Age effects on radiation response: summary of a recent symposium and future perspectives

Abstract

One of the principal uncertainties when estimating population risk of late effects from epidemiological data is that few radiation-exposed cohorts have been followed up to extinction. Therefore, the relative risk model has often been used to estimate radiation-associated risk and to extrapolate risk to the end of life. Epidemiological studies provide evidence that children are generally at higher risk of cancer induction than adults for a given radiation dose. However, the strength of evidence varies by cancer site and questions remain about site-specific age at exposure patterns. For solid cancers, there is a large body of evidence that excess relative risk (ERR) diminishes with increasing age at exposure. This pattern of risk is observed in the Life Span Study (LSS) as well as in other radiation-exposed populations for overall solid cancer incidence and mortality and for most site-specific solid cancers. However, there are some disparities by endpoint in the degree of variation of ERR with exposure age, with some sites (e.g., colon, lung) in the LSS incidence data showing no variation, or even increasing ERR with increasing age at exposure. The pattern of variation of excess absolute risk (EAR) with age at exposure is often similar, with EAR for solid cancers or solid cancer mortality decreasing with increasing age at exposure in the LSS. We shall review the human data from the Japanese LSS cohort, and a variety of other epidemiological data sets, including a review of types of medical diagnostic exposures, also some radiobiological animal data, all bearing on the issue of variations of radiation late-effects risk with age at exposure and with attained age. The paper includes a summary of several oral presentations given in a Symposium on “Age effects on radiation response” as part of the 67th Annual Meeting of the Radiation Research Society, held virtually on 3–6 October 2021.

Keywords:

• Ionizing radiation
• age at exposure
• Japanese atomic bomb survivors
• in vivo radiobiological data
• attained age

Acknowledgements

The authors are grateful for the detailed and helpful comments of the two referees.

Disclosure statement

The authors declare no conflicts of interest.

Additional information

Funding

This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention.

Notes on contributors

Mark P. Little

Mark P. Little, DPhil, joined the National Cancer Institute, Radiation Epidemiology Branch as a Senior Scientist in 2010, and was promoted to a Senior Investigator in 2012. Previously (2000-2010), he worked in Imperial College London, and before that (1992-2000) at UK National Radiological Protection Board (now part of UK Health Security Agency). He is a member of Council of NCRP, and has served as consultant to UNSCEAR, to IAEA, to ICRP (in particular on ICRP Task Group 91 and ICRP Task Group 119), to the UK COMARE, and to NCRP committees SC 1-21 (NCRP Commentary No. 24) and 1-26 (NCRP Report No. 186). He has particular statistical interests in machine learning algorithms and dose measurement error models. He has over 320 publications in the peer-reviewed literature.

Alina V. Brenner

Alina Brenner, MD, PhD, is a Senior Scientist in the Department of Epidemiology at the Radiation Effects Research Foundation (RERF), Hiroshima since 2017, and for the period 2005-2017 was a Staff Scientist in the Radiation Epidemiology Branch, National Cancer Institute. The overall goal of her research is to improve our understanding and quantification of cancer risk following exposure to ionizing radiation. Current research interests include a comparison of radiation risk patterns (by sex, age, and time) across different cancer sites and tissues in the LSS cohort of atomic bomb survivors and how these might be related to lifestyle factors and underlying biology. A special emphasis is placed on etiology of radiation-related breast, endometrial, central nervous system and thyroid cancers and includes collaboration with pathologists and geneticists at RERF. An additional area of interest concerns uncertainty in low dose risk estimates as related to different cancer outcomes: mortality and incidence.

Eric J. Grant

Eric J. Grant, PhD, is trained in epidemiology with a background in engineering, his research is primarily focused on cancer after ionizing radiation exposure. Dr. Grant has a 20-year career working for RERF and previously served as the Assistant Chief of the Department of Epidemiology at RERF. Dr. Grant was the Scientific Co-Chair of the 2018 Conference on Radiation and Health. He is a member of the US National Council on Radiation Protection and Measurements as well as a contributing author on an UNSCEAR expert group on cancer after radiation exposure, among other societal memberships.

