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The researches at Nagasaki University on atomic bomb survivors
International Congress Series 1258 (2003) 39 – 49
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The researches at Nagasaki University on atomic bomb survivors Ichiro Sekine * Department of Molecular Pathology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
Abstract. The Nagasaki Medical College, the present Nagasaki University School of Medicine, has the longest history in Japan with western-style medical education and has a tragic history of the atomic bomb which destroyed the college and caused the loss of more than 890 staff members and students. In these 50 years after the atomic bombing, many epidemiological studies conducted by the Atomic Bomb Casualty Commission (ABCC) and followed by the Radiation Effects Research Foundation (RERF) have elucidated the increased incidence of many kinds of neoplasm such as leukemia and solid tumors in atomic bomb survivors. The Atomic Bomb Disease Institute, Nagasaki University School of Medicine, has conducted collaborative studies with RERF. Some characteristic and representative studies on atomic bomb survivors conducted by research staff of the School of Medicine and the Atomic Bomb Disease Institute are described here, including leukemia studies, incidences of meningioma and skin cancer by distance from the hypocenter, mental health conditions, and epidemiological and molecular studies using the Nagasaki Tumor and Tissue Registry. D 2003 Published by Elsevier B.V. Keywords: Atomic bomb; Leukemia; Meningioma; Skin cancer; Microarray; FISH
1. Introduction As Prof. Saito, the president of Nagasaki University, mentioned briefly during his opening address of this meeting, Nagasaki has two characteristic aspects in Japan. One is that Nagasaki was the only city with an open port for foreign countries for about 300 years when the government enforced the policy of national seclusion. During that period, all foreign cultures entered Japan only through Nagasaki. That is why Nagasaki has developed its unique and exotic culture. Another aspect is that Nagasaki was the second city after Hiroshima to suffer atomic bombing on 9 August 1945.
* Tel.: +81-95-849-7105; fax: +81-95-849-7108. E-mail address: [email protected] (I. Sekine). 0531-5131/ D 2003 Published by Elsevier B.V. doi:10.1016/S0531-5131(03)01211-1
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I. Sekine / International Congress Series 1258 (2003) 39–49
Fig. 1. Urakami area of Nagasaki city.
Fig. 2. Dr. Nagai, who was in Nagasaki Medical University at the time of the atomic bombing, treated many survivors.
I. Sekine / International Congress Series 1258 (2003) 39–49
41
Nagasaki University School of Medicine has a similar history as Nagasaki city. The Nagasaki Medical College, the present Nagasaki University School of Medicine, was destroyed by the second atomic bomb which was detonated at a distance of about 500 m from the college (Fig. 1). The predecessor of Nagasaki University School of Medicine was established in 1857 by Dr. J.L.C. Pompe van Meedervoort, who was invited from the Netherlands. The Nagasaki University School of Medicine has the longest history in Japan with western-style medical education. More than 890 staff members and students were killed by the atomic bomb. At that time, there was no medical school in Hiroshima, so the oldest medical school in Japan became the first victim of atomic bombing in the world. Although many staff members of Nagasaki Medical College died instantly or were seriously injured after the explosion, survivors of the Medical College Hospital organized medical rescue teams and started treatment of burned and injured citizens in the worst circumstances, regardless of their own injuries. Among them, Dr. Takashi Nagai was a most famous doctor, who was an assistant professor in the Department of Radiology at Medical College. After the loss of his dearest wife as a result of the atomic bombing, he wrote many books about the atomic bomb and about his family. He died of leukemia 6 years after the war, and he was recognized as the first honorary citizen of Nagasaki. During the rescue activity, a lot of medical records were written, and they were highly valued later as significant documentation of the medical damage caused by the atomic bomb and were recently translated to English (Fig. 2). 2. Outlines of atomic bomb injuries In Nagasaki, about 78 000 citizens were killed by atomic bomb injuries. The atomic bomb injuries are divided into three groups in accordance with the major forms of energy: atomic bomb burns, atomic bomb wounds, and atomic bomb radiation injuries. 2.1. Atomic bomb burns One second after the explosion, a big ball of fire exceeding 200 m in diameter was formed, and its surface temperature reached up to 6000 jC. Because of this strong heat, many people within 4 km from the hypocenter suffered from burns, mainly in exposed parts of the body. 2.2. Atomic bomb wounds The explosive power was calculated to be equal to 21 kt of TNT. These wounds were caused directly by the explosion power or indirectly by the debris from collapsing houses (Fig. 3). 2.3. Atomic bomb radiation injuries The explosion of the atomic bomb released a large quantity of radiation, mostly gamma rays and neutrons. Strong direct radiation with more than the dose of LD50 caused severe
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I. Sekine / International Congress Series 1258 (2003) 39–49
Fig. 3. Destruction of houses and buildings in Nagasaki city.
Fig. 4. Contamination by radiation at Nagasaki.
