4
HEALTH CONSEQUENCES OF RADIATION EXPOSURE

This chapter discusses briefly how radiation can lead to deleterious effects, such as cancer, and then reviews the evidence on the health effects seen in various populations exposed to external radiation (for example, from atomic bombs) or to internal radiation from isotopes of iodine. Among the nuclear power plant accidents discussed, particular attention is paid to the 1986 Chornobyl accident because of the high levels of fallout to which a large population was exposed. One of the most important conclusions is that evidence on both external and internal radiation shows that very young children are the most sensitive to the carcinogenic effects of radiation to the thyroid; the risk decreases with increasing age, and there is no appreciable risk to adults, particularly those over 40 years old. Young children are therefore the group requiring particular attention for prophylaxis.

Understanding the consequences to human health of exposure to radioisotopes of iodine depends largely on experience with its use



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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident 4 HEALTH CONSEQUENCES OF RADIATION EXPOSURE This chapter discusses briefly how radiation can lead to deleterious effects, such as cancer, and then reviews the evidence on the health effects seen in various populations exposed to external radiation (for example, from atomic bombs) or to internal radiation from isotopes of iodine. Among the nuclear power plant accidents discussed, particular attention is paid to the 1986 Chornobyl accident because of the high levels of fallout to which a large population was exposed. One of the most important conclusions is that evidence on both external and internal radiation shows that very young children are the most sensitive to the carcinogenic effects of radiation to the thyroid; the risk decreases with increasing age, and there is no appreciable risk to adults, particularly those over 40 years old. Young children are therefore the group requiring particular attention for prophylaxis. Understanding the consequences to human health of exposure to radioisotopes of iodine depends largely on experience with its use

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident in investigation and treatment of thyroid disease and on studies of populations exposed to fallout from various nuclear incidents. Radiation effects can result from external radiation (from a source of radiation outside the body, such as x rays) and from internal radiation (from a source of radiation in the body, such as radioisotopes absorbed from food or drink or absorbed from the air). The effects of internal radiation from iodine radioisotopes on the thyroid depend on the gland’s ability to concentrate and store the isotopes, which lead to a much higher radiation dose to the thyroid than to other tissues. Some other tissues (such as salivary glands, breast, and stomach) concentrate radioiodine but do not store it, so their dose, although more than that to most tissues, is much less than that to the thyroid. Radiation from any source—including ingested or inhaled isotopes, medical or dental investigations with x rays, and direct radiation from an atomic bomb—can damage DNA and thus pose a risk of tumors and, in high doses, cell death. The main expected consequences of exposure of the thyroid to radiation are an increase in the incidence of thyroid tumors and an increase in the occurrence of loss of thyroid function (hypothyroidism, myxedema). Tumors occur because DNA damage can lead, in a small minority of cells, to activation of genes that stimulate cell growth, to loss of function of genes that suppress cell growth, or to various other changes that give cells and their progeny the ability to multiply more rapidly than normal. Radiation can damage DNA directly or through the formation of free radicals. The damage can be double strand breaks, with resultant loss of a portion of a chromosome (deletions), or rearrangement, in which a piece of a chromosome is reinserted inappropriately. Misrepair of radiation-induced damage, including single strand breaks, can also lead to point mutation, in which a base is replaced by an inappropriate one. Many mutagenic chemicals lead to point mutations, but radiation causes mostly deletions and rearrangements (Sankaranarayanan, 1991). Much attention has recent been focused on genetic instability, a phenomenon observed in vitro in which radiation, of both high- and low-energy-transfer types, leads not only to mutations in irradiated cells but also to a persistent increase in mutation rate in the non-irradiated daughter cells (Little et al., 1997). Surprisingly, it has been shown that such instability is

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident shared by the descendants of non-irradiated cells adjacent to those irradiated, the so called bystander effect (Lorimore and Wright, 2003). Those observations are of considerable potential importance in the understanding of human carcinogenesis. The observations so far on thyroid carcinoma induced by radiation show that the main mutation observed has been rearrangement of the RET oncogene, the type of mutation expected as a result of radiation-induced double strand breaks (Williams, 2002). These can be explained as direct radiation effects without the need to postulate the involvement of genomic instability. The chance of tumor development rises with increasing radiation dose up to a level that is high enough to kill all or most thyroid cells. Very high doses do not cause tumors, because cells that are fatally damaged cannot proliferate to produce tumors. However, such extensive damage can lead to hypothyroidism. In addition to tumors and cell death, a third possible thyroid-related consequence of radiation is autoimmune disease of the thyroid: the body’s own lymphocytes become sensitized to thyroid cells and can destroy them and in a small proportion of cases lead to hypothyroidism. More rarely, the antibodies produced by the lymphocytes can react with the hormone-receptor switch that turns up thyroid function and thus lead to thyrotoxicosis (Graves disease, or hyperthyroidism). The mechanism through which radiation causes autoimmune disease has been postulated to be due to a differential effect of radiation on different types of lymphocytes. The health effects of use of iodine isotopes in investigation and treatment of adults with thyroid disease have been well studied; no significant consequences have been found in association with the small radiation doses used in investigation. Several large studies of the higher doses used in treatment for thyroid hyperfunction have shown no increase in thyroid cancer but have shown a high incidence of hypothyroidism due to destruction of thyroid cells—easily treatable with hormone replacement (Holm et al., 1991). Population exposure to radioisotopes in fallout began in 1945 with the atomic bombs in Japan, although these detonations were more relevant to direct external radiation from neutrons and gamma rays. Between 1951 and 1962, the aboveground testing of nuclear weapons in Nevada led to the release of large amounts of 131I, the

