Eighty years of cancer research after the atomic bombings of Hiroshima and Nagasaki

Abstract

The year 2025 marks the 80th anniversary of one of the worst human-caused tragedies: the atomic bombings of Hiroshima and Nagasaki, with acute death tolls of approximately 140,000 in Hiroshima and 74,000 in Nagasaki by the end of 1945. This editorial provides historical and social context for the articles in this special issue of Carcinogenesis.

1. Introduction

The year 2025 marks the 80th anniversary of one of the worst human-caused tragedies: the atomic bombings of Hiroshima and Nagasaki, with acute death tolls of ∼140 000 in Hiroshima and 74 000 in Nagasaki [1, 2]. More deaths and harms followed for the survivors (referred to as the hibakusha) and their families. Yet, the hibakusha have made an enduring and beneficial contribution to mankind by volunteering to participate in ongoing research on the health consequences of exposure to ionizing radiation. For the last 50 years, much of that research has been carried out by the binational Radiation Effects Research Foundation (RERF)—the successor to the Atomic Bomb Casualty Commission (ABCC) established in 1947 [3]. The findings of the survivor research have guided efforts to minimize the risks of radiation exposure worldwide.

This editorial provides historical and social context for the articles in this special issue of Carcinogenesis. The history of the development of the atomic bomb and the still-debated decision to drop Little Boy (Hiroshima) and Fat Man (Nagasaki) are well documented and not a topic for this commentary. John Hersey and others provide accounts of the struggles of survivors [4]. Most recently, Sheftall [5, 6] has authored new books with stories from each city. The almost 80-year story of the ABCC and RERF can be found in a patchwork of accounts, as research was initiated and then sustained after the bombings in the two devastated cities. The immediate postbombing period and formation of the Joint Commission, the ABCC’s precursor, are captured in Nolan’s Atomic Doctors [7]. Lindee [8] covers the initial years of the ABCC in Suffering Made Real: American Science and the Survivors at Hiroshima. James Neel and Jack Schull, pioneering geneticists, had an influential role in ABCC’s research from its early years, particularly on the genetic consequences of radiation exposure. Neel’s autobiography, Physician to the Gene Pool: Genetic Lessons and Other Stories, covers the lead-up to the establishment of the ABCC, the early years of the ABCC, and the decades of efforts to study potential genetics consequences of the bombings [9]. Schull’s Effects of Atomic Radiation: A Half-Century of Studies from Hiroshima and Nagasaki provides in-depth coverage of a half-century of research; a brief introduction to this complex history can be found in Putnam’s 1998 paper [10, 11].

Here, our purpose is to provide background for the scientific research presented in this issue of Carcinogenesis. The elements of scientific papers describe what has been learned from research, but tables and figures do not reflect the unique situation of research carried out by ABCC and RERF, which originated in difficult postwar circumstances, nor do they capture the participation of the survivors who are engaging in research that describes harms they have sustained. Our coverage extends from the immediate postwar period through the present, as institutions around the world continue to bring cutting-edge research approaches to address scientific questions that date to the bombings’ aftermath.

2. By 1945, ionizing radiation had known health consequences

The 1945 bombings took place a half-century after Roentgen produced and described x-rays, famously imaging his wife’s hand with her wedding ring [12]. Within a few years, the damaging potential of x-rays was recognized by injuries sustained by those working directly with x-ray tubes. By the 1920s, cancer and blood diseases began to occur in excess among radiologists. The Curies discovered radium in 1898, linked within decades to cancer in women who painted radium dials for watches and ingested radium by tipping the brushes with their tongues [13, 14]. Thus, a rise in cancer following the radiation exposure from the bombs could be anticipated. Muller’s 1927 publication in Science showed that x-rays induced mutations in the sperm of fruit flies (Drosophila): “It has been found quite conclusively that treatment of the sperm with relatively heavy doses of X-rays induces the occurrence of true ‘gene mutations’ in a high proportion of the treated germ cells” [15]. This seminal discovery established the foundation for investigating transgenerational effects of radiation, and was critical in the rationale for studies of potential genetic consequences of the bombings.