I. Sekine / International Congress Series 1258 (2003) 39–49
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injures to the people within 1 km from the hypocenter. Other types of radiation damage were caused by residual radioactivity and fallout materials (Fig. 4). Those who were close to the hypocenter and were neither severely burned nor wounded began to show the symptoms of acute radiation damage, such as general fatigue, appetite loss, diarrhea, fever, hemorrhage, stomatitis, leucopenia, thrombocytopenia, and were gradually dying. The death started from the hypocenter and spread radially in a circle, which has been referred to as ‘‘the concentric circle of death.’’ Acute radiation damage and acute atomic bomb diseases were essentially caused by cell death, the so-called apoptotic death of proliferating cells. It is notable in bone marrow, lymph nodes, thymus, and intestines. The first cause of death was intestinal death, and after that, bone marrow death. Bone marrow death includes hemorrhage due to thrombocytopenia, infection and inflammation due to leucopenia, and state of immune suppression. 3. Researches at Nagasaki University on atomic bomb survivors The Atomic Bomb Disease Institute of Nagasaki University School of Medicine was established in 1962 for the purpose of universal basic research on radiation medicine and the late effects of radiation on the human body. The Scientific Data Center for Atomic Bomb Disaster was established in 1972 for the purpose of the collection, arrangement, and preservation of a lot of materials such as clinical medical records, photographs, microscopic specimens, and paraffin blocks for pathological research. Some characteristic and representative studies on atomic bomb survivors conducted by research staff of the School of Medicine and Atomic Bomb Disease Institute are described below. 3.1. Leukemia For many years, the Radiation Effects Research Foundation (RERF) and the Atomic Bomb Disease Institute have conducted collaborative studies on atomic bomb irradiationinduced leukemia, which is well known as one of the most frequent malignancies among survivors. A group of about 120 000 people, including some 93 700 atomic bomb survivors, was established by the Atomic Bomb Casualty Commission, the present RERF, and its Life Span Study (LSS) was started to follow up all members of this cohort. The data coming from this study is very informative: this study provided the clear evidence of increased incidence of leukemias among survivors. In parallel with LSS, we have conducted another group study called Open City Study (OCS) following up all leukemia cases found in survivors irradiated within 9 km of the hypocenter. The number of leukemia patients found in OCS was three times greater than those in LSS. Although the incidence of leukemia cannot be calculated directly using OCS data, it allowed us to compare the incidence rate by age and leukemia type (Fig. 5). The FAB (French – American – British) classification was adopted to diagnose and classify acute leukemias. We found that the radiation has greater effect on the incidence
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Fig. 5. Leukemia registry for atomic bomb survivors since 1950 (Hiroshima and Nagasaki).
of acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML) than on acute myelogenous leukemia (AML). Differential effects of atomic bomb irradiation to the induction of three major types of leukemia provide us with the insights into human leukemogenesis (Fig. 6). In addition to leukemia, many hematological disorders were found among survivors. Among them, myelodysplastic syndrome (MDS) showed the highest excess relative risk. MDS is a clonal hematological disorder that sometimes transforms into leukemia. It is an elderly person’s disease, and the survivors are now in the middle of MDS age. It is necessary to confirm the relative risk of MDS among atomic bomb survivors (Table 1).
Fig. 6. Type-specific proportion of leukemia in open city study. ALL = acute lymphocytic leukemia; AML = acute myelogenous leukemia; CML = chronic myelogenous leukemia; MDS = myelodysplastic syndrome.
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Table 1 Excess relative risk (ERR) of hematological disorder (other than leukemia) Hematological disorder
Cases
ERR
90% CIa
p-valueb
MDSc Non-MDS Anemia Aplastic Non-aplastic Total
13 123 101 36 65 136
15 1.9 1.5 0.25 2.3 2.7
4.8 – 56 0.8 – 3.4 0.4 – 3.1 < 0 – 2.4 0.8 – 5.0 1.5 – 4.4
< 0.001 < 0.001 < 0.001 > 0.5 0.003 < 0.001
a
90% confidence interval. Significance probability for testing that ERR = 0. c Myelodysplastic syndrome. b
3.2. Solid tumors In the 50 years after the atomic bombing, many epidemiological studies conducted by ABCC and followed by RERF have elucidated an increased incidence of many kinds of neoplasm such as leukemia and solid tumors of thyroid, lung, breast, stomach, and colon among atomic bomb survivors. These observations were highly valued in the world and became reference materials for safety standards of radiation. Many researchers at the Nagasaki University School of Medicine participated in those studies. Among solid tumors, the researcher of our institute disclosed increased incidence of meningioma and skin cancer by distance from the hypocenter. 3.2.1. Meningioma There were no reports indicating increased incidence of intracranial tumors including meningioma among the atomic bomb survivors. Sadamori et al. [1,2] collected 45 cases of surgically treated meningioma during the period from 1973 to 1992. Since 1981, 36 years
Fig. 7. Incidence of skin cancer in Nagasaki atomic bomb survivors by distance from the hypocenter (both sexes).