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident main radioisotope used in therapy (half-life, 8 days). The amounts released and the exposure of the US population have been carefully documented, and a full report is available (NCI, 1997). One particular US test carried out in the Pacific Ocean led to a significant exposure of the population of the Marshall Islands. Aboveground tests were also carried out by the USSR and in smaller numbers by the UK and France, mostly in the Southern Hemisphere, and other countries have tested a small number of nuclear weapons. Releases of radioiodine from the Hanford facility in Washington state led to population exposure through fallout, and this too is well documented, as is the release of iodine isotopes from an accident at the Windscale nuclear plant in the UK in 1957 (Crick and Linsley, 1984, Cate et al., 1990, Robkin, 1992, Ramsdell et al., 1996). Releases similar to those from Hanford took place around the Mayak plant in the USSR. A very small release followed the accident at the Three Mile Island plant in 1979. By far the largest release of radiation from a nuclear reactor took place in 1986 after an accident at the Chornobyl nuclear power plant. The estimated amounts of 131I released during those incidents are shown in Table 4.1. The observed health consequences of events that are the most relevant to this report will be dealt with in turn, with particular attention to Chornobyl because of the size of the release and the studies that have been carried out in the 17 years since the accident.

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident Table 4.1 Environmental Releases of 131Ia Site Location Year Amount of Ci 131I release Bq Scale of Release Compared with Windscale Accident Hanford Facilityb,d Washington State 1945-1947 7×105 2.6×1016 35 Hanford “green run”e Washington State 1949 1.1×104 4×1014 0.5 Windscale NPPc,f UK 1957 2×104 7.4×1014 1 Aboveground testsb,g Nevada 1951-1962 1.5×108 5.6×1018 7,500 Three Mile Island NPP Pennsylvania 1979 15 5.6×1011 0.00075 Chornobyl NPPh Ukraine (former USSR) 1986 4.6×107 1.7×1018 2,300 aNot comprehensive. bRelease over a long period. cThe first significant nuclear power plant accident. dRamsdell, et al., 1996. eRobkin, 1992. fCrick and Linsley, 1982. gNCI, 1997. hUNSCEAR, 2000. Radiation from Atomic Bombs Hiroshima and Nagasaki The detonation of an atomic bomb releases a huge blast and thermal wave, large amounts of neutrons and gamma rays, and a variety of isotopes, including isotopes of iodine. The health effects in a populated area are dominated by the blast and thermal waves and the direct radiation. The external radiation from neutrons and gamma rays, unlike internal radiation from isotopes of iodine, does not irradiate the thyroid gland to a greater extent than the other tissues of the body, and KI will not prevent thyroid damage from external radiation. Studies of the survivors of the atomic bombs in Hiroshima

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident and Nagasaki have shown increases (by a factor of about 2-3) in cancers of many different tissues in survivors who were close to the point of detonation (hypocenter) (Thompson et al., 1994). The approximately 2 fold increase in thyroid cancer incidence was similar to that in many other cancer types—such as cancer of the colon, breast, ovary or bladder—and this suggests that it was due to direct whole-body external radiation and that exposure to iodine isotopes made no observable contribution to the occurrence of thyroid cancer in the population studied. Atomic-Bomb Tests Atomic-bomb testing has been carried out in unpopulated areas to avoid significant exposure of population to direct radiation from neutrons and gamma rays. However, fallout may occur at a considerable distance, and exposure may be cumulative if many tests are carried out at the same site. One test of a large nuclear device led to the release of large amounts of iodine isotopes, and an unpredicted weather change led to exposure of the population of some of the Marshall Islands to large amounts of radioisotopes of iodine. Marshall Islands On March 1, 1954, on Bikini Atoll in the northern Marshall Islands, a 15-megaton thermonuclear device was detonated on a tower in an atmospheric nuclear test code-named BRAVO. The yield was 3 times greater than anticipated, about 15 megatons, and an unexpected wind-shear condition resulted in heavy fallout outside the test area. About 4-6 hours after the explosion, the radioactive cloud deposited particulate, ash-like material on 65 inhabitants of Rongelap and 18 Rongelapese on Sifo Island on the nearby Ailinginae Atoll. In addition, 23 fishermen on the Japanese fishing boat Fukuryu (Lucky Dragon) Maru were heavily contaminated (cloud deposits were 4-6 hours after the explosion and 160 Km eastward). Twenty-eight American servicemen on Rongerik were also exposed. After 22 hours, the cloud reached Utirik, where 167 people were contaminated.

