Ooe et al. EJNMMI Physics(2019) 6:13
https://doi.org/10.1186/s40658-019-0249-8

EJNMMI Physics

ORIGINAL RESEARCHOpen Access

Quantitative measurement of 219Rn
radioactivity in exhaled breath frompatients with bone metastasis of castrationresistant prostate cancer treated with
223
RaCl2
Kazuhiro Ooe1,2* , Tadashi Watabe1,2, Takashi Kamiya1,2,3, Takashi Yoshimura4, Makoto Hosono5,
Atsushi Shinohara6,7 and Jun Hatazawa1,7* Correspondence: ooe@tracer.med.
osaka-u.ac.jp
1
Department of Nuclear Medicine
and Tracer Kinetics, Osaka University
Graduate School of Medicine, 2-2
Yamadaoka, Suita, Osaka 565-0871,
Japan
2
Division of Science, Institute for
Radiation Sciences, Osaka University,
1-1 Machikaneyama, Toyonaka,
Osaka 560-0043, Japan
Full list of author information isavailable at the end of the article

Abstract
Background: The α-emitting radionuclide radium-223 (223Ra) is widely used for thetreatment of bone metastasis in patients with castration-resistant prostate cancer.
However, 223Ra decays into radon-219 (219Rn) which is a noble-gas isotope, and219
Rn may escape from patients treated with 223Ra via their respiration. In this study,
we quantified the amount of 219Rn contained in the breath of patients treated with223
Ra to estimate its effect on the internal exposure dose of caregivers.
Methods: A total of 12 breath samples were collected using a breath collection bagfrom a total of six patients treated with 223RaCl2. Approximately 300 mL of exhaled
breath was collected in a breath bag at 1 min and at 5 min after the start of 223RaCl2
administration. The contents of each bag were measured using an HPGe detector,
and the amount of 219Rn was quantified based on the detection of the γ peak of
211
Bi, which is a descendant nuclide of 219Rn, persisting in the breath bag. The
effective dose to caregivers arising from the inhalation of 219Rn was estimated byreferring to the scenario for the calculation of release criteria established for 131I
therapy in Japan.
Results: A small peak for the 351-keV γ ray of 211Bi originating from the exhalationof 219Rn was observed. Using the observed γ peak of 211Bi, the average amounts of219
Rn per unit breath volume at 1 min and 5 min after the start of 223RaCl2
administration were calculated as 90 ± 56 Bq/mL and 28 ± 9 Bq/mL, respectively. The
effective dose of 219Rn to caregivers was estimated to be 3.5 μSv per injection.
Conclusions: The amount of 219Rn in the exhaled breath of patients treated with223
RaCl2 was quantitatively calculated using breath collection bags. The internalradiation exposure of caregivers from 219Rn in the exhaled breath of patients treatedwith 223RaCl2 is relatively small.
Keywords: Radium-223, Radon-219, Breath of patients, Effective dose to caregivers© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International
License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium,provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, andindicate if changes were made.

Ooe et al. EJNMMI Physics(2019) 6:13

Background
Recently, radium-223 (223Ra) dichloride (223RaCl2; Xofigo®) has been widely used forthe treatment of bone metastases in patients with castration-resistant prostate cancer(CRPC) [1, 2]. This radionuclide emits α-particles within a short range in tissues andwith a high linear energy transfer, making it suitable for the treatment of cancer cellswith minimal side effects in the surrounding tissues. As shown in the decay chain of223
Ra (Fig. 1), some descendant nuclides of 223Ra also emit α-particles and contributeto its killing effect on cancer cells. However, 223Ra decays into radon-219 (219Rn) which
is an isotope of a noble-gas element, and this 219Rn may escape from patients treatedwith 223Ra. Although the escape of 219Rn from patients is probably minor because of
the very short half-life of 219Rn (3.96 s), the amount of 219Rn escaping from patientsshould be quantified to allow the internal radiation exposure experienced by medical
staff and caregivers to be estimated. Yamamoto et al. mentioned that 219Rn may escapevia the respiration of patients and reported that the concentration of the descendantnuclides of 219Rn in a room increased during radionuclide therapy with 223Ra, compared with that without the patients [3]. However, the amount of 219Rn exhaledthrough the respiration of patients has not been quantified in a hospital setting. In thisstudy, the breath of patients treated with 223Ra was collected using a breath collection
bag and the 219Rn radioactivity was quantified by measuring the γ rays of 211Bi, which
is a descendant nuclide of 219Rn, persisting in the breath bag. The purpose of this study
was to evaluate the level of 219Rn radioactivity in the exhaled breath of patients treatedwith 223Ra to enable a precise estimation of the internal radiation exposure dose experienced by caregivers.

