there was a very minimal amount of radiation received, an estimated 14 rads of whole-body radiation. Table 1 lists the populations exposed with estimated doses. During the first 2-day period, before the Rongelap people wei-e evacuated, many of them became anorexic and had nausea and a few vomited. The majority also com- plained of itching and burning sensations of the skin, usually on the exposed sur- faces Of skin that Were 'lot 'Overed by FIGURE3. Rongelap Village today. The old village clothing. was completely rebuilt. Annals of I220 NATIONAL INSTITUTES 01-7 HEALTH CLINICAL STAFF Internal Medicine

Rongelap with the exposed people. This group makes up our comparison population and is a rather good one since [I] most of the people are blood relatives of the exposed people; [2] they match reasonably well for age and sex; and [3] they live under the same environmental conditions. Now, biiefly, what acute effects were noted? In about 2 weeks the deposit of fallout material on tlie skin resulted in the developmeiit of radiation burns that first appeared as pigmented areas. About 90% of the people developed these so-called “beta bu~-ns.”These pigmented areas usually desquamated in a few days leaving raw depigmented areas, sometimes ulcerations. Figure 4 shows extensive lesions in a young boy. Fortunately, most of these burns were fairly superficial and healed and repig- mented within several weeks without any special tieatment. Epilation was noted in about 90% of the children and 40% of the adults. This was spotty in nature. In Figure 5 we see epilation in tlie temple area of a young girl. The hair regrew in all of these people, starting at about 3 months, and bv the end of G months it had com- FIGURE4. Numeious superficial ”beta bums“ in a young boy who had little clothing on at time of exposure.

We carry out annual medical surveys on these people. The surveys are sponsored by the Atomic Energy Commission and Brook- haven National Laboratory and are carried out in conjunction with the Medical De- partment of the Trust Territory of the Pacific Islands. Numerous publications have described the 1 esults of these annual surveys (1-10). In 1957 the Island of Rongelap was moni- tored and was pionounced safe for habita- tion, and the people were moved back. Figure 3 shows Kongelap Island today with new construction that is far superior to what they had previously. Over 200 Ronge- lap people who were not on the island at FIGURE5. Epilation in the temporal area of the the time of tlie accident moved back to scalp of a young girl.

1004242 Volume 66, No. 6 LATE EFFECTS OF RADIOAC TIJ’E IODIKE IK FALLOUT I221 June 1967 was noted, however, except perhaps for some increased menses in a few women. By 1 year the blood counts recovered, but not quite to the exact level of the comparison populations. There was a slight weight loss noted in the majority of the people during the first 2 months, but we were not sure whether this was related to radiation exposure or u’as due to change in environment. How- ever, no illnesses occurred that we could ielate to radiation effect. We did not have to use any special form of treatment in these people as a result of exposure to the penetrating gainma radiation. Antibiotics were used for ordinary infections that oc- rurred, but these showed no obvious relation to radiation exposure.

FIGUREG. Recently developed benign nevi in an In addition to the whole-body and skin area previously affected with “beta burns.’’ exposure, a third type of radiation exposure was from the internal absorption of radio- pletely regrown and was of normal color active materials by inhalation and inges- and texture. As a residual effect of these tion. The island was quite contaminated “beta burns” we see scarring in some 20 from the fallout, and the people absorbed cases at this time with pigment aberrations significant amounts of radioactive materials persisting in some. Retcntly we have noted in the food and water. We were able to the development of benign nevi in areas detect this by radiochemical urinalyses be- that had been in\ olvetl with “beta burns.” ginning a few weeks after the accident. Figuie 6 shows such lesions. However, there Table 2 shon-s the radioisotopes that were have not been any degenerative changes calculated to be present in these people, noted in the skin or any evidence of malig- extrapolating back to the first day as com- nancy. pared with the activity calculated to be The whole-body exposure from gamma radiation resulted in potentially the most serious effects. This was reflected largely in + 25 !- i depression of the blood cells (Figure 7). -1 2; ,-CCNTROL BASELINE The lymphocyte count dropped to about 0: half that of the coriipaiison population by I 3 to 4 days, and in the children the lymphocyte count dropl)etl even lower. The neu- trophils fell to about half the comparison -PL >.TELETS population levels by about 6 weeks, but for- -75 ’- :LCEP2.G~ C3-.NTS! -,

tunately no infections developed that we ~ -‘--J+ !~---.-.:-.L--!.1 ! I ’ I could blame on the depression of neutro- 2553 6 I 2 3 4 5 6 7 8 9 IO I,/ --D&iYj --:I>.------YEARS phils. The platelet5 became depressed to TlhME LFTER FALLOUT about one third to one eighth of the level FIGURE7. Depression of blood elements in Ronge- of the comparison populations, reaching a lap people (percent depression compared with aver- nadir at about 28 to 30 days. No bleeding age counts of unexposed people). I222 NAllUllrAL liU>IIIUltb Ut HEALTH CLINICAL STAP-k In ternai Medicine

TABLE2. Estimated Body Burden of ple as in the unexposed comparison popu- Rongelap People lation. Mortality has been slightly greater in the exposed people, and we are not cer- Isotopes Activity Activity at Day 1 at Day82 tain if this is related to radiation or not; but there arc a larger number of older W people in the exposed group, which may YSr 1.G2.2 0.19 partly account for this. Based on birthrates, 140Ba 0.34-2.7 0.02 1 Rare earth group 0-1.2 0.03 fertility appears to have been about the same 13II (in thyroid gland) 6.4-1 1.2 0.0 in the exposed and the unexposed people. - laaRu 0-0.013 An increase was noted in miscarriages and ‘Ta 0-0.019 0.0 Fissile material 0-0.01G (pg) 0.0 stillbirths during the first 4 years after exposure of the women. During this period 13 of 30 pregnancies in the exposed group present at 82 days alter exposure. The most (4IyO)ended in stillbirths or miscarriages, abundant isotopes were those of strontiurn compared with only 8 of 49 (16%) in the and iodine. However, the people excreted unexposed women. this material quite rapidly. When they U7e have carried out studies to see if moved back to their home island we were radiation produced any enhancement of able to detect an increase in body burdens aging by attempting to quantify such things in both exposed and comparison popula- as measurement of skin elasticity, hair tion due to the slight residual activity per- graying, baldness, visual acuity, accom- sisting on the island. This activity was modation and ai.cus senilis of the eyes, largely due to 13iCs, GSZn, and 90Sr. The audiometric measurements, blood pressure, body burdens of these elements have been strength, neuromuscular function, and body ascertained from rvhole-body counting tech- potassium levels. Most of these criteria niques and ratlioclieinical urinalyses. Dur- showed good correlation with aging. By ing the first few years after tlie people of combining values for these parameters we Rongelap moved back the levels showed were able to arrive at a biological age score slight increases in these elements but have for each individual. We have not, however, since leveled off, and it is believed the peo- detected any significant difference in aging ple are in equilibrium now with these ele- in rlie exposed as compared with the un- ments in their environment. The levels at.(! exposed population. Indeed, the subtle ef- far below the accepted pel-rnissible levels. fects of aging would probably be most diffi- Until the recent development of thyi-oitl cult- to assess, and perhaps the tests we are nodules in tlie hlarsliallese people there using are not sensitive enough to detect were only a few late cffects of radiation that the effects of radiation at this dose level. we could relate to 1-adiation with any tlc- Ilegenei-ative diseases have been studied gree of certainty. A persisting lag in i-ecov- and compared in the two groups, and we ery of the ivhite blood cells and platelets have not seen any difference in prevalence. until about 11 years’ postexposure was bc- There have been three cases of cancer: two lieved perhaps to be ;1 lingering elfect of 01 the female genital tract in the exposed radiation exposure on the bone marroiv. women and one case of cancer of the thy- Figure 7 shows the percent difference in tlie roid, which I will discuss later. Since the blood counts OF the exposed Rongelap peo- number of cases is so small, we do not know ple as compared with those of the unex- whether this represents any radiation- posed population. induced increase in malignancy or not. We The general health of the people re- have noted only one case of cancer in the mained about as good in the exposed peo- unexposed group. There were no radiation-