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after the bombing, the incidence of meningiomas among the survivors, especially in those exposed closely to the hypocenter, appears to be increased inversely with the distance from the hypocenter. 3.2.2. Skin cancer Although no evidence of increased incidence of skin cancer in atomic bomb survivors was reported until 1990, Sadamori et al. [3] analyzed 140 survivors who had skin cancer among more than 66 000 survivors registered in our institute and found a high correlation between the incidence of skin cancer and the distance from the hypocenter (Fig. 7). 3.3. Mental health conditions Investigations on mental or psychological effects of atomic bomb have not been received much attention. Honda et al. [4] conducted a mental health survey on atomic bomb survivors
Table 2 Incidence rate (number of cases per 100 000 persons per year) of female cancer by site and distance from the hypocenter (1973 – 2001) Site
Total cases
Digestive system Esophagus Stomach Colon Rectum Pancreas Respiratory system Nasal cavity Larynx Trachea, bronchus, and lung Skin Basal cell Female breast Urogenital system Uterine cervix Uterine corpus Ovary Bladder Kidney Renal pelvis and ureter Nervous system Meningioma Thyroid Total a b
Distance from the hypocenter (km) 0.9
1.0 – 1.4
1.5 – 1.9
2.0 – 2.4
2.5 – 2.9
3.0 –
Relative riska
p-valueb
36 842 565 307 36
0 130.0 77.8 34.5 0
6.9 101.2 39.0 32.1 2.3
3.0 89.8 53.2 27.3 6.1
2.9 94.6 61.5 32.9 4.3
3.9 80.8 68.2 32.1 3.1
3.7 85.1 57.3 31.6 3.7
0.72 0.96 0.99 0.97 0.77
0.03 0.14 0.74 0.48 0.09
18 10 250
0 0 17.2
2.3 0 41.2
4.5 1.5 30.3
1.4 1.4 21.4
1.6 2.3 27.4
1.7 0.8 24.4
0.56 0.65 0.86
0.003 0.17 0.01
143 85 598
43.1 34.5 122.3
27.5 13.7 145.8
13.6 7.6 73.2
10.0 8.6 68.9
11.7 7.0 51.0
14.5 8.4 55.2
0.89 0.81 0.84
0.1 0.02 < 0.001
331 108 84 120 35 27 28 56 91 3861
17.2 25.8 8.6 17.2 0 0 0 25.8 43.2 539.6
32.1 16.0 13.7 22.9 9.2 4.6 2.3 18.3 9.2 503.7
33.5 12.1 4.5 15.2 3.0 6.1 3.0 10.6 7.6 417.8
40.1 4.3 8.6 21.4 4.3 1.4 5.7 4.3 18.6 453.9
33.7 11.7 10.2 9.4 6.2 3.1 2.3 3.9 7.0 408.4
34.0 11.0 8.4 10.8 2.7 2.4 2.7 4.6 8.4 391.4
0.99 0.91 0.90 0.77 0.63 0.68 0.77 0.65 0.75 0.95
0.89 0.24 0.26 < 0.001 < 0.001 0.02 0.12 < 0.001 < 0.001 < 0.001
For 1-km increase of the distance from the hypocenter. Significance probability for testing that relative risk is 1.
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using the 12-item version of the General Health Questionnaire (GHQ-12) which is frequently used for screening minor psychiatric disorders, paying attention to exposure conditions and lifestyle. Their results indicated an increase of GHQ-12 scores in survivors who lost family members by atomic bombing and had symptoms of acute radiation damage and indicated that the mental disorders still remain though more than 50 years passed. Their reports consequently might have helped and supported the citizen’s campaign to the Ministry of Welfare and Labor for demanding the expansion of areas of atomic bomb disaster. 3.4. Epidemiological studies using Nagasaki Tumor and Tissue Registry The Nagasaki Tumor and Tissue Registration (NTTR) Committee was organized in 1973 by representative pathologists in Nagasaki, who have been registering tumor and tissues with their pathological diagnosis found in Nagasaki. A total of 31 746 cases of neoplastic lesions have been registered among 111 000 Nagasaki atomic bomb survivors Table 3 Incidence rate (number of cases per 100 000 person per year) of male cancer by site and distance from the hypocenter (1973 – 2001) Site
Digestive system Esophagus Stomach Colon Rectum Liver Gallbladder Pancreas Respiratory system Nasal cavity Larynx Trachea, bronchus, and lung Skin Basal cell Urogenital system Prostate Bladder Kidney Pelvis and ureter Nervous system Meningioma Thyroid Total a b
Total cases
Distance from the hypocenter (km)
141 1049 505 303 157 40 22
0.9
Relative riska
p-valueb
1.0 – 1.4
1.5 – 1.9
2.0 – 2.4
2.5 – 2.9
3.0 –
30.6 281.7 108.0 0 0 30.6 0
40.5 281.6 122.1 81.2 34.7 2.9 5.8
28.3 190.4 94.8 63.8 16.5 2.4 4.7
21.8 156.4 90.1 38.9 17.0 0 2.4
27.0 173.1 100.6 54.2 37.9 9.5 0
21.8 174.1 79.6 50.0 26.8 7.5 4.4
0.86 0.96 0.92 0.94 0.92 0.75 0.79
0.03 0.08 0.02 0.24 0.21 0.05 0.2
20 88 337
0 15.3 61.4
5.8 29.0 107.2
4.7 28.3 73.2
7.3 14.5 53.4
8.1 18.9 50.1
1.8 11.7 53.6
0.61 0.71 0.87
0.008 < 0.001 0.002
118 59
30.7 15.3
46.4 29.0
26.0 14.2
29.1 14.5
18.9 6.8
16.4 8.1
0.79 0.71
0.001 < 0.001
215 206 54 35 16 16 10 3275
61.5 76.9 15.3 0 0 0 0 781.6
72.5 49.3 8.7 20.3 2.9 5.8 11.6 921.6
42.5 28.4 18.9 7.1 2.4 4.7 0 631.5
29.1 24.3 7.3 4.8 4.8 7.3 2.4 508.9
37.9 43.3 16.2 6.8 0 0 2.7 623.7
33.3 33.9 7.0 4.7 3.1 2.3 0.8 534.8
0.87 0.93 0.74 0.63 0.74 0.76 0.42 0.93
0.01 0.19 0.007 < 0.001 0.17 0.21 < 0.001 < 0.001
For 1-km increase of the distance from the hypocenter. Significance probability for testing that relative risk is 1.