Fig. 1 Main decay chain of 223Ra

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Ooe et al. EJNMMI Physics(2019) 6:13

Methods
Measurement of expired gas from patients

The study protocol was approved by the institutional review board of Osaka University
Hospital. First, we investigated whether the breath of the patients contains radionuclides emitting α-particles using an α survey meter (Hitachi TCS-232b, Tokyo, Japan).
A patient (body weight 55.0 kg) received 223RaCl2 of 3.0 MBq (55 kBq/kg) for the treatment of bone metastases from CRPC. After informed consent was obtained from thepatient, the α survey meter was placed closely to the mouth of the patient from thestart of 223RaCl2 administration, and α-particles in the breath of the patient were directly measured until 3 min after the start of administration. Additionally, the count rate
at 5 min after the start of administration was also measured.
Then, a total of 12 breath samples were collected using breath collection bags
(Otsuka Pharmaceutical, Tokyo, Japan) from a total of six patients (71.3 ± 5.4 years old,body weight 59.5 ± 11.7 kg) received 223RaCl2 (3.4 ± 0.8 MBq). The administration of223
RaCl2 to the patients was conducted slowly over a period of approximately 1 min.
After informed consent was obtained from each patient, approximately 300 mL of exhaled breath was collected into a breath bag at 1 min and at 5 min after the start of223
RaCl2 administration. A breath sampling time of 1 min after the start of administration was selected because the amount of 219Rn contained in a patient’s breath is expected to reach a peak value at this time because of the slow administration of 223RaCl2(see also Fig. 3 which is the result of the direct measurement of the breath of the patient by the α survey meter). A sampling time of 5 min is expected to correspond to
the time at which the patient is likely to leave the injection room. After sampling, thebreath sample was removed from the bag using a syringe (volume 50 mL, minimum
volume scale 1 mL) to enable the bag to be folded into a small, fixed geometric shape(see also Fig. 2) for measurement using a high-purity germanium (HPGe) detector(Canberra BE-2020, Connecticut, USA). The volume of the breath collected in the bag

Fig. 2 Photographs of a the breath bag with the glass-fiber filter after the removal of the breath sample
and b the folded breath bag for the measurement with an HPGe detector

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Ooe et al. EJNMMI Physics(2019) 6:13

was measured using the volume scale printed on the syringe (the uncertainty forthe measured volume of the breath sample was estimated to be several milliliters).
Because 219Rn and its descendant nuclides may escape from the bag during the useof the syringe, the bag was allowed to stand for more than 80 s until almost all the219
Rn atoms in the breath bag had decayed into non-volatile descendant nuclides
prior to the removal of the breath sample. Then, the breath sample was removed
through a glass-fiber filter (ADVANTEC GB-100R, Tokyo, Japan) attached to thesyringe to catch the descendant nuclides of 219Rn. After the removal of the breath
sample, the breath bag, together with the glass-fiber filter, was subjected to γ-ray
spectrometry using an HPGe detector for 1800 s at almost zero distance. The
amount of 219Rn in the breath sample was estimated as follows. Based on the observed γ peak of 211Bi (351 keV), the radioactivity of 211Pb in transient radioactive
equilibrium with 211Bi was calculated [4]. Then, from the 211Pb radioactivity at theend of the breath collection, the amount of 219Rn contained in the breath sample
was estimated assuming that the number of 211Pb atoms at the end of the breathcollection would be equivalent to that of 219Rn because of the very short half-lifeof 219Rn. The measurement efficiency for the 351-keV γ peak of 211Bi at the same
distance with the measurement of the breath bag was evaluated based on themeasurement of a self-produced 223Ra point source, the radioactivity of which was
determined using a 133Ba standard source. The measurement efficiency was determined to be 2.63 ± 0.13%. The uncertainty for the efficiency is including theuncertainty of the radioactivity of the 133Ba standard source (4.8%) and counting
errors for the measurements of the 133Ba standard source and the 223Ra point
source (less than 1%).