1004244 Volume 66. No. 6 LATE EFFECTS OF RADIOACTIVE IODINE IN FALLOUT June 1967 1223 induced opacities of the lens noted in these people as have been seen in cyclotron work- ers and the Japanese people esposed to the bombs in Hiroshima and Nagasaki. 130~- ever, the Marshailese people were not exposed to any iieutroii iri-acli;ition, the rela- tive biological effectivctiess of neutron radiation being much higlier for cataract formation. One of the most important findings resulted from growth and tlevelopincnt studies of the children. These studies have been carried out under tlie direction of Dr. l\T. IV. Sutow oi the >I. D. Anderson Hospital. Extensive anthropometric meas- urenients and skeletal maturation studies, using S rays of thc hand and wrist for bone age, have been carried out oxkr the years sincc exposure (1 1). It appears that there has been retart1;ition of growth in sonic children, particulal-ly boys esposcd at less than 5 ycars of age. The growtli reraidation was iiiost marked in two bo),s exposed 15 to 1s months of age. Figure S shows these two retarded bo)^. Figure 9 shows the lag FXCUKE8. TIYO12-year-old boys sliowing greatest in skeletal age in boys esposecl at less than xrowth ret;irdation. No obvious mental retardatiotl 5 years of agc coinparcd with the unexposed !!';ls notctl. boys. In tlie females tile lag was less marked. l

MALES FEMALES s;I +I0 t

------EXPOSED -CONTROL

I I 1 I I I I I U 0- 2 3-5 6-8 U 0-2 3-5 6-0 AGE AT EXPOSURE (YRS) FIGIJRL9. Comp;nisoii of skeletal age (SA) and chronological age (CA), 1'361 ;ind 19G2 (poolcd hta). NATIONAL IhbrITlJ I'ES 01' HEALTI1 CLINICAL STAFF Annals of I224 Internal Medicine

Before we go into the development of rads of gamma radiation. That most of thyroid abnormalities in the Rongelap these people had beta burns in the neck people, i would like to say a few words region over the thyroid was not believed about the calculations of the radioiodine to contribute significantly to the dose to dose to the thyroid gland that they sus- the thyroid gland because of the low energy tained during the first 2 clays on the island. of the beta radiation in the fallout material. There WIS no doubt considerable absorp- Over the years we have carried out care- tion of radioactive iodines from both in- ful thyroid examinations during the annual halation as the radioactive cloud passed surveys. Until 3 years ago the people were over them and also from contaminated food considered to have normal thyroid function and drinking water. Their drinking water with no obvious evidence of any thyroid ab- was caught in cisterns drained from the normality. Numerous serum protein-bound roo[, and contamination of the water was iodine (PBI) determinations were done, no doubt increased by a slight rainfall on and all appeared in the normal range for the night of the fallout. There were few these people. The PBI levels in the Mar- direct data available on which to make an shallese are considerably higher than Ameri- evaluation of the dosimetry, so we had to can levels, which was found to be because rely on indirect methods-that is, on radio- there is a large amount of iodoprotein chemical urinalyses. The first of these were piesent (12), as we shall discuss later. This obtained at 15 days after exposure. It was may have misled us during these early estimated that 0.1% of the isotope would years. The diet of these people apparently be present at 15 days, and extrapolating had sufficient iodine but with no over- back, it was calculated that the thyroid abundance apparent. Urinary excretion gland contained roughly 11.2 pc of I3'I. Dr. studies showed that they averaged about Rall pointed out that there are several 105 pg in 24 hr in 28 people, which is in iodine isotopes present in fallout. In addi- the nornial range. Cliolesterol studies have tion LO 1311, the isotopes 1321, 1331, and lZ5I not shown any significant differences in the contributed substantially to the dose. in exposed and the unexposed people. Thus, making the calculations, energy dependence there was no reason to suspect that theie per disintegration and the time of absorption was any thyroid trouble. of the different isotopes were considered. Three years ago we detected the first thy- It was estimated that the adult thyroid roid nodule in a 12-year-old girl. Since that glxnd received approximately 160 rads from time the prevalence has been increasing, radioiodines and of course an additional and we now have 1s cases of ~liyroitlab- 175 rads From the gamma 1-atliation. In normalities, 16 with nodules and 2 with approximating the dose to 3- to 4-year-old 11) pothyroitlism, [he latter showing 110 nod- children, the above factors were consitlercd, ules. All of these except 1 case occn~tetlin and, in addition, we considered the tiif- the mol e heavily exposed Rongelap g~oup ference in pulmonary function and smaller that ieceivcd 175 rads of whole-body radia- size of the thyroid gland in the child. We tion. Table 3 lists the thyroid abnormal- know that water rationing was in effect at ities with age at exposure, sex, and time of the time of the fallout, so it is assumed detection. It is noteworthy that the 2 cases that the chilclren drank as much contam- of hypothyroidism occurred in the 2 inated water as the adults did, thus absorb- dwarfed boys. ing the same amount of radioiodine. Table 4 shows the distribution of thyroid It is estimated that the child's thyroid pathology in the different populations ex- received roughly between '700 to 1,400 rads amined. The interesting fact emerges that from the radioiodines in addition to 175 rlie highest incidence, 7S.9%, of these ab- Volume 66, No. 6 LATE EFFECTS OF RAI)IOhCTI\~I: 1OI)lNl~~IN FALLOUT June 1967 I 225

TABLE3. Thyroid Abnormalities in Exposed Rongelap People, 1966

Case Present Age at Sex Date 1:indings .%ge Exposure Xljnormalit) h'oted ___~____ Y' 17 15 3 3/63 Iknign nodules, complete thyroidectomy 1964. No recurrence. 21 15 3 3/64 Benign nodules, complete thyroidectomy, para- thyroidectomy 1961. No recurrence. 69 16 4 3/64 Henigii nodules, partial thyroidectomy 1964. No recurrence. 20 19 7 3/65 Iknign nodule, partial thyroidectomy 1965. ATii rccurrence. 2 13 1 3/65 13cnigir noclule, partial thyroidectomy 1965. No rrcurrencc. 64 42 30 3/65 Malignant nodule, thyroidectomy-surgical antl with radioiodine 1965. So recurrence noted on physical exatiiination.* 5 13 1 3/65 Hypothyroid, protein-bound iodinc (PBI) less than 2pg/100 nil March 1965, marked retardation of growlh; March 1966 growth spurt and iiiiproved appearance on hormone. 3 13 1 3/65 Hypothyroid, PRI less than 2 pg/lOO ml March 1965, marked retardation of growth; March 1966 growth spurt and iniproved appearance on hormone. 72 1s 6 0/65 3-nini nodule left lobe. No exam March 1966. 42 15 3 9/65 2-nim nodule right lower lobe; March 1966- iiodulnr cnlargciiient cnlirc gland; firm 5-mm notlulc right 1ot)c. 61 20 S 9/65 6- to 8-mm smooth nodule left lower pole; March 1066 1-ctii nodule left lobc. 40 41 29 9/65 2-mi11 nodule right lower pole; March 1966 no nodules detected. 59t 46 36 9/65 5-nim nodule midline; March 1966 same. 54 13 1 3/66 Nodular enl;trgement left lobe and isthmus with 2-nini firm nodule. 19 li 5 3/66 Multinodular soft goiter-gland 13 X normal size; 1 -ciii nodule right lower pole. 36 19 7 3/66 About 1-cm nodule-not clearly demarked- right IOUer pole. Many tiny nodules on surface 01 gland. 33 13 1 3/66 In Septemlier 1065 questionable irregular gland. Kow definite 5-mm nodule left lobe. 7 pre- tracheal Ipiiiph node. 35 13 1 3/66 In Septemlier 1965 questionable small nodule; now .j-min nodule right lobe.