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from 1973 through 2001, and 7136 cases have been registered as malignant solid tumors. We have recently investigated the incidence of several tumors among Nagasaki atomic bomb survivors from 1973 to 2001 in relation to the distance from the hypocenter. Table 2 shows the incidence rate (number of cases per 100 000 persons per year) of female cancer in each site by the distance from the hypocenter. A significant correlation ( p < 0.001) between distance and incidence was suggested in sites such as breast, urinary bladder, kidney, meningioma, and thyroid. Similarly, in male survivors, a significant correlation between distance and incidence rate of cancer was observed in sites of larynx, basal cell of skin, pelvis, ureter, and thyroid (Table 3). 3.5. Microarray analysis of atomic bomb carcinogenesis using fluorescence in situ hybridization We are going to epidemiologically analyze molecular abnormalities in these tumorigenesis in relation to the distance from hypocenter. Resected tumors from these cases have been preserved as formalin-fixed paraffin-embedded tissues. It is quite difficult to extract sufficient quantity and quality of DNA/RNA from pathological materials stored for many years. In order to use these valuable materials effectively for realizing radiation effects on human carcinogenesis, we have just started to make tissue microarray of cancers from atomic bomb survivors and analyze aberrant oncogenes with fluorescence in situ hybridization (FISH). Fig. 8 shows ret/PTC rearrangements in paraffin-embedded papillary cancers of thyroid from atomic bomb survivors with FISH. Ret signals are labeled by orange and centromere of chromosome 10 are labeled with green fluorescence. The upper two panels showing
Fig. 8. Ret rearrangements in papillary thyroid carcinoma by FISH.
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three ret signals in a nucleus suggest inversion of ret gene, and the lower two panels showing a ret signal presenting separately from CEP10 green signal suggest translocation of ret gene. Our pilot study with FISH demonstrated two cases possessing possible ret gene rearrangements in 10 cases of thyroid cancers in survivors. Thus, FISH with tissue microarray should be a useful technique to analyze aberrant genes with numerous archival materials from atomic bomb survivors. 4. Concluding remarks Nagasaki city was reconstructed from the ruins by atomic bombing and became more beautiful than before the atomic bombing. Since then, more than 50 years have passed, and the memories of the atomic bomb have been fading gradually in the citizens. But now in the city, about 50 000 atomic bomb survivors are alive, and every year about 1000 survivors are dying. With this 21st century COE (Center of Excellence) program as a turning point, our staff members and researchers have to promote the studies on atomic bomb survivors. The Nagasaki atomic bomb should be the last nuclear weapon detonated by human beings in the world. References [1] N. Sadamori, S. Shibata, M. Mine, H. Miyazaki, H. Miyake, M. Kurihara, M. Tomonaga, I. Sekine, Y. Okumura, Incidence of intracranial meningiomas in Nagasaki atomic-bomb surviviors, Int. J. Cancer 67 (1996) 318 – 322. [2] S. Shibata, N. Sadamori, M. Mine, I. Sekine, Intracranial meningiomas among Nagasaki atomic-bomb survivors, Lancet 344 (1994) 8939 – 8940. [3] N. Sadamori, M. Mine, H. Miyazaki, T. Honda, Incidence of skin cancer among Nagasaki atomic bomb survivors, J. Radiat. Res. (Suppl. 2) (1991) 217 – 225. [4] S. Honda, Y. Shibata, M. Mine, Y. Imamura, M. Tagawa, Y. Nakane, M. Tomonaga, Mental health conditions among atomic bomb survivors in Nagasaki, Psychiatr. Clin. Neurosci. 56 (2002) 575 – 583.
