ICRP ref: 4840-7205-6121

Joint RERF-ICRP Workshop on Health Risk of Radiationand the System of Radiological Protection
Sunday, October 9, 2016
Organised by Radiation Effect Research Foundation (RERF)
and the International Commission on Radiological Protection (ICRP)
with support from the Nippon Foundation

Abstracts

Radiation Effects Research Foundation
A Cooperative Japan-US Research Organization

INTERNATIONAL COMMISSION ON RADIOLOGICAL PROTECTION

Joint RERF-ICRP Workshop on
Health Risk of Radiation and the System of Radiological Protection
The University of Tokyo
Sunday, October 9, 2016
Organised by Radiation Effect Research Foundation (RERF) and the International Commission
on Radiological Protection (ICRP) with support from the Nippon Foundation

Background
RERF is a world-leading research institute on radiation effects. Their studies of atomic bomb
survivors are considered the gold standard in epidemiological research on the health effects ofradiation exposure, and are often cited by UNSCEAR. ICRP has worked with RERF scientists
for many years, as the work of RERF is considered a key element in the scientific foundation of
the system of radiological protection. This joint workshop provides an opportunity to continue toexchange information between RERF and ICRP in an open forum on the most advanced researchfrom RERF for the purpose of using scientific findings for the protection of people from the risksof radiation.

Objectives
RERF and ICRP welcome this opportunity to discuss the current work with Japanese scientists,covering radiation related topics including: the risk of hereditary effects, cancer and non-cancer.
In addition, the future of radiation health risk science and the system of radiological protection
will be discussed.

Symposium venue
Room number 221, Faculty of Engineering Build. 2, Hongo Campus, The University of Tokyo
Access: http://www.t.u-tokyo.ac.jp/soee/access.html

Program
13:00 – 13:05: Opening address
By Christopher Clement (ICRP) (5 min)13:05 – 13:55: Session 1: Risk of hereditary effects
Chair: Yoshiya Shimada (NIRS)
Speaker:
Nori Nakamura (RERF): “Hereditary effects of radiation in men and in mice”(30 min)
Questions and answers (20 min)
13:55 – 14:55: Session 2: Dose response of radiation associated cancer and DDREF
Chairs: Ludovic Vaillant (CEPN), Michiaki Kai (ICRP)
Speakers:
Eric Grant (RERF) on “Dose response of solid cancer in atomic bomb survivors”(20 min)
Werner Ruehm (ICRP) on “Current ICRP stance on DDREF” (20 min)Questions and answers (20 min)
14:55 – 15:55: Session 3: Risk of non-cancer: current controversy on the disease type
Chairs: Kazunori Kodama (RERF), Mark Little (NCI)
Speakers:
Kotaro Ozasa (RERF) on “Current research on non-cancer diseases in atomic bombsurvivors” (20 min)Tamara Azizova (ICRP) on “Circulatory disease in Mayak workers” (30 min)Questions and answers (20 min)
15:55 – 16:10 Coffee break
16:10 – 17:30 Round table discussion on “Futures of Health Risk Research and theSystem of Radiological Protection”
Discussion leaders:
Robert Ullrich (RERF) on “Future of radiation research at RERF” (15 min)Nobuhiko Ban (ICRP) on “Future of radiation protection” (15 min)Comments from the floor2Hereditary effects of radiation in men and in mice
N. Nakamura
Radiation Effects Research Foundation, 5-2 Hijiyama park, Minami-ku, Hiroshima 732-0815, Japane-mail: nori_nakamura@rerf.or.jp

Abstract–Ionizing radiation is a mutagen capable of inducing heritable genetic damage in various species.
In humans, however, clear evidence for the increased risk of genetic damage represented by chromosome
aberrations, malformations or Mendelian disorders in the offspring of exposed parents (either atomicbomb survivors or childhood cancer survivors) has not been observed. Our past study in mice indicatedthat the mutation induction rate in spermatogonia cells was of the order of 10-6/DNA fragment/Gy whenabout 1,000 sites in the genome were screened with the two-dimensional electrophoresis (2DE) techniqueof DNA. More recently, over 1,000,000 sites were screened with the array-based comparative genomic
hybridization (aCGH) technique. The results indicated that the mutation induction rate was even lower, ofthe order of 10-7/probe site/Gy. Compared with the mean induction rate of the order of 10-5/locus/Gy withthe classic specific-locus tests at 7 genes, it appears that the mean mutation induction rate decreased with
the increase in the number of genes or sites examined per genome. These results indicate two
possibilities; one is that deletions are induced evenly in the genome but many of them are not recovered
as viable F1 due to loss of haploid sensitive genes in the deletion. Alternatively, DNA breaks may notoccur randomly in the genome.