~~~~ ~~ * Unable to carry out follow-up thyroid uptake antl X-ray slutlies rlur lo l)rcgnancy. t Exposed to onlj. 69 rads whole-body radiation antl presumal)ly Ijri)I~i)rtion:rtcl~less thyroid dose. normalities has occurred in childicn exposure, thele have been no nodules found posed at less than 10 years of age and in in the 6 children in that age range. On the more heavily exposed Rongelap gioup. Utirik Island there were 40 children in the There were 19 children in this group ex- same age range, who received an estimated posed to 175 rads 01 whole-body irradiation. 55 to 110 rads to their thyroid glands, and The 2 seveiely hypothytoid cases arc also there were no cases of thyroid abnormalities in this group. Note that in the Ailinginae seen. In the GI unexposed children in the group, who 1 ecei.id considerably less ex- comparison population on Rongelap of the NATIONAL INSTITUTES OF HEALTH CLINICAL STAFF Annals of 1226 Internal Nedicine

same age range, again no thyroid abnormalities have been noted. On Rongelap, aniong those exposed at an age greater than 10 years, there have been 3 adults with

m thyroid nodules (5.5y0).In the sinaller s Ailinginae group there was 1 case that "j represents 12.5y0. It should be noted that several notlules have been detected in older people of the Uririk arid Rongelap com- 2 Y parison populations. These latter cases were in people over 50 years of age, whereas in the Rongelap exposed adults, the nodules occurred before the age of 50 years. In view of the seriousness of this development, thc highest exposure group on Ron- gelap was started on thyroid hormone u therapy in order to protect the glands -c against further thyroid-stimulating hormone ('T'SH) stimulation and hopefully to reduce the possibility of further developnlent of nodules as well as to cause regression of existing nodules. Accoi-dingly, in September of 1965 daily treatment was begun with synLhetic thyroxine, 0.3 mg to thosc under 50 yeai-s of age and 0.2 mg to those over 50 years. Sui-gery has been performed on 11 subjects. Three were taken to Guam in 1964, where thyroidectomy was carried out at the Naval Hospital. Eight other cases were taken back to the United Stalcs to Brook- haven National Laboratory where we carried out a number of thyroid studies before surgery was clone in Boston. These studies included iodine uptake, serum TSH level, thyroitl scan, basal metabolic rate, PUI, and serum thyroxine level. Thyroglobulin anti- body tests were made, but no increase was secn. Dr. Robbins will speak further about these studies. Subtotal thyroidectomy was carried out in Boston by Dr. Bentley Col- cock. Total thyroidectomy was carried out on the patient who showed a mixed papil- lary and follicular carcinoma of the thyroid. Clinically these nodules have appeared in some cases to be single nodules, but at surgery they were nearly all found to be multinodular. They were usually soft to firm in Volume 66, No. 6 LATE EFFECTS OF RADIOACTIVE IODINE IN FALLOUT June 1967 1227 consistency, movable, and nontencler. We did not detect general glandular enlarge- ment in most cases. Figure 10 shows one of these glands at surgery, indicating the nature of the nodules. Although some clini- cians have tloubtetl tli~twe could palpate 2- to himnodules, our clinical estimate of these tiny notlules was substantiated at surgery. All subjects except adults (one with cancer) were found to have adenomatous goiter. Figure 11 shows a typical microscopic picture ol a riodule with the biz;~rre characteristics of \~ii-ioussize follicles, soiiie of which '~\rerecystic a tit1 filled with colloitl, olhers hemorrhagic, others inicrofollicular, others macrofolliculai-, and some with hyperplasia with inlolcling of the epithelium. This hyperplasia is tlcmonstrated in Figure 12. Sections ol these nodules have beeii studied by a iiunil~ci 01 pathologists, ant1 ;I tim effects histologically. Figure 13 shows a reseniblaiice to tIic p:i~.teriiof iodine clr- the mixed follicular and Inpillary carci- liciency goiter has Ixen remarked upoii. noma of the thyroid with l~lootlvessel in- Most chiin that they cannot see actual radi- vasion found in ;I ~iI-)ear-oltl exposed

FIGURE11. Microscopic section of benign atlennmatous nodule showing bizarre nature of follicles, some cystic, sonic microfollicular, sonic mactofollicular. arid some hypei-plastic. (Hema- toxylin-eosin, x 16.) 122s NATIONAL INSTI-I-UTES OF HEALTH CLlNICAL STAFF Internal Xedicine Annals Of

woman. ‘Tliere was also localized metastasis into a lymph node. Subsequent studies aher complete ablation of her thyroid gland have revealed no indication OC metastases. The earlier cases of Lhyroitl abnormalities have been prt>viously described (10, 13). I woiiitI like new to say a few words about thyroid abnormalities as related to growth retarclatioll in the children. As 1 indicated earlier, we had long been puzzled ;IS LO why these children had shown a slight tlcgree oE I-etardation in growth. We knew illat tlie Japanese cliiltlren had been re- poi-Led 10 linve some slight retardation, particularly the male Japanese children at I-Iiroshima, but that picture was confused by such factors its physical and psychic trauma and nutritional deficiencies. We felt tliat the bone dose in the case of the Mar- sliallese children vas too small to account lor ;Iny direct ellect on epiphyseal growth.

1004250 Volume 66, No 6 LATE EFFECTS OF RADIOACTIVE IODlNE IN FALLOUT 229 June 1967 I

We know that it takes several thousand rads hormone treatment. At this point I think of local radiation to bone to produce re- the results are encouraging. T.Ve still have tardation of bone growth. Our estimates of to evaluate the data on many children, but the dose to the bones from the absorption it does look as though there is an effect. of internal isotopes in the children The two most retarded boys have shown amounted to only 3 to 4 rads, and it was definite spurts in bone age and stature. Dr. believed this dose was far too low to be of Kall and I have just returned from the any signifiance. In searching for an answer, Rlarshall Islands, and we feel that the hor- we carried out studies on weanling rats, mone therapy is also causing some regres- giving them sublethal doses of radiation sion in the four tabes that still have nod- and shielding one leg (14). We found that ules. One nodule in a 40-year-old man has the tibial growth wis retarded in both legs, ciisappeared. These cases will be reevaluated including the shielded leg, the latter repi-e- for surgery on the next survey in March senting an indirect effect of radiation. We 1967. We have hopes that the hormone carried out further pair feeding studies and treatment will prevent further developmeilt measured the growth rate of the tibia in of nodules. Whether it will have any effect unexposed rats who were fed the same re- on the carcinogenic action of radiation reduced amount of food as ingested by the mains to be seen. irradiated animals. We found that there was a radiation-induced reduction in THYROIDFUNCTIOK IN MARSHALL ISLANDERS food consumption that apparently resulted DR. ROBBINS:I shall carry on the discus- in nutritionally induced retarded bone sion myself now and bring up first some of growth. However, in regard to the Mai-- the studies that were done on thyroid func- shallese, although some weight loss was tion in the Marshallese individuals. A COIII- noted in the children, it is not belie\.ed plete I-eport of the measurements up until that a nutritional effect was of great sig- 1966 has been published by Drs. Rall and nificance in contributing to bone grolvtll Conard (12). As Dr. Conard said, in the retardation. carlier days of the studies attention was With the recent development of thyroid given to the problem of thyroid clysfunc- abnormalities in the Rongelap children, we tion. Although this was looked for quite have fairly strong eirideiice for the correla- actively, none was found. Table 5 shows tion of such abnormalities with growth re- one of the reasons for this, and that is the tardation. The most striking correlation finding to which he alluded, that the Mar- occurred in the case of the two boys with shallese people have a higher average PBI growth retardation who had bonc. ages of ;ind a higher range of PBI than do peo- 3 and 5 years at the chi-onological age ol ple living in our part of the world. Table 12. Their PUIS tlropped to less than 2 pg/ 5 presents thc results of studies carried 100 ml, they showed coarse facies, dry skin, out at various times over the years. When sluggish achilles refiex returns, aid appear- the first values for serum PBI came out ance of bony dysgenesis in one case. As will high, the question of contamination was be shown later, their TSH values rose to brought up. In 1964 the members of the very high levels, which indicated a primary medical team had their blood drawn under type of hypothyroidism. Figure 8 show exactly the same conditions, and their PBI these stunted boys. The earlier lack of cor- levels fell in the range that we have come relation of growth retardation and thyroid deficiency may have been due to the falsely to expect for the PBI in North America. high PBIs. The crucial test of all this is The Marshallese, however, continued to the response of these children to thyroid show an elevated PBI with a high mean NATIONAL INSTITUTES OF HEALTH CLINICAL STAFF .+nnals of 1230 Internal lledicine