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The researches at Nagasaki University on atomic bomb survivors Ichiro Sekine * Department of Molecular Pathology, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan
Abstract. The Nagasaki Medical College, the present Nagasaki University School of Medicine, has the longest history in Japan with western-style medical education and has a tragic history of the atomic bomb which destroyed the college and caused the loss of more than 890 staff members and students. In these 50 years after the atomic bombing, many epidemiological studies conducted by the Atomic Bomb Casualty Commission (ABCC) and followed by the Radiation Effects Research Foundation (RERF) have elucidated the increased incidence of many kinds of neoplasm such as leukemia and solid tumors in atomic bomb survivors. The Atomic Bomb Disease Institute, Nagasaki University School of Medicine, has conducted collaborative studies with RERF. Some characteristic and representative studies on atomic bomb survivors conducted by research staff of the School of Medicine and the Atomic Bomb Disease Institute are described here, including leukemia studies, incidences of meningioma and skin cancer by distance from the hypocenter, mental health conditions, and epidemiological and molecular studies using the Nagasaki Tumor and Tissue Registry. D 2003 Published by Elsevier B.V. Keywords: Atomic bomb; Leukemia; Meningioma; Skin cancer; Microarray; FISH
1. Introduction As Prof. Saito, the president of Nagasaki University, mentioned briefly during his opening address of this meeting, Nagasaki has two characteristic aspects in Japan. One is that Nagasaki was the only city with an open port for foreign countries for about 300 years when the government enforced the policy of national seclusion. During that period, all foreign cultures entered Japan only through Nagasaki. That is why Nagasaki has developed its unique and exotic culture. Another aspect is that Nagasaki was the second city after Hiroshima to suffer atomic bombing on 9 August 1945.
* Tel.: +81-95-849-7105; fax: +81-95-849-7108. E-mail address: [email protected] (I. Sekine). 0531-5131/ D 2003 Published by Elsevier B.V. doi:10.1016/S0531-5131(03)01211-1
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I. Sekine / International Congress Series 1258 (2003) 39–49
Fig. 1. Urakami area of Nagasaki city.
Fig. 2. Dr. Nagai, who was in Nagasaki Medical University at the time of the atomic bombing, treated many survivors.
I. Sekine / International Congress Series 1258 (2003) 39–49
41
Nagasaki University School of Medicine has a similar history as Nagasaki city. The Nagasaki Medical College, the present Nagasaki University School of Medicine, was destroyed by the second atomic bomb which was detonated at a distance of about 500 m from the college (Fig. 1). The predecessor of Nagasaki University School of Medicine was established in 1857 by Dr. J.L.C. Pompe van Meedervoort, who was invited from the Netherlands. The Nagasaki University School of Medicine has the longest history in Japan with western-style medical education. More than 890 staff members and students were killed by the atomic bomb. At that time, there was no medical school in Hiroshima, so the oldest medical school in Japan became the first victim of atomic bombing in the world. Although many staff members of Nagasaki Medical College died instantly or were seriously injured after the explosion, survivors of the Medical College Hospital organized medical rescue teams and started treatment of burned and injured citizens in the worst circumstances, regardless of their own injuries. Among them, Dr. Takashi Nagai was a most famous doctor, who was an assistant professor in the Department of Radiology at Medical College. After the loss of his dearest wife as a result of the atomic bombing, he wrote many books about the atomic bomb and about his family. He died of leukemia 6 years after the war, and he was recognized as the first honorary citizen of Nagasaki. During the rescue activity, a lot of medical records were written, and they were highly valued later as significant documentation of the medical damage caused by the atomic bomb and were recently translated to English (Fig. 2). 2. Outlines of atomic bomb injuries In Nagasaki, about 78 000 citizens were killed by atomic bomb injuries. The atomic bomb injuries are divided into three groups in accordance with the major forms of energy: atomic bomb burns, atomic bomb wounds, and atomic bomb radiation injuries. 2.1. Atomic bomb burns One second after the explosion, a big ball of fire exceeding 200 m in diameter was formed, and its surface temperature reached up to 6000 jC. Because of this strong heat, many people within 4 km from the hypocenter suffered from burns, mainly in exposed parts of the body. 2.2. Atomic bomb wounds The explosive power was calculated to be equal to 21 kt of TNT. These wounds were caused directly by the explosion power or indirectly by the debris from collapsing houses (Fig. 3). 2.3. Atomic bomb radiation injuries The explosion of the atomic bomb released a large quantity of radiation, mostly gamma rays and neutrons. Strong direct radiation with more than the dose of LD50 caused severe
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I. Sekine / International Congress Series 1258 (2003) 39–49
Fig. 3. Destruction of houses and buildings in Nagasaki city.
Fig. 4. Contamination by radiation at Nagasaki.