3Solid cancer incidence among the Life Span Study of atomic bomb
survivors: 1958–2009
E. J. Grant,a A. Brenner,b H. Sugiyama,c R. Sakata,d A. Sadakane,e M. Utada,f E. K.
Cahoon,g C. M. Milder,h M. Soda,i H. M. Cullings,j D. L. Preston,k K. Mabuchi,l K.
Ozasam
Department of Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiroshima, 732-0815, Japan;
e-mail: egrant@rerf.or.jpb
Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda,Maryland, U.S.A.; email: brennera@mail.nih.gov
cDepartment of Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiroshima, 732-0815, Japan;
e-mail: sugi@rerf.or.jpdDepartment of Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiroshima, 732-0815, Japan;
e-mail: rsakata@rerf.or.jp
eDepartment of Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiroshima, 732-0815, Japan;
e-mail: sadakane@rerf.or.jpfDepartment of Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiroshima, 732-0815, Japan;
e-mail: utada@rerf.or.jp
gRadiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda,Maryland, U.S.A.; email: elizabeth.cahoon@nih.gov
hVisiting Scientist, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiroshima, 732-0815, Japan;
e-mail: caitlin@milder.com
iDepartment of Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiroshima, 732-0815, Japan;e-mail: soda@rerf.or.jp
jDepartment of Statistics, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiroshima, 732-0815, Japan;
e-mail: cullings@rerf.or.jpk
Hirosoft International Corporation, Eureka, California, USA;e-mail: preston@hirosoft.net
lRadiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda,Maryland, U.S.A.; email: mabuchi@mail.nih.gov
mDepartment of Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Hiroshima, 732-0815, Japan;
e-mail: ozasa@rerf.or.jp

Abstract–This analysis of all solid cancer incidence among the Life Span Study (LSS) cohort of atomicbomb survivors adds eleven years of follow-up data since the last report and includes updated dose
estimates and adjustment for smoking. 105,444 cohort members who were alive and had no known
history of cancer were analyzed from 1958–2009 using Poisson regression methods. Risk estimates arereported for a person exposed at age 30 years with attained age 70 years. 22,538 incident first primarysolid cancer cases were identified. For females, the dose response was consistent with linearity with anestimated excess relative risk (ERR) of 0.64 per Gy (95% CI: 0.52 to 0.77). For males, significant upwardcurvature was observed and therefore a linear-quadratic model was used, which resulted in an ERR of0.20 (95% CI: 0.12 to 0.28) at 1 Gy and an ERR of 0.010 (95% CI: −0.0003 to 0.021) at 0.1 Gy. In
conclusion, solid cancer risks remained elevated more than 60 years after radiation exposure. Smoking
adjustment had little or no impact on the shape of the dose response. At this time, uncertainties in theshape of the dose response preclude definitive conclusions to confidently guide radiation protectionpolicies.

4Current ICRP stance on DDREF
W. Rühm
Helmholtz Center Munich, Institute of Radiation Protection, Ingolstädter Landstr. 1, 85764 Neuherberg, Germany;e-mail: werner.ruehm@helmholtz-muenchen.deAbstract–In the ICRP 103 Recommendations, the International Commission on Radiological Protection(ICRP) confirmed the use of a Dose and Dose Rate Effectiveness Factor (DDREF) with a numerical valueof 2, which had been introduced by ICRP in the earlier ICRP 60 Recommendations. This factor is used byICRP to rescale risks of radiation-induced solid cancers obtained from the cohort of atomic bomb
survivors, which were exposed to higher dose and dose rates as compared to workers who are usually
exposed to lower dose and dose rates. Other international bodies such as the United Nations ScientificCommittee on the Effects of Atomic Radiation (UNSCEAR), the BEIR VI Committee of the American
National Academy of Sciences, or the German Radiation Protection Commission (SSK), however,suggest alternative approaches or propose other numerical values for the DDREF. Currently, members ofICRP Task Group 91 are reviewing the scientific literature on sub-cellular and cellular effects relevant for
carcinogenesis, combine animal data from various studies, and analyse most recent epidemiological datafrom cohorts exposed to ionizing radiation. The present paper gives an overview on the current activitiesof this Task Group.

5Current research on non-cancer diseases in atomic bomb survivors
K. Ozasa
Department of Epidemiology, Radiation Effects Research Foundation, 5-2 Hjiyama-koen, Minami-ku, Hiroshima, 732-0815,
Japan; e-mail: ozasa@rerf.or.jp

Abstract–Radiation-associated risks of non-cancer diseases among atomic bomb survivors have been
evaluated by the Life Span Study (LSS) and the Adult Health Study (AHS). Information regarding noncancer diseases in the LSS is obtained only from death certificates while precise and detailed information
is obtained in the AHS, a sub-cohort of the LSS, of which members are clinically examined biennially.
But, such information was obtained by medical procedures that were available for limited participants inselected periods, so that the results might not be generalized in comparison with the LSS. In addition,mortality and morbidity trend and pathogenesis of non-cancer diseases in Japan has changed over the long
follow-up period since the devastated post-war through economic development and lifestylewesternization. Radiation-associated risk of cardiovascular disease may be mediated by radiationassociated hypertension as hypertension was a major basis of cardiovascular disease in Japan.
Atherosclerotic predisposition was slightly elevated with radiation exposure, but it remains unclear how
strong the elevation affected the pathogenesis of cardiovascular disease among atomic bomb survivors.
Radiation-associated mortality risk was apparently observed for cardiovascular and non-cancer
respiratory deaths potentially accompanied with uncertain conditions at death, which made theinterpretation of results complicated and inconclusive.