TABLE5. Serum Iodide Measurements in the Marshall Islands

Date Group NO. Average Range Percent Samples Over S pgl 100 1111

Protein-bound iodine, pg/100 ml 1959 Xarshallese I2 6.2 4.1-9.2 16 1962 hIarshallese 14 S.6 4.612.0 64 1964 Afedical team 10 4.9 2.5-6.9 0 1965 Marshallese-exposed 31 7.6 4.1-1 1.9 12 1965 hlarshallese-uneRposed 19 7 .o 3.9- 10.7 2s Bntanol extractable iodine, pg/l00 ntl 1950 Marshallese 12 4.9 2.7-8.7

level and indivitlual values going up well prevalence that woulcl indicate a genetic into the hyperthyroid range. abnormality or any evidence of two genetic In 1965 a comparison was carried out be- populations in the Islands with respect to tween exposed and nonexposed indivicl- 1’131 levels in blood. uals; there was no difference between them. Table 6 shows some later studies in which One evaIuation of the butanol extractable chromatography on Dowex-1 coluinns was serum iodine (REI) done as far back as performed in order to identify tlie non- 1959 indicated that the BEI-which would hormonal iodine in serum. This procedure be tlie hormonal iodine-was in the nor- (15) separates iodoprotein from iodoamino mal range lor North America, suggesting acids not in peptide linkage. In North thal the elevated PIS1 was not thyroxinc- Americans (these were normal controls like. Figure 14 shows the distribution of thc drawn at the NLH) the iodoprotein aver- PIi1 in tlic popu1;ition. Thc valley at onc aged 0.8 pg/ 100 nil, whereas in the Mar- point was thought to be an artifact due to shallese the value was considerably higher tlie small number of individuals sampled, with a mean of 2.2 pg/lOO ml. The thy- and it was concluded that the PBI levels roxine iodine average was slightlj. higher formed a normal distribution. There TV:~S in the Marshallese but probably not sig- no bimodal distribution or any familial n ifi ca n t 1y . Recently, with the development ol thyroid abnormalities in the exposed Marshall- ese, it was possible to examine serum iodoprotein levels in patients with thyroid hypofunction. The results, presented in Table 7, suggest that the iodoprotein was # 8- largely from an estrathyroidal source since CASES the level was still elevated in patients with atrophic thyroid glands due to radiation (Cases 3 and 5); in thyroidectomized patients, one of whom (Case 69) had little, if - any, uptake of 1321 into the thyroid (as we 4 6 8 IO 12 will discuss later); and in subjects who had P8I pq/lOOml been on suppressive therapy with levothy- FIGLIRE14. Distribution of seruni protein-l,ountl roxine. iodine in Marshallesc individuals. Reproduced with permission from Rall and Consid: Amer. J. Alcd. Dr. Conard mentioned that the iodine 40: 882, 19GG (12). analyses of urine, which were carried out

1004252 Volume 66, No. 6 LATE EFFECTS OF RADIOACTIVE IODINE IN FALLOUT June 1967 1231 in 1965, were in the range that we find in TABLE6. Column Chromatographic Analysis the northeastern United States. In 28 sam- of Serum Iodine* ~~ ples, the 24-hr urine excretion was 19 to Group No. Total Iodo- TI +Tit 279 pg with a mean of 105 g.This indi- Samples Iodine protein cated that there was no excessive intake of iodine in the Marshall Islands that might +pg/la) ?7tb Slarshallese 19 i.0 2.2 4.5 be related to the iodoprotein in the blood Sorth Americans 25 5.1 0.8 3.8 and, secondly, that there was no deficiency ~~ of iodine that could be ielated to the later * Average values. development of goiters. The thyroxine- t Ta = thyroxine, T3 = triiodothyronine. binding capacity of the thyioxine-binding further into the iodine metabolism in these alpha globulin (TUG) was also measured pple. He was more interested in the ab- in sera with elevated I’UI levels, arid no normality in Marshallese in general than he elevation was found. An increase in TBG was in abnormalities that might exist in the could explain an elevated 1’131 but not a people who were beginning to form nodules high seruni iodoprotein level. just about this time, and all of these stud- To conclude with this part of the study, ies were done on individuals without nod- the detection of a high blood iodine in ules. There were 21 Marshallese (all adults) blaishallese was an unexpected fincling, one rrho were studied. Twelve of them were in that is still not explained. People living in the exposed group; 9 of them were never the Mat shall Islands, for 1 easons that are exposed to radiation. The results presented not kno-run, have ail u~iusualelevation of ill Table S showed no difference between seiuin iodopiotein. t liese groups of individuals, and they arc When Dr. liall went on one of the expe- compared with average normal values that ditions to the hlaishall Islands in hlarch u.e would find in the United States.

1965, the situation with the abnormal PBIs These studies were done with lS2I; this was known, and lie tlecjcled to look a little isotope was used because of the very low

TABLE7. Serum Iodoprotein Levels in Relation to Thyroid Function

Case No. Total Iodine 1’131% Ti17 Iodoprotein$ ___.____~~_ ___ ~____ g,y/lOO ml + Hypothyroids 2 3.2 1.0 (2.2) 5 3.1 1.8 (1.3) 6 5 3.1 1.9 (1.9) Thyroidectotnized~ 17 1.s <0.5 (>1.3) 21 1.3 0.8) 64 5.0 2.0 2.9 69 5.7 1.7 (4.0) Ixvothyroxine treated (1 34 10.8 c9.11 6.5 C4.61 3.2 C3.31 59 S.2 5.3 2.8 6s 11.8 5.8 6.0

* 1’131 = protein-l,ound iodine. t T41 = thyroxine iodine. 1: Iodoprotein levels in parentheses are the difference lietween PBI and TJ levels. The others were measured directly by the column method. Levothyroxine stopped approximately 3 weeks before sampling. 11 Treated with levr~thyroxine,0.3 mg/day, for 6 nionths. Values in brackets are determinations made before starting thyroxine. 1232 NATIONAL INSTITUTES OF HEALTII CLINICAL STAFF Internal Annals,Medicine d

TABLE8. Kinetic Analysis of 1321 Studies (March 1965) in Subjects Without Thyroid Abnormality

Group No. Utine* Thyroid? Thyroid Subjects Fraction1

Xf arshallese-exposed 12 1.10 0.67 0.40 (0.34-2.57) (0.33-1.27) (0.25-0.65) i\9arshallese--unexposed 9 0.81 0.79 0.52 (0.17-1.99) (0.23-1.47) (0.26-0.77) Korth Americans 2.0 1.0 0.33

