Leukemia: Lessons from the Japanese Experience STUART C. FINCH Cooper Hospital, Camden, New Jersey, USA Key Words. Leukemia. Japan Life Span Study Atomic bomb. Radiation ABSTRACT Probably more has been learned about radiation-induced leukemia from intensive study of Japanese atomic bomb survivors than about radiation damage to any other organ system. This has been the result of an intensive binational effort at the Atomic Bomb Casualty Commission and the Radiation Effects Research Foundation in Hiroshima and Nagasaki to monitor the occurrence of leukemia in a large group of atomic bomb survivors over a period of more than 50 years (the Life Span Study). The focus in the leukemia studies has been on disease latency, time of peak incidence rates, clinical course, shape of the dose-response curve and changes in risk over time for various types of leukemia in relationship to shielded kerma and bone marrow radiation dose, age at time of exposure, and gender. The extreme understanding and cooperation of the Japanese atomic bomb survivors, control subjects, physicians of Hiroshima and Nagasaki, government authorities, and the citizens of both cities has resulted in an epidemiological study that is almost unparalleled in medical history. Stem Cells 1997:lS(suppl2):13S-l39 INTRODUCTION It is important that the data for radiation-induced leukemia in the Japanese atomic bomb be placed into context when comparisons are made with other studies. The Life Span Study (LSS), which has provided the basic population with the evaluation of radiation-induced cancer mortality and incidence, has many attributes but also some weaknesses [l-31. One of its major strengths is the large size of the population, with representation from all ages and both sexes and without selection because of disease or occupation. The basic population consists of about 94,000 persons, for 92% of whom there are both shielded kerma and bone marrow dose estimates. The range of radiation doses was broad, ranging from zero to greater than 4 Gy, and consisted mostly of low linear energy transfer (LET) y radiation with a small neutron component. Individual dosimetry was comprehensive with careful attention to shielding and extensive use of biological dosimetry. The observation periods, leukemia mortality and incidence for which results have been published most recently are 35 and 37 years, respectively, after exposure to the atomic bombs of 1945 [2, 31. All cases of leukemia for incidence studies are carefully reviewed by a binational team of expert hematologists [4]. This includes the cases identified between 1945 and 1950, which was before initiation of the LSS. Leukemia ascertainment since 1950 is believed to be virtually complete as a result of the strong cooperative clinical arrangements in Hiroshima and Nagasaki for the incidence studies and the compulsory Japanese family registration system for the mortality studies. Characteristics of the atomic bomb radiation also impose some restrictions on the direct transfer of risk estimates for radiation-induced leukemia to persons exposed to radiation from other sources [ 11. Radiation from the atomic bombs was delivered at a very high-dose rate with minimal ground contamination. The Radiation Znjury and the Chernobyl Catastrophe. STEM CELLS 1997;15(suppl2):135-139 0 1997 AlphaMed Press. All rights reserved.
136 Leukemia: Lessons from the Japanese Experience risks of leukemia from this type of exposure, however, are likely to overestimate those from the more gradual low-dose rate occupational, environmental, and medical exposures experienced at random throughout civilian Me. Although the major exposure in both cities was to low LET y radiation, the precise amount of the much smaller neutron component remains uncertain, and estimates have fluctuated over the years 151. It has been suggested recently that the neutron component of the radiation from the bombs in both cities may have been larger than has been estimated in the current dosimetry system [6]. The small neutron contribution has generally been accepted to have a relative biological effectiveness (BE) of ten, but this is another uncertainty. The extent of individual dose imprecision in the exposed population also is uncertain. The population and sex composition of the LSS population was slightly over 55% female, with a lower than normal number of males being mainly in the 15-30-year age groups. 131. Although a leukemia registry was started in both cities about three years after the bombing, uncertainties remain as to the precise latency period for leukemia. The LSS was not initiated until 1950, as this was the fest time since cessation of hostilities in 1945 that accurate population information became available for both Hiroshima and Nagasaki. LEUKEMIA INCIDENCE AND MORTALITY The most recent mortality risk estimates are based on the analysis of 202 cases of leukemia that occurred between the years 1950 and 1985 in a population of about 76,000 survivors with radiation dose estimates [2]. The leukemia cases represent about 20% of the excess cancer deaths due to radiation exposure during that period. The incidence study includes an analysis of 231 cases of leukemia recorded between the years 1950 and 1987 in about 86,000 survivors with radiation dose estimates 131. About half of the survivors included in th~s study had bone marrow dose estimates of 0.005 Sv or less [7]. Classification of leukemia types in both studies has been made in accordance with the International Classification of Diseases, 9th edition (ICD-9). Additional analysis using the French-American-British (FAB) leukemia types has been made for persons with leukemia in the open city populations of Hiroshima and Nagasaki from 1945 through 