ICRP ref: 4827-7056-2433
Released 26 November, 2018

Third Announcement

ICRP-QST-RERF Workshop on
Individual Response to Ionising Radiation
Current Scientific Evidence on Factors that Influence Individual Response
National Cancer Center, Research Institute, Tokyo, Japan
12 December, 2018
Organised by the International Commission on Radiological Protection (ICRP),
National Institutes for Quantum and Radiological Science and Technology (QST) andRadiation Effect Research Foundation (RERF)
In collaboration with National Cancer Center Japan (NCC), Japanese Society for
Radiation Oncology (JASTRO), Japan Radiological Society (JRS), Japan Health
Physics Society (JHPS) and the Japanese Radiation Research Society (JRRS)Registration
Attendance at the workshop is free of charge. However, advance registration is required
as attendance is limited. Please send your name, affiliation, and e-mail address to Hiroki
Fujita (ICRP Assistant Scientific Secretary) at register@icrp.org by 30 November 2018.

Workshop venue
Main Lecture Hall, National Cancer Center Research Building, Tsukiji Campus,
National Cancer Center, Tokyo, JAPANAccess: https://www.ncc.go.jp/en/about/access/index.html

Program
09:00 – 09:30

Welcome and Greetings (and Group Photo)
T. Hirano (QST), R. Ullrich (RERF), T. Nishida (NCC)

09:30 – 17:00

Scientific Session

Chair: W. Rühm (ICRP), K. Ozasa (RERF)
Speaker:
1. W. Rühm and K. Applegate (ICRP): Setting the Scene
2. A. Wojcik (ICRP): Human Individual Radiation Sensitivity and Prospects for
Prediction Factors(10:30 – 10:45 Coffee break)
3. M. Hauptmann (ICRP): Genetic susceptibility to radiation induced breast cancer after
Hodgkin Lymphoma.
4. A. Brenner (RERF): Age-dependence of breast cancer risk
5. K. Ozasa (RERF): Lifestyle-related cancer risk: Smoking and cancer(12:15 – 13:15 Lunch break)
Chair: K. Applegate (ICRP), R. Kanda (QST)
6. M. Bourguignon (ICRP): Radiosensitivity and radiotherapy patients
7. Y. Suto (QST/NIRS): Individual difference of chromosome aberration in accidentally
exposed workers
8. H. Onishi (JASTRO): Individual difference of post irradiated antitumor effect andlung damage in patients with lung cancer
9. M. Akahane (JRS): Individual variation in clinical practices and protocols(15:15 – 15:30 Coffee break)
Chair: W. Rühm (ICRP), K. Applegate (ICRP)
10. Moderated Discussion

17:00

Closing
C. Clement (ICRP)Abstracts

(1) Setting the Scene –The ICRP Task Group on “Factors Governing theIndividual Response of Humans to Ionising Radiation”
Werner Rühm1 and Kimberly E. Applegate2
1 Helmholtz Center Munich, German Research Center for Environmental Health, Institute ofRadiation Protection, 85764 Neuherberg, Germany;e-mail: werner.ruehm@helmholtz-muenchen.de2 University of Kentucky, USA;email: keapple@uky.edu

