Atomic Bombing (A-bomb) in Hiroshima and Nagasaki 
 
 Early days of Hiroshima and Nagasaki after atomic bombing (adopted from 6 August 2015 issue of the Asahi Daily News
 
A. Density map of survivors resitered in LSS cohort to whom T65D doses have been assigned [1].      B. Survival rate (inverese of death rate) as of 10 August 1946 [2]. 
Scenario [1-5] 

     Fission-type atomic bombs (A-bomb) were detonated over Hiroshima and Nagasaki cities on August 1945. The damage in the cities was caused by a combination of burns, concussions and radiation. Out of a total of about 660,000 persons in the two cities, about 200,000 persons died by the end of 1945, and about 340,000 persons died during the first 5 years [1, 2]. To examine the medical and biological effects of atomic bombings, the Atomic Bomb Casualty Commission (ABCC) was established in Hiroshima and Nagasaki on 26 November 1946 with funding by the U. S. Atomic Energy Commission through reputation of U. S. National Academy of Science. The organization was later succeeded by the US-Japan binational funding organization, Radiation Effects Research Foundation (RERF), in 1975.

     In the nationwide survey, National Census, conducted in 1950, a total of 284,000 survivors were identified throughout the country. A group of about 110,000 subjects was sampled from those exposed survivors (< 2.5 km from hypocenter) and non-exposed controls (2.5-10 km from hypocenter) who were resident in Hiroshima and Nagasaki. This group, established in 1958, was called Life Span Study (LSS) cohort, comprising the exposed and control groups of comparable in size, sex and age except for exposure, and periodically followed up for the mortality. When the subject died, the cause of death has been confirmed by autopsies.

     The LSS cohort includes a subset of about 20,000 people, called Adult Health Study (AHS) cohort, comprising 5,000 exposed within 2 km and showed acute radiation symptoms, 5000 exposed within 2 km but no acute radiation symptom, 5000 who were 3 km or far, and 5000 people who were not in city at the time of bombing. Detailed biennial medical examinations have been carried out in this cohort.

     In addition, the in utero exposed group (about 2,800 subjects), and F1 mortality study cohort (77,000 subjects) have been set.

    The cytogenetics program was initiated in 1968 and analysis have been carried out in samples from the cohort of AHS group and children born to the exposed parents (F1 and in utero cohorts). 
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City Date and time of Bomb parameters Population Death LSS cohort AHS cohort Blood sampling for cytogenetic study*
bombing type yield (TNT) burst height ATB within 1945 by 1950 AHS (1960-1990) F1 (1967-1980)
Hiroshima 6 August 1945; 8:15 am Uranium (235U) 16±2 kt 600±20 m about 420,000 122,338 about 200,000 73,430 13,339 1,980 6,318
Nagasaki 9 August 1945; 11:02 am Plutonium (239Pu) 21±2 kt 503±10 m about 240,000 73,884 about 140,000 31,997 5,757 1,062 4,502
Total - - - - about 660,000 196,222 about 340000 105,427 19,096 3,042 10,820
*) number of subjects who were dealt with in the study in the largest cohort.
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Dosimetry [6, 7] 

     The early dose estimates for survivors, called tentative 1957 dose (TD57D) have been made by the experimental data of the A-bomb explosion in the Nevada Test Site. This was revised to a TD65D in 1965. In these early dosimetry systems, the neutron component was very comparable to that of gamma-rays in Hiroshima. Based on the accumulation of new output spectra and measurement data on activation, the dosimetry system was revised to DS86, dosimetry system in 1986, and further with minor revisions to the current DS02 dosimetry system in 2002 [ref. 6]

     The A-bomb radiation is a mixture of gamma-rays and neutrons. In the evaluation of medical and biological effect of A-bomb radiation, including chromosome damage, the relative biological effectiveness (RBE) of neutrons is critical. In the A-bomb survivors, historically the neutrons have been weighted by constant RBE of 10. That is, the dose to survivors (D in Sv) is expressed by D=Dg+10×Dn, Dγ and Dn are gamma-ray and neutron dose in tissue kerma (in Gy), respectively. Recently, the doses are further modified by so-called adjustment factor (ε), like in D=ε(Dg+10×Dn). The adjustment factor is the dose modification factor derived from the limits of random dosimetry errors, and dependent on dose and differs by city. The modified dose is called ‘survivor dose’ [ref. 7 for review]. For organ dose, DS86 bone marrow dose is shown below because the chromosome aberration analysis has been so far discussed on the basis of DS86 dosimetry system. 
 