1980 [8,9]. This analysis included 493 cases of leukemia, of which 177 were in the LSS. The mortality and incidence risk estimates for radiation-induced leukemia of all types combined from the LSS studies correspond quite closely [lo]. The average excess relative risk over a period of about 35 years for the population exposed to about 1 Sv of bone marrow dose is about five. The excess absolute risk per 104 person-year (PY) Sv bone marrow dose is about 2.8. The attributable risk from radiation exposure for leukemia types combined from incidence studies is about 50% 12, 31. Best estimates for a latent period for radiation-induced leukemia after exposure are two to three years based on the observations of Folley et al. [ 113. Leukemia incidence and mortality studies of the atomic bomb survivors have provided much important information regarding the influences of age at time of exposure or changes in risk estimates over time [2, 31. The relative leukemia mortality risk at 1 Gy of shielded kerma with all sexes and ages combined 5-10 years after exposure was almost 12. At 25 years it had fallen to about two, where it remained for the next 20-25 years. The increased relative risk continuing through the years 1981-1985 was probably due to the excess observed only in persons exposed between the ages of 30 and 49 [2]. The interactions of age at time of exposure and sex appear to have had an additional influence on radiation-induced leukemia mortality. The absolute risk of leukemia mortality appears to be moderately greater for males than females at any age of exposure with moderately increased excess deaths after exposure under the age of ten, falling to considerably lower levels for both sexes with exposures in the 10-19 age group, and then either remaining slightly elevated or rising progressively in persons exposed later in life. [2] The overall data, however, suggest that the relative risk for radiation-induced leukemia actually varies little by sex. The higher absolute risks for males are commensurate with their higher background rates, so that relative risks generally show little difference between the sexes [2]. The interactions of sex and age at time of exposure appear to influence absolute leukemia risks later in life, as has been demonstrated clearly in studies of leukemia incidence [3]. The absolute risk for males
Finch 137 is three to four times greater than for females when observed about five years after exposure. Thereafter, the absolute leukemia risks for males fall off rapidly and more slowly for females, so that by 20-39 years after exposure, the absolute risks for males and females are very similar, irrespective of the age at time of exposure. Although the absolute risks for males in all exposure groups and for females in the two younger exposure groups continued to fall gradually during the next 10-20 years, the absolute excess risk for women exposed over age 40 continues to increase to rates that are several times greater than those of the other groups. This suggests that the excess absolute risk for exposed young men decreases rapidly with time, whereas the risks for older exposed females continue or may even increase with time. Another important lesson learned from the Hiroshima-Nagasaki experience is that susceptibility factors for each of the major types of radiation-induced leukemia vary considerably depending on many variables, including sex, age at time of exposure, and probably a great many other environmental exposures that we understand poorly at this time [3]. It is for this reason that risk analysis for radiation-induced leukemia alone without reference to type of disease and other qualifying factors provides only partial information. For example, the most recent incidence report indicates that about 60% of the leukemia in exposed males was acute lymphocytic or chronic myelogenous in type. In exposed females, however, acute myelogenous leukemia was slightly more frequent than the other two types under the age of 40, whereas in the later years of life acute lymphocytic and chronic myelogenous leukemias were moderately more frequent. As shown in studies by Preston et al., the estimates of both absolute and relative risk for various types of radiationinduced leukemia varied according to leukemia type [3]. The highest excess absolute risk was for acute myelogenous leukemia at 1.1, followed by chronic myelogenous leukemia at 0.9 and acute lymphoblastic leukemia at 0.6 cases per lo4 PY Sv. The highest excess relative risk was for acute lymphoblastic leukemia at 9.1, followed by chronic myelogenous leukemia at 6.2 and acute myelogenous leukemia at 3.3 per Sv. Exposure at a young age resulted in the highest excess absolute risks for acute myelogenous and lymphocytic leukemias but not for chronic myelogenous leukemia. The excess risk for all combined types of leukemia declined with time at a rate of about 6.5% per year. On the other hand, the excess risk for acute lymphocytic leukemia declined about 14% per year, whereas the risk for acute myelocytic leukemia declined rapidly for younger exposed persons but has remained constant or has increased for persons exposed at older ages. Chronic myelogenous leukemia decreased rapidly in the early years for males, but the excess risk for females has remained constant over time. Variations in attributable radiation risks for the different types of leukemia are notable. The attributable risks for acute lymphocytic and chronic myelocytic leukemias are about 70% and 62%, respectively [3]. In contrast, the attributable risk for acute myelogenous leukemia is only about 46%. No new or unusual types of radiation-induced leukemia have been observed in the studies in Japan. The clinical cancers and