Exposure dose for a third party from a patient administered the labeled somatostatin analogue
The exposure dose for third parties such as caregivers and the general public includes external exposure to radiation emitted by radioactive material in the body of a patient administered the labeled somatostatin analogue and internal exposure due to contamination from a patient’s excreta. The dose to which a third party is exposed is comprehensively evaluated as follows:
Evaluation of the dose from external exposure
Effective dose rate of external exposure at a distance of 1 m from a patient administered the labeled somatostatin analogue
The formula for calculation of the dose rate for external exposure to a third party exposed to a patient administered the labeled somatostatin analogue.
$$I=A \times C \times {F_{\text{a}}} \div {L^2},$$
(5.2.1)
Here I effective dose rate [µSv/h] at a determined reference point, A residual radiation in the body [MBq] of a patient administered the labeled somatostatin analogue, C effective dose rate constant for Lu-177 [µSv m2 MBq−1 h−1]: the value 0.00517 [µSv m2 MBq−1 h−1] from Table 2 in “Characteristics of Lu-177” will be used. Fa effective dose transmission (when multiple shields are used, the sum of the transmission of each shield will serve as the total transmission), L distance [m] from a radiation source to a reference point.
Cumulative dose to which a third party is exposed from a patient administered the labeled somatostatin analogue
The formula for calculation of the cumulative effective dose when a third party is continuously exposed to radiation from a patient administered the labeled somatostatin analogue.
$$E=A \times \int_{0}^{\infty } {{{\left( {\frac{1}{2}} \right)}^{\frac{t}{T}}}{\text{d}}t} \times C \times {f_0},$$
(5.2.2)
Here E cumulative effective dose [µSv] to which a third party is exposed. A residual radiation in the body [MBq] of a patient administered the labeled somatostatin analogue. C effective dose rate constant for Lu-177 [µSv m2 MBq−1 h−1]. The value 0.00517 [µSv m2 MBq− 1 h− 1] from Table 2 in “Characteristics of Lu-177”. T physical half-life of Lu-177. f0 exposure factor (caregivers: 0.5; members of the general public besides caregivers: 0.25).
Factors for evaluation of the cumulative dose for caregivers and the general public from a patient administered the labeled somatostatin analogue
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1)
The cumulative dose to which a third party is exposed after a patient administered the labeled somatostatin analogue is released or discharged is calculated based on the effective dose rate at a distance of 1 m from the surface of the patient’s body.
-
2)
Radiation in the body of a patient administered the labeled somatostatin analogue depends on the effective half-life of Lu-177, which involves both its physical half-life and in vivo dynamics of the labeled somatostatin analogue. After administration of the labeled somatostatin analogue, the cumulative dose for a third party is based on 2 aspects. One is the fact that residual radiation in the body decreases to about 30% of the dose 24 h after administration and to about 20% of the dose 48 h after administration. As was mentioned in 3.2.2, this finding is from a study by Wehrmann et al. [14] that estimated the radiation in excreta from patients administered a labeled somatostatin analogue. The second aspect is the fact that Lu-177 is metabolized in two phases [effective half-life in the early phase: 1.28 h (range: 0.93–1.52 h); effective half-life in the late phase: 49.5 h (range: 45.1–56.6 h)]. This finding is from a study by Sandström et al. [15] that examined Lu-177 metabolism after administration of a labeled somatostatin analogue.
-
3)
1) and 2) summarize the factors used to provisionally calculate the cumulative dose to which a third party is exposed from a patient administered the labeled somatostatin analogue. These factors are used to provisionally calculate changes in Lu-177 radiation in the body.
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①
Dose of the labeled somatostatin analogue: 7400 MBq
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②
Effective half-life in a patient after administration of the labeled somatostatin analogue: early phase: 1.52 h, late phase: 56.6 h.
Sandström et al. [15] reported effective half-lives of Lu-177. The effective half-life of Lu-177 in a patient administered the labeled somatostatin analogue is a conservative estimate based on these half-lives. The effective half-life during the first phase will be 1.52 h and that during the second phase 56.6 h.
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③
Accumulation (%) of the labeled somatostatin analogue in the tumor and organs [14]: 30% of the dose.
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④
Distribution (%) of the labeled somatostatin analogue in tissue and organs other than the tumor and affected organ [14]: 70% of the dose.
Provisional calculation of the cumulative dose of external exposure for a third party exposed to radiation from a patient administered the labeled somatostatin analogue
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1)
Estimation of the effective dose rate over time at a distance of 1 m from the surface of the patient’s body after administration of the labeled somatostatin analogue.