Abstract- Since a number of years, Committee 1 on “Radiation Effects” and Committee
3 on “Protection in Medicine” of the International Commission on RadiologicalProtection (ICRP) have identified individual response of humans to ionizing radiation asa topic with growing importance for international radiation protection. Accordingly, at
its last meeting in October 2018 in Stockholm, Sweden, the ICRP Main Commission
has approved a new Task Group (TG) on “Factors Governing the Individual Responseof Humans to Ionising Radiation“, jointly organized by ICRP Committee 1 andCommittee 3. The TG will review the currently available information on individual
radiation responses with special focus on the following questions and issues: 1) What is
the impact of age, sex and other determinants on normal tissue reactions and incidenceof cancers and other diseases following radiation exposure? 2) What is the contributionof genetics to individual, normal tissue responses with respect to adverse reactions tovarying doses such as given during radiotherapy? Would predictive tests contribute to abetter radiation protection of radiotherapy patients without compromising cancer curerates? 3) What is the contribution of genetics and epigenetic factors to tissue radiation
response with respect to cancer induction at relevant doses and dose rates? 4) What isthe evidence that modifiable factors can affect individual risk of radiation-induced
cancer, tissue reactions and other non-cancer diseases? 5) What are the ways to quantify
the potential impact of individual response to radiation on the incidence of cancers, noncancer diseases and normal tissue reactions? The final goal of the TG is development ofa report for publication in the Annals of the ICRP that presents a review of the current
science relevant to the topic of individual response to radiation.

(2) Human Individual Radiation Sensitivity and Prospects for Prediction
Factors
Andrzej Wojcik
Centre for Radiation Protection Research, Stockholm University, Sweden;
e-mail: andrzej.wojcik@su.se

Abstract- The idea of individual sensitivity to radiation in humans with respect to tissue
effects has long been supported by data from patients with certain rare hereditaryconditions such as ataxia telangiectasia or Nijmegen breakage syndrome. However,these monogenetic syndromes affect only a small proportion of the general population.
More relevant to the majority of the population is that the genetic contribution defining
radiation sensitivity follows a polygenic model, which predicts elevated risk resulting
from the inheritance of an unknown number of low penetrance risk alleles. In this way
individual radiosensitivity, both with respect to tissue effects and stochastic effects, canbe regarded as a multifactorial trait. It is well known that multifactorial traits are
influenced by the genotype and the environment. More recent investigations show thatin addition to these two factors, there are non-inherited parental genetic variants,
parental environment at the epigenetic level and stochastic molecular variations (noise).
With respect to radiation sensitivity, an additional factor contributing to variability is
the stochastic nature of radiation induced cell death. Hence, predicting the risk ofadverse tissue reactions in a radiotherapy patient based on genotyping a single cell type(usually peripheral blood leukocytes) isolated from the patient or from the results of afunctional assay may be difficult. Indeed, results of reports published so far are notpromising. Also, as stated in the ICRP 79 report, in vitro human cellular radiosensitivity
is not a reliable predictor of in vivo cancer proneness nor, by implication, tumorigenic
radiosensitivity.
The aim of the presentation is to set the stage for discussions about factors modifying
the risk of overreacting to radiation exposure by explaining the nature and relationshipof monogenic and polygenic traits. Recent publications aiming at validating markers ofindividual radiosensitivity will be presented and the possible reasons for the conflicting
results explained.

(3) Genetic susceptibility to radiation induced breast cancer after Hodgkin
Lymphoma
Michael Hauptmann
Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, Netherlands;e-mail: m.hauptmann@nki.nl

Abstract- Female Hodgkin lymphoma (HL) patients treated with chest radiotherapy(RT) have a very high risk of breast cancer. The contribution of genetic factors to thisrisk is unclear. We therefore examined 211,155 germline single nucleotide
polymorphisms (SNPs) for gene-radiation interaction on breast cancer risk in a caseonly analysis including 327 breast cancer patients after chest RT for HL and 4,671 firstprimary breast cancer patients. Nine SNPs showed statistically significant interaction
with RT on breast cancer risk (false discovery rate <20%), of which one SNP in the
PVT1 oncogene attained the Bonferroni threshold for statistical significance. A
polygenic risk score (PRS) composed of these SNPs (RT-interaction-PRS) and apreviously published breast cancer PRS (BC-PRS) derived in the general population
were evaluated in a case-control analysis comprising the 327 chest-irradiated HLpatients with breast cancer and 491 chest-irradiated HL patients without breast cancer.
Patients in the highest tertile of the RT-interaction-PRS had a 1.6-fold higher breast
cancer risk than those in the lowest tertile. Remarkably, we observed a 4-fold increased
RT-induced breast cancer risk in the highest compared with the lowest decile of the BCPRS. On a continuous scale, breast cancer risk increased 1.4-fold per standard deviationof the BC-PRS, similar to the effect size found in the general population. This study
demonstrates that genetic factors influence breast cancer risk after chest RT for HL.
Given the high absolute breast cancer risk in radiation-exposed women, these results
can have important implications for the management of current HL survivors and future
patients.

