Report of a nationwide survey on actual administered radioactivities of radiopharmaceuticals for diagnostic reference levels in Japan
Ann Nucl Med
Report of a nationwide survey on actual administered radioactivities of radiopharmaceuticals for diagnostic reference levels in Japan
Hiroshi Watanabe 0 1 2 3 4 5 6 7 8 9
Kazunari Ishii 0 1 2 3 4 5 6 7 8 9
Makoto Hosono 0 1 2 3 4 5 6 7 8 9
Etsuko Imabayashi 0 1 2 3 4 5 6 7 8 9
Koichiro Abe 0 1 2 3 4 5 6 7 8 9
Masayuki Inubushi 0 1 2 3 4 5 6 7 8 9
Kazuko Ohno 0 1 2 3 4 5 6 7 8 9
Yasuhiro Magata 0 1 2 3 4 5 6 7 8 9
Kinya Ono 0 1 2 3 4 5 6 7 8 9
Kei Kikuchi 0 1 2 3 4 5 6 7 8 9
Kei Wagatsuma 0 1 2 3 4 5 6 7 8 9
Tadashi Takase 0 1 2 3 4 5 6 7 8 9
Kyoko Saito 0 1 2 3 4 5 6 7 8 9
Yasuyuki Takahashi 0 1 2 3 4 5 6 7 8 9
0 Department of Radiology, Kindai University Faculty of Medicine , Ohnohigashi 377-2, Osakasayama, Osaka 589-8511 , Japan
1 Department of Radiological Technology, Japan Labour Health and Welfare Organization Yokohama Rosai Hospital , 3211, Kozukue, Kohoku, Yokohama, Kanagawa 222-0036 , Japan
2 & Kazunari Ishii
3 Department of Radiology, Kawasaki Municipal Hospital , 12-1 Shinkawadori, Kawasaki-ku, Kawasaki, Kanagawa 210-0013 , Japan
4 Preeminent Medical Photonics Education and Research Center, Hamamatsu University School of Medicine , 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 , Japan
5 Department of Radiological Technology, Kyoto College of Medical Science , 1-3 Oyamahigashimachi Sonobe-cho Nantan, Kyoto 622-0041 , Japan
6 Division of Nuclear Medicine, Department of Radiology, Kawasaki Medical School , 577 Matsushima, Kurashiki, Okayama 701-0192 , Japan
7 Department of Diagnostic Radiology and Nuclear Medicine, Tokyo Women's Medical University , Kawada-cho 8-1, Shinjuku-ku, Tokyo 162-8666 , Japan
8 Integrative Brain Imaging Center, National Center of Neurology and Psychiatry , 4-1-1, Ogawa-Higashi, Kodaira, Tokyo 187-8551 , Japan
9 Institute of Advanced Clinical Medicine, Kindai University Faculty of Medicine , 377-2, Ohno-Higashi, Osakasayama, Osaka 589-8511 , Japan
Objective The optimization of medical exposure is one of the major issues regarding radiation protection in the world, and The International Committee of Radiological Protection and the International Atomic Energy Agency recommend establishing diagnostic reference levels (DRLs) as tools for dose optimization. Therefore, the development of DRLs based on the latest survey has been required for nuclear medicine-related societies and organizations. This prompted us to conduct a nationwide survey on the actual administered radioactivity to adults for the purpose of developing DRLs in nuclear medicine. Methods A nationwide survey was conducted from November 25, 2014 to January 16, 2015. The questionnaire was sent to all of the 1249 nuclear medicine facilities in Japan, and the responses were collected on a website using an answered form.