-- ~ - Xean and ranges are given. * Fraction of extrathyroidal iodide excreted in urine per day (hGlj t Fraction of extrathyroidal iodide transferred to the thyroid per day (h). 1 Theoretical thyroid uptake (2___J- amount of radiation that it would deliver Berman, Mathematical Research Branch, to the thyroid gland. A 132Te generator was National Institute of Arthritis and Meta- used, capable of producing a supply of 13?I bolic Diseases, using the computer progranl for a period of several weeks. Radioiodine that he has in operation for kinetic studies accumulation in the neck was measured and particularly for thyroid studies (16). 3 111- after the oral dose and at hourly inter- The calculation used the gross neck uptake, vals for approximately 4 hr. (Details are uncorrected for extrathyroidal iodine, antl given in reference 12.) Urirlc was collected the analysis indicated that the counter at the end of this time and measured for “saw” more than 99yo of the thyroidal ra- 13t’I.’The data were analyiecl by Dr. Mones dioactivity and that 8% of the neck radioactivity was extrathyroidal. In Table 8 we have listed the fraction of the body iodide that is taken up in the thyroid per day antl rhe fraction going into the urine per day. Interestingly enough, both of these values compared with United States values are low, again an abnormality for which thet e is no explanation. The balance between these two depressions was such that when the theoretical maximal thyroid uptake is calculated it actually comes out higher than is normal in the United States. Although the low urinary excretion rate might well be due to incomplete urine collection, which was very difficult under field condi- noms tions, this does not significantly alter the FIGURE15. Neck accumulation of 1321 in subjects rate. with thyroid abnormality. Values are gross neck calculated thyroid accumulation counts, as percent of dose, uncorrected for blood I joined the survey for the first time in background after oral administiation of 13zI. Com- March 1966. At this time we were interested puter analysis of these data indicates that 7% of the cxtrathyroidal iodide pool is “seen” by the neck in doing some further studies on the indi- counter, At the vertical lines, 500 rng potassium viduals who had developed thyroid nodules, perchlorate (KCIO,) was given by month. = Case and we were able to carry out a few such 54; = Case 2 (partial thyroidectomyj; = Case 0 studies. The patients stopped their thy- 62; A = Cnse 5; = Case 3; 0 = Case 69 (partial t 11 yroidectomy) . roxine therapy 3 weeks before testing. In Volume 66. KO.6 LATE EFFECTS OF RADIOACTIVE IODINE IN FALLOUT June 1967 1233

Figure 15 are shown results of the I3?I u P- In Table 9 we have attempted to summa- take into the neck as a function of time. rire some of the pertinent findings in the The uptake patterns fall into two groups. hlarshallese who developed clinical thyroid One group had an abrupt rise in neck abnormality. The subjects with thyroid radioactivity, but this was mostly blood nodules are listed in the order in which the iodide. From there on there was very little abnormality was detected. The results of change, indicating that these individuals kinetic analysis of 13-1studies are presented had very little accumulation of iodine in in Table 10. The data in these two tables their thyioids. Two of these three subjects are presented here in detail since, for the were the severely retarded boys to whom most part, they have not appeared in the Dr. Conard referred, and the results indi- earlier publications. The 13?I studies per- cate a severe deficiency of thyroid function. formed at the Brookhaven National Lab- The third was a girl who had had a sub- oratory weie done on the patients who had total thyroidectomy approximately a year come to the United States for surgery. earlier. The 1321study showed that she had These studies were done preoperatively. little or no iemaining thyroid function, The methods were similar except that the perhaps due to radiation damage to the neck counts were taken with and without thyroid remnant. The other three individ- lead interposed between the crystal and the uals had what appeared to be normal up- neck in order to correct for the extrathy- take of 1321. One of them had had a subtotal roidal radioiodine “seen” by the counter, thyroidectomy 1 year before. One subject, and the measurements were continued for who was late1 operated upon, was a girl 6 hr in some cases. Computer analysis of with moderate retardation in growth who the data obtained at the Brookhaven Na- was found to have a depressed thyroxine tional Laboratory in June 1966 was evalu- level in the blood and so was mildly hypo- ated in several ways: with or without the thyroid despite the normal uptake of 1321. corrected neck counts using a lead shield, As pait of this study we looked to see with or without inclusion of urine data. whether the iodine that was accumulating None of these made an important differ- in the thyroid was being organically bound. ence in the value for thyroid accumulation There had been some studies earlier (17, rate, but the uncorrected data gave some- 18) on patients treated with radioiodine for what greater reliability. The very low urine hyperthyloidism indicating that radiation excretion rates in some cases are probably damage to the function of irradiated glands due to incomplete urine collection and re- may affect diBerent chemical systems dif- sult in comparable errors, in the opposite ferently. The finding was that iodide sense, in the computed thyroid fraction. In trapping proceeds normally whereas or- Table IO, uncorrected neck counts are used ganification docs not, and the iodide that except for the data at Brookhaven National accumulates in the gland could be dis- Labmator), June 1965. In the group stud- charged by giving a competing ion such as ied in the Rfarshall Islands in March 1966, potassium perchlor ate. The Marshallese pa- blood 1321 was measured at 2 and 4 hr in tients were, therefore, given 500 mg potas- order to calculate the iodide space. All sub- sium perchlorate by mouth at about the jects had been off levothyroxine therapy for 4-hr point, and neck measurements were at least 3 weeks unless otherwise indicated. continued. There was no discharge, and The TSIl level in serum was kindly per- therefore we could conclude that there was formed by Dr. William Ode11 of the Na- no defect in oiganification in the subjects tional Cancer Institute by a radioimmuno- with normal IS2l uptake. assay method. NATIONAL ISSTITUTES OF HEALTH CLINICAL STAFF .4nnals of Internal hledicine

Several points of interest are revealed by latter finding indicates that the growth re- these data. The two subjects with severe tardation was due to primary thyroid fail- growth retardation (Cases 3 and 5) had very ure and not to pituitary failure, which was low thyroxine iodine levels, little or no suspected before the appearance of clear-cut accumulation of 1321 by the thyroid, and thyroid findings. Several of the patients very high levels of TSH in blood. The who had had partial thyroidectomy (Cases

TABLE9. Thyroid Studies in Subjects with Thyroid Abnormality*

Case Thyroid Age \‘ear Neck 1321 Each 4 Hrt Serum Iodine Serum Abnormality ’I ested TSHT I’re. Post- FBI T41 TSJJ TSH - ____ .- ?r 5 of dose 1t1pgjn1l 3 Atrophy 13 1965 1.4 0.8 > 120 1966 > 3.2 1.o 159 5 Atrophy 13 1965 1.9 0.8 119 1966 s 3.1 I .8 248 17 Nodular 15 1964 6.8 goiter 19668 1.8 <0.5 372 21 Kodular 15 1964 8.1 goiter 19663 1.3

* TSH = thyroid-stimulating hormone, I’IIT = protein-bound iodine, TJ = thyroxine iodine. t Values in parentheses are “corrected” counts obtained at Brookhaven National Laboratory (see text). The others are not corrected for extrathyroid counts. $ Assays in 1965 could not detect levels helow 3 mpg/ml. Seven unexposed children in the same age group had <3 mpg/ml. Assays in 1966 could not detect levels below 17 rnpg/ml. Three exposed childrenwithout thyroid disease (Cases 6, 8, 32) had <17 mpgjml. 7‘no children exposed in utero (Cases 84, 86) and two unexposed children had <17 mpg/inl. 8 After partial thyroidectomy (foi- C:m 61,total thyroidectomy). ji iV’hile taking thyroxine. Volume 66, No. 6 LATE EFFECTS OF RAI)IOACTIVE IODINE IN FALLOUT June 1967 I235

TABLE10. Kinetic Analysis of 1321 Studies in Subjects with Thyroid Abnormality

Location and Case Yo. Urinef Thyroid$ Thyroid Iodide Year* Fractions Space

BNL- 2 Pre-TSH 1.20 1.71 0.41 June 1965 Post-’rsiI 0.80 1.19 0.60 20 Pre-TSH 2.12 2.30 0.49 Post-TSH 1.10 1.s1 0.62 64 Pre-TSH 1 .88 1.os 0.36 Post-TSH 0.81 1.56 0.66 Marshalls- 3 0.52 0.005 0.01 h1;irch 1966 5 0.86 0.14 0.14 69 (Partial thyroidectomy j 1.13 0.15 0.12 33.3 2 (Partial tliyroidectoiii~-) 1.53 0.92 0.37 20.0 61 (On thyroxine) 1.26 0.58 0.31 20.0 !! 54 0.50 0.69 0.55 65 1.08 0.72 0.4 20.4 59 (On thyroxine) 1.65 0.10 0.06 16.9 RX- 42 Pre-TSH 1.87 1.29 0.41 June 1966 Post-TSH 0.69 1.30 0.65 61 Pre-TSH 0.13 0.4s 0.7s Post-TSI r 0.50 1.67 0.77 33 Pre-TSH 0.20 0.97 0x2 Post-TSH 0.45 1.57 0.78 65 T’re-TSH 1.83 0.s2 0.31 Post-TSH 2.35 1.14 0.33 59 Pre-TSH 3.53 1.51 0.30 Post-TST’L 1.29 3.09 0.71

* EKI, = 13rookhavcn National LalioratorJ-. -1 Fraction ol cstrathyroidal iodide excreted in the urine per day (A6,), 1 Fraction of cstr:ithvroidal iodide transferred to the thyroid per day (A:,)

