Keynote
Speech【Chair】Hiroo Dohy

【Speaker】Fred A. Mettler, JR., M.D., M.P.H.

President, The Japanese Red Cross Chugoku-Shikoku Block Blood
Center
PhD, Hiroshima University School of Medicine, 1970

Professor Emeritus and Clinical Professor at the Department ofRadiology at the University of New Mexico School of Medicine

Medical associate Hiroshima University, lecturer
appointed by the Ministry of Education at Hiroshima
Univ. and Otake National Hospital, 1977-1984. Director
internal medicine Hiroshima Red Cross Hospital,
1984-2004, president, since 2004, Atomic Bomb Survivor's
Hospital, 2004-2012, Director, Japanese Red Cross
Chugoku -Shikoku Block Blood Center, since 2012.

Dr. Mettler received a B.A. from Columbia University, an
M.D. degree from Thomas Jeﬀerson University and
Master's Degree in Public Health from Harvard
University.
He has authored over 360 scientiﬁc publications, including
21 textbooks. He is an Emeritus Commissioner of ICRP,
an emeritus member of NCRP and a member of the
Nuclear and Radiation Studies Board of the US National
Academies. He was the US Representative to UNSCEAR
for 28 years. He was the Health Eﬀects Team Leader of
the International Chernobyl Project. He has served as anexpert on radiology and radiation eﬀects and accidents
for the U.S. Department of HHS and Homeland Security,
WHO and IAEA. He is currently a health advisor to theJapanese Cabinet for the Fukushima nuclear disaster.

70 years: Learning from Sadako
I would like to thank K. Hiramatsu, K. Kodama,
HICARE and the organizers of this symposium for givingme the honor to present the keynote lecture on the occasionof the 70th anniversary of the atomic bombings.
Sadako Sasaki is a symbol of innocent victims of war
especially children. She died of leukemia as a result ofradiation from the atomic bomb in Hiroshima. There weretens of thousands of others who also suﬀered from radiationeﬀects. My intent is to show how the vast amount ofknowledge and expertise that has been accumulated fromthis tragic event has been eﬀectively used to help other1

radiation exposed persons having impact upon millions of persons worldwide. It is important to reﬂect uponthis experience especially in light of a conﬂuence of anniversaries in 2015-15 including the 70th anniversary of
the bombing, the 40th anniversary of RERF, the 30th anniversary of Chernobyl, the 25th anniversary of
HICARE and the 5th anniversary of the Fukushima nuclear accident. It has been aptly pointed out by T.
Okubo that the achievements in understanding of radiation eﬀects and the derivative beneﬁts would not havebeen possible without the cooperation of the participants in the health programs.

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There are 4 general categories of health eﬀects thathave emerged from studies of atomic bomb survivors
including potential hereditary eﬀects, cancer induction,eﬀects on pregnancy and non-cancer eﬀects（such as
cataracts and possibly cardiovascular disease）. There has
been a shift over time in the realization of the eﬀects andfocus of the studies. The early period from 1945 to about
1960 dealt primarily with acute eﬀects and genetic eﬀects.
By the 1960ʼs there was a realignment in focus with therealization that radiogenic cancer was likely the major longterm eﬀect. In the period 1970-2000 and with the creation of
RERF, evaluation of speciﬁc cancer types, statistical analysis

2modeling and risk over time was studied. After 2000 there was additional interest and evaluation of non-cancer
mortality and eﬀects.
By the mid and late 1960ʼs it had become clear thatgenetic eﬀects did not seem to be occurring. In spite of thisRERF has continued to study the risk of death amongchildren of atomic bomb survivors. A 2015 publication by
Grant et.al. with 62 years of follow-up concluded that there
was no indication of deleterious health eﬀects in theoﬀspring. This ﬁnding has been corroborated by other longterm studies of the oﬀspring of cancer patients treated withradiation as children. Lack of evidence however is notevidence of no eﬀect and such eﬀects may take generations
to appear. The fact that there has been no identiﬁable
hereditary risk is an important and comforting fact for3