10 Department of Radiology, Kitasato University Hospital,
1-15-1 Kitasato, Minami-ku, Sagamihara,
Kanagawa 252-0375, Japan
11 Research Team for Neuroimaging, Tokyo Metropolitan
Institute of Gerontology, 35-2, Sakae-cho, Itabashi-ku,
Tokyo 173-0015, Japan
12 Department of Radiology, Showa University Hospital, 1-5-8
Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan
13 Department of Radiological Technology, Faculty of Health
Sciences, Nihon Institute of Medical Science, 1276,
Shimogawara, Moroyama-machi, Iruma-gun,
Saitama 350-0435, Japan
14 Department of Nuclear Medicine Technology, Gunma
Prefectural College of Health Sciences, 323-1 Kamioki-cho,
Maebashi, Gunma 371-0052, Japan
Results Responses were obtained from 516 facilities, for a
response rate of 41 %. 75th percentile of 99mTc-MDP and
99mTc-HMDP: bone scintigraphy, 99mTc-HM-PAO,
99mTcECD and 123I-IMP: cerebral blood flow scintigraphy,
99mTc-Tetrofosmin, 99mTc-MIBI and 201Tl-Cl; myocardial
perfusion scintigraphy and 18F-FDG: oncology PET
(inhouse-produced or delivery) in representative diagnostic
nuclear medicine scans were 932, 937, 763, 775, 200, 831,
818, 180, 235 and 252, respectively. More than 90 % of the
facilities were within the range of 50 % from the median of
these survey results in representative diagnostic nuclear
medicine facilities in Japan. Responses of the administered
radioactivities recommended by the package insert, texts
and guidelines such as 740 MBq (99mTc-MDP and
99mTcHMDP: bone scintigraphy), 740 MBq (99mTc-ECD and
99mTc-HM-PAO: cerebral blood flow scintigraphy) and
740 MBq (99mTc-Tetrofosmin and 99mTc-MIBI:
myocardial perfusion scintigraphy), etc. were numerous. The
administered activity of many radiopharmaceuticals of
bone scintigraphy (99mTc-MDP and 99mTc-HMDP),
cerebral blood flow scintigraphy (99mTc-HM-PAO) and
myocardial perfusion scintigraphy (99mTc-Tetrofosmin and
99mTc-MIBI), etc. were within the range of the EU DRLs
and almost none of the administered radioactivity in Japan
exceeded the upper limit of SNMMI standard administered
Conclusions This survey indicated that the administered
radioactivity in diagnostic nuclear medicine in Japan had
been in the convergence zone and nuclear medicine
facilities in Japan show a strong tendency to adhere to the texts
and guidelines. Furthermore, the administered
radioactivities in Japan were within the range of variation of the EU
and the SNMMI administered radioactivities.
The International Committee of Radiological Protection
(ICRP) recommended three fundamental principles
(justification, optimization of protection, and application of dose
limits) for radiation protection. It should be noted that with
regard to medical exposure of patients, it is not appropriate
to apply dose limits or dose constraints, because such limits
would often do more harm than good [
]. Therefore, the
justification and optimization of protection are very
important in clinical practice. However, with the
development of radiation medical technology increases in the
medical exposure dose are of concern. The optimization of
medical exposure is one of the major issues regarding
radiation protection in the world, and the ICRP and the
International Atomic Energy Agency (IAEA)
recommended establishing diagnostic reference levels (DRLs) as
tools for dose optimization [
]. In Europe, the European
Union (EU) required establishment of DRLs by Council
Directive 97/43/Euratom in 1996 [
]. It is suggested that
DRLs should be set by countries, regions, academic
societies or associations and they have been defined in Europe
and North America [
]. On the other hand, in Japan the
Japanese Society of Nuclear Medicine (JSNM) or other
research groups have recommended the standard
administration radioactivity dose [
]. The Japan Association
of Radiological Technologists (JART) recommended the
reduction target dose [
] and the JART conducted a
nationwide survey of radiopharmaceutical doses [
Unfortunately this survey was not strictly limited to
‘‘actual’’ administered doses but included radioactivity doses
determined by the time and date of assay of
radiopharmaceuticals. Until 2015, neither a nationwide survey of
‘‘actual’’ administered doses had been conducted nor had
DRLs been proposed by any nuclear medicine-related
societies or organizations.
Concerning pediatric nuclear medicine, the European
Association of Nuclear Medicine (EANM) dosage card has
been proposed and developed by the Pediatric Task Group
EANM in Europe [
] and consensus guidelines have
been proposed and developed by the Society of Nuclear
Medicine and Molecular Imaging (SNMMI) in North
]. In 2014, the Japanese consensus
guidelines for pediatric nuclear medicine were provided by
JSNM in Japan .