Estimation of radiation exposure experienced by medical staff

The descendant nuclides of 219Rn exhaled through the breath of patients may float
through the air by attaching to dust or aerosol particles. These nuclides can contribute to medical staff and caregivers being exposed to radiation internally. Therefore, we also investigated whether the inhalation of descendant nuclides of 219Rn
can be blocked by the use of a mask. Medical staff wore an N95 mask (3M 1870+,
Tokyo, Japan) during the administration of 223Ra to the patients. After administration, the outside and inside (face side) of the mask were measured using an α survey meter (Hitachi TCS-232b, Tokyo, Japan). A total of five masks worn by
medical staff who stood close to the patients during 223RaCl2 therapy were measured during two injections (three medical staff for one injection [administrationdose 3.9 MBq] and two staff for the other [administration dose: 3.0 MBq]). The
measurements using the survey meter were conducted while placing the survey
meter in close contact with the surface of each mask, and the count rate was recorded at 2 min after the start of measurement with a time constant of 30 s.

Estimation of radiation exposure experienced by caregivers

The radiation exposure experienced by caregivers was calculated based on documentation regarding the calculation of release criteria established for 131I therapy by the

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Ooe et al. EJNMMI Physics(2019) 6:13

Ministry of Health and Welfare in Japan [5]. The blood concentration of 223Ra immediately after injection (CRa) was estimated using the following formula:
C Ra ¼

Ainjection;
V blood

where Ainjection is the injection dose of 223Ra and Vblood the blood volume in thehuman body. In this calculation, we used Ainjection = 3.4 × 103 kBq which is the average
injection dose in this study and Vblood = 5.0 × 103 mL, and CRa was estimated to be
0.68 kBq/mL. The area under the curve (AUC) for the blood concentration of 223Ra
was obtained using the clinical trial data (phase I) for 223RaCl2 published in Japan by
the Pharmaceutical and Medical Devices Agency (PMDA) (https://www.pmda.go.jp).
Duration (T), which corresponds to the AUC up to 72 h post injection (0.674 kBq·h/mL)
with the assumption that the blood concentration level immediately after the injection of223
Ra is maintained, was calculated using the following equation:
T¼

AUC
;
C Ra

and T was estimated to be 0.99 h. The concentration of 219Rn in the exhaled breath
was assumed to be proportional to the blood concentration of 223Ra. The total exhaledamount of 219Rn was calculated by multiplying the radioactivity in the exhaled breath
immediately after the injection by a factor of 0.99 h, assuming that the respiration rate
was 12 breaths per minute and the volume of breath was 500 mL per single respiration.
The effective dose coefficient for the inhalation of 219Rn was calculated as 7.9 × 10−9 mSv/Bq,
with reference to the 222Rn data (6.5 × 10−6 mSv/Bq) [6] corrected by the effective half-life.
Regarding the exposure scenario for caregivers, the volume of the room containing the patient was estimated to be 30 m3, air changes were regarded as once per hour, the daily respiration rate of the caregivers was estimated to be 20 m3, and the caregiver was assumed toalways be present in the same room as the patient based on the release criteria for 131I in
Japan [5]. To estimate the internal exposure dose experienced by caregivers, an exposure factor of 0.5 was applied [7].