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident Most of the people from Rongelap developed acute radiation sickness. Between 1954 and 1985, thyroid nodules developed in about 33% of the Rongelap population, including 63% of the children who were less than 10 years old at the time of exposure. And 10% of the Utirik population also developed thyroid nodules. Those populations have been carefully and closely followed by several teams of investigators. A major problem has been uncertainty about the exact radiation exposure. The major data from which thyroid exposure was derived came from analysis of a single pooled-urine 131I assay obtained 17 days after exposure. Early calculations of accumulated whole-body dose of gamma rays were about 1.9 Gy (190 rad) on Rongelap, 1.10 Gy (110 rad) on Ailinginae, and 0.11 Gy (11 rad) on Utirik (Adams et al., 1987). Recalculated doses from the internal radionuclide burden would be derived later from estimated thyroid content of five radioiodine isotopes and two tellurium radionuclides, all with shorter half-lives than 131I. Most of the thyroid absorbed dose was from short-lived isotopes. Only a minor portion of the thyroid dose could be attributed to inhalation and to a negligible amount of beta-particle irradiation from skin deposits; thus, the internal thyroid dose was due almost entirely to ingested radionuclides. Significant early radiation effects were seen, including leukopenia to about 50% of the comparison level when first examined 3 days after exposure. Thrombocytopenia was maximal at 30% by 4 weeks, and neutropenia was evident by 5-6 weeks. During the first decade after exposure, the general health of this population appeared to be no different from that of the nonexposed Marshallese control group. Late radiation effects were noted when 9 years after the accident a 12-year-old Rongelap girl was found to have a thyroid nodule. Within the next 3 years, 15 of the 22 Rongelap people who had been under 10 years old at the time of exposure had developed thyroid lesions; and 15 years after the accident, the first thyroid nodule appeared in the exposed people on Utirik. The first thyroid abnormality to appear in the thyroid glands themselves in the exposed Marshallese, however, was radiation-induced thyroid atrophy which resulted in profound growth failure in

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident two boys; the etiology was not recognized until after thyroid nodules began to appear. Later surveys with thyroid stimulating hormone (TSH) measurements and stimulation tests, in addition to routine measurements of thyroid hormone, showed 12 cases of subacute thyroid hypofunction that could not be attributed to thyroid surgery. The first thyroid cancer was diagnosed 11 years after exposure in a Rongelap woman who was 30 years old at the time of the detonation. An excess of thyroid cancer was also seen in exposed Rongelap and Utirik people, and all were papillary carcinomas. Thyroid nodules and thyroid cancer are major causes of late morbidity. Mild hypothyroidism in a large number of people might have occurred through radiation effect resulting in increased TSH secretion. Thyroid-hormone therapy was instituted generally in the Rongelap exposed population in 1965 to decrease the risk of thyroid tumorogenesis. The short-lived isotopes of iodine and tellurium contribute 80-90% of the absorbed thyroid dose in the Marshall Islands data. Follow-up data can therefore provide no information about the risk posed by radiation associated with 131I, which has a longer half-life of 8 days. Study of this population raised the issue of multiple exposures. There were 66 announced nuclear tests in the Marshall Islands between 1946 and 1958, and many of these tests took place in Eniwetok Atoll, which is 200 miles west of Bikini. The BRAVO test was the largest of the 66. Several studies have explored the affected populations to examine the relation between exposure to fallout from nuclear-weapon tests and the occurrence of subsequent thyroid abnormalities. It has proved particularly difficult to examine that relationship because of the need to determine the individual thyroid radiation dose of each person. Attempts to use distance from the explosion site as a proxy for radiation dose has produced conflicting results (Hamilton et al., 1987, Takahashi et al., 2001). Additional available data suggest that fallout from the tests spread over a wider area than originally thought. The Marshall Islands Nationwide Thyroid Disease Study found a high prevalence of thyroid nodules in the entire population of the Marshall Islands that appears to correlate with increasing age