(4) Age-dependence of breast cancer risk
Alina V. Brenner
Department of Epidemiology, RERF, Hiroshima, Japan;
e-mail: brennera@rerf.or.jp

Abstract- Studies of patients irradiated for diagnostic and therapeutic purposes, atomic
bomb survivors, and environmentally exposed populations establish a strong andconsistent association between breast cancer risk and radiation dose consistent withlinearity. In a pooled analysis of eight cohort studies, age at exposure and attained age
were important modifies of radiation risk on excess relative risk (ERR) and excess
absolute risk (EAR) scales, although the pattern was different. The ERR decreased withincreasing age at exposure and attained age, while the EAR decreased with age at
exposure and increased with attained age. In the Life Span Study (LSS) cohort ofatomic bomb survivors, the relative importance of attained-age and age-at-exposure
effects on radiation risks has evolved over the years. As follow-up increased, thecorrelation between attained age and age at exposure decreased markedly making
possible an examination of age at exposure and attained age as separate effect modifiers.
Over time, the evidence and estimated magnitude of a simple trend in the ERR with age
at exposure has lessened, especially when the ERR was allowed to vary with attained
age. In the most recent LSS breast cancer report with a follow-up through 2009, there
was only weak evidence of a significant monotonic trend in the ERR per Gy with ageat-exposure without allowance for attained-age effect modification. By contrast, after
allowing for attained age effect, the EAR decrease persisted. This study also provided
new evidence that age-at-exposure effects on ERR and EAR might differ before andafter menarche, with highest risks for exposures around menarche. For exposures prior
to menarche, radiation effect increases (ERR) or remains stable (EAR) as the exposure
age approaches menarche while, for exposures after menarche, radiation effects (ERR
and EAR) decrease as exposure age increases. Independent of age-at-exposure andattained age effects, ERR and EAR also decreased with later age at menarche. While the
new LSS findings require replication in independent studies, these suggest heightenedbreast tissue sensitivity to ionizing radiation during puberty. The LSS experience
underscores the importance of long, perhaps life-long, follow-up of exposed populations
in discerning the complex age patterns of radiation risk.

(5) Lifestyle-related Cancer Risk: Smoking and Cancer
Kotaro Ozasa
Department of Epidemiology, RERF, Japan;
e-mail: ozasa@rerf.or.jp

Abstract- Smoking is a definite and well-known carcinogen and causes many cancers,
especially for lung cancer. In Japan, smoking habits became popular rapidly throughrecovery and development of economy after the World War II, peaked around 1970s at
which more than 80% of adult men smoked, but smoking prevalence has decreased
thereafter and reached at a level of 30% in 2010s. In women, smoking prevalence has
been traditionally low as less than 20% although smoking prevalence among young
women had peaked over 20% around the year of 2000. Mortality of lung cancer
followed the trend of smoking habits in Japan, i.e., rapidly increased during the 20th
century, but has decreased thereafter. It has been suggested that relative risk of smoking
for lung cancer observed in Japanese population might be smaller than those observedin Western countries. The lower risk might be induced by possible overestimation ofsmoking intensity based on the surveys of epidemiological studies conducted in the late
20th century. Smoking status and its risk was examined in the LSS, which indicated low
smoking intensity in older birth cohorts and smoking risks comparable to Westerncountries among smokers who started smoking at their young ages [1]. Smoking risk ishigh for small cell carcinoma among lung cancer subtypes, then squamous cell
carcinoma, and the risk for adenocarcinoma was relatively low. In contrast, radiation
risk of squamous cell carcinoma was relatively low compared to adenocarcinoma
although small cell carcinoma showed the highest radiation risk. A positive interaction
between radiation exposure and smoking was observed among smokers of low smoking
intensity [2,3].
Recently it has been shown that mutations in the epidermal growth factor receptor genes(EGFR) are common in adenocarcinoma developed in East Asian non-smoking women.
Smoking was not associated with EGFR-mutation lung cancer, but strongly associatedwith EGFR-wild-type lung cancer [4]. This finding may partially explain lower relative
risks of smoking for lung cancer among Japanese and East Asian populations.
Carcinogenetic process of smoking could be investigated through these analyses andthat of radiation exposure might be, too.
1) Sakata R, et al. BMJ, 2012;345:e7093.
2) Furukawa K, et al. Radiat Res, 2010;174:72-82.
3) Egawa H, et al. Radiat Res, 2012;178:191-201.
4) Matsuo K, et al. Cancer Sci 2007;98:96-101.