Results
The time activity curve obtained in the direct measurement of α-particles in the breathof the patient by the α survey meter is shown in Fig. 3. The count rate of α-particles
exceeded the measurable range (more than 100 kcpm) at several tens of seconds after
the start of administration and then gradually decreased to 20 kcpm until 5 min after
the start of administration, showing that radionuclides emitting α-particle were exhaledthrough the respiration.
A typical γ-ray spectra obtained for the measurement of a breath bag is shown in
Fig. 4 a. A small peak for the 351-keV γ ray of 211Bi was observed. On the other hand,no γ peak of 269 keV from 223Ra was observed. The 351-keV peak disappeared approximately 4 h after the collection of the breath sample, as shown in Fig. 4 b. This finding
unambiguously shows that the breath samples from patients treated with 223RaCl2 did
not contain 223Ra.
The amount of 219Rn contained in the breath samples as determined using γ-ray
spectrometry is summarized in Table 1, together with the administration dose of 223Ra

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Ooe et al. EJNMMI Physics(2019) 6:13

Fig. 3 Time activity curve obtained in direct measurement of α-particles in breath of patient by an α survey
meter from the start of 223RaCl2 administration. The count rate exceeded the measurable range (100 kcpm)
at several tens of seconds after the start of administration

Fig. 4 Typical γ-ray spectrum obtained for breath bag measurements using an HPGe detector.
Administration dose, 3.8 MBq; breath sampling time, 5 min after the start of administration; measurement
start, a 17 min and b approximately 4 h after the end of breath collection

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Table 1 Summary of the amounts of 219Rn contained in breath samples from patients treatedwith 223RaCl2
Administrationdose of 223RaCl2

Breath sampling timefrom administration start

Volume ofcollected breath

Activity of 219Rn
in breath

2.5 MBq

1 min

293 mL25 ± 4 kBq

2.5 MBq

5 min

384 mL

7.8 ± 1.4 kBq

2.5 MBq

1 min

349 mL59 ± 6 kBq

2.5 MBq

5 min

329 mL

13 ± 2 kBq

3.2 MBq

1 min

294 mL14 ± 3 kBq

3.2 MBq

5 min

284 mL8.4 ± 1.5 kBq

3.8 MBq

1 min

339 mL19 ± 3 kBq

3.8 MBq

5 min

329 mL9.1 ± 1.4 kBq

3.9 MBq

1 min

299 mL45 ± 5 kBq

3.9 MBq

5 min

297 mL

11 ± 2 kBq

4.3 MBq

1 min

418 mL16 ± 3 kBq

4.3 MBq

5 min

344 mL5.8 ± 1.3 kBq

and the volume of collected breath. The amount of 219Rn exhaled in the breath at 1 minafter the start of administration varied widely from 14 to 59 kBq, while the amount of
219
Rn at 5 min after the start of administration was around 10 kBq. The mean value of219
Rn per unit volume of breath is shown in Fig. 5. The values were calculated as 90 ± 56
Bq/mL and 28 ± 9 Bq/mL (mean ± standard deviation) at 1 min and 5 min after the startof administration, respectively.
The results of the mask measurements using the α survey meter are summarized inTable 2. Small count rates of less than 100 cpm for α-particles were detected on theoutside of the masks. On the other hand, no α-particles were detected on the inside of
the masks. The count rate on the outside of the masks varied widely depending on the
medical staff, and the measurement for one mask showed no detection of α-particles
even on the outside of the mask.
The cumulative amount of exhaled 219Rn from the patient via exhaled breath until
72 h after the start of administration (ARn,cumulative) was calculated as follows:

Fig. 5 Mean value of 219Rn per unit volume of exhaled breath at 1 min and 5 min after the start of223
RaCl2 administration

Ooe et al. EJNMMI Physics(2019) 6:13

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Table 2 Summary of measurement results obtained using an α survey meter for N95 masks wornby medical staff
Administrationdose of 223RaCl2