Chromosome analysis in survivors: Studies in RERF [8-12] 

     Blood samples were collected the Adult Health Study (AHS) cohort between 1968 and 1980 from proximally exposed survivors (within 2 km from hypocenter), and their controls who were non-exposed (NIC) or exposed distally (2.5 km or more away from hypocenter). The dosimetry system referred to here was Free-in-Air (FIA) kerma in DS86 dosimetry system.
     Chromosome aberration analysis was carried out in the short-term (52 hrs) lymphocyte culture and in preparations made by conventional solid Giemsa staining. Chromosome aberrations were scored by visual karyotyping under the microscope by identifying the presence of apparently abnormal chromosomes and changes in the components of normal karyotype. Detailed methodology is available on the RERF website (http://www.rerf.or.jp/Gene/eng/giemsa.htm). 
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. [A] Blood sampling in 1968-1980: Awa, A. A. (1991), J. Radiat. Res., Supplement, 265-274.
DS86 Hiroshima Nagasaki
dose group Mean dose No. of No. of Aberrant Mean dose No. of No. of Aberrant
(Gy) (Gy) subjects cells cells** (Gy) subjects cells cells**
Distantly exposed* 0-0.004 0 362 34,299 363 0 251 24,539 345
Proximally exposed 0.005-0.09 0.048 13 1,188 13 0.7 19 1,853 22
0.10-0.49 0.295 60 5,624 105 0.299 48 4,584 83
0.50-0.99 0.779 90 8,697 436 0.738 49 4,768 140
1.00-1.99 1.43 152 14,500 1,309 1.42 61 5,990 433
2.00-2.99 2.45 83 8,057 1,340 2.39 23 2,215 369
3.00-3.99 3.37 28 2,643 577 3.45 6 600 111
*) Distantly exposed group include persons who were not in city (NIC) at the time of bombing.
**) The aberrations involed were mostly stable-type aberration (reciprocal translocations and inversions), and unstable aberrations were less than 10% of total aberrations. .

     In the later studies, chromosome aberration frequencies were plotted against bone marrow dose, the difference in the dose-response curves between Hiroshima and Nagasaki did not disappeared as shown by the difference in the equi-effective doses between two cities (see below). For alternative implication of dose-response, see M. S. Sasaki et al. 
 

Chromosome examination in F1 offspring: Studies in RERF [13, 14, 15] 

     The analysis of chromosome constitutions in the F1 children born to A-bomb survivors was initiated in 1967 [5]. This cohort includes children born between 1 May 1946 and 31 December 1958 to parents, one or both of whom were residents of Hiroshima and Nagasaki ATB. The samples were later expanded to include children who were born after 1959 through the end of 1972. The later samples constitute about 10% of the total.
     The results of the analysis have been consecutively reported. In the latest large scale study [14], the analysis were carried out in 8,322 offspring belonging to 5,823 families of A-bomb survivors who were proximally exposed (within 2000 m) and compared with 7,976 offspring in 6,473 families who were distally exposed (2500km or more from hypocenter and assumed to have received less than 1 rad in T65D dosimetry system) or who were not in city (NIC) at the time of bombing as controls. 
Hiroshima Nagasaki Two cities
Types of chromosome abnormalities and number of cases examined Controls Exposed Controls Exposed Controls Exposed
Father Mother Both Total Father Mother Both Total Father Mother Both Total
Number of cases examined 5,112 1,274 2,838 604 4,716 2,864 1,166 2,035 405 3,606 7,976 2,440 4,873 1,009 8,322
Autosome structural aberrations Balanced rob(D/D) 4 2 3 - 5 2 2 - - 2 6 4 3 - 7
rob(D/G) - - 1 - 1 - 1 - 1 2 - 1 1 1 3
rec 6 3 2 2 7 7 - - - - 13 3 2 2 7
inv 6 - 1 - 1 - - - - - 6 - 1 - 1
Unbalanced rob - - - - - - - - - - - - - - -
rec - - - - - - - - - - - - - - -
del - - - - - - - - - - - - - - -
supern - 1 - - 1 - 1 - - 1 - 2 - - 2
others - 1 1 - 2 2 - 1 - 1 2 1 2 - 3
Sex chromosome abnormalities Male XYY 5 - - - - - 2 1 - 3 5 2 1 - 3
XXY 4 1 4 1 6 5 - 1 - 1 9 1 5 1 7
Mosaic - 1 - - 1 - - - - - - 1 - - 1
others 2 - - - - - - 1 - 1 2 - 1 - 1
X - - - - - - - - - - - - - - -
Female XXX 3 2 1 1 4 1 1 - - 1 4 3 1 1 5
Mosaic 3 - - 1 1 - - 1 - 1 3 - 1 1 2
others - - - - - 1 - - - - 1 - - - -
Notes: (1) All Robertsonian translocations, rob(D/D) and rob(D/G) were familial.
(2) A balanced reciprocal translocation in one child born to the exposed parentand (Hiroshima) and one in unexposed (Hiroshima) was new mutation. The heritability of others were not determined.
(3) In the sex chromosome mosaic, one of the controls had 45,X/46,X,r(X) mosaiism. In Nagasaki, a male child born to the exposed mother was 46,XX male.
(4) Average parental gonadal dose was 0.603 Sv based on DS86 dosimetry system.

