Offspring Of Atomic Bomb Survivors Research Articles

First Peoples of the Atomic Age

In this article, I explore the history of biological materials that scientists and physicians collected from those who survived the atomic bombings at Hiroshima and Nagasaki. Originally acquired beginning in 1946 to track the genetic effects of radiation in the offspring of atomic bomb survivors, these materials gradually became relevant to other kinds of biological and biomedical research. Many of the samples still held at the Radiation Effects Research Foundation are from individuals (approximately 65 percent) who are no longer alive. To scientists and others engaged with their management and use, these samples are uniquely valuable, timeless, a legacy for “all mankind.” Like materials taken from isolated populations around the world, the atomic bomb samples are both unique and universalized. They join other forms of Big Data in their seamless transition from dramatic specificity to general relevance. My paper explores what such legacies mean, and what they might teach us about the history of biology, the practices of biobanking, and the post-1945 Pacific world. This essay is part of a special issue entitled Pacific Biologies: How Humans Become Genetic, edited by Warwick Anderson and M. Susan Lindee.

Detection of de novo single nucleotide variants in offspring of atomic-bomb survivors close to the hypocenter by whole-genome sequencing

Ionizing radiation released by the atomic bombs at Hiroshima and Nagasaki, Japan, in 1945 caused many long-term illnesses, including increased risks of malignancies such as leukemia and solid tumours. Radiation has demonstrated genetic effects in animal models, leading to concerns over the potential hereditary effects of atomic bomb-related radiation. However, no direct analyses of whole DNA have yet been reported. We therefore investigated de novo variants in offspring of atomic-bomb survivors by whole-genome sequencing (WGS). We collected peripheral blood from three trios, each comprising a father (atomic-bomb survivor with acute radiation symptoms), a non-exposed mother, and their child, none of whom had any past history of haematological disorders. One trio of non-exposed individuals was included as a control. DNA was extracted and the numbers of de novo single nucleotide variants in the children were counted by WGS with sequencing confirmation. Gross structural variants were also analysed. Written informed consent was obtained from all participants prior to the study. There were 62, 81, and 42 de novo single nucleotide variants in the children of atomic-bomb survivors, compared with 48 in the control trio. There were no gross structural variants in any trio. These findings are in accord with previously published results that also showed no significant genetic effects of atomic-bomb radiation on second-generation survivors.

On the genetic effects of low-dose radiation

There is a discrepancy between the reportedly significant elevation in a minisatellite DNA mutation rate in the children of parents, who had been exposed to radiation from the Chernobyl accident, and absence of significant inherited genetic effects found among the offspring of atomic bomb survivors. At the same time, average doses received by the residents of the contaminated areas, where the studies of the children of exposed parents were performed, had been comparable to those from the natural radiation background. Several publications exaggerating medical consequences of elevated radiation background were discussed earlier. The following flaws can be found in such papers: interpretation of spontaneous conditions as radiation-induced, indication of radioactivity or dose levels without confrontation with the natural radiation background, conclusions about incidence increase of certain conditions without an adequate comparison with a control. In conclusion, arguments in favor of inapplicability of the linear non-threshold theory to the radiation doses, comparable to those from the natural radiation background, are discussed here.

Prevalence of Adult-Onset Multifactorial Disease among Offspring of Atomic Bomb Survivors

The first study to examine whether parental radiation exposure leads to increased heritable risk of common adult-onset multifactorial diseases (i.e., hypertension, diabetes mellitus, hypercholesterolemia, ischemic heart disease, and stroke) was conducted among 11,951 participants in the clinical examination program out of a potential of 24,673 mail survey subjects who were offspring of survivors born from May 1946 through December 1984. Logistic regression analyses demonstrated no evidence of an association between the prevalence of multifactorial diseases in the offspring and parental radiation exposure, after adjusting for age, city, gender and various risk factors. The odds ratio (OR) for a paternal dose of 1 Gy was 0.91 [95% confidence interval (CI) 0.81-1.01, P = 0.08], and that for a maternal dose of 1 Gy was 0.98 (95% CI 0.86-1.10, P = 0.71). There was no apparent effect of parental age at exposure or of elapsed time between parental exposure and birth, but male offspring had a low odds ratio (OR = 0.76 at 1 Gy) for paternal exposure, but cautious interpretation is needed for this finding. The clinical assessment of nearly 12,000 offspring of A-bomb survivors who have reached a median age of about 50 years provided no evidence for an increased prevalence of adult-onset multifactorial diseases in relation to parental radiation exposure.