millions of radiation workers and other exposed persons who have had, or are planning to have, children.
The RERF data with the associated sophisticatedstatistical analysis have been crucial to the understanding ofradiation-induced cancer. The LSS and AHS are regarded as
the gold standard epidemiological studies of radiation eﬀects.
The data show that there is a statistically signiﬁcant excess
of cancer which increases almost linearly at doses above
about 150 mGy and up to about 3 Gy（Figure 4）. At very
low doses, the data is not statistically powerful enough to be
sure whether there is a cancer risk which is too small todetect（my opinion）or perhaps no risk.
Figure 4. Increase in excess relative risk（ERR）of

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mortality with increasing radiation dose（Ozasa et.al. Rad. Res. 177:229-243, 2012）.Trend estimates provided forlinear（L）and linear quadratic models. Black circles represent ERR for dose categories with vertical lines
sowing 95% conﬁdence intervals.
The data of Ozasa et.al. published in 2012 also indicate how much excess cancer mortality was due tothe bombing. The LSS data through 2003 has a cohort of 86,111 subjects and there were 50,620 total deaths ofwhich 10,929（22%）were due to solid cancer and an estimated 527（1%）excess solid cancer deaths due toradiation. This is a much smaller percentage than is typically assumed by the public.

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The RERF data has partially clariﬁed the risk ofcancer at diﬀerent ages of exposure and at diﬀerent times
after exposure. Full characterization will require complete
follow-up of all the subjects in the cohort over the next 2-3
decades. It has become apparent that after a latent period,
the risk of some radiation caused cancers increases
throughout lifetime, while for other neoplasms the risk isrelatively stable and for a few（such as leukemia）the risk
decreases or even disappears after a few decades（ﬁgure 5）.
This information has been extremely important for many
people who have been radiation exposed. As an example,
the risk of radiation induced leukemia among children

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exposed during Chernobyl has essentially passed（since the exposure occurred 30 years ago）.
Figure5. Schematic representation of induction period and risk of leukemia as a function of age at
exposure（Ishimaru et. al J Radiat Res.16[Suppl]:S89-96 1975）. The curves show that at young age of exposure,leukemia risk peaks at about 5-10 years later（as was the case with Sadako）.

One of the most interesting ﬁndings is that the riskof radiation-induced cancers in diﬀerent tissues is quite
variable（ﬁgure 6）. Most people incorrectly think that all
types of cancer are equally caused by radiation. It can beseen that bladder, breast and lung tissue are relatively
susceptible to radiation caused cancer while there is no
signiﬁcant excess of prostate, uterine or renal cell cancer
after radiation exposure. This information has been criticalfor assessment of causation among the many cases of cancer
that occur in workers and other exposed individuals years
after radiation exposure.

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Figure 6. LSS cancer incidence data clearly show that there is a great variation in the sensitivity ofvarious tissues to radiogenic cancer induction（Preston et.al. RERF Update 2007）

The radiation expertise of Japanese scientists andphysicians is recognized worldwide and their involvement
has impacted hundreds of thousands of people. For example,
the International Chernobyl Project（which took several
years）was headed by Dr. I Shigematsu of RERF and there
were many Japanese team members who worked evaluating
conditions in highly contaminated areas（ﬁgure 7）.