I. Sekine / International Congress Series 1258 (2003) 39–49
43
injures to the people within 1 km from the hypocenter. Other types of radiation damage were caused by residual radioactivity and fallout materials (Fig. 4). Those who were close to the hypocenter and were neither severely burned nor wounded began to show the symptoms of acute radiation damage, such as general fatigue, appetite loss, diarrhea, fever, hemorrhage, stomatitis, leucopenia, thrombocytopenia, and were gradually dying. The death started from the hypocenter and spread radially in a circle, which has been referred to as ‘‘the concentric circle of death.’’ Acute radiation damage and acute atomic bomb diseases were essentially caused by cell death, the so-called apoptotic death of proliferating cells. It is notable in bone marrow, lymph nodes, thymus, and intestines. The first cause of death was intestinal death, and after that, bone marrow death. Bone marrow death includes hemorrhage due to thrombocytopenia, infection and inflammation due to leucopenia, and state of immune suppression. 3. Researches at Nagasaki University on atomic bomb survivors The Atomic Bomb Disease Institute of Nagasaki University School of Medicine was established in 1962 for the purpose of universal basic research on radiation medicine and the late effects of radiation on the human body. The Scientific Data Center for Atomic Bomb Disaster was established in 1972 for the purpose of the collection, arrangement, and preservation of a lot of materials such as clinical medical records, photographs, microscopic specimens, and paraffin blocks for pathological research. Some characteristic and representative studies on atomic bomb survivors conducted by research staff of the School of Medicine and Atomic Bomb Disease Institute are described below. 3.1. Leukemia For many years, the Radiation Effects Research Foundation (RERF) and the Atomic Bomb Disease Institute have conducted collaborative studies on atomic bomb irradiationinduced leukemia, which is well known as one of the most frequent malignancies among survivors. A group of about 120 000 people, including some 93 700 atomic bomb survivors, was established by the Atomic Bomb Casualty Commission, the present RERF, and its Life Span Study (LSS) was started to follow up all members of this cohort. The data coming from this study is very informative: this study provided the clear evidence of increased incidence of leukemias among survivors. In parallel with LSS, we have conducted another group study called Open City Study (OCS) following up all leukemia cases found in survivors irradiated within 9 km of the hypocenter. The number of leukemia patients found in OCS was three times greater than those in LSS. Although the incidence of leukemia cannot be calculated directly using OCS data, it allowed us to compare the incidence rate by age and leukemia type (Fig. 5). The FAB (French – American – British) classification was adopted to diagnose and classify acute leukemias. We found that the radiation has greater effect on the incidence
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I. Sekine / International Congress Series 1258 (2003) 39–49
Fig. 5. Leukemia registry for atomic bomb survivors since 1950 (Hiroshima and Nagasaki).
of acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML) than on acute myelogenous leukemia (AML). Differential effects of atomic bomb irradiation to the induction of three major types of leukemia provide us with the insights into human leukemogenesis (Fig. 6). In addition to leukemia, many hematological disorders were found among survivors. Among them, myelodysplastic syndrome (MDS) showed the highest excess relative risk. MDS is a clonal hematological disorder that sometimes transforms into leukemia. It is an elderly person’s disease, and the survivors are now in the middle of MDS age. It is necessary to confirm the relative risk of MDS among atomic bomb survivors (Table 1).
Fig. 6. Type-specific proportion of leukemia in open city study. ALL = acute lymphocytic leukemia; AML = acute myelogenous leukemia; CML = chronic myelogenous leukemia; MDS = myelodysplastic syndrome.
I. Sekine / International Congress Series 1258 (2003) 39–49
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Table 1 Excess relative risk (ERR) of hematological disorder (other than leukemia) Hematological disorder
Cases
ERR
90% CIa
p-valueb
MDSc Non-MDS Anemia Aplastic Non-aplastic Total
13 123 101 36 65 136
15 1.9 1.5 0.25 2.3 2.7
4.8 – 56 0.8 – 3.4 0.4 – 3.1 < 0 – 2.4 0.8 – 5.0 1.5 – 4.4
< 0.001 < 0.001 < 0.001 > 0.5 0.003 < 0.001
a
90% confidence interval. Significance probability for testing that ERR = 0. c Myelodysplastic syndrome. b
3.2. Solid tumors In the 50 years after the atomic bombing, many epidemiological studies conducted by ABCC and followed by RERF have elucidated an increased incidence of many kinds of neoplasm such as leukemia and solid tumors of thyroid, lung, breast, stomach, and colon among atomic bomb survivors. These observations were highly valued in the world and became reference materials for safety standards of radiation. Many researchers at the Nagasaki University School of Medicine participated in those studies. Among solid tumors, the researcher of our institute disclosed increased incidence of meningioma and skin cancer by distance from the hypocenter. 3.2.1. Meningioma There were no reports indicating increased incidence of intracranial tumors including meningioma among the atomic bomb survivors. Sadamori et al. [1,2] collected 45 cases of surgically treated meningioma during the period from 1973 to 1992. Since 1981, 36 years
Fig. 7. Incidence of skin cancer in Nagasaki atomic bomb survivors by distance from the hypocenter (both sexes).