The Japan Network for Research and Information on
Medical Exposures (J-RIME) was established in 2010 with
the cooperation of related academic societies [
J-RIME decided to establish the first DRLs (Japan DRLs)
of common modality as all medical radiation-related
societies and organizations at the annual meeting held in
2013. Therefore, the establishment of DRLs based on the
latest survey results was required by nuclear
medicine-related societies and organizations. This survey was
performed voluntarily by medical radiation-related societies
and organizations but was not forced by national offices.
The JSNM and JSNMT conducted a nationwide survey
on the actual administered radioactivity in adults for the
purpose of establishing DRL in nuclear medicine.
In Japan there is a unique system for delivered
radiopharmaceuticals. When radiopharmaceuticals are provided
from radiopharmaceutical manufacturers to nuclear
medicine facilities, the radioactivity dose has been determined
by the time and date of assay of radiopharmaceuticals. For
example, in the case of 99mTc and 123I agents, the
radiopharmaceutical to be delivered to the nuclear medicine
facility has been assayed as the assay radioactivity
(radioactivity at 12 am) of the delivery date (examination
date). In addition, in the case of 201Tl and 67Ga agents,
radioactivity in the two days after the delivery date is
delivered (radioactivity at the delivery day is about 1.6
times the assay radioactivity). That is, the assay
radioactivity does not actually mean the true administered
Distribution, collection, and contents of the questionnaire
A nationwide survey on the actual administered
radioactivity of adults for the purpose of providing DRLs in
nuclear medicine was conducted from November 25, 2014
to January 16, 2015. The questionnaire was sent to all 1249
facilities where nuclear medicine examinations are
performed in Japan, and the responses were sent to a website.
The questionnaire included items such as the average
administered radioactivity dose of an adult for each
diagnostic nuclear medicine examination, number of scanners,
number of staff members, number of board certified
nuclear medicine physicians and nuclear medicine
How to calculate or evaluate the average administered radioactivity in each facility
The average administered radioactivity was obtained from
the responses following this questionnaire.
1. The average value of the actually measured doses at
the administered time or the average value of the assay
dose that was corrected for the administered time.
2. The average administered radioactivity per week or the
average administered radioactivity of several dozen
3. When the administered time is set at the facility, the
average dose at that time.
4. The target administered radioactivity.
5. In the case of rare nuclear medicine examinations, the
average administered radioactivity for several months
or 1 year, or, the administered radioactivity in standard
6. For positron emission tomography (PET), the above 2
or 3 are used as a reference. The estimated
radioactivity when using an automatic injecting machine for
When calculating the average doses, responses that
appeared clearly erroneous were excluded.
Results and discussion
Response rate and the distribution of administered radioactivity
Replies were obtained from 516 facilities (response rate
41 %). The average, 75th, 80th and 90th percentile of each
administered radioactivity are shown in Table 1.
The 75th percentile of 99mTc-MDP, 99mTc-HMDP (bone
scintigraphy), 99mTc-HM-PAO, 99mTc-ECD, 123I-IMP
(cerebral blood flow scintigraphy), 99mTc-Tetrofosmin,
99mTc-MIBI, 201Tl-Cl (myocardial perfusion scintigraphy)
and 18F-FDG for oncology (in-house-produced and
delivery) administered radioactivity were 932, 937, 763, 775,
200, 831, 818, 180, 235 and 252, respectively.
Distribution of administered radioactivity in a representative diagnostic nuclear medicine examination
The administered radioactivity distributions of bone
scintigraphy, cerebral blood flow scintigraphy, myocardial
perfusion scintigraphy for single photon emission
computed tomography (SPECT) and 18F-fluorodeoxyglucose
(FDG) tumor scintigraphy in PET are shown in Figs. 1, 2,
3, 4, 5, 6 and 7. It should be noted that in Figs. 1, 2, 4 and 6
the numbers of different response facilities are adjusted.