Hiromi Sugiyama

Hiromi Sugiyama, PhD, is an epidemiologist, she assumed her position at RERF in 2004. Dr. Sugiyama has studied the effects of radiation on risks of mortality and cancer incidence among atomic bomb survivors. She has also led a study of mortality in individuals exposed to the atomic bombings in utero, with interpretations that include not only radiation effects but also social factors. She is responsible for the management of the population-based cancer registry in Hiroshima Prefecture and provides academic support. She has conducted descriptive epidemiological studies based on population-based cancer registry data in Japan.

Dale L. Preston

Dale L. Preston, PhD, is a biostatistician who worked on atomic-bomb survivor studies at RERF for 23 years. He developed statistical modeling software that is widely used for dose‐response modeling in radiation epidemiology and other areas, and took a lead role in reports of radiation-associated cancer and noncancer risk in the survivor cohorts, and oversaw the implementation of two new dosimetry systems. Since returning to the United States in 2004, Dr. Preston has continued to work on the analyses of cancer risks in various other exposed groups, including the Mayak Nuclear Workers, Techa River residents and U.S. radiologic technologists. He has served as a consultant to UNSCEAR and various Biological Effects of Ionizing Radiation committees, as a member of ICRP Committee 1, and as an associate editor of Radiation Research. In 2017 he was awarded the Failla Memorial Lecture Award by the Radiation Research Society in recognition of his contributions to radiation research.

Ritsu Sakata

Ritsu Sakata, PhD, is trained in epidemiology and biostatistics, she serves as the Assistant Chief of the Department of Epidemiology. Dr. Sakata studies radiation effects among atomic-bomb survivors by incorporating an LSS mail survey data on lifestyle factors as well as other information that was accumulated by the ABCC-RERF during the long-term study period but has not been used in risk estimation previously. She oversees data collection and LSS follow-up activities and collaborates with the internal and external investigators who use the RERF data.

John Cologne

John Cologne, PhD, ELS, is a Senior Scientist in the Statistics Department at RERF, Hiroshima where, for over 30 years, he has been analyzing radiation effects on health outcomes in the major RERF study cohorts of atomic-bomb survivors, in collaboration with RERF epidemiologists, clinical researchers, and laboratory scientists. Much of his applied work has been related to quantifying radiation-associated cancer risk in the LSS, assessing radiation-related risk of liver disease associated with viral hepatitis in the Adult Health Study, and evaluating laboratory markers as potential biodosimeters. He has particular expertise in the design and analysis of epidemiologic studies based on sampling from a cohort. He has published methodological work on the choice of primary time scale for Cox regression, omitted-variable bias with general risk models, and the effect of mis-specified background rate models on inference about the shape of the dose response. Current research interests include application of structural equations to causal modeling with latent factors and mediation, genomic analyses using pathways and gene sets rather than individual single nucleotide polymorphism loci, risk regression based on joint analysis of multiple disease endpoints, and joint modeling of longitudinal and event-time outcomes using novel summaries of longitudinal trajectories as risk factors.

Raquel Velazquez-Kronen

Raquel Velazquez-Kronen, PhD, is a research epidemiologist who joined the Field Research Branch of the National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention in 2018. Dr. Velazquez-Kronen currently studies chronic disease risks associated with occupational cosmic radiation exposure among aircrew. Previously, she studied risks of cancer and cataract associated with protracted low-dose occupational radiation exposure in U.S. radiologic technologists with the Radiation Epidemiology Branch, National Cancer Institute.

Mai Utada

Mai Utada, PhD, is an epidemiologist who joined RERF in 2014. She studies age at exposure effects on radiation risk and carcinogenesis. She led assessment of risks for uterine and ovarian cancers among the LSS women. Currently, Dr. Utada investigates the impact of prostate specific antigen testing in the Adult Health Study on radiation risk estimates for prostate cancer. Dr. Utada collaborates extensively with researchers from different disciplines and institutions.