Measured mask

Measured side

Measurement
start time fromadministration

Observedcount rate

211

3.9 MBqa

Outside40 min 7 s

8 cpm

0.8 Bqb

Outside42 min 22 s

53 cpm

5.2 Bqb

Inside49 min 16 s

0 cpm

0 Bq

c

Outside77 min 40 s

26 cpm

2.6 Bqc

Inside80 min 0 s

0 cpm

0 Bq

3.0 MBq

Bi radioactivity
calculated basedon count ratedOutside7 min 0 s

0 cpm

0 Bq

d

Inside10 min 0 s

0 cpm

0 Bq

f

Outside24 min 48 s

80 cpm

7.9 Bqf

Inside27 min 5 s

0 cpm

0 Bq

ARn;cumulative ¼ ARn;breath  V breath  N respiration  T ;where ARn, breath is the amount of 219Rn contained in the unit volume of exhaled breath,
Vbreath the volume of breath per single respiration (500 mL/respiration), Nrespiration the respiration rate per min (12 respiration/min) and T the duration with the assumption thatthe blood concentration level immediately after the injection of 223Ra is maintained (0.99h). Using 90 ± 56 Bq/mL as ARn,breath, which is the amount of 219Rn contained in thebreath at 1 min after the start of administration, ARn,cumulative was calculated as 32 MBq.
By referring to the release criteria for patients treated with 131I, the amount of 219Rn inhaled by caregivers (ARn,inhaled) was estimated using the following formula:ARn;inhaled ¼ ARn;cumulative V daily;
V room  N air change

where Vdaily is the daily respiration rate of the caregivers (20 m3/d), Vroom the volume of
the room containing the patient (30 m3) and Nair change the air changes per hour (1/h);ARn,inhaled was calculated as 0.89 MBq. The effective dose of 219Rn to caregivers (Deff ) was
estimated as follows:
Deff ¼ ARn;inhaled  E  F;
where E is the effective dose coefficient for the inhalation of 219Rn (7.9 × 10−9 mSv/Bq)
and F the exposure factor (0.5 [7]); Deff was estimated to be 3.5 μSv per injection.
Discussion This study showed that the amount of 219Rn contained in the breath of patients can be quantitatively measured using an HPGe detector based on the detectionof the γ peak of the descendant nuclide 211Bi and a breath collection bag. In addition,
the internal radiation exposure of caregivers from 219Rn was estimated to be as small as
3.5 μSv per injection. The high count rate of α-particles observed in the direct measurement of the breath of the patient by the α survey meter would be attributed to 219Rn,
not to the descendant nuclides of 219Rn, exhaled through the respiration because theaverage radioactivity of 211Bi measured using the HPGe detector was in the order of 10
Bq and the count rate of α-particles from 211Bi in the measurement with α survey
meter would be quite low compared with that from 219Rn (in the order of 10 kBq).

Ooe et al. EJNMMI Physics(2019) 6:13

Although the high count rate of α-particles from 219Rn exhaled through the respiration
was observed using the α survey meter, the quantitative measurement of the descendant nuclide of 219Rn using the HPGe detector in this study clearly shows that the effective dose of 219Rn to caregivers is small. The amount of 219Rn contained in the breath ofa patient at 1 min after the start of administration varied widely, as is shown in Table 1.
The reason for this variation can be attributed to the peak shift in the exhalation of219
Rn from the breath of patients caused by the manual administration of 223RaCl2.
Since the effective dose coefficient for inhaled 219Rn has not been reported, the value for219
Rn was estimated based on the effective dose coefficient of 222Rn (6.5 × 10−6 mSv/Bq) [6].
α-Particles emitted from the descendant nuclides are thought to be the main contributors
to the effective dose coefficient because their radiation weighting factor is very highcompared with those of electrons and γ rays. Since the descendant nuclides of 219Rn
would decay before clearance because of their short half-lives, analogous to those of222
Rn [8], and the total α-particle energy from the descendant nuclides of 219Rn would
be roughly the same as that of 222Rn, the effective dose coefficient of 219Rn can be estimated by correcting the effective dose coefficient of 222Rn with its effective half-life.
Using the biological half-life of 55 min for Rn [9] (effective half-lives of 3.95 s for219
Rn and 54.5 min for 222Rn), the effective dose coefficient of 219Rn was estimated tobe 7.9 × 10−9 mSv/Bq (= 6.5 × 10−6 mSv/Bq × 3.95 s/54.5 min).
For the mask measurements, the observed α-particles were considered to haveoriginated from 211Bi, which was in transient radioactive equilibrium with a 211Pb
parent (half-life 36.1 min) because the half-life of 219Rn is very short. The N95
mask was capable of catching the descendant nuclides of 219Rn, that had attachedto dust or aerosol particles, on the surface of the mask, but it was not thought tobe capable of blocking the inhalation of 219Rn. If 219Rn had passed through the
N95 mask, α-particles from the descendant nuclides of 219Rn that had decayed
during and after passing through the mask would have been detectable on the inside of the mask. However, α-particles were not detected on the inside of themasks in the present study. Therefore, 219Rn is considered to have not reached themouths of the medical staff. The reason for the variation in the count rate observed for measurements made for the outside of the masks, as shown in Table 2,
is probably due to the change in the amounts of 219Rn and its descendant nuclides
reaching the medical staff via the airflow in the injection room. The radioactivityof 211Bi caught by the mask, as calculated based on the measured count rate of αparticles, is expected to correspond to less than 10 Bq at the measurement start
time using the instrument efficiency of 35.1%/2π written in the calibration certificate of the survey meter and an α branch of 99.724% for 211Bi. Although theradioactivity of the descendant nuclides of 219Rn caught by the mask was relatively
small, wearing the N95 mask appeared to protect the internal exposure of the
medical staff.
The effective dose from the inhalation of 219Rn experienced by caregivers was estimated to be 3.5 μSv per patient injection. This value is significantly lower than the doseof 5 mSv per episode for caregivers recommended by the International Commission on
Radiological Protection (ICRP) [10, 11]; therefore, the internal radiation exposure from219
Rn should not affect the release criteria for patients who have been treated with223
RaCl2 in Japan.