Based on 3) in "Factors for evaluation of the cumulative dose for caregivers and the general public from a patient administered the labeled somatostatin analogue", the effective dose rate of external exposure at a distance of 1 m from the surface of the patient’s body can be determined at a certain point after administration of the labeled somatostatin analogue using the following formula.
$${I_{\text{d}}}=7400\left[ {{\text{MBq}}} \right] \times \left( {{e^{ - \left( {\frac{{0.693}}{{\left( {{\raise0.7ex\hbox{${56.6}$} \!\mathord{\left/ {\vphantom {{56.6} {24}}}\right.\kern-0pt}\!\lower0.7ex\hbox{${24}$}}} \right)}} \times {\text{d}}} \right)}} \times 0.3+e{}^{{ - \left( {\frac{{0.693}}{{\left( {{\raise0.7ex\hbox{${1.52}$} \!\mathord{\left/ {\vphantom {{1.52} {24}}}\right.\kern-0pt}\!\lower0.7ex\hbox{${24}$}}} \right)}} \times {\text{d}}} \right)}} \times 0.7} \right) \times 0.00517\left[ {{\raise0.7ex\hbox{${\mu {\text{Sv}}}$} \!\mathord{\left/ {\vphantom {{\mu {\text{Sv}}} {\left( {{\text{MBq}} \times {\text{h}}} \right)}}}\right.\kern-0pt}\!\lower0.7ex\hbox{${\left( {{\text{MBq}} \times {\text{h}}} \right)}$}}} \right] \times 1,$$
(5.2.4)
Id effective dose rate [µSv/h] × d after administration
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①
Effective dose rate at a distance of 1 m from the surface of the patient’s body 24 h after administration of the labeled somatostatin analogue
$${I_{1{\text{h}}}}={\text{ }}\left( {8.56{\text{ }}+{\text{ }}4.74 \times {{10}^{ - 4}}} \right)={\text{ }}8.56{\text{ }}\left[ {\mu {\text{Sv}}/h} \right].$$
-
②
Effective dose rate at a distance of 1 m from the surface of the patient’s body 48 h after administration of the labeled somatostatin analogue
$${I_{2{\text{h}}}}={\text{ }}\left( {6.38{\text{ }}+{\text{ }}8.39 \times {{10}^{ - 9}}} \right)={\text{ }}6.38{\text{ }}\left[ {\mu {\text{Sv}}/{\text{h}}} \right].$$
The effective dose rate at a distance of 1 m from the surface of the patient’s body is calculated to be 8.56 [µSv/h] 24 h after administration of the labeled somatostatin analogue and 6.38 [µSv/h] 48 h after administration. These dose rates are close to the effective dose rates of 8.0 ± 3.0 [µSv/h] and 6.2 ± 1.7 [µSv/h] that Archer et al. [20] measured 24 and 48 h after administration. When the in vivo dynamics of all of the radiation from the labeled somatostatin analogue are assumed to change depending solely on the early phase (effective half-life: 1.52 h), the effective dose rate at a distance of 1 m 24 h after administration can be determined using the following formula.
$${I_{1.52 - 1{\text{h}}}}=7400\left[ {{\text{MBq}}} \right] \times {e^{ - \left( {\frac{{0.693}}{{(1.52/24)}} \times 1} \right)}} \times 0.00517\left[ {\mu {\text{Sv}}/\left( {{\text{MBq}} \times {\text{h}}} \right)} \right]=6.77 \times {10^{ - 4}}\left[ {\mu {\text{Sv}}/{\text{h}}} \right].$$
Compared to 8.56 [µSv/h] as was determined in (5.2.4.1) ①, 6.77 × 10−4 [µSv/h] is a markedly lower dose rate. Thus, the extent of the residual radiation 24 h after administration depends on the effective half-life in the late phase (56.6 h).
-
2)
The conditions under which to calculate the cumulative dose for a third party exposed to radiation from a patient administered the labeled somatostatin analogue at a dose of 7400 MBq are as follows:
-
(1)
Estimation of the cumulative dose of external exposure for a third party immediately after administration of the labeled somatostatin analogue
The effective dose rate immediately after administration of the labeled somatostatin analogue (d = 0) can be determined using Eq. 5.2.4:
$${I_0}={\text{ }}11.48{\text{ }}+{\text{ }}26.78{\text{ }}={\text{ }}38.26{\text{ }}\left[ {\mu {\text{Sv}}/{\text{h}}} \right].$$
The cumulative dose of external exposure will be calculated for caregivers and the general public when they come into contact with a patient immediately after, 24 h after, and 48 h after administration of the labeled somatostatin analogue (①–③).