Figure 1 shows the administered radioactivity
distribution of 99mTc-methylene diphosphonate (MDP) and
99mTcHydroxymethylene diphosphonate (HMDP). In Japan,
99mTc-MDP and 99mTc-HMDP have been used in bone
scintigraphy as radiopharmaceuticals and there are two
methods of on-site preparation of kits and ready-to-use
radiopharmaceuticals. Two manufacturers have provided
radiopharmaceuticals for bone scintigraphy. One has 555
and 740 MBq and the other has 370, 555, 740 and
925 MBq as assay radioactivity for one patient. For the
present survey, information regarding whether kits were
prepared on-site or ready-to-use radiopharmaceuticals was
not obtained. The administered radioactivity distribution of
99mTc-MDP and 99mTc-HMDP was almost the same, and,
the numbers of 740 MBq in both agents were the highest
because administration of radioactivity of 555–740 MBq is
recommended by the package insert, texts and guidelines as
a standard administration activity in Japan. The
percentages of response rates in the range of 740 MBq ± 5 % of
99mTc-MDP and 99mTc-HMDP were 30 and 31 %,
respectively. The latter is around 930 MBq because the
dose of 930 MBq corresponds to the case of administration
of 740 MBq (assay activity at 12 am) at 10 am. Two
radiopharmaceuticals for bone scintigraphy are
recommended to be scanned from 2 to 3 h after administration.
This may reflect the reality that many nuclear facilities are
imaging at 1 pm after administration at 10 am using an
assay radioactivity of 740 MBq (ready-to-use
Figure 2 shows the distribution of
99mTc-hexamethylpropylene amine oxime (HM-PAO) and 99mTc-ethyl
cysteinate dimer (ECD). In Japan, 99mTc-HM-PAO and
99mTc-ECD are used for cerebral blood flow scintigraphy
of 99mTc agents as a radiopharmaceutical. 99mTc-HM-PAO
is used only by on-site preparation of kits and 99mTc-ECD
either by on-site preparation of kits or ready-to-use
radiopharmaceuticals. The assay radioactivities of
99mTcECD are 400 and 600 MBq for one patient. Concerning
99mTc-HM-PAO, the number of the responses of 740 MBq
was the highest because administration radioactivity of
370–740 MBq is recommended by the package insert, texts
and guidelines as a standard administration radioactivity in
Japan. For 99mTc-ECD, the number of responses of around
740 MBq was the most because an administration dose of
around 370–740 MBq is highest by the package insert,
texts and guidelines as a standard administration dose as
well as 99mTc-ECD. The percentages of response rates in
the range of 740 MBq ± 5 % of 99mTc-HM-PAO and
99mTc-ECD were 61 and 33 %, respectively.
Figure 3 shows the results of the distribution of
N-isopropyl-p-[123I]iodoamphetamine (IMP). In Japan, for
cerebral blood flow scintigraphy 123I-IMP is provided by
only delivery. 123I-IMP has more kinds of assay
radioactivities than other radiopharmaceuticals. One manufacturer
has 111, 148, 167, 185 and 222 MBq and another has 111,
167 and 222 MBq as assay radioactivity for one patient. In
addition, for 123I-IMP, a wide range of administration
doses of 111–222 MBq is recommended by the package
insert, texts and guidelines as a standard administration
dose. In particular, a wide range of administration
radioactivity (37–222 MBq) is recommended in the
package insert. Thus, the distribution of radioactivity of
123IIMP is scattered, which may reflect the various uses to
which it is put at individual facilities. The response rate in
the range of 111 MBq ± 5 % of 123I-IMP was 7 %.
Figure 4 shows the distribution of 99mTc-Tetrofosmin
and 99mTc-hexakis-2-methoxyisobutylisonitrile (MIBI). In
Japan, 99mTc-Tetrofosmin and 99mTc-MIBI have been used
for myocardial perfusion scintigraphy as 99mTc agents, and,
both agents have two methods of on-site preparation of kits
and ready-to-use radiopharmaceuticals. 99mTc-Tetrofosmin
has 296, 592 and 740 MBq and 99mTc-MIBI has 370, 600
and 740 MBq for one patient as the assay radioactivity.
The response of around 740 MBq was the most common
because an administration dose of 370–740 MBq is
recommended by the package insert, texts and guidelines as a
standard administration dose. The response rates in the
range of 740 MBq ± 5 % of 99mTc-Tetrofosmin and
99mTc-MIBI were 37 and 30 %, respectively.