6Circulatory diseases in the cohort of Mayak PA workers occupationallyexposed to radiation
T.V. Azizova, E.S. Grigorieva, M.V. Bannikova, M.B. Moseeva
Southern Urals Biophysics Institute, Ozyorskoe shosse 19, Ozyorsk, 456780 Russian Federation; e-mail: clinic@subi.su

Abstract–The study was aimed to investigate incidence and mortality from circulatory diseases (CDs)including ischaemic heart disease (IHD), cerebrovascular diseases (CeVD) and lower extremity arterial
disease (LEAD) in Mayak workers occupationally exposed to low dose rate radiation. The cohort
included 22,377 individuals first employed in 1948–1982 and followed up to 2008. 8,717 cases and 1,578
deaths from CeVD, 7,225 cases and 2,848 deaths from IHD, 943 cases of LEASO and 5,010 deaths fromCDs were registered. A significant linear association of IHD, CeVD and LEAD incidence was found withdose from external gamma-rays adjusting for non-radiation factors and dose from internal alpha-radiation.
Significant increasing linear trend in IHD and CD mortality with increasing gamma-dose was observed.
Dose-response analysis for internal alpha-radiation due to incorporated plutonium showed a significant
linear association of IHD and CeVD incidence with total absorbed dose from internal alpha-radiation to
the liver including adjustments for non-radiation factors and dose from external gamma-rays. Significant
increasing linear trends in mortality from IHD, CeVD and CDs with increasing dose from internal alpharadiation were revealed only for a subcohort of workers who were Ozyorsk residents exposed to internalalpha-radiation at total absorbed dose to the liver < 1.0 Gy.

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Future of radiation research at RERF
R. Ullrich
Radiation Effects Research Foundation, 5-2 Hijiyama park, Minami-ku, Hiroshima 732-0815, Japane-mail: ullrich@rerf.or.jp

Abstract–A unique characteristic of research at RERF is the opportunity to conduct multidisciplinary
studies in a single setting taking advantage of the LSS and AHS cohorts. Such studies can be used toquantify radiation effects as a function of dose as well as approach underlying mechanisms of direct
applicability to basic radiation biology. Such basic research, in combination with epidemiological andclinical studies, also provides essential information with respect to effects of ionizing radiation at low
doses, which are often difficult to directly measure. At present an important new activity is aimed atquantifying and characterizing heritable effects of radiation exposure in the children of the atomic bomb
survivors using next generation sequencing. In previous studies previously conducted at RERF, heritable
mutations have been undetectable using a variety of endpoints. More recently, observations in a mousemodel using CGH have indicated that the frequency of new mutations in offspring was substantiallylower than would be expected based on the specific locus test. Integrated multidisciplinary studies on
effects of radiation exposure on the incidence and underlying mechanisms of organ-specific cancers andnon-neoplastic effects (principally cardiovascular disease) are also being developed. Such studies takeadvantage of the RERF biobank as well as animal models with an emphasis on “omics” approaches.

8Future of radiation protection
N. BanNuclear Regulation Authority, 1-9-9 Roppongi, Minato-ku, Tokyo 106-8450, Japan;
e-mail: nobuhiko_ban@nsr.go.jp

Abstract–The objective of radiological protection for human health is to prevent deterministic effects andreduce the risks of stochastic effects to the extent reasonably achievable. This principle is based on thepremise that deterministic effects are due to injury in population of cells at high doses and that stochastic
effects arise from mutation of somatic cells or germ cells. While the notion has a solid base, accumulating
data suggest there are challenges to be overcome. One of the emerging issues is tissue reactions,particularly increase in the risk of circulatory disease after moderate exposure. It is not a typicaldeterministic effect that is attributed to radiation-induced cell killing/malfunction in individual tissues, buta tissue reaction that is caused jointly by radiation and other factors involving multiple tissues.
Consequently the threshold is obscure, and the contributing dose could be unclear in non-uniform
exposure. These features raise a question about the classification of effects and the shape of dose response
curve for this type of effect. As to stochastic effects, recent epidemiological data indicate the dose-rate
effect may not be significant in cancer induction, and there is doubt and criticism about the use of doseand dose rate effectiveness factor (DDREF). On the other hand, review of the studies on tissue stem cells
suggest long-term kinetics of target/stem cells in the tissue may modify the dose response in the case ofprotracted exposure. While it may take long before reconciling these opposing views, looking into eachclass of cancer will be a necessary step towards resolution. Biologically it is little wonder that thetumorigenic process differs between cancer types, and response to radiation may not follow a simple rule.
In this context, analyses and experiments on the basis of cancer site/type is desirable for realisticassessment. At the same time, modifying effects of sex, age and lifestyle factors should not be dismissed
since they often have a great impact on sensitivity and the baseline risk. Addressing these issues does notnecessarily mean future radiological protection will be more elaborate and complex. Rather, we have to
make best efforts to integrate recent findings into a simple, robust and practical system. Careful
examination of the available data and promotion of strategic research on priority issues are needed toward
this end.

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