2, 17, 2i, and 69) liatl low thyroxine iodine t1,lm;ige. Other subjects, on the other hand,

1 and elewtetl blood T’SH levels. ThereTorc. and in particular the adults (Cases 59 and the thyroid remnant had not devclopctl lid), hat1 normal response to TSH or no quantitatively normal ~liyroid function. clevation of blood TSH or both. Three of rhesc subjects (Cases 17, 21, and To summarize the studies on thyroid 69) had their tliyioidectomies in 1964 ant1 function, several things of inteiest haw had not recc.i\nl replacement thyroxine come to light. First of all, people living in therapy lor tlic first 15 months or longer. the hlalshall Islands, whether or not ex- Five subjects si iitlietl preoperatively (Cases 1)owd to radiation, were found to have cer- 2, 20, 42, 33, and 65) showed evidence of tain peculiar and unexplained findings. hypofunct ioniiig thyroid glands or glands They have an unusual amount of iodo- that were pooi-ly responsive to excess en- 111olein circulating in the blood, which dogenous or erogenous TSH. In at least seem to persist even after suppression of two (Cases 2 and 20) ilierc was no response thyroid gland function. They also have a to TSH, so tha1 the glands appeared to be somewhat lower rate of radioiodine accu- maximally stimulated by endogenous TSH. mulation in the thyroid gland, compared to Analyses of growth data in the ilfarshallesc North Americans, and perhaps a lower uri- children are in progress to determine if nary excretion rate of iodide as well. Radia- there is any growth retardation that can I ion clamage to the thyroid gland resulted in be correlarctl with iliese findings of thJ.roi(l total tlestriiction of thyroid function in two NATIONAL INSTITUTES OF HEALTH CLINICAL STAFI' ~nnais.of I 236 Internal Mediclne

subjects. In others, there appeared to be thyroid gland is unique among mammalian partial destruction with the result that tissues, complete destruction can be readily TSH secretion was increased; and the attained by administering a suitably large glands, although maintaining normal or al- dose of the isotope. This is achieved with most normal hormone production, were a dose delivering about 50,000 to 75,000 operating at their maximal ability. They rads. The thyroid tissue is then subject to could not respond to further TSH stimu- acute radiation injury, with subsequent in- lation. The possible relationship between flammation, tissue destruction, and fibrotic this state of affairs and the formation of healing. This is the desired end result in thyroid nodules will be considered in the heal t disease and in thyroid carcinoma. In next discussion. hyperthyroidism, however, the usual aim is to leave the patient with sufficient thyroid RADIATIONEFFECTS ON THE THYROIDGLAND function to achieve euthyroidism. By prop- The foregoing presentation has clearly erly adjusting the isotope dosage, this aim shown radiation of the thyroid gland by can be achieved in a high percentage of isotopes of radioiodine to be a major fea- patients given about 10,000 rads to the ture of the late results of exposure to radio- gland. active fallout. I shall now discuss the sub- Studies of these patients after partial thy- ject of thyroid radiation. This subject takes roid destruction have led to some interest- on practical importance in the etiology of ing observations. Injury to the various certain thyroid tumors and in the clinical thyroid metabolic processes may not be uni- use of iodine isotopes for diagnosis and form. Thus, in some of the patients the therapy of thyroid diseases. Roughly (luring accumulation of radioiodine by the thyroid the period over which the Marshall Island gland remains greater than normal al- observations have extended and to some though hormone secretion falls to normal extent before that time, a considerable or below. This is due to an injury to the number of experimental and clinical obser- iodine organilication mechanism exceeding vations on this problem have been 1)ub- [hat to the iodide transport system (17, 18). lished and have been the subject of several As discussed earlier, the trapped but non- reviews, notably by Doniach (19) and by organifietl iodine can be demonstrated by Lindsay and Chaikoff (20). This work has disrharging it with an ion such as per- led to at least a general understanding of chlorate, which competes with iodide for radiation-induced thyroid abnormality. membrane transport. Other examples of un- As demonstrated by the Marshall Island- even metabolic injury have not been cle- ers, the abnormalities fall into two cate. scribed but probably exist. gories-one related to interference with On the other hand, thyroid function with thyroid cell function and the other con- respect to iodine metabolism and hormone cerned with the development of neojilastic production may appear to be normal in changes. The Marshal1 Island findings also aery respect, although the cell is gravely demonstrate very well the interplay be- injuied. This phenomenon has aroused tween these two radiation effects. considerable interest in recent years because In clinical practice, one of the major uses only long after successful radiotherapy does of radioiodine is to produce destruction of this injury become manifest by the late thyroid tissue--either the normal gland in onset of hypothyroidism (21, 22). One pos- patients with intractable angina pectoris, sible explanation for this phenomenon is the hyperplastic gland in hyperthyroidism, that the radiation has led to lethal muta- or neoplaslic tissue in metastasizing thyroid tions in the chromosomes of the thyioid carcinoma. Since retention of iodine in the epithelial cells without damage to the rela-

1004258 Volume 66, No. 6 LATE EFFECTS OF RADIOAClIVE IODINE IN FALLOUT June 1967 I237 tively small number of genes regulating the net result could be the development of synthesis of proteins responsible for thyroid mild hypothyroidism or the maintenance cell function, Cell division in the adult: thy- of euthyroidism only as a result of con- roid gland occurs very rarely, and mitosis tinued, overstimulation by TSH. Under is almost never seen in histological sections such circumstances, those cells capable of of the normal gland. Consequently, the responding may grow and multiply. Fur- lethal mutation may not be evident for a thermore, if the radiation has produced a very long time. After many years, the cell nonlethal mutation, the progeny of the cell begins to divide and perishes in the process. may be abnormal. The cumulative effect of cell death could This chain of events appears responsible readily account for the observed accrual of for the majority of the cases of thyroid ab- hypothyroid cases at the rather steady rate normality among the Marshall Islanders of about 2%/year of those treated. and is found in animals treated with ap- Thus, it is not unexpected to find that propriate doses of radioiodine especially hypothyroidism developed insidiously in when further stimulated by low-iodine diet certain of the exposed Marshallese children. or antithyroid drugs (19, 20). As pointed The radiation dose was not so large as to out in connection with the histological cause extensive cell destruction in the acute findings, the thyroid glands of the exposed phase, but only later did the injured cells Marshallese children showed results charac- succumb. teristic of excessive and prolonged thyroid The two clearly hypothyroid iV1arshallese ytimulation. Such stimulation, with or children, like patients developing hypothy- without preceding irradiation, leads to the roidism after radioiodine therapy for hyper- formation of thyroid nodules with a wide thyroidism, did not have any goiter forma- variety of histological cell types. Nodular tion. Evidently, the cells are sufficiently in- goiter formation of this sort, however, is jured in these instances so that they fail not limited to children. The explanation to respond to the influence of the excess for the high prevalence of goiter in the TSI-I secretion that milst accompany falling children and the much lower prevalence in thyroid function. This phenomenon was the exposed adults is most likely attribut- deinonstrated directly by Doniach (23) who able to the fact that the small thyroid showed that rats treated with 30 pc 1311, or glands of the children received a