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident (Takahashi at al., 2001). A further difficulty in follow-up became apparent when thyroid ultrasound diagnostic procedures were added to palpation for case-finding; it greatly increased the sensitivity of nodule detection (Takahashi et al., 2001) and doubled the estimated prevalence of nodules. Nevada Tests Over 90 aboveground tests were carried out at the Nevada Test Site between 1951 and 1962; after this period, aboveground tests ceased, and the underground tests that followed released negligible amounts of radioactive iodine into the atmosphere. The exposure of the US population has been estimated by taking into account age, residence, and dietary variation (NCI, 1997). Epidemiologic studies investigating the health consequences have been carried out, relating both incidence and mortality from thyroid cancer to dose estimates from the NCI study. Data from the Surveillance, Epidemiology, and End Results (SEER) tumor registries was used, these derived largely from some of the less exposed areas of the United States. An association was found between dose and thyroid cancer in children under 1 year old at exposure (Gilbert et al., 1998). The theoretical calculations of Charles Land (NRC, 1999) suggest that the number of lifetime excess cases of thyroid cancer in the United States resulting from exposure to fallout from the aboveground tests can be estimated at 49,000 (range of 11,300-212,000). The estimate assumes that significant risk was restricted to those under 20 years old at exposure and that the excess risk persisted unchanged throughout life. The figure of 49,000 represents just over 12% of the number of cases of thyroid cancer expected in the absence of radiation exposure. The number of assumptions in the calculations and the lack of reliable data from the most exposed areas suggest that although it can be accepted that there has been an increase in thyroid cancer incidence due to exposure to fallout from the aboveground tests, it is not now possible to rely on these figures to provide a basis for estimating risk from radioiodine exposure generally.

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident Other Tests No detailed studies of the consequences of population exposure to the fallout from the Russian or Chinese testing programs are available, but a possible link between exposure from the Novaya Zemblya tests and the incidence of thyroid cancer in Scandanavia has been suggested (Lund et al., 1999). Nuclear Power Plant Accidents The Windscale Accident The Windscale reactor in the United Kingdom was of the air-cooled type with a graphite core and lacked secondary containment. In reactors of this type, the structure of the graphite is gradually distorted by the energy released during normal use, and the energy stored in the structural change (Wigner energy) must be periodically released. That is achieved by controlled heating; but in one particular operation in early October 1957, the process was carried out too rapidly. Excessive energy was released, and some of both the graphite core and the metallic uranium fuel overheated. It was not at first detected, because the heat sensors were in the areas of the expected greatest heat during normal operation, not of the heat that occurred during the release of the Wigner energy. The overheating led to a fire in the graphite core that proved extremely difficult to extinguish; the reactor was eventually flooded with water the day after the fire had been detected. The release of isotopes took place through the plant stack; the filter removed particulate material and the main radioactivity released was about 20,000 Ci of 131I. Detection of the release led to a ban on the distribution of milk originating in an area of about 200 square miles. This ban was continued for over a month in the most affected areas. The avoidance of contaminated milk, the main route through which radioisotopes of iodine in fallout reach the human thyroid, greatly reduced the risk to the population. The collective thyroid dose to the UK population was estimated to be 2.5 × 104 person-Sv, and one estimate suggested that

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident this could lead to 260 excess thyroid cancers, of which 13 would be fatal. It is not surprising that no significant increase in thyroid cancer has been observed in the exposed population, the excess cases were predicted to occur at a rate of about 6.5 per year, and the expected natural incidence in the UK was over 600 per year (Crick and Linsley, 1982). Three Mile Island Accident On March 28, 1979, a nuclear accident occurred at the Three Mile Island Nuclear Power Station Unit 2, in south-central Pennsylvania. The accident began when the plant experienced a total loss of feed water and a simultaneous tripping (shutting down) of the main turbine (USNRC, 1979, Nuclear Information Bulletin, 1990). Emergency feed water pumps started, as designed, and the reactor continued to operate at full power. Unbeknownst to the operators, valves had been closed so that the emergency feed water pumps could not discharge water from the auxiliary pumping system. When the reactor core cooling system temperature and pressure began to increase the reactor scrammed (control rods were suddenly inserted into the reactor core). Simultaneously, a pilot-operated relief valve (PORV) opened to relieve pressure as the reactor’s cooling water rapidly began to heat up. Once the pressure decreased to desired levels, the PORV stayed in the open position. That led to the loss of cooling water in the reactor vessel. Operators failed to recognize that the PORV had stayed open. That and other human errors caused the reactor core to be deprived of necessary cooling water, and an estimated 50% of the reactor core melted down (Langer et al., 1989). As a result of the meltdown, an estimated 52% of the reactor core inventory of radiocesium and 40% of the radioiodine were released from the core into the reactor building, (FDA, 1979) but no detectable amount of the radiocesium and only a minute proportion (0.00002%) of the radioiodine escaped to the environment. Considerable environmental monitoring followed the accident, and the maximum concentrations of 131I found in milk were 41 pCi/L (1.52 Bq/L) in goat’s milk and 36 pCi/L (1.33 Bq/L) in cow’s milk (Weidner et al., 1980)—0.003 of the concentrations at which the FDA

