The atomic bombings of Hiroshima and Nagasaki on August 6 and 9, 1945, resulted in an estimated 90,000-120,000 deaths in Hiroshima and 60,000-80,000 in Nagasaki. The devastation prompted the formation of the Joint Commission for the Investigation of the Effects of the Atomic Bomb in Japan, leading to the establishment of the Atomic Bomb Casualty Commission (ABCC) in 1947. In 1975, ABCC was restructured into the Radiation Effects Research Foundation (RERF), continuing research with joint US and Japanese funding. This research aimed to understand the long-term health consequences of the bombings, focusing on a large population with a wide range of ages and radiation exposures. The study's unique features, such as longitudinal follow-up, high participation rates, and accurate dose reconstructions, made it a gold standard for radiation epidemiology. The research question is to comprehensively assess the long-term health effects (cancer and non-cancer) of the atomic bomb radiation exposure on the survivors and their descendants. The purpose is to quantify these effects and better understand the long-term impact of ionizing radiation on human health for the benefit of the survivors and future generations. The importance of the study lies in its ability to provide crucial data for understanding and mitigating the risks associated with radiation exposure, informing radiation protection standards and guiding future research.

Early ABCC studies focused on specific topics like leukemia, birth defects, and cataracts, often in the form of case reports. A notable exception was Neel and Schull's study on the genetic effects of the A-bombs. The Francis Committee in 1955 established a unified study program, initiating the Life Span Study (LSS) for mortality and cancer incidence and the Adult Health Study (AHS) with biennial health examinations. The inclusion of in utero-exposed individuals and children of exposed parents (F1 cohort) further expanded the scope. This review article builds upon these previous studies by providing a comprehensive overview of the long-term health effects observed in these cohorts.

The LSS enrolled approximately 120,000 individuals, including A-bomb survivors with varying radiation doses and unexposed controls. The AHS followed a subset of LSS participants with high radiation exposure, conducting biennial examinations. The in utero cohort comprised individuals exposed in utero, and the F1 cohort included their children. The Japanese koseki family registration system enabled near-complete mortality follow-up. Accurate individual dose estimations were crucial and refined over time, employing various methods, including DS02, using information on distance from the hypocenter, shielding, and body self-shielding. The study used excess absolute risk (EAR), relative risk, and excess relative risk (ERR) to describe the magnitude of radiation-associated health effects, considering factors like age, sex, and smoking. Statistical models, including regression models, were employed to analyze the data and assess dose-response relationships. The methodology also incorporated data from autopsy programs, questionnaire surveys, clinical examinations, and laboratory analyses of stored biosamples.

The study found a significant increase in leukemia deaths, particularly in the early years after exposure, especially in those exposed at a young age. A nonlinear dose-response curve was observed for leukemia. Solid cancers showed a gradual increase in risk, starting years after the bombings, with significant excess risks observed at numerous organ sites. The highest ERRs were found for bladder, female breast, and lung cancers. Pooled solid cancer data showed a linear dose-response relationship, with an ERR/Gy of 0.47 estimated for solid cancer incidence. Women showed approximately 50% higher ERRs and EARs for solid cancers compared to men. Risk was significantly dependent on age at exposure and attained age. Non-cancer health effects included increased risks of lens opacities (cataracts), thyroid diseases, hyperparathyroidism, and cardiovascular diseases. Significant dose-related increases in cardiovascular mortality were observed. Psychological effects, including anxiety and somatization, were also reported. Life span shortening was observed, estimated at about 1.3 years/Gy. Cytogenetic changes and somatic mutations persisted for over 65 years. Immunological changes, including altered T-lymphoid cell composition, were also detected. The in utero cohort showed no increase in leukemia or cancer deaths in the first 15 years of life, but there was evidence of mental retardation and reduced IQ in those exposed at 8-15 weeks postconception. The F1 cohort showed no significant increase in cancer or non-cancer mortality or disease prevalence linked to parental radiation exposure.

The findings address the research question by providing robust estimates of radiation-related health risks across a wide range of health outcomes, considering various modifying factors. The consistent observation of linear dose-response relationships for solid cancers strengthens the evidence for the harmful effects of ionizing radiation, even at low doses. The differences in risks between men and women underscore the importance of sex-specific risk assessments. The long-term follow-up of the cohorts provides valuable insights into late-onset health effects that may not manifest until decades after exposure. The study highlights the importance of continued surveillance, given the late-onset nature of many radiation-induced diseases. The results significantly contribute to our understanding of the long-term effects of ionizing radiation on human health and inform the development of radiation protection standards.

The ABCC/RERF study provided invaluable risk estimations for health effects after acute ionizing radiation exposure. Continued follow-up of the existing cohorts, particularly the F1 generation, will refine risk estimates and address remaining uncertainties. Advanced DNA analysis techniques and the extensive biosample collection will further clarify the mechanisms of radiation-induced health effects. The study's legacy extends to informing international radiation protection standards and guiding future research on the biological effects of ionizing radiation.

The study's inherent limitations include the retrospective nature of the dose estimation process, which introduced uncertainties related to survivor location, shielding, and individual dose reconstructions. While extensive, the follow-up period for the F1 generation is still ongoing; therefore, some long-term effects might not yet be fully apparent. The study primarily focuses on the Japanese population, so the generalizability to other populations may be limited. Selection bias in the cohort composition is also a factor to be considered in the interpretation of findings. Although these limitations exist, the study's comprehensive nature and the robustness of the findings outweigh the constraints.