Figure 5 shows the distribution of 201Tl-Cl. In Japan,
201Tl-Cl for myocardial perfusion scintigraphy has been
made available only by delivery. The assay radioactivities
of 201Tl-Cl are 74, 11, 148 MBq for one patient provided
by two manufacturers. The responses of 111 and 180 MBq
were the most common. In Japan the manufacturers usually
provide 201Tl-Cl to the nuclear medicine facility within
2 days before the assay date; therefore, 180 MBq
corresponds to the radioactivity 2 days before the assay
radioactivity 111 MBq. The administration radioactivity of
around 74–111 MBq is recommended by the package
insert, texts and guidelines as a standard administration
activity for 201Tl-Cl. This study indicated that many
nuclear medicine facilities administered the assay
radioactivity 111 MBq for one patient in Japan (actual
administered radioactivity is 180 MBq). The response rate
in the range of 180 MBq ± 5 % of 201Tl-Cl was 43 %.
The distribution of administered radioactivity for
18FFDG oncology PET is shown in Fig. 6 and the responses of
185 MBq were the greatest. In Japan, nuclear medicine
facilities have two methods, in-housed-produced and
delivery for 18F-FDG oncology PET. Provided
manufacture of 18F-FDG is one and it has an assay radioactivity of
only 185 MBq for one patient. For these reasons, it is
presumed that the responses of 185 MBq were diverse. The
response rate in the range of 185 MBq ± 5 % of 18F-FDG
in-housed-produced and delivery were 19 and 27 %,
respectively. In addition, the administered radioactivity per
body weight (MBq/kg) was also investigated (Fig. 7).
However, whether in-housed-produced or delivery was not
distinguished by the survey items. An administered
radioactivity per body weight of 2–5 MBq/kg (three
dimensional collection) is recommended by the guidelines
] and it was found that most of the facilities
administered within the recommended radioactivity doses per body
weight. Furthermore, the numbers of responses of 3.0, 3.7
and 4.0 MBq/kg were the highest, and the administered
radioactivity dose per body weight was considered is be
determined in accordance with the guidelines.
This survey reveals that many nuclear facilities
determined the administered radioactivity dose according to the
package insert, texts and guidelines.
Comparison with EU and North America
Basically DRLs are determined based on 75th percentile of
the survey results. To compare the administered
radioactivity between Japan and EU, a summary of Japanese and
EU DRLs for diagnostic nuclear medicine is shown in
Table 2 following a list of the EU DRLs [
]. Many DRL
doses of radiopharmaceuticals: bone scintigraphy
(99mTcMDP and 99mTc-HMDP), cerebral blood flow scintigraphy
(99mTc-HM-PAO) and myocardial perfusion scintigraphy
(99mTc-Tetrofosmin and 99mTc-MIBI), etc. were within the
range of the EU DRLs. Concerning 201Tl-Cl (myocardial
perfusion scintigraphy), Japan DRL 180 MBq exceeds the
range of the EU DRL (75–150 MBq). For
99mTc-pertechnetate (thyroid scintigraphy), Japan DRL 300 MBq
exceeded the range of the EU DRLs (75–222 MBq).
However, in the 18F-FDG for oncology PET and 123I-NaI
for thyroid scintigraphy, Japan DRLs were at the lowest
level in the range of the EU DRLs. These variations reflect
the situation of each country, and so it is not considered
that Japan DRLs are particularly high as compared with
those of EU. Next, the results of this study were compared
with SNMMI standard administered radioactivity in
representative diagnostic nuclear medicine procedures: the
upper limit of SNMMI standard administration
radioactivity (bone scintigraphy: 1110 MBq [
], cerebral blood
flow scintigraphy: 1110 MBq [
], myocardial perfusion
99mTc agents: 1110 MBq, 201Tl-Cl: 148 MBq [
18FFDG oncology PET: 740 MBq [
]) following facilities
were bone scintigraphy (99mTc-MDP: 99.4 %,
99mTcHMDP: 99.7 %), cerebral blood flow scintigraphy
(99mTcHM-PAO: 100 %, 99mTc-ECD: 100 %), myocardial
perfusion (99mTc-Tetrofosmin: 100 %, 99mTc-MIBI: 100 %,
201Tl-Cl: 41 %) and oncology PET (18F-FDG of both
DRLs in EUa (MBq)
Most common value
a European Commission, 2010, DDM2 project report part 2: diagnostic reference levels (DRLs) in Europe
housed-produced and delivery: 100 %), respectively.