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident Belarus, and Russia. The reactor accident was first detected in Western Europe when it triggered alarms at nuclear power stations in Finland and Sweden. The initial wind direction blew the radioactive cloud to the Northwest, so the earliest and the heaviest fallout affected the population along this route. Weather changes led to a more varied distribution, and some radioactivity from Chornobyl could be detected throughout the Northern Hemisphere. By far the largest exposure to fallout, mainly iodine isotopes, occurred in the southern regions of Belarus (Gomel province) and immediately around the reactor in northern Ukraine and the neighboring provinces. The population of Pripyat, the town closest to the reactor, was evacuated about 2 days later, and the population of all the villages within 30 km of the site was evacuated later than that; return is still forbidden because of the ground contamination, mostly with cesium. In all, about 30,000 Km2 was contaminated to more than 185 kBq/m2, and this led to the evacuation of some 116,000 people. In the years after the accident, an additional 210,000 people were resettled into less-contaminated areas, and the initial 30 km radius exclusion zone (2,800 km2) was modified and extended to a 37-km-radius exclusion zone (4,300 km2). Retrospective dose-reconstruction studies (Vargo et al., 2000) indicated that in the city of Pripyat, 40-60% of children up to 3 years old, 20% of children 4-7 years old, and less than 4% of adults had thyroid doses of 2 Gy (200 rad) or higher. Estimates of thyroid doses for residents of various locations in Belarus were made for three age groups (0-6 years, 7-17 years, and adults) (Gavrilin et al., 1999). There were over 250,000 thyroid doses; the arithmetic means were 0.08-4.7 Gy (8-470 rad) in the 0- to 6-year group, 0.029-2.1 Gy (2.9-210 rad) in the 7- to 17-year group, and 0.018-1.6 Gy (1.8-160 rad) in adults. In Kiev, where the radioiodine contamination was lower, the estimated individual thyroid doses for five age groups were assessed; these range from 104 mGy (10.4 rad) for those born in 1983-1986 to 14 mGy (1.4 rad) for those born before 1971. The collective thyroid doses were estimated as 83 × 103 person-Gy for those born before 1971 and 38 × 103 person-Gy for younger people. In the west of Poland, bordering Belarus, it has been estimated (Pietrzak-Flis, et al., 2003) that in the absence of countermeasures, the

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident highest thyroid doses from inhalation and ingestion of 131I would have been 178 mGy (17.8 rad) in 5-year-olds, 120 mGy (12 rad) in 10-year-olds, and 45 mGy(4.5 rad) in adults. The countermeasures, including administration of stable iodine to children and teenagers, reduced those doses by about 30%. About 150 of the personnel involved at the reactor in the immediate aftermath of the accident were exposed to large amounts of whole-body radiation from fuel elements; 32 of them have died from acute radiation sickness (UNSCEAR, 2000). The stress of known or suspected radiation exposure, lack of information, concern for children, and the forced evacuation also had considerable health consequences. Apart from those related to stress, the first indication of health problems in the population exposed to fallout came 4 years after the accident with reports from hospitals in Minsk, the capital of Belarus, and Kiev, the capital of Ukraine, of an increase in the numbers of children with thyroid carcinomas. Reports of the increase and its validation were published in 1992 (Kazakov et al., 1992, Baverstock et al., 1992). The increase continued. Thyroid carcinoma in children is extremely rare, affecting perhaps one in a million children. The reported incidence varies somewhat among countries; it is usually 0.5–3 per million per year; but some registries report up to six per million per year. The incidence in Belarus as a whole after the Chornobyl accident rose to about 30 per million per year, and in the Gomel region it rose to about 90 per million per year in the years after the initial reports. By the year 2000, about 2,000 cases of thyroid cancer attributed to exposure to fallout from Chornobyl had been reported in Belarus, northern Ukraine, and the adjacent parts of the Russian Federation that also received high levels of fallout. Details of the distribution of fallout and numbers of cases and a discussion of risk in relation to dose received can be found in a United Nations Scientific Committee on Effects of Atomic Radiation report (UNSCEAR, 2000), and a recent review discusses the pathology, molecular biology, and age-related sensitivity (Williams, 2002). Cases are still occurring, and the full consequences will not be known for decades. One observation that is central to the understanding of the consequences of exposure to iodine isotopes in Chornobyl fallout

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident concerns age-related sensitivity of the thyroid to carcinogenesis. Early studies showed that the age of incidence of thyroid carcinoma in exposed children was changing: the peak age of exposed children diagnosed with thyroid carcinoma in 1992 was about 7 years, but the peak age of children diagnosed in 1994 was about 9 years. It soon became apparent that the difference was due to a rapid decrease in the risk of developing thyroid cancer with age at the time of exposure to radioiodine; children who were youngest at exposure were carrying an increased risk that continued as they aged (Williams, 1996). Children who were newborn at the time of Chornobyl are now 17 years old, and the exposed population continues to show an increased risk of developing new cases of thyroid cancer. Calculations suggest that the relative risk in children 0-1 year old at exposure to the Chornobyl fallout is 40 or more times that of children 10 years old or older at exposure (Cardis et al., 1999), but this ratio may change with study over a longer period. It appears that the risk in those exposed as adults is extremely small. The thyroid gland of the fetus begins to concentrate iodine at about the 3-month stage of pregnancy; those who were in utero at the time of the accident show an increase in thyroid cancer, but much less than those who were newborn. Those who were born more than 6 months after the accident show no increase in thyroid cancer; because of the short half-life of the iodine isotopes they would not have had appreciable exposure. Three factors contribute to the high sensitivity of very young children to the risk of thyroid cancer after exposure to iodine isotopes: a high intake of isotopes mainly through milk, the high uptake of radioiodine by the infant thyroid, and increased biologic sensitivity. The intake of milk is important as an exposure pathway because in the absence of precautions it is the main route through which radioiodine reaches individuals. Grazing animals collect fallout from a considerable area of ground, and iodine, including radioactive iodine, is concentrated in milk. Other foods, such as green vegetables, may also be contaminated. If a nursing mother consumes contaminated food, in particular milk from cows or goats exposed to fallout, she will pass the radioactivity on to her child through breast-feeding. The relatively high breathing rate of children will increase the amount of