Kiyohiko Mabuchi

Kiyohiko Mabuchi, MD, DrPH, joined the Radiation Epidemiology Branch at NCI in 2000 where he has been a Senior Scientist since 2008 and served as a head for the Chernobyl Research Unit. Before joining the NCI, he had been head of the Department of Epidemiology at RERF, leading follow-up studies in the LSS cohort and in the F1 mortality study. He was a member of ICRP Committee 1 between 1993 and 2001, consultant to the 2006 UNSCEAR Report on cardiovascular disease, the ICRP Tissue Reaction Task Group and the NCRP, Scientific Committee on Biological Effectiveness of Photons. His research interests include the radiation risk of solid and hematological cancers and their temporal patterns in atomic bomb survivors and Chernobyl populations.

Kotaro Ozasa

Kotaro Ozasa, MD, PhD, is an epidemiologist for community-based cohort studies and others targeting cancer and lifestyle-related health conditions and was also involved in public health activities. He has been the Chief of the Department of Epidemiology, RERF since 2008, and has been involved in the cohort studies of health effects due to atomic bomb radiation exposure among the survivors, in utero-exposed people, and survivor's children.

John D. Olson

John D. Olson, MS is a Research Associate with 16 years of experience in preclinical research. Most of his work has been in preclinical imaging, quantitative image analysis, experimental design, and data analysis. He is now the Resource Manager for the NIAID Wake Forest Primate Late Effects Program (U01 AI150578).

Gregory O. Dugan

Gregory O. Dugan, DVM, is a veterinarian with over 10 years’ experience in the clinical management and study of late effects of radiation in nonhuman primates, in support of the Wake Forest Radiation Late Effects Program.

Simonetta Pazzaglia

Simonetta Pazzaglia, PhD, is a senior scientist group leader at the “Division of Health Protection Technologies” of ENEA (Italian National Agency for the New Technologies, Energy and Sustainable Economic Development). She has considerable experience in experimental oncology and molecular biology, with particular emphasis on in vivo experiments using genetically modified mice. She also has a considerable experience in studying molecular events associated with radiation-induced cancer, with notable concentration on brain cancers. She is also interested in radiation-associated normal tissue effects and induction of non-cancer diseases, with a main focus on neurocognitive effects and lens opacity at low radiation doses.

J. Mark Cline

J. Mark Cline, DVM, PhD, is an experienced researcher with over 25 years of continuous NIH funding. He is a board-certified veterinary pathologist with many years’ experience in the discovery and development of animal models of cancer and radiation effects. Much of his past work focused on primate studies of hormonal and dietary effects on pathophysiology of breast and reproductive cancer risk, with comparative work in rodents, and translational studies in human subjects. He is now the Principal Investigator for the NIAID Wake Forest Primate Late Effects Program (U01 AI150578), funded from 2007-2027, which includes assessments of multiple organ systems in male and female primates, and serves a network of over 50 investigators across the US. Finding to date from this program include hematopoietic, immune metabolic, cardiovascular, pulmonary, neurovascular, and skeletal abnormalities, and gonadal injury in both males and females.

Kimberly E. Applegate

Kimberly Applegate, MD, is the chair of Committee 3 of the ICRP, focusing on radiation protection in medicine. Dr Applegate is a retired professor of radiology and pediatrics from the University of Kentucky in Lexington. Dr. Applegate’s policy and research work, including 200 publications, has contributed to an improved understanding of the structure, process, and outcomes of the practice of imaging, especially in pediatric groups, toward its improvement and standardization. She has worked collaboratively around the world in a number of medical specialties to improve imaging practice. From its start in 2007 to the present, she has worked on the Steering Committee for the Image Gently Campaign to improve children’s care worldwide. Kimberly has received a number of awards that include the 2019 AAPM’s Honorary Membership and the American Association for Women in Radiology’s Marie Sklowdoska Curie Award for her unique roles in leadership and outstanding contributions to the advancement of women in the Radiology professions.