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I. Sekine / International Congress Series 1258 (2003) 39–49
after the bombing, the incidence of meningiomas among the survivors, especially in those exposed closely to the hypocenter, appears to be increased inversely with the distance from the hypocenter. 3.2.2. Skin cancer Although no evidence of increased incidence of skin cancer in atomic bomb survivors was reported until 1990, Sadamori et al. [3] analyzed 140 survivors who had skin cancer among more than 66 000 survivors registered in our institute and found a high correlation between the incidence of skin cancer and the distance from the hypocenter (Fig. 7). 3.3. Mental health conditions Investigations on mental or psychological effects of atomic bomb have not been received much attention. Honda et al. [4] conducted a mental health survey on atomic bomb survivors
Table 2 Incidence rate (number of cases per 100 000 persons per year) of female cancer by site and distance from the hypocenter (1973 – 2001) Site
Total cases
Digestive system Esophagus Stomach Colon Rectum Pancreas Respiratory system Nasal cavity Larynx Trachea, bronchus, and lung Skin Basal cell Female breast Urogenital system Uterine cervix Uterine corpus Ovary Bladder Kidney Renal pelvis and ureter Nervous system Meningioma Thyroid Total a b
Distance from the hypocenter (km) 0.9
1.0 – 1.4
1.5 – 1.9
2.0 – 2.4
2.5 – 2.9
3.0 –
Relative riska
p-valueb
36 842 565 307 36
0 130.0 77.8 34.5 0
6.9 101.2 39.0 32.1 2.3
3.0 89.8 53.2 27.3 6.1
2.9 94.6 61.5 32.9 4.3
3.9 80.8 68.2 32.1 3.1
3.7 85.1 57.3 31.6 3.7
0.72 0.96 0.99 0.97 0.77
0.03 0.14 0.74 0.48 0.09
18 10 250
0 0 17.2
2.3 0 41.2
4.5 1.5 30.3
1.4 1.4 21.4
1.6 2.3 27.4
1.7 0.8 24.4
0.56 0.65 0.86
0.003 0.17 0.01
143 85 598
43.1 34.5 122.3
27.5 13.7 145.8
13.6 7.6 73.2
10.0 8.6 68.9
11.7 7.0 51.0
14.5 8.4 55.2
0.89 0.81 0.84
0.1 0.02 < 0.001
331 108 84 120 35 27 28 56 91 3861
17.2 25.8 8.6 17.2 0 0 0 25.8 43.2 539.6
32.1 16.0 13.7 22.9 9.2 4.6 2.3 18.3 9.2 503.7
33.5 12.1 4.5 15.2 3.0 6.1 3.0 10.6 7.6 417.8
40.1 4.3 8.6 21.4 4.3 1.4 5.7 4.3 18.6 453.9
33.7 11.7 10.2 9.4 6.2 3.1 2.3 3.9 7.0 408.4
34.0 11.0 8.4 10.8 2.7 2.4 2.7 4.6 8.4 391.4
0.99 0.91 0.90 0.77 0.63 0.68 0.77 0.65 0.75 0.95
0.89 0.24 0.26 < 0.001 < 0.001 0.02 0.12 < 0.001 < 0.001 < 0.001
For 1-km increase of the distance from the hypocenter. Significance probability for testing that relative risk is 1.
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using the 12-item version of the General Health Questionnaire (GHQ-12) which is frequently used for screening minor psychiatric disorders, paying attention to exposure conditions and lifestyle. Their results indicated an increase of GHQ-12 scores in survivors who lost family members by atomic bombing and had symptoms of acute radiation damage and indicated that the mental disorders still remain though more than 50 years passed. Their reports consequently might have helped and supported the citizen’s campaign to the Ministry of Welfare and Labor for demanding the expansion of areas of atomic bomb disaster. 3.4. Epidemiological studies using Nagasaki Tumor and Tissue Registry The Nagasaki Tumor and Tissue Registration (NTTR) Committee was organized in 1973 by representative pathologists in Nagasaki, who have been registering tumor and tissues with their pathological diagnosis found in Nagasaki. A total of 31 746 cases of neoplastic lesions have been registered among 111 000 Nagasaki atomic bomb survivors Table 3 Incidence rate (number of cases per 100 000 person per year) of male cancer by site and distance from the hypocenter (1973 – 2001) Site
Digestive system Esophagus Stomach Colon Rectum Liver Gallbladder Pancreas Respiratory system Nasal cavity Larynx Trachea, bronchus, and lung Skin Basal cell Urogenital system Prostate Bladder Kidney Pelvis and ureter Nervous system Meningioma Thyroid Total a b
Total cases
Distance from the hypocenter (km)
141 1049 505 303 157 40 22
0.9
Relative riska
p-valueb
1.0 – 1.4
1.5 – 1.9
2.0 – 2.4
2.5 – 2.9
3.0 –
30.6 281.7 108.0 0 0 30.6 0
40.5 281.6 122.1 81.2 34.7 2.9 5.8
28.3 190.4 94.8 63.8 16.5 2.4 4.7
21.8 156.4 90.1 38.9 17.0 0 2.4
27.0 173.1 100.6 54.2 37.9 9.5 0
21.8 174.1 79.6 50.0 26.8 7.5 4.4
0.86 0.96 0.92 0.94 0.92 0.75 0.79
0.03 0.08 0.02 0.24 0.21 0.05 0.2
20 88 337
0 15.3 61.4
5.8 29.0 107.2
4.7 28.3 73.2
7.3 14.5 53.4
8.1 18.9 50.1
1.8 11.7 53.6
0.61 0.71 0.87
0.008 < 0.001 0.002
118 59
30.7 15.3
46.4 29.0
26.0 14.2
29.1 14.5
18.9 6.8
16.4 8.1
0.79 0.71
0.001 < 0.001
215 206 54 35 16 16 10 3275
61.5 76.9 15.3 0 0 0 0 781.6
72.5 49.3 8.7 20.3 2.9 5.8 11.6 921.6
42.5 28.4 18.9 7.1 2.4 4.7 0 631.5
29.1 24.3 7.3 4.8 4.8 7.3 2.4 508.9
37.9 43.3 16.2 6.8 0 0 2.7 623.7
33.3 33.9 7.0 4.7 3.1 2.3 0.8 534.8
0.87 0.93 0.74 0.63 0.74 0.76 0.42 0.93
0.01 0.19 0.007 < 0.001 0.17 0.21 < 0.001 < 0.001
For 1-km increase of the distance from the hypocenter. Significance probability for testing that relative risk is 1.