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident radioiodine absorbed through inhalation, although this is only a small proportion of the total. The radiation dose to the infant thyroid is therefore higher than that to older children or adults because infants take in relatively more iodine radioisotopes, have a smaller thyroid gland, and have a higher uptake by the thyroid, leading to a thyroid dose estimated to be up to 5 times that of adults (IAEA, 1991). Infants are also more sensitive to the risk of carcinogenesis, probably because of the way the thyroid develops—growing rapidly during the early years of life but hardly at all during adult life. Although thyroid cancer has been the main thyroid consequence of exposure to fallout from Chornobyl, benign thyroid tumors also appear to be increasing in frequency; this is similar to the findings after exposure to x rays (Shore et al., 1993). The long-term incidence of hypothyroidism in those exposed to fallout from Chornobyl is not known. One study reported higher levels of thyroid-stimulating hormone in children from the more heavily exposed areas than in those from the less exposed areas (Yamashita et al., 2002); this suggests that some degree of thyroid damage occurred. An alternative explanation could be iodine deficiency, but the main exposed areas do not appear to have more iodine deficiency than the rest. Juvenile hypothyroidism was found in about 0.1% of a large population of children exposed to fallout from Chornobyl; the evidence that it was exposure-related depended on correlation with the body burden of 137Cs (Goldsmith et al., 1999). Radiation may also lead to an increase in circulating antibodies to the thyroid; this has been demonstrated to occur after treatment of thyrotoxicosis with high doses of radioactive iodine. The same study also examined circulating thyroid antibodies in more and less exposed areas and found no correlation. A separate study compared circulating thyroid antibodies in villages with different levels of fallout exposure and concluded that there was a relationship between radiation exposure and the development of autoimmune disease of the thyroid (Yamashita et al., 2002). The clinical significance of those observations is uncertain but is likely to be small. No adequate studies have been published of possible effects of exposure to fallout from Chornobyl on the incidence of diseases of the breast, salivary glands, or stomach, which concentrate radioiodine to

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident some degree but do not store it. It is the combination of concentration and storage that leads to a thyroid dose around 1,000 times higher than the average body dose after administration of radioactive iodine. Tissues that can concentrate but not store iodine would receive doses much lower than the thyroid. As yet unconfirmed reports suggest that there has been no great increase in tumors of those tissues. Further studies are needed to clarify this issue and to determine whether particular susceptibility groups, such as lactating mothers, are at higher risk of breast cancer than the general population. Another subject that needs more study is the possibility that exposure to fallout can lead to inherited DNA damage. In theory, that is less likely to occur after exposure to isotopes that concentrate little or not at all in the gonads than after whole-body exposure to external radiation, but sensitive tests have shown minisatellite instability in nonexposed children born to parents who were exposed to Chornobyl fallout (Dubrova et al., 2002). The instability involves the insertion or deletion of one or two base pairs in simple repeat sequences in DNA that have no known function. The likelihood that that instability will be translated into identifiable health effects is not clear, but the observation is important, and long-term studies are needed. It should be noted that no similar effects were found in studies of those exposed to external radiation from the atomic bombs (Kodaira et al., 1995). An accurate estimate of the overall effect of the Chornobyl accident on the incidence of thyroid disease can be made only when all those alive at the time have died. However, the number of cases of thyroid tumors that have occurred so far in those exposed as children or adolescents to fallout from the Chornobyl accident in Belarus, northern Ukraine, and the adjacent parts of Russia can be used to predict the total consequences of the accident. Because no previous accident is comparable with Chornobyl, such estimates are necessarily imprecise. The type of thyroid cancer that has occurred usually carries a good prognosis. The deaths so far due to thyroid cancer in the exposed children in Belarus are still in single figures, but this is a slowly growing tumor, and death can occur decades after diagnosis.