Almost none of the administered radioactivity doses in
Japan exceeded the upper limit of SNMMI standard
administration radioactivity except for 201Tl-Cl for
myocardial perfusion. In 18F-FDG for oncology PET, none
of the doses at any of the facilities (100 %) exceeded the
lower limit of SNMMI recommended administered
Convergence rate of the administered radioactivity, and the role of academic societies and experts
Table 3 shows the percentage of facilities that were within
the range (25, 30 and 50 %) from the median of
Procedure and radiopharmaceutical
Cerebral blood flow: 99mTc-HM-PAO
Cerebral blood flow: 99mTc-ECD
Cerebral blood flow: 123I-IMP
Myocardial perfusion: 99mTc-Tetrofosmin
Myocardial perfusion: 99mTc-MIBI
Myocardial perfusion: 201Tl-Cl
Tumor: 18F-FDG (in-house-produced)
Tumor: 18F-FDG (delivery)
DRLs in Japan (MBq)
representative diagnostic nuclear medicine examinations in
Japan. More than half of the facilities were within the range
of 25 %. In addition, more than 90 % of the facilities were
within the range of 50 %. In particular, the percentage of
facilities was greater than 95 % in the range of 50 % in
representative diagnostic nuclear medicine procedures
except for the 99mTc-Tetrofosmin (myocardial perfusion
scintigraphy) and 201Tl-Cl (myocardial perfusion
scintigraphy). Our findings indicate that the administered
radioactivity for diagnostic nuclear medicine has been in
convergence zones in Japan.
Essentially, optimization of the dose by DRL is
performed at each facility, and is believed to lead to
optimization in the whole country or region. However, nuclear
medicine facilities have a strong tendency to adhere to the
texts and guidelines in Japan. Therefore, in the
optimization of radiopharmaceutical doses in Japan, a greater role
of societies and organizations or experts is needed. As the
finding of this study shows and the current state of Japan, to
optimize radiopharmaceutical doses, Achievable Doses
] might be useful, too.
Development of Japan DRLs
Based on the results of this study, a draft of Japan DRLs
was prepared by the JSNM radiological protection
Subsequently, it was approved by the JSNM board of
directors, board of directors of the societies and
organizations that performed the collaboration investigation,
J-RIME general meeting and J-RIME constituent bodies,
respectively, and Japan DRLs were officially published on
June 7, 2015 [
Although the actual administered radioactivity doses to a
standard body weight patient were obtained, the weight of
the patients was not specified. It is necessary to pay
attention to determine doses for DRLs when the standard
body weight is different, because it is likely that the
standard weight differs between Westerners and Asians.
For the first time a nationwide survey by nuclear
medicinerelated societies and organizations for the development of
the Japanese DRLs of nuclear medicine was conducted in
Japan. This study demonstrated that the administered
radioactivity in diagnostic nuclear medicine in Japan has
been in the convergence zone. Nuclear medicine facilities
in Japan show a strong tendency to adhere to the package
insert, texts and guidelines. Furthermore, the Japan
administered radioactivities were within the range of
variation of the EU and the SNMMI administration
radioactivities. Whether nuclear facilities can optimize the
dose, or whether this is required, depends on the role of the
academic societies and experts.
Acknowledgments This study was performed with financial support
from the Japanese Society of Nuclear Medicine (JSNM). This study
was carried out by JSNM, JSNMT, Japanese Society of Radiological
Technology and JART. We would like to sincerely thank everyone in
the nuclear medicine facilities who responded to and with this survey.
Prof. Fumio Shishido, a committee member of the Japanese
Radiological Society, supported the preparation of Japan DRLs in Nuclear
Medicine. Part of this study was presented at JSNM/JSNMT Joint
Symposium, the 55th Annual Meeting of the JSNM on September 14,
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