(6) Radiosensitivity and radiotherapy patients
Michel Bourguignon
University of Paris Saclay (UVSQ) and IRSN, France;
e-mail: michel.bourguignon@irsn.fr

Abstract- In a pragmatic clinical approach of the individual response to ionizing
radiation (IR) in patients (Foray et al., 2016), three abnormal situations can be identified
or envisaged: complications and undesirable side effects of radiotherapy with no error indose delivery which affect the quality of life of patients, cancer proneness anddegenerative diseases after exposures to IR. For the sake of clarity we have named thecorresponding
individual
statusradiosensitivity,
radiosusceptibility
andradiodegeneration respectively. This presentation deals with “Radiosensitivity andradiotherapy”.
Radiosensitivity was identified at the beginning of the XX th century but has beenforgotten since. A first major classification of human diseases exhibitingradiosensitivity has been made on the basis of the cell survival fraction in vitro after
exposures to IR (Deschavanne and Fertil, 1981). Radiosensitivity is clearly related to an
excess of cell death after exposure even though the tissue response is important as wellin vivo. All these diseases have a genetic component and about 70% of them concern agene/protein directly involved in the DNA damage response (DDR), the most severe
disease being related to mutated ATM-/- in ataxia telangiectasia and the least severe withvarious heterozygous status. The other 30% are composed of genetic disease, mostly
neuro-degenerative diseases with some degree of immunologic deficiency, where theabnormal gene/protein is not related to DDR. All these diseases account for about 5% of
the population, ATM+/- accounting by itself for 1.5% of the population.
Cohorts have been constituted with hundreds of patients exhibiting clinicalradiosensitivity, e.g., the Copernic cohort (Granzotto, 2016) and most of them do nothave the genetic diseases mentioned above since these patients are usually not treatedby radiotherapy. Thus the status of radiosensitivity is observed in more than 5% of
patients treated by radiotherapy and may reach up to 15 or 20 % if all grades from 2 to 4
(as classified by radiation oncologists with the EORTC or CTCEA scales) are included.
These grades demonstrate some continuity between normality and severe syndromes.
Clonogenic survival, cytogenetic, DSB repair and gene expression assays have been
proposed to predict radiosensitivity but these tests are difficult to use in routine practicemostly because of the delay in response. Among the most recent assays, CD8 Tlymphocyte apoptosis has been proposed to predict late toxicity after radiotherapy(Azria et al., 2015) but the inverse correlation with IR dose is surprising and still notunderstood. Gene expression assay of CDKN1A is also promising to identify severe
early radiation toxicity (Finnon et al., 2012). Numerous immunofluorescence assays arenowadays available and allow to follow the cell kinetics of proteins in space(cytoplasm/nucleus) and time and thus to perform cell functional assessment. The
kinetics of ATM has been modelled and it appears that the aforementioned neuro-degenerative diseases exhibit an absence or a delay of translocation of ATM from thecytoplasm where it resides as dimers in the direction of nucleus as pATM monomers
after exposure to IR (Granzotto, 2016). In the absence or delayed appearance of pATM
in the nucleus the DNA DSBs are not properly repaired and this is the first time that asecond clear mechanism of radiosensitivity, i.e., an indirect abnormal DDR is identified.
Subsequently a pATM ELISA assay has been successfully developed in skin fibroblasts
and lymphocytes for clinical use (Pereira et al., 2018).
At this stage it appears that radiosensitivity is clearly a public health issue since about
10 millions of patients benefit from radiotherapy worldwide every year and certainly
more than 500,000 of them have a durable altered quality of life after their treatment. In
order to progress in the prediction of radiosensitivity with the hope to avoid such poor
clinical outcomes an international collaboration is necessary. Cross comparisons of
assays in the different international cohorts of patients are certainly a good way to makesignificant progress and thus should be initiated.
Finally, about 8% of patients treated for cancer by radiotherapy exhibit a second cancer(Cosset et al., 2018). Although the issue is to know if it is a secondary cancer or asecond primary cancer, these patients may be radiosusceptible and such a status ofcancer proneness need to be explored in the future with pertinent biomarkers.
In conclusion, radiosensitivity, radiosusceptibility and radiodegeneration are key issuesof the individual response to ionizing radiation and need to be addressed by the ICRPTG 111.
Main references-Deschavanne PJ and Fertil B. A review of human cell radiosensitivity in vitro. Int J
Radiat Oncol Biol Phys. 1996; 34(1):251-66-Foray N, Bourguignon M, Hamada N. Individual response to ionizing radiation.
Mutation Research 770 (2016) 369–386-Granzotto a. et al. Influence of Nucleoshuttling of the ATM Protein in the Healthy
Tissues Response to Radiation Therapy: Toward a Molecular Classification of HumanRadiosensitivity. Int J Radiation Oncol Biol Phys, 2016, 94: 450-460-Pereira S. et al. Fast and Binary Assay for Predicting Radiosensitivity Based on the
Theory of ATM Nucleo-Shuttling: Development, Validation, and Performance. Int J
Radiation Oncol Biol Phys, 2018, 100: 353-360