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident The number of benign thyroid tumors is more difficult to assess; they are less closely monitored than malignant tumors, and studies after exposure to external radiation suggest that benign tumors have a longer latent period than malignant tumors. Although benign tumors do not directly cause death, they require investigation and operation to exclude cancer or the possibility of progression to cancer. While accurate predictions are not possible, it can be speculated that the deaths from Chornobyl related thyroid cancer will probably be in the hundreds, the number of cases of thyroid cancer in the thousands, and the number of people requiring thyroid operations in the tens of thousands. Relevance of Fallout Exposure to Stable Iodine Prophylaxis One of the most important findings in the studies of the largest exposure to have occurred is the greatly increased sensitivity of the youngest children to thyroid carcinogenesis after exposure to radioactive iodine in fallout. Thyroid cancer has also been shown to occur after external radiation from x-rays used in treatment of nonthyroid diseases, and both here and in atomic-bomb follow-up studies it has also been shown that young children are more likely than older children to develop carcinoma (Ron et al., 1995). For external radiation such as x-rays not involving isotopes, uptake and concentration of iodine are irrelevant. The risk of thyroid carcinogenesis in adults from radiation exposure is absent or extremely low (Ron et al., 1995), although some studies have suggested that high-dose external radiation in a patient with an existing thyroid tumor may lead to development of a more serious lesion (Getaz and Shimoaka, 1979). Studies carried out on adult patients given small doses of radioiodine for investigation of thyroid problems or larger doses for treatment of thyroid hyperfunction have shown no subsequent increase in thyroid cancer later. A pooled analysis of seven studies of thyroid cancer after exposure to external radiation, found an excess relative risk per Gy of 7.7 for children under 15, with little risk apparent after the age of 20

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident (Ron et al., 1995). The youngest children were the most susceptible, with an excess relative risk (ERR) of 9.0 for those 0-4 years old at exposure, 5.2 for those 5-9 years old, and 2.4 for those 10-14 years old.2 A study of A-bomb survivors (included in the pooled analysis) found no significant excess of thyroid cancers in those over 20 at exposure (Thompson et al., 1994). The increased risk in younger children after exposure to external radiation shows that a biologic mechanism is involved, probably related to the kinetics of growth of the gland (Williams, 1999). The risk is magnified after exposure to radioiodine isotopes in fallout by the greater intake of iodine (especially from milk) and the greater uptake by the thyroid. The relevance when one is considering KI prophylaxis is that the youngest children are the most vulnerable group and must be given the highest priority for KI administration in any situation where exposure to radioiodine cannot be avoided. It is also especially important to avoid ingestion of contaminated milk and other foodstuffs in this group. Because iodine, including radioactive iodine, is concentrated in breast milk, lactating mothers must take every precaution to reduce exposure (see Chapter 2). The great drop in sensitivity to thyroid carcinogenesis with increasing age suggests that iodine prophylaxis in adults is of little value. Although the qualitative results after Chornobyl are valuable, the quantitative results cannot be transposed to the United States situation without many caveats. First, the risk of an accident involving a large release of radioactive iodine is greatly influenced by the reactor design. The type of reactor in the four units at Chornobyl contained a number of design flaws particularly the lack of secondary containment (Vargo et al., 2000), as described in Chapters 3 and 4. Second, even if an event in the United States did involve large-scale releases, it could not be concealed from the population in the way it was after the Chornobyl accident. After Chornobyl, the population at risk was not informed of the nature of the accident, or of the precautions that should be taken, until long after the precautions would have been effective. Milk with a high radioiodine content 2   Data from Elaine Ron.

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident continued to be used, as did contaminated food; the population was not told to take shelter; stable iodine was not immediately distributed or used; and even limited evacuation was not started until about 36 hours after the accident. If contaminated milk and food had been avoided, most of the resulting thyroid cancers would almost certainly have not occurred. If KI had been effectively distributed within the appropriate time, the numbers of resulting thyroid cancers would have been even more greatly reduced. Third, the concentration of stable iodine intake in the diet is probably relevant. In experimental studies, fewer tumors develop when radioiodine is administered to animals that have a high iodine intake than in animals that have a low-iodine diet. The population around Chornobyl had a low iodine intake; in the United States, dietary stable iodine is 3-5 times higher than in much of the area around Chornobyl. The greater dietary iodine is associated with a smaller thyroid gland and also with a lower uptake of radioiodine than in areas that have iodine deficiency. The population around Chornobyl would therefore be predicted to take up more radioiodine into their thyroids than a US population exposed to similar levels of contamination. The evidence derived from studies of the effects of internal irradiation of the thyroid for medical reasons, of external radiation from the atomic bombs, and of internal radiation from iodine isotopes after Chornobyl shows that the group most susceptible to the development of thyroid cancer is young children and that the risk falls rapidly with increasing age at exposure. The studies also suggest that there was no appreciable risk of thyroid cancer in those who were adults at the time of exposure to radiation from radioiodine, although reliable information on the risk to those who were adults at the time of exposure to fallout from Chornobyl is not available, and future work in this area is needed. Studies from external radiation show no significant risk above the age of 20 years (Thompson et al., 1994), although there might be a very small risk between the ages of 20 and 30 years. A number of countries and the World Health Organization have adopted a precautionary approach, stating that 40 years is the age above which there is no risk that thyroid cancer will occur as a result of radiation to the thyroid and that therefore there is no