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from 1973 through 2001, and 7136 cases have been registered as malignant solid tumors. We have recently investigated the incidence of several tumors among Nagasaki atomic bomb survivors from 1973 to 2001 in relation to the distance from the hypocenter. Table 2 shows the incidence rate (number of cases per 100 000 persons per year) of female cancer in each site by the distance from the hypocenter. A significant correlation ( p < 0.001) between distance and incidence was suggested in sites such as breast, urinary bladder, kidney, meningioma, and thyroid. Similarly, in male survivors, a significant correlation between distance and incidence rate of cancer was observed in sites of larynx, basal cell of skin, pelvis, ureter, and thyroid (Table 3). 3.5. Microarray analysis of atomic bomb carcinogenesis using fluorescence in situ hybridization We are going to epidemiologically analyze molecular abnormalities in these tumorigenesis in relation to the distance from hypocenter. Resected tumors from these cases have been preserved as formalin-fixed paraffin-embedded tissues. It is quite difficult to extract sufficient quantity and quality of DNA/RNA from pathological materials stored for many years. In order to use these valuable materials effectively for realizing radiation effects on human carcinogenesis, we have just started to make tissue microarray of cancers from atomic bomb survivors and analyze aberrant oncogenes with fluorescence in situ hybridization (FISH). Fig. 8 shows ret/PTC rearrangements in paraffin-embedded papillary cancers of thyroid from atomic bomb survivors with FISH. Ret signals are labeled by orange and centromere of chromosome 10 are labeled with green fluorescence. The upper two panels showing
Fig. 8. Ret rearrangements in papillary thyroid carcinoma by FISH.
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three ret signals in a nucleus suggest inversion of ret gene, and the lower two panels showing a ret signal presenting separately from CEP10 green signal suggest translocation of ret gene. Our pilot study with FISH demonstrated two cases possessing possible ret gene rearrangements in 10 cases of thyroid cancers in survivors. Thus, FISH with tissue microarray should be a useful technique to analyze aberrant genes with numerous archival materials from atomic bomb survivors. 4. Concluding remarks Nagasaki city was reconstructed from the ruins by atomic bombing and became more beautiful than before the atomic bombing. Since then, more than 50 years have passed, and the memories of the atomic bomb have been fading gradually in the citizens. But now in the city, about 50 000 atomic bomb survivors are alive, and every year about 1000 survivors are dying. With this 21st century COE (Center of Excellence) program as a turning point, our staff members and researchers have to promote the studies on atomic bomb survivors. The Nagasaki atomic bomb should be the last nuclear weapon detonated by human beings in the world. References [1] N. Sadamori, S. Shibata, M. Mine, H. Miyazaki, H. Miyake, M. Kurihara, M. Tomonaga, I. Sekine, Y. Okumura, Incidence of intracranial meningiomas in Nagasaki atomic-bomb surviviors, Int. J. Cancer 67 (1996) 318 – 322. [2] S. Shibata, N. Sadamori, M. Mine, I. Sekine, Intracranial meningiomas among Nagasaki atomic-bomb survivors, Lancet 344 (1994) 8939 – 8940. [3] N. Sadamori, M. Mine, H. Miyazaki, T. Honda, Incidence of skin cancer among Nagasaki atomic bomb survivors, J. Radiat. Res. (Suppl. 2) (1991) 217 – 225. [4] S. Honda, Y. Shibata, M. Mine, Y. Imamura, M. Tagawa, Y. Nakane, M. Tomonaga, Mental health conditions among atomic bomb survivors in Nagasaki, Psychiatr. Clin. Neurosci. 56 (2002) 575 – 583.