(7) Individual difference of chromosome aberration in accidentally exposed
workers
Yumiko Suto
National Institute of Radiological Sciences, National Institutes for Quantum and Radiological
Science and Technology, Japan;
e-mail: suto.yumiko@qst.go.jp

Abstract- Ionizing radiation exposure causes DNA strand breaks that lead tochromosome aberrations. Among radiation-induced chromosome aberrations, dicentricchromosomes have been considered sensitive and specific bio-indicators for assessing
radiation dose. The dicentric chromosome assay (DCA) has been the ‘gold standard’ forbiological dosimetry in accidental radiation exposure for more than three decades. A
dicentric yield from a radiation-exposed patient is referred to a calibration curve (dose–
response curve) experimentally prepared in advance from dicentric scoring data atseveral dose points from peripheral blood samples of one healthy donor or by poolingscoring data from several donors in considering inter-individual variability. In the latter
cases, Van Buul and Natarajan (1980) and Kakati et al. (1986) noted a remarkable interindividual variability. On the other hand, some reports showed moderate or no
significant inter-individual variability so that data of all donors could be pooled(Vinnikov and Maznyk 2013; Al-Hadyan et al. 2014).
Recently, the translocation analysis combined with fluorescence in situ hybridization(FISH) using differentially colored chromosome painting probes are also applied forbiological dosimetry. This technique is useful particularly for retrospective dose
assessment because translocations are more stable, allowing dose estimates to be madelong time after exposure or after protracted exposures. It is well-known, however, thatthe background levels of translocations increase with age due to confounding factors(Sigurdson et al., 2008). Inter-individual variability of translocation yields could belarger than that of dicentric yields.
In the present session, current issues concerning inter-individual variability ofchromosome aberration yields will be demonstrated and discussed.