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident requirement for this group to take stable iodine to prevent the development of cancer after exposure to radioiodine. It is logical to use the risk to the most vulnerable group, young children, as the basis for deciding whether to use stable iodide to avert the risk of thyroid cancer after exposure to radioiodine. Evidence on the quantitative risk of thyroid cancer after thyroid exposure to external and internal radiation is available. For external radiation, the lifetime risk estimates are derived from observations over much of the lifetime of those who were children at the time of the atomic bomb, or were irradiated for medical reasons as children in the 1930s and later. The lifetime risk posed by exposure to iodine isotopes from Chornobyl fallout is based on the experience of less than 17 years since the accident and on dose estimates that are less certain than those for external radiation. Experimental studies suggest that external radiation is 1-3 times as effective as radiation from 131I in inducing thyroid tumors (Lee et al., 1982). We therefore use the data from external radiation to estimate the relationship between thyroid radiation dose from iodine isotopes and risk of thyroid cancer, knowing that the actual risk is likely to be lower than the predicted risk. At very low doses of radiation, it is not certain that the direct relationship between thyroid-cancer induction and dose continues. Some predictions suggest that radiation is proportionally less effective in inducing tumors at very low doses. We have assumed that the straight-line relationship continues and that radiation from 131I is equally effective as external radiation in inducing thyroid cancer. The best available data are based on a pooled analysis of seven studies of the development of thyroid cancer after exposure to radiation (Ron et al., 1995). Data derived from the study show that for children under 5 years old at exposure the excess relative risk (ERR) per gray was 9.0; that is, those exposed to 1 Gy (100 rad) of radiation before the age of 5 years would develop up to 9 times as many extra cases of thyroid cancer during their lifetime as they would have developed without such exposure. The ERR per Gy for children 5-9 years old at exposure was 5.2, and for children 10-14 years old at exposure 1.7.3 On the basis of the lifetime risk of developing thyroid 3   Data from Elaine Ron.

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident cancer in the United States and the lifetime risk of dying from thyroid cancer (SEER Cancer Statistics Review 1975-2000, National Cancer Institute) and a linear relationship between dose and risk, the chance of developing thyroid cancer in those exposed to different doses of radiation as children can be calculated. Evidence on the risk to the unborn from maternal exposure to radioiodine after Chornobyl suggests that it is considerably less than the risk to very young children. We believe that the risk to the most vulnerable group (children under 5 years old) should be the basis for determining precautionary measures. The predicted radiation dose to the thyroid for each of the age groups can be calculated for a variety of accident scenarios. We will base the risk on the so-called design-base accident (DBA), which is the most severe accident that has more than an extremely remote chance of occurring. It is assumed, for example, that there is a complete failure of secondary containment with a large-scale rupture of fuel rods and loss of various control mechanisms. The dose used to estimate the risk is the averted dose, that is, the dose derived from inhalation. The potential dose from ingestion will be avoided through measures that take contaminated milk and other foodstuffs out of the food chain immediately after a major accident occurs. The averted dose would in practice be reduced or abolished by evacuation or sheltering. We have assumed that neither sheltering nor evacuation take place and that no stable iodine is taken, again, to avoid underestimating the risk. With those assumptions, the estimates that already exist for emissions in the event of a DBA and the estimated dose to the population exposed because of these emissions can be used to calculate the risk of thyroid carcinoma in the most vulnerable group. The results can be presented as idealized contours; in practice, the plume from any accident is likely to be concentrated in one direction, so risk in that direction will extend beyond the idealized contour, and risk in other directions will be much lower. The plan for each NPP will differ, depending on the design and capacity of the reactor and on the prevailing weather patterns. The information given here can be used to determine the risk contours for each NPP; taken together with other local variables such as population density and distribution, these

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Distribution and Administration of Potassium Iodide in the Event of a Nuclear Incident provide the basis for determining the extent and method of distribution of KI. In summary, a review of experience with thyroid cancer in populations exposed to the consequences of nuclear events shows that: Exposure to external radiation or internal radiation from radioactive iodine is linked to a dose-dependent increase in thyroid-cancer incidence. Young children are by far the most sensitive to the carcinogenic effect of radiation on the thyroid, especially after exposure to radioactive iodine in fallout. The risk of thyroid carcinoma in adults exposed to radioactive iodine in fallout is very low, and can be assumed to be absent for adults over 40 years old although at very high doses there is a risk of hypothyroidism. The probability of a large release of radioactive iodine from the type of reactor used in the United States is much lower than the chance of a large release in countries that use reactors of the type used at Chornobyl. Therefore, the risk of thyroid carcinoma in the US population in the event of a nuclear accident is likely to be considerably less than the risk after Chornobyl both because of the level of dietary iodine and because of the use of precautionary measures.