Ionizing Radiation and Childhood Leukemia

I read with interest the recent review by Belson et al. (2007) on childhood leukemia, particularly the sections dealing with radiation exposure. Like the authors, I believe that ionizing radiation is strongly associated with childhood acute leukemia. I would like to point out that several critical pieces of information were overlooked; these support stronger and more meaningful conclusions. Although atomic bomb survivors offer the clearest evidence of leukemia risk after childhood exposures to ionizing radiation, studies of children exposed to fallout in other contexts should not be downplayed. Belson et al. (2007) stated that “radiation exposure secondary to the Chernobyl accident has not been shown to increase the risk of leukemia in children who were exposed after birth …,” but they failed to mention the case–control study of Noshchenko et al. (2002), which found significant increases in childhood and acute leukemias in association with estimated childhood exposures. Children living downwind of the Nevada Test Site have also shown a significant increase in leukemia related to estimated fallout exposure (Stevens et al. 1990). In utero exposure to ionizing radiation has been a known causal factor for childhood cancer for > 50 years. Although Belson et al. (2007) stated that the lack of evidence for a childhood leukemia risk among atomic bomb survivors constitutes the “most notable reason for doubt of a true association,” they overlooked the reviews of Wakeford and Little (2002, 2003); these authors demonstrated that the highly uncertain atomic bomb survivor data are statistically compatible with the robust set of data found in the Oxford Survey of Childhood Cancers and related X-ray exposure cohorts. There is no valid reason to doubt this association at present. The association between preconception paternal irradiation (PPI) and childhood leukemia has always been controversial. Two of the major objections to the “Gardner hypothesis,” as Belson et al. (2007) pointed out, have been mixed evidence from studies of radiation-exposed fathers and a lack of positive evidence in the children of the atomic bomb survivors. Regarding the first objection, Belson et al. overlooked the two largest studies of the children of radiation workers. Draper et al. (1997) conducted a UK-wide case–control study of childhood cancers in relation to paternal radiation exposure. This study showed, based on > 13,000 cases not included in the study of Gardner et al. (1990), that children with leukemia or non-Hodgkin lymphoma were significantly more likely than controls to have fathers who were radiation workers. Dickinson and Parker (2002) conducted a cohort study of > 250,000 births in Cumbria, England, including the cases of Gardner et al. (1990), and found a significant 2-fold increase in the risk of leukemia and non-Hodgkin lymphoma among the children of radiation workers. These and other studies, taken together, give statistical support to the idea that paternal radiation work is a risk factor for childhood leukemia. When interpreting the evidence for a PPI effect in atomic bomb survivors, it is important to consider what is known about potential mechanisms. As reviewed by Niwa (2003), Nomura (2003), and others, animal studies have consistently demonstrated that PPI can cause or increase the susceptibility to leukemia in offspring. In addition to fascinating evidence of postconception genomic instability after preconception exposure, many studies suggest that there may a window of sensitivity corresponding to post-meiotic stages of spermatogenesis; in humans, this would mean the few months leading up to conception (Adler 1996). Of the roughly 30,000 children of atomic bomb survivors, only about 2% were conceived in the 6 months after the bombings. Based on the spontaneous leukemia rate reported by Yoshimoto (1990), the expected number of spontaneous cases in this subcohort would be < 1, and an excess on the order suggested by the radiation worker studies would not be statistically apparent. For this and other reasons, the atomic bomb survivors may not be an appropriate comparison group. To summarize, it is not unreasonable to observe that the weight of evidence generated to date supports the idea that preconception, prenatal, and postnatal exposures to ionizing radiation are all risk factors for childhood leukemia.

Genetic Effects of Radiation in Atomic-bomb Survivors and Their Children: Past, Present and Future

Genetic studies in the offspring of atomic bomb survivors have been conducted since 1948 at the Atomic Bomb Casualty Commission and its successor, the Radiation Effects Research Foundation, in Hiroshima and Nagasaki. Past studies include analysis of birth defects (untoward pregnancy outcome; namely, malformation, stillbirth, and perinatal death), chromosome aberrations, alterations of plasma and erythrocyte proteins as well as epidemiologic study on mortality (any cause) and cancer incidence (the latter study is still ongoing). There is, thus far, no indication of genetic effects in the offspring of survivors. Recently, the development of molecular biological techniques and human genome sequence databases made it possible to analyze DNA from parents and their offspring (trio-analysis). In addition, a clinical program is underway to establish the frequency of adult-onset multi-factorial diseases (diabetes mellitus, high blood pressure, and cardiovascular disease etc) in the offspring. The complementary kinds of data that will emerge from this three-pronged approach (clinical, epidemiologic, and molecular aspects) promise to shed light on health effects in the offspring of radiation-exposed people.

James Neel and the doubling dose concept.

The doubling dose (DD) is a very valuable concept in attempts to assess the genetic risks of radiation in man. It was long thought that the value of the doubling dose obtained from specific locus experiments in mice could be applied to man. James Neel, as a result of his studies on the offspring of atomic bomb survivors, showed that this was not so, but that different doubling doses could be inferred from different endpoints.

Prenatal carcinogenesis. An Appraisal

Prenatal carcinogenesis. An Appraisal

Mortality and Cancer Risk among the Offspring (F1) of Atomic Bomb Survivors

The Atomic Bomb Casualty Commission (ABCC) and its successor Radiation Effect Research Foundation (RERF) has over the years conducted many studies to determine possible genetic effects of atomic bomb radiation among the offspring of atomic bomb survivors. Findings concerning mortality and cancer incidence of the offspring are summarized in this chapter.