Exploratory missions related to the medical consequences of the bombings began soon after the bombings. In the weeks following the bombings, a team led by Dr Tsuzuki from the Japanese National Research Council collected clinical data. By September 1945, three US teams with radiation and medical expertise had entered Japan, including a group from the Manhattan Project [7]. Initially independent, General Douglas MacArthur merged them into the Joint Commission for the Investigation of the Effects of the Atomic Bomb in Japan (the Joint Commission) along with a Japanese Government group. While the US government initially attributed casualties to the blasts and burns, minimizing the role of radiation, observations from the US teams and those of Japanese physicians left no doubt that some survivors were experiencing radiation sickness. The Joint Commission documented these findings in a six-volume report published in 1956 [16].

3. The Atomic Bomb Casualty Commission (1947–1975)

Succeeding the Joint Commission in 1947, the ABCC was established following a letter from US Secretary of the Navy, James Forrestal, to President Truman requesting: “That the Presidential Directive instruct the National Academy of Sciences-National Research Council-to undertake a long range, continuing study of the biological and medical effects of the atomic bomb on man” [17]. Funding for the ABCC came to the National Research Council-National Academy of Science (NRC-NAS) from the newly formed Atomic Energy Commission (AEC), an arrangement that continued for 28 years. In 1950, the current facility, which has been the major locus for survivor research, was constructed on Hijiyama Hill in Hiroshima. This directive and the engagement of the NRC-NAS set the stage for long-term research on the survivors, albeit with the USA in the lead at that time.

Under the direction of Neel, later joined by Schull, a program was developed to identify possible hereditary consequences of the bombings [9, 10]. Its components included a study of pregnancy outcomes for more than 70 000 women that generated a data set re-analyzed across the ensuing decades, most recently for a 2021 publication using updated dosimetry. ABCC/RERF studies of hereditary effects are reviewed by in this issue by Nakamura et al. [18]. Other early papers addressed cataract, hematological abnormalities, and the rise in acute leukemias within 5 years of the bombings [19–21].

The question of whether parental exposure to radiation can affect the health of their unexposed future offspring remains pertinent even today. Yoshida et al. [22] describe current ethical, social, and legal considerations for a planned study of whole-genome sequencing of trios comprising two parents (at least one exposed to A-bomb radiation) and their unexposed offspring, and Machiela et al. [23] present results indicating that low-to-moderate ionizing radiation exposure was not associated with clonal hematopoesis in the Chernobyl Family Study, a risk factor for leukemia,.

While there was an organized program of research on genetic implications of radiation exposure, other research areas were not as cohesive, and ABCC was beset with organizational and funding uncertainties. Consequently, the NRC-NAS convened a three-member committee, led by Dr Thomas Francis, Jr. (hence its label as the “Francis Committee”), to review the ABCC. The committee found organizational and scientific disarray and proposed the development of fixed cohorts of survivors, selected by location at the blast—a surrogate for dose. It recognized the potential to make scientific advances: “The frontier here created for investigations in the field of human biology is unlimited” and noted “But, above all, the processes under observation can change the outlook from a static to a dynamic one.” These foundational cohorts, still followed by RERF (and described in greater detail in the review by Kamiya et al. in this issue [24]), can be traced to the Francis Committee report.