(8) Individual difference of post irradiated antitumor effect and lungdamage in patients with lung cancer
Hiroshi Onishi
Department of Radiology, University of Yamanashi, Japan;
e-mail: honishi@yamanashi.ac.jp

Abstract- In the treatment of lung cancer, radiotherapy is one of the important therapies,
despite its sometimes unpredictable side effects. Stereotactic body radiotherapy(SBRT)
is a highly dose concentrated radiotherapy technique which can spare normal organ dosemuch more than conventional radiotherapy technique. Severe radiation pneumonitis(RP) after stereotactic SBRT for the patients with early stage primary lung cancer isgenerally rare toxicity but sometimes gets to be severe adverse effect. It is important but
has not been achieved to predict patients who are at high risk of developing severe RP
and its monitoring techniques. Therefore, identifying lung cancer patients who are athigh risk of developing severe RP and applying effect intervention or monitoring
techniques are important. Although human diversity to a certain amount is explained byclinical and dosimetric factors, the presence of specific genetic variants also influences
the occurrence of radiation-induced damage.
In our multi-institutional study to search reliable biologic markers to predict the risk of
RP after SBRT, we investigated the association between single nucleotide
polymorphisms (SNPs) in inflammation-related genes and risk of radiation pneumonitis(RP) in the patients with stage I non-small-cell lung cancer (NSCLC) treated by SBRT.
Using genomic DNA samples from totally 223 patients with stage I NSCLC treated by
SBRT were acquired and genotyped 21 SNPs of inflammation-related genes by mainly
MassARRAY system to detect the difference in the mass of nucleotides. In the result,grade > or = 2 RP and inflammatory shadow outside of the irradiated volume wereobserved in 36 (16.1%) and 34 (15.2%), respectively. Multivariate analysis found a
history of heart failure or steroid administration, the ratio of volume irradiated 10Gy or
more in the total normal lung volume (V10), and genotypes of EGFR (rs11543848) tobe significantly higher risk factors of grade > or = 2 RP combined with inflammatory
shadow outside of the irradiated volume. When excluding six cases with a history ofsteroid administration, only genotype of EGFR (rs11543848) was a significantly higher
risk factor of grade > or = 2 RP combined with inflammatory shadow outside of theirradiated volume. Though Replication studies with more patients are required tovalidate these results, the showed that the SNP with genotypes of EGFR might be ahigher risk of severe RP in patients with NSCLC treated with SBRT.
In my presentation, the individual or racial difference of the ratio of RP and relationshipof EGFR to post irradiation pneumonitis would be discussed.

(9) Individual variation in clinical practices and protocols
Masaaki Akahane
Department of Radiology, School of Medicine, International University of Health and Welfare,Japan;
e-mail: akahane-tky@umin.ac.jp

Abstract- Justification in radiological protection of patients in clinical practices isdifferent from justification of others, in that the very same person enjoys the benefits
and suffers the risks associated with that particular radiological examination. The
particular application of the examination should be judged to do more good than harmto the individual patient if properly optimized.
Imaging protocols are prepared for typical purposes or demands of the examination ineach hospital, and an appropriate protocol for each examination is assigned byconsensus of the referral physician and the radiologist. Tube current and voltage isadjusted and modulated to suit the body thickness of each patient. It is recommended
prepare special protocols for pediatric and young patients, who are considered to besmaller in body size and more radiosensitive than the older patients. Tube current would
be modified referring to some attributions of the patients, such as prognosis, expected
life, planned therapy, past history (especially of the radiosensitivity syndromes such as
ataxia telangiectasia), because these factors would affect the risk-benefit balance of theindividual patient, although such modification tends to be subjective and not
reproducible. Establishment of the system for objective and reproducible modificationof the parameter of exposure should be warranted for further individualized patient care.