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Ooe et al. EJNMMI Physics(2019) 6:13

Conclusions
The amount of 219Rn contained in the breath of patients treated with 223Ra was determined using γ-ray spectrometry with an HPGe detector and breath collection bags.
Although a small peak for γ rays of 211Bi originating from 219Rn contained in the breath
was observed, the estimated internal radiation exposure to caregivers via the inhalationof 219Rn was small and should not affect the release criteria of patients who have beentreated with 223RaCl2.
Abbreviations
AUC: Area under the curve; CRPC: Castration-resistant prostate cancer; HP: High purity; ICRP: International Commission
on Radiological Protection; PMDA: Pharmaceutical and Medical Devices Agency
Acknowledgements
We would like to thank Yoshihide Nakamura, Japan Radioisotope Association, for his excellent technical supervision.
We also thank Atsushi Toyoshima, Institute for Radiation Sciences, Osaka University, for his useful comments on thearticle. Finally, we are grateful to Kazuya Yamaguchi and Shuuhei Kawaguchi, Osaka University Hospital, for theirsupport on the breath collection and the measurement.
Authors’ contributions
KO, TW, and TK contributed the study design and conducted the study. KO drafted the manuscript. TW, MH, and JH
contributed the revise of the manuscript. TY, AS, and JH were the supervisors of the study. All authors read andapproved the final manuscript
Funding
This study was funded by a radiation safety regulation research strategic promotion project from the Nuclear
Regulation Authority, Japan.
Availability of data and materials
The datasets generated during and/or analyzed during the current study are available from the corresponding author
on reasonable request.
Ethics approval and consent to participate
The study protocol was approved by the institutional review board of Osaka University Hospital.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1
Department of Nuclear Medicine and Tracer Kinetics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka,
Suita, Osaka 565-0871, Japan. 2Division of Science, Institute for Radiation Sciences, Osaka University, 1-1
Machikaneyama, Toyonaka, Osaka 560-0043, Japan. 3Division of Radiology, Department of Medical Technology, Osaka
University Hospital, 2-15 Yamadaoka, Suita, Osaka 565-0871, Japan. 4Radioisotope Research Center, Institute for
Radiation Sciences, Osaka University, 2-4 Yamadaoka, Suita, Osaka 565-0871, Japan. 5Institute of Advanced Clinical
Medicine, Department of Radiology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka
589-8511, Japan. 6Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama,
Toyonaka, Osaka 560-0043, Japan. 7Division of Education, Institute for Radiation Sciences, Osaka University, 1-1
Machikaneyama, Toyonaka, Osaka 560-0043, Japan.
Received: 13 March 2019 Accepted: 10 July 2019

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