4. The Radiation Effects Research Foundation (1975–now)

By 1975, conditions called for a truly binational organization to supplant the ABCC. Consequently, the RERF was created under the Act of Endowment of 1975 (replaced by the Articles of Incorporation in 2012 when RERF was chartered as a Public Interest Incorporated Foundation), as a private, nonprofit foundation to “carry out research and studies, for peaceful purposes, on the medical effects of radiation on man…with a view to contributing to the maintenance of the health and welfare of atomic bomb survivors and to the enhancement of the health of all mankind” [3]. These words from Article 3 of the Act of Endowment reflect the duality of RERF’s mission: its direct responsibility to the survivors and its broader mandate to benefit “all mankind.” RERF has addressed this unique charge by continuing its core research and by actively disseminating its findings to decision-makers in Japan, to the survivors, and to international entities that use RERF’s risk estimates to guide global radiation protection, such as the International Commission on Radiological Protection (ICRP) and the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), as described by Wakeford et al. in this issue [25]. These estimates are further used by countries around the world to set limits in various occupational, environmental, and medical settings—including radiation protection in space, as described by Stegeman et al. [26]; pediatric medical exposure, assessed by Berrington de Gonzalez et al. [27], and uranium mining, reviewed by Samet and Richardson in this special issue [28].

Over its 50 years, RERF researchers have published hundreds of papers, many based in the cohorts under follow-up while others are from laboratory research that complements the epidemiological studies. In this issue, for example, Matsuda and Tanabe [29] describe the genomic landscape of radiation-induced somatic mutations. The periodic updates to the findings of the Life Span Study have driven estimation of the cancer incidence and mortality risks associated with radiation exposure. The most recent cancer incidence risks are summarized by Brenner et al. in this issue [30]. Beyond cancer, the Life Span Study unexpectedly found that greater radiation dose was associated with shorter lifespan and possible increases in cardiovascular disease mortality [31, 32]. Research on radiation and cataract in the Adult Health Study, a clinical subcohort of the Life Span Study, has influenced protection against nonstochastic effects of radiation [33]. Fulfilling the potential called out in the Francis Committee report, biosamples from the Adult Health Study have been used in biomarker and mechanistic research with laboratory research providing complementary findings.

5. The future of radiation science

Looking forward, the integration of data from epidemiology, clinical studies, and molecular biology holds great promise for resolving long-standing scientific questions regarding disease risk following radiation exposure. In this special issue, Gray and Feinberg [34] outline several directions for future research in the atomic bomb survivors and other radiation-exposed populations, including querying new and archived biosamples with novel measurement tools for -omic compositions (e.g. of DNA, RNA, and proteins) and single-cell analysis, using powerful computational analysis methods while leveraging the growing number of public reference databases cataloging annotated genetic and epigenetic sequences. Meanwhile, continued follow-up of new and existing cohorts, along with improved radiation dosimetry (as described by Cullings et al. [35]) and statistical methodology (as described by Cologne et al. [36]), will enable better characterization of the radiation dose–response curve, particularly at low doses, and help elucidate patterns of effect modification by intrinsic and extrinsic factors such as age, sex, genetic and epigenetic factors, and behaviors such as smoking and alcohol consumption.

6. The contributions of the Hibakusha

Viewed through an 80-year retrospective lens, the contribution made by the hibakusha and their families through the research of the ABCC and RERF has been extraordinary. With studies beginning in the lingering shadow of World War II and the atomic bombings, initiation of the work was emotionally difficult, and practical logistics were complicated. Yet, cohorts were established, maintained, and continue to generate results informing the health and welfare of survivors and their families, as well as managing radiation risks. Beyond their contribution to mankind through support of biomedical research, the hibakusha have been a powerful global voice against nuclear weapons. The survivor organization Nihon Hidankyo received the 2024 Nobel Peace Prize for “its efforts to achieve a world free of nuclear weapons and for demonstrating through witness testimony that nuclear weapons must never be used again.” This special issue marking the 80th anniversary of the atomic bombings of Hiroshima and Nagasaki honors the resilience and generosity of the survivors and their families, and their support of work that has shaped, and will continue to shape, our understanding of the effects of radiation on human health. The unprecedented contributions of the hibakusha and the body of science built from their experience compel us to pursue the next generation of research with rigor and an enduring commitment to the responsible use of radiation in science and medicine.

Funding

None declared.

Data Availability

No new data were generated or analysed in support of this research.