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57With the generous ﬁnancial support of Mr. Sasakawa, Japanese scientists conducted another verylarge 5 year study which was the most complete thyroid evaluation ever done of the more than 160,000
children exposed from Chernobyl.
Major international consensus scientiﬁc reports on radiation sources and eﬀects are publishedperiodically by the United Nations Scientiﬁc Committee on the Eﬀects of Atomic Radiation（UNSCEAR）.
Virtually every report since 1957 has relied on atomic bomb survivor data and the committee has beneﬁtted
greatly from having had I. Tsukamoto, T. Kumatori, Y. Sasaki and Y. Yonekura as oﬃcers of the Committee andthe input of the Japanese scientiﬁc delegations. The most recent report of UNSCEAR included an evaluation of
the radiation doses and potential radiation impact of the Fukushima Daiichi Nuclear Power Plant Accident.
When a consensus on radiation eﬀects is reached,another group, the International Commission on RadiologicalProtection（ICRP）, reviews the data and then recommends
pubic and occupational dose limits to the international
community. Since cancer has been the major long term
health issue, the RERF data is the main pillar upon which
the recommendations are made. This has been true since the1960ʼs. A particular example of the inﬂuence of RERF data
can be seen in the 1990 recommendations of the Commission.
A t t h a t t i m e t h e C o m m i s s i o n（ w h i c h i n c l u d e d I .
Shigematsu）recommended that the annual dose limit to the
public be reduced from 5 mSv to 1 mSv. This was primarily

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based on the emerging RERF data that showed increased sensitivity to cancer induction when a person was
exposed as an infant or child. Obviously, this RERF data causing a reduction in the recommended annual
public dose limit has had an impact on hundreds of millions of people to date and even more in the future.
The popular wisdom over the last few decades wasthat children are about 3 times more sensitive to radiogenic
cancer induction than are adults. Recently, the issue ofradiation eﬀects on children was reexamined by a Task
Group of UNSCEAR. By using the RERF data summarized
by R. Shore it became clear that the situation regarding
radiation eﬀects on children is not straightforward anddepends to some extent on the statistical models used. The
results are shown below（ﬁgure 9）and indicate that ﬁndings
from exposed adults cannot directly be used to assess risk
from exposure at young ages.

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The biodosimetry techniques that have been
employed and advanced at RERF have found wide usage
around the world. They have been used to estimate doses in
the reactor workers at Chernobyl, in management ofpatients in the Tokaimura criticality accident as well as inmany other accidental and epidemiological investigations.
The study of cataracts in a-bomb survivors published by
Choshi et.al showed that cataracts can occur a much lower
doses than previously thought. This information has now
been corroborated in studies of other groups and has
particular relevance to the thousands of cardiologists andinterventional radiologists who perform ﬂuoroscopically