References 

     1. Milton, R. C. and Shohoji, T. (1968): Tentative 1965 radiation dose estimation for atomic bomb survivors. ABCC/RERF Technical Report TR-1-68.
     2. Oughterson, A. W. and Warren, S. (1956): ‘Medical effects of the atomic bomb in Japan’. McGraw-Hill.
     3. Shigematsu, I. and Akira, S. (1986): Sampling of atomic bomb survivors and method of cancer detection in Hiroshima and Nagasaki. Gann Monogr. Cancer Res., 37:1-8.
     4. Kodama, K., Mabuchi, K. and Shigematsu, I. (1996): Research activities of epidemiology in Japan: A long-term cohort study of the atomic-bomb survivors. J. Epidemiol., 6 (Supplement):S95-S105.
     5. Awa, A. A., Bloom, A. D., Yoshida, M. C., Neriishi, S. and Archer, P. G. (1968): Cytogenetic study of the offspring of atomic bomb survivors. Nature, 218:367-368.
     6. RERF (2005): ‘Reassessment of the atomic bomb radiation dosimetry for Hiroshima and Nagasaki – Dosimetry system 2002’, Vol. 1. Radiation Effects Research Foundation.
     7. Cullings, H. M., Fujita, S., Funamoto, S., Grant, E. J., Kerr, G. D. and Preston, D. L. (2006): Dose estimation for atomic bomb survivor studies: its evolution and present status. Radiat. Res., 166:219-254.
     8. Awa, A. A. (1991): Persistent chromosome aberrations in the somatic cells of A-bomb survivors. J. Radiat. Res., Supplement: 265-274.
     9. Stram, D. O., Sposto, R., Preston, D., Abrahamson, S., Honda, T. and Awa, A. A. (1993): Stable chromosome aberrations among A-bomb survivors: an update. Radiat. Res., 136:29-36.
    10. Kodama, Y., Pawel, D., Nakamura, N., Preston, D., Honda, T., Itoh, M., Nakano, M., Ohtaki, K., Funamoto, S. and Awa, A. A. (2001): Stable chromosome aberrations in atomic bomb survivors: results from 25 years of investigation. Radiat. Res., 156:337-346.
    11. Nakano, M., Kodama, Y., Ohtaki, K., Itoh, M., Delongchamp, R., Awa, A. A. and Nakamura, N. (2001): Detection of stable chromosome aberrations by FISH in A-bomb survivors: comparison with previous solid Giemsa staining data on the same 230 individuals. Int. J. Radiat. Biol., 77:971-977.
    12. Awa, A. (2003): Mutation research at ABCC/RERF: cytogenetic studies of atomic bomb exposed populations. Mutation Res., 543:1-15.
    13. Awa, A. A. (1983): Chromosome damage in atomic bomb survivors and their offspring – Hiroshima and Nagasaki. In; Ishihara, T. and Sasaki, M. S., eds. ‘Radiation-induced Chromosome Damage in Man’. Alan R. Liss, Inc., New York, pp.433-453.
    14. Awa, A. A., Honda, T., Neriishi, S., Sofuni, T., Shimba, H., Ohtaki, K., Nakano, M., Kodama, Y., Itoh, M. and Hamilton, H. B. (1987): Cytogenetic study of the offspring of atomic bomb survivors, Hiroshima and Nagasaki. In; Obe, G. and Basler, A., eds. ‘Cytogenetics’, Springer-Verlag, Berlin, pp.166-183.
    15. Neel, J. V., Schull, W. J., Awa, A. A., Satoh, C., Kato, H., Otake, M. and Yoshimoto, Y. (1990): The children of parents exposed to atomic bombs: estimates of the genetic doubling dose of radiation for humans. Am. J. Hum. Genet., 46:1053-1073.