therapeutic responses of exposed persons with leukemia have not appeared to be different from those of unexposed persons with leukemia. None of the several comprehensive leukemia incidence reports concerning radiation-induced hematological disease in Hiroshima or Nagasaki have shown an increased risk for chronic lymphocytic leukemia. Reclassification of the LSS and other Hiroshima and Nagasaki leukemia cases in the open city populations according to the FAB system also indicates that the relative risks for acute lymphocytic and chronic myelocytic leukemias are greater than those for acute myelogenous leukemia [9]. An important aspect of the FAB reclassification of leukemia in Nagasaki was that most of the previously classified cases of atypical chronic lymphocytic leukemia or leukosarcoma leukemia were consistent with the diagnosis of adult T cell leukemia [8, 9, 121. The study also showed that there was no evidence of a radiation risk for either chronic lymphocytic leukemia or adult T cell leukemia [9]. The bone marrow dose-response curve for all types of leukemia combined in the incidence study is slightly concave and curved upward in the 0-4 Gy range (suggestive of a linear-quadratic equation) [3]. The dose-response curves for acute lymphoblastic and chronic myelogenous leukemias appear linear, whereas the curve for acute myelogenous leukemia appears nonlinear (quadratic or spline). The nonlinear concave upward dose-response curve for acute myelogenous leukemia probably accounts for the
138 Leukemia: Lessons from the Japanese Experience slight curvature of the dose response for all leukemias combined. The dose-response curve for all types of leukemia combined in the mortality study for persons exposed to less than 2 Gy bone marrow dose fits a linear-quadratic model slightly better than a linear model [2, 131. The dose-response curve for mortality showed some downward bending for bone marrow exposure doses over 2-3 Gy. This effect in a small number of patients registered with high radiation doses in the range of 4 Gy or higher is presumably due to a cell killing effect. The risk of leukemia based on the incidence data for persons exposed to bone marrow doses in excess of 4 Gy was not estimated because of the many dose uncertainties and the relatively small number of persons in this category [3]. A significant increase in leukemia mortality was not demonstrated for persons in the LSS with bone marrow-absorbed doses of less than 20-30 cgy or from shielded kerma doses of less than 0.5 to 0.99 Gy. This information on exposure from studies of mortality does not imply a threshold level. It most likely means only that the populations studied are not large enough to evaluate risks at lower levels of exposure accurately. The LSS leukemia incidence study showed evidence of increased leukemia risks below 0.5 Gy exposure, which provided strong evidence against a threshold at that level. Follow-up of about 1,791 children exposed in utero and their controls between the years 1945 and 1984 has shown an unexplained low leukemia risk for those in the high-risk group [14, 151. There has also been no observation of a significant excess risk of leukemia in about 72,000 children born to exposed parents [15, 161. It is believed that the leukemia in the F, generation is due to somatic mutations that occurred after birth [15]. The average excess absolute and relative risks for radiation-induced leukemia incidence and mortality from the Japanese LSS in comparison to a number of other studies of radiation-induced mortality are almost invariably higher, as summarized in the 1994 report of the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) [ 11. This may be the result of the radiation having been delivered at a high-dose rate, a larger neutron component than currently is estimated, an RBE higher than 10 for the neutron component, inaccuracies in dose estimates, differences in composition of study populations, or other unknown factors [17]. CONCLUSIONS There is no doubt that the information from Hiroshima and Nagasaki has contributed greatly to our knowledge of radiation-induced leukemia, although a great many uncertainties remain. It is clear, however, that many variables exist for the risks of radiation-induced leukemia for each type of leukemia. The quality and quantity of radiation exposure may be the most important factor, but age, sex, temporal factors, and most likely the genetic structure of persons at risk must also be taken into consideration. A linear response represents the most conservative approach to risk in the lowdose range, but much greater amounts of information with greater precision must be obtained to resolve this important problem. ADDENDUM Subsequent to this presentation a new Life Span Study mortality report was published by investigators at the Radiation Effects Research Foundation in Japan [ 181. This report extended the previous report by five years (1986-1990), and added information on an additional 10,500 survivors with recently estimated radiation doses. Absolute and relative leukemia risk estimates for each sex were provided by weighted bone marrow dose. These risks differed little from the previous report, but the investigators cautioned that great care should be taken in their interpretation because of the imprecision in radiation dose estimates. The dose response curve for all leukemia combined was nonlinear. The report emphasized temporal patterns for excess risk. Excess lifetime leukemia risks at 1 Sv for both males and females exposed at either 10 or 30 years of age were estimated at about 0.015 and 0.008, respectively. Persons exposed at age 50 had about two-thirds those risks.
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