larger, 1,100 rads by X rays, failed to develop and hence more destructive, dose of radia- goiter when treated briefly with propylthio- tion. uracil. Maloof, Dobyns, and Vickery (24) Sheline, Lindsay, McCormack, and Ga- also observed this phenomenon and postu- lante (25) also found in their follow-up of lated that, since the stimulated glands patients treated with thyroid radiation for showed cellular hypertrophy but no in- thyroid disease that of the 8 patients decrease in weight, there must have been an veloping thyroid nodules out of a total of impairment of the ability of such irradiated 256, 6 had been irradiated before the age cells to divide. of 20 years and 4 before the age of 10 In the spectrum of radiation dosage to years. Indeed, the latter 4 represented two thyroid cells, one might expect to find the thirds of all those treated at an age younger situation in which the cell’s function is than 10 years. Most of them had multiple partially impaired but its growth potential nodules, much as were found in the Mar- is not. Alternatively, unequal damage to shall Islanders. It may be that these cells in the same gland may result in some younger subjects actually received larger with impaired function and growth poten- radiation doses than the older ones. On the tial and others with lrss severe injury. The other hand, this seems unlikely to be the NATIONAL INSTITUTES OF HEALTH CLIXICAL STAFF Annals of 1238 Internal Medicine case in these children, who had enlarged clinically to be solitary thyroid nodules in thyroid glands when treated, and it may be these children. That is the problem of that the nodule formation was induced in ratliation-induced thyroid carcinoma. Two the children by whatever stinlulus there ii sorts of evidence have led to the clear dem- that causes the thyroid to grow to its adult onstration that irradiation is a contribut- size. Radiatioll injury in general may be ing cause in the development of thyroid expressed as the product of the degree ol cancer. Although thyroid cancer can be cell damage times the mitosis rate of the produced in animals simply by prolonged cells (26), and the child's thyroid grows thyroid stimulation resulting from iodine from about 2 g at age 1 year to 17 g in the, deficiency or chronic administration of anti- adult (27). thyroid drugs (29), there is abundant ex- The role of thyroid stimulation by 1311 perimental evidence to show that the in the nodule formation after irradiatioii prevalence is increased by antecedent thy- is clearly indicated by the findings of M:t- roid irradiation (19, 20) just as it is by coil- , loof (28). In rats treated with 1311, hypo- comitant treatment with a carcinogen such I physectomy or treatment with thyroxine as acetaniinofluorene (1 9, 29). As demon- prevented the cellular hypertrophy that strated by the experiments of Doniach (19), was otherwise observed. It was of consitl- sunimarized in Table 11, the effect of 30 pc erable interest that this treatment also of 1311 in the rat is similar to that of 1,100 greatly reduced the development of abnor- rads of X-ray radiation. This is in the range malities in the thyroid cell nuclei (character- of radiation dosage to which the hfarshall ized by increase in size, irregularity, and 11y Island children were exposed. It is of in- perchroma tism), rhus indicatiilg that these terest, also, that the radiation in Doniach's changes were due to cell stimulation rather rats increased the prevalence of multinodu- than to irradiatio~lper se. M'lien thyroxine larity ol the thyroid glands in response to therapy was stopped, the lesions reap- goitrogen. peared. This underscores the fact that thy- 'The failure to find thyroid carcinoma in roid radiation not producing obvious atro- any of the Marshallese children can be at- phy, inflammation, and fibrosis does not tributed, it seems, to a happy chance. There appear to cause any specific cell abnormal- remains a high likelihood that carcinoma ity recognizable by ordinary histological es- would develop in the thyroid remnants re- amination. maining in the operated cases, as well as in Last, I shall discuss the subject that was those not operated upon, unless this is pre- uppermost in the minds of those who 01)- vented by the administration of suppres- served the development of what appeared sive doses of thyroid hormone. The ability

TABLE11. Induction of Thyroid Tumors in Rats*

Treatment Rats With With With Adei~omas Adenomatous Carcinomas Replacement

< no. --i None 11 0 0 0 hlethylthjouracil (MTU) 50 39 0 0 30 pc 1311 (1,500 rads to thyroid) 52 21 0 0 30 1311 + MTU 4s 4i 27 11 1,100 rads X rays to thyroid 13 4 1 1 1,100 rads X rays + MTU 22 21 17 7

*From Doniach, I: Brit. Med. Bdl. 14: 181, I058 (19). Volume 66, No 6 LATE EFFECTS OF RADIOACTIVE IOUINE IN FALLOUT June 1967 I239 of such TSH suppression to prevent the plasms in a significant number of exposed development of thyroid carcinoma has been individuals. It would also seem likely that shown experimentally in rats (30). lesser amounts of radiation, every direct hit The one carcinoma in the Marshallese on a gene being effective, might also lead adult is quite different from the type of to cancer formation. This, however, be- disease about which we have thus far been conies a problem in disease statistics and concerned, since there was no hyperplasia is one that is currently engaging the inter- of the surrounding thyroid gland. This was est of many, thus far with no clear-cut typical, then, of the usual case of thyroid answers. The experience in the Marshall carcinoma occurring in a nonirradiated Islands has, at least, served to illuminate population. On the other hand, there is one portion of the spectrum of thyroid considerable ei7idence that thyroid carci- radiation effects in man. noma in young adults, and especially in I would now like to call for questions. children, is frequently caused by radiation DR. TYOLFF: What fraction of the radia- of the cervical area in childhootl. Lindsay tioli xvas from 131I? and ChaikofT (20) have reviewed the vari- DR. CONARD:Probably less than half. ous clinical reports on this subject, and DR.WOLFF: In connection with that, was Winship and Rosvoll (3 1) reported that as there any lao1?Have you gotten any counts many as SO% ol childreti with thyroid car- on the material that was removed surgi- cinoma, in a seriey ol 562 cases, have a cal 1y ? history of prior cervical in-adiation. The DR. RALL:la0I has a half-life of approxi- amount of radiation, w~liichis illy given mately 15 niillioii years, so that essentially in the form of X-ray therapy for thymic it is unratlioactive. For any such molecules hypertrophy or tonsillitis, can be even in the lifetime we are talking about, they smaller than that in the Marshnllese popu- do not decay but are still there to be mea- lation, being in the range of 90 to 1,300 sured by neutron activation. The question rads. This was the dose r-arige in a prospec- is, would there be any there? Well, we do tive study of over 4,500 patients in whom not know. Maybe ye should have mea- thyroid carcinoma developed, on the av- sured it. Maybe there is still tissue left. I erage, 11 years later in approxiniately 0.5% am afraid that 10 years of biological turn- of persons exposed to such radiation (20, over in the affected individuals would leave 32, 33). Although adults may not be iin- almost none of the original iodine around inune to ratliatiori-intluced tumors-as sug- for measurement. gested by the a1)parent increxed pi-e1.a- DR. JESSE ROTM:With hyperthyroid pa- lence of thyroid cancer in adults exposed tients who have been treated with radio- to the atomic bomb in Hiroshima (34) ;ind iodine it is common to see a defect where other types of radiation (33, SG)-the pro- the early uptake of iodine is high, but then pensity for this sequela in children is al- :I large portion ol this iodine is not organi- most surely related t.o the fact that in [hc fied. I was curious as to why it did no1 cells oC the growiiig thyroid gland there seem to show up in these radiated groups. must be numeroiis mitoses, whereas mitoses DR. ROBIHNS:I have no real answer. in the adult gland are rare. The gene al- There is a difference in the radiation de- terations leading to cancer formation pre- livered: The hyperthyroid patients get sumably require cell division for their ex- ilbout 10,000 rads, and these children got pression. about 1,000 rads. Also, these were children It appears clear that the sizable amounts who did not have so much damage that of irradiation that we have been discussing they could not grow nodular goiters. The have the potential to produce thyroid neo- hyperthyroid patients are probably dam- Annals of I 240 NATIONAL INSTITUTES OF WEALTH CLINICAL STAFF Internal Medicine