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guided procedures each year. In addition, this RERF data has resulted in the ICRP recommending lower
international occupational dose limits for the lens of the eye.
Radiation eﬀects on the fetus are a major concern of both workers and the public after radiation
exposure. The data from RERF clearly show that there are eﬀects on the brain and intelligence level at highdoses and in the period 8-25 weeks of pregnancy. The data also show that at low doses and other times ofpregnancy no eﬀect can be detected（ﬁgure 10）. This information has proven crucial in counselling the many
pregnant women who have been exposed either during medical procedures or during accidents（such as
Fukushima）. Without this information there would likely have been tens of thousands of unwarranted
pregnancy terminations around the world.
Figure 10. Incidence of small head size（microcephaly）at various dose levels and gestational ages at
exposure（Miller et.al. Teratology 14:355-357, 1976）. It can be seen that at high doses of 1 Gy and higher
received early in pregnancy the incidence approaches 100% but at lower doses and later in pregnancy there
appears to be little or no eﬀect.
Evaluation, health care management and predicted heath risk of the persons exposed during the
Fukushima Daiichi Nuclear Power Plant Accident is based largely upon environmental measurements,
modelling and RERF/Chernobyl data. This data has been used by the faculty at Fukushima Medical University
to design and begin to conduct health studies. The issue of an apparent increase in thyroid cancer incidence atearly age and issues with thyroid cancer detection and diagnosis was portended by the ﬁnding of occult
sclerosing thyroid cancers among the A-bomb survivors. I would also like to add a note that in 2014, heath
recommendations of an International Advisory Committee on Fukushima were delivered to Prime Minister
Abe and the recommendations were to some extent based on the experience of the a-bomb survivors.
The beneﬁts of the A-bomb data extend now and into the future to untold thousands of people
through HICARE outreach and training programs. With all the immense knowledge base and experience that
RERF has accumulated in the past 40 years, what remains to be done ? Both O. Niwa and R. Ullrich who bothrecently arrived at RERF have several signiﬁcant tasks. Many atomic bomb survivors remain alive and thelife-long follow-up will not be complete for 2-3 decades. This information is required to complete the picture ofcancer and other risks. There is an issue of what to do with tissue samples that have been obtained andwhether any new technologies（such as genomics）can be usefully applied. There is always the continuing
issue of budget issues especially when government administrators do not fully understand the impact andremarkable nature of RERF work. Finally there is the important issue of non-cancer mortality.
By the early 1990ʼs researchers（Wong et.al.）at RERF reported that there was a dose related increasein non-cancer diseases and mortality. These ﬁndings were further elucidated in a 2004 publication（Yamada
et.al.）.The work has been carried on with recent publications by Shimizu et. al. and Ozasa et al. In summary
there appears to be an increase in mortality from both cardiovascular disease and respiratory diseases. The
matter regarding cardiovascular disease is especially complicated due to major risk factors other than radiationand confounding factors（such as diet, smoking, obesity, genetics etc）. In addition there have been changes
over time in advancing diagnostic methods, disease coding, accuracy of death certiﬁcates, diagnostic criteria
and medical treatment. At a 2013 RERF workshop it was clear that the various types of cardiovascular disease
did not all display the same risk from radiation and in addition many of the conditions have diﬀerent
underlying pathology and etiology. For example, rheumatic heart disease was increased but only in the
1950-1968 period, cardiac failure deaths were increased but mostly in the 1980-1990ʼs and there was no increase
in ischemic heart disease or myocardial infarction. Thus more work is required on these topics that potentiallycould aﬀect millions of people and future radiation protection standards.
I would like to express a note of gratitude to the Japanese news media who are remarkably
well-informed about radiation matters and who always have been gracious to me and who have reported my59

views accurately.
It is only recently that I became aware of aremarkable and inspirational story involving Dr. Ritsuko
Komaki in which Sadakoʼs legacy has been directly carriedon for over 60 years. Dr. Komaki was a running mate intrack with Sadako at elementary school and during her
illness Dr. Komaki helped her fold the paper cranes. When
Sadako died Dr. Komaki helped start the fund raising for the“Statue of AB Children”. Wanting to help sick patients like
Sadako, Ritsuko entered Hiroshima University School of
Medicine and worked at ABCC（RERF）in the summertime.
She ultimately went to the leading U. S. cancer center（MDAnderson Cancer Institute）and became one of the countryʼs

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leading specialists. As part of her remarkable career she has
been President of the American Radium Society and hasreceived at least 5 gold medals from various professionalsocieties including the Japan Radiological Society and theJapan Lung Cancer Society. Dr. Komaki has been involved
with development of radistion therapy here in Hiroshima
and is married to Dr. James Cox who is on a councilor of
RERF. In her own words Dr. Komakiʼs motivation is “Manypeople have lost their lives to radiation, but it can be used tosave lives. Until the very end Sadako hoped to recover. My
goal is to continue saving lives of children who are battlingdisease as Sadako did”.

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In summary, although it is not widely known to the
public, the tragic experience of the atomic bomb survivors（and Sadako）has provided knowledge and a resource thathas been used to help counsel hundreds of thousands ofradiation exposed persons around the world and which
provides the main pillar and foundation for internationalradiation protection recommendations impacting millions
worldwide. In spite of past eﬀorts, more important work stillneeds to be done13
As I end this presentation, I would like to note that
although nuclear weapons have not been used for over 70
years, it is concerning that there are now more countries
than ever, who possess or are developing them. Thus wecome back to Sadako and the quote “This is our cry, This is
our prayer, Peace in the world”.

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