aged further, but the Marshallese who had SUMMARY greater damage had no uptake, and so we The presence of radioactive isotopes of could not test for an organification defect. iodine in fallout from atomic explosions is It is probably a dose effect. well known. In the accidental exposure of DR. WELLINGTONMOORE: We investi- the inhabitants of one of the Marshall gated chromosome changes in Chinese ham- Island after a fusion-type explosion in ster thyroid cells after the administration 1954, thyroid radiation from radioiodine, of different doses of 1311 to animals 7 to 10 particularly in the children, was sizable. days of age. Thirty days and a year after This resulted in the late development of injection the thyroids were removed, tryp thyroid insufficiency or thyroid nodules or sinized, and cells grown in tissue culture both in SO% of those children exposed at for 3 days. The cells were arrested in metn- less than 10 years of age. At the present phase, fixed, and stained for c1iomosonl;~l time, the thyroid effects constitute the analysis. It was found that thyroid cells only important overt iiiedical problem in were quite sensitive to irradiation. Doses the exposed population. Detection of thy- as low as 6 rads produced a tenfold in- roid damage was hindered by its insidious crease in the number of cells containillg onset and by the unexpected occurrence of aberrations at 30 days (3.3% versus 0.31% elevated blood levels of iodoprotein in the in the control cells). Twenty-five percent of Marshallese population. The greater preva- the thyroid cells contained aberratiolls at lence of thyroid abnormality in the chil- a dose of approximately 1,000 rads at 90 dren is probably due to two factors: a days. After 1 year the aberration rate had larger radiation dose due to small thyroid decreased by three- to fourfold. This MXS six ;ind a greater likelihood of the grow- due in part to the increase in gland size ing organ to manifest changes resulting associated with the normal growth of tlie froin chromosomal alterations. The spec- animals. The persistence of the aberrant trum of radiation exposure of the thyroid thyroid cells (approximately one third of glands in any population is very wide, the lire span) suggests that some of these ranging from stratospheric fallout froin damaged cells may persist for the remain- atomic explosions and clinical testing with der of the animal’s life. radioiodine isotopes to high radiation rates DR. ROI$BINS:Thank you for the com- intentionally produced in therapy of thy- ment. ‘That is another area I did not Set roid diseases. The Marshall Island experi- into because oE time. It is o[ interest that ence will help to define the range in which Drs. A. A. Al-Saadi and W. H. Uierrvaltes significallt thyroid damage may occur. at the University of Michigan School of Medicine have been studying chro~nosomal ACKNOWLEDGMENTS aberrations in animals and find aberrations We arc clccply indebted to the mxny mein- resul ling from iodine deficiency and other Ixrs of the medical survey teams oiw the past I:! )’cars for their participation and for the ma- forms of thyroid stimulation, so they may tcrial presented here. We are also grateful to not be limited to radiation effects, ;ilthough III;III~other people for invaluable advice and certainly that could be a contributing ;issist;rnce, including Drs. C. L. Dunham and 1.1. 1). Bruner of tlie Atomic Energy Commis- cause. sion; Drs. V. P. Bond, E. P. Cronkite, H. A. DR. CONARD:Attempts were made to do Johnson, L. K. Dahl, J. E. Jesseph, and H. L. chromosome studies on cultured thyroid Atkins of Brookhaven National Laboratory; tissue from the operative specimens on the Drs. S. Warren, B. P. Colcock, and W. A. hleisnner of Boston: Drs. G. H. KIinck, E. D. iV1arshallesc. Unfortunately, they were not Henley, C. J. Stahl, C. A. Broaddus, S. Lindsay, successful. ;ind A. Hicking; and to other members of the Volume 66. No. 6 LATE EFFECTS OF RADIOACTIVE IODINE IN FALLOUT June 1967 1241

.Atomic Energy Commission in Honolulu and 4. CONARD, R. A. HUGGINS,C. E., CANNON,B., also to the Trust Territory of the Pacific Islands LOWREY,A,, RICHARDS,J. B.: Medical survey (Department oE Interior) for assistance in carry- of Marshallese two years after exposure to fallout radiation. ]AMA 164: 1192, 1957. ing out these surveys. 5. CONARD,R. A,, MEYER, L. M., RALL,J. E., , LOIVREY,A,, BACS, S. A., CANNON,B., CARTER, SUMMARIOIN INTERLINGUA E., EICHEK,hf., HECHTER,H.: March 1957 Le presentia de isotopos radioactive de iodo medical survey of Rongelap and Utirik peo- in le precipitation atmospheric ab explosiones ple three yeai-s after exposure to radioactive atomic es lien cognoscite. In le exposition ac- fallout. U. S. AEC Brookhaven Nat. Lab. 501 (T-119): 1, 1958. cidental tlcl habitantes de 1111 del Insulas Mar- shall a1 clfectos de tin explosion del typo 6. COXARD,K. A,, ROBERTSON,J. S., MEYER,L. bf., SUTOIV, \V. XV,, \\'OLlNs, LOWREY,A., fusional iii 1954, le irradiation radio-iodic del \v., URSCHEL,H. C., JR., BARTON,J. hf., GOLDMAN, tliyroitles-p;irtic~Ilnn-nente de juveniles-es- hl., HFCHTER,H., EICHER,M., CARVER, R. K., seva considcrabile. Isto resultava in le clis- POTTER,1). I!'.: Medical survey of Rongelap veloppaniento tardive tlc insufficientia thyroide people, 1958, four years after exposure to elo de Iiodulos tliyroide in 80 pro cent0 de fallout. U. S. AEC nrookllave?~Nut. Lab. 534 ille juvenilcs. AI tcmpore presente, le effectos (T-135): I, 1959. thyroide coiistitue le sol importante patentc 7. CONAW,R. A,, MACDONALD,H. E., LOWREY,A., problerna medical in le exponitc population. MIEYER,L. M., COHN, S., Surow, W. W., Le detection de tI;imnificatioii tliyroide ess~va BLUMI,ERG,I<. S., Hoi.LiNc;swoxrH, J. \V., impedite per le lente niotlo de su declaration LYON,H. TV.. LEWIS,T.V. H., JAFFE,A. A., EICHEK, I'OTTXR, D., LANWI,I., RIKLON, e per le inespectatemeiitc nlte coiicentrationcs &I., E., IAXAN, J., HEt.KEN,\, J.: Medical survey of sanguinee de iodoprotciiia in le population Kongelap lxople five and six years after cs- marshallese in pimil. 11 cs probabile que le posurc to fallout (with an addencium on elevate incidentia de anorninlitates tlryroide vcgetatioti). (I. S. AEC Iirookluwen Nat. Lab. in le juvcnilcs cs IC cffccto rlc duo factores: GOO (T-179): 1, 1960. (I) 1711 major inteiisit;ite del irrx1i;ition in 8. CONAHD,R. A,, MACDONALD,H. E., MEYEII,L. conseqneiitia tlrl minor tlimensioiics tlcl thy- hl., COFIS,S., SLITOW,TV, TV., KARNOFSIIY,D., roide e (2) iin 1'111s forte susccptibilitatc de JAiw., A. A,, RIKLON,E.: Medical SLI~VC),of 1111 org;iiio in trcscciitia pro manifcstx ;iltei-'i- Rongelap pcoplc scvcii years after exposure to fnllout. S. AZCC Brooklurzieu Nut. Lnh. tiones caus;ttc pcr iiiterlurcn tias c1iroiiiosom;il. b'. 725 (T-260): 1, 1962. Le spectro de possibilitates de exposition del 9 CONARI),R. A,> hIixEiI, L. M., Swrow, I\'. IV., glaiidii1;is thyroide ;I irrachtion es estciise in hIOtONE>, \V. c., LOWRIY, A,, I-ItCKlKG, A., omne popii1;ition. 1110 include precipitation RIKI.OS,IC.: hlcdical survey of Ror~gclappeo- strntosplicric all csplosioncs atomic, tats clinic ple ciglit years aftcr cxposuie to f;illout. con isotopos r;itlio;ictivc tle iodo, c alte iiitensi- U. S. AEC I3,-oo/thnuen Nat. Lab. 780 (T-296): tzitcs (le irr;itliation iiitcntion;ilmcnte protlucitc I, 19G3. in le tliernpia tlc moi-bo thyroitle. Lc espel-i- IO CONARD,R. A,, HIWING,A,: Medical findings in entia m:uslmllt:sc va at1jiit;rr in tlcfriir le Mal-sliallcse pcoplc exposed to fallout radia- region de iritensitxtes iri.xIi:itori iissot ixtc con tion: icsiilts from ten-year study. JA/lnf14 192: le occurrcritia tlc signific;i Live damiios thyi-oitle. 457, 196.5. 11. Sw~o\!', \V. IV., CONARD,11. I\., GRiFImH, I<. 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