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①
The cumulative dose of external exposure for a third party at a distance of 1 m from the surface of the patient’s body immediately after administration
(11.48 [μSv/h] × (2.36 [day]/0.693) + 26.78 [μSv/h] × (0.063 [day]/0.693)) × 24 [h/day] × 4 [rounds/course of treatment] ÷ 1000 [μSv/mSv] = 3.99 [mSv/course of treatment].
-
Cumulative dose for caregivers (exposure factor: 0.5): 3.99 [mSv/course of treatment] × 0.5 = 2.00 [mSv/course of treatment].
-
Cumulative dose for the general public (exposure factor: 0.25): 3.99 [mSv/course of treatment] × 0.25 = 1.00 [mSv/course of treatment].
-
②
The cumulative dose of external exposure for a caregiver or the general public from a patient 24 h after administration.
(8.56 [μSv/h] × (2.36 [day]/0.693) + 4.74 × 10−4 [μSv/h] × (0.063 [day]/0.693)) × 24 [h/day] × 4 [rounds/course of treatment] ÷ 1000 [μSv/mSv] = 2.80 [mSv/course of treatment].
-
Cumulative dose for a caregiver (exposure factor: 0.5): 2.80 [mSv/course of treatment] × 0.5 = 1.40 [mSv/course of treatment]
-
Cumulative dose for the general public (exposure factor: 0.25): 2.80 [mSv/course of treatment] × 0.25 = 0.70 [mSv/course of treatment]
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③
The cumulative dose of external exposure for a caregiver or the general public from a patient 48 h after administration.
(6.38 [μSv/h] × (2.36 [day]/0.693) + 8.39x10−9 [μSv/h] × (0.063 [day]/0.693)) × 24 [h/day] × 4 [rounds/course of treatment] ÷ 1000 [μSv/mSv] = 2.08 [mSv/course of treatment].
-
Cumulative dose for a caregiver (exposure factor: 0.5): 2.08 [mSv/course of treatment] × 0.5 = 1.04 [mSv/course of treatment]
-
Cumulative dose for the general public (exposure factor: 0.25); 2.08 [mSv/course of treatment] × 0.25 = 0.52 [mSv/course of treatment]
The cumulative dose to which a third party is exposed immediately after and at a certain point after a patient is administered the labeled somatostatin analogue at a dose of 7400 MBq was calculated. Results of those calculations are shown in Table 7.
Table 7 Calculation of the cumulative dose to which a third party is exposed immediately after and at a certain point after a patient is administered the labeled somatostatin analogue at a dose of 7400 MBq
As shown in Table 7, the cumulative dose of external exposure for a caregiver who is exposed immediately after a patient is administered the labeled somatostatin analogue would be 2 mSv. This figure is sufficiently lower than 5 mSv per course of treatment, which is the “criterion for a reduced dose” described in the release criteria. The cumulative dose of 1 mSv for the general public is the same value as the dose limit for the general public as recommended by the ICRP. Without considering the in vivo dynamics of the labeled somatostatin analogue and assuming that the cumulative dose decreases with the physical half-life of Lu-177 (6.647 days).
38.26 [μSv/h] × (6.647 [day]/0.693) × 24 [h/day] × 4 [rounds/course of treatment] × 0.25 ÷ 1000 [μSv/mSv] = 8.81 [mSv/course of treatment].
When a patient is released immediately after administration of the labeled somatostatin analogue (7400 MBq), the cumulative dose to which the general public is exposed is estimated to range from 1.00 to 8.81 [mSv/course of treatment]. In such an event, the cumulative dose might exceed 1 mSv per year.
In this Manual, the effective dose rate at a distance of 1 m 24 h after administration of the labeled somatostatin analogue at a dose of 7400 MBq was provisionally calculated to be 8.56 [µSv/h]. Archer et al. [20] measured the effective dose rate at a distance of 1 m from patients 24 h after administration and reported that the effective dose rate was 8.0 ± 3.0 [µSv/h]. Thus, the cumulative dose to which an individual is exposed 24 h after a patient is administered the labeled somatostatin analogue was 11.0 [µSv/h] (8.0 + 3.0 [µSv/h]) according to Archer et al. [20]. Using this figure and the effective half-life of Lu-177 in a labeled somatostatin analogue [15] (56.6 h = 2.36 days), the integrated value of the dose from a patient 24 h after administration can be determined.
11.0 [μSv/h] × (2.36 [day]/0.693) × 24 [h/day] × 4 [rounds/course of treatment] × 0.25 ÷ 1000 [μSv/mSv] = 0.90 [mSv/course of treatment].
The cumulative dose to which the general public is exposed 24 h after a patient is administered the labeled somatostatin analogue at a dose of 7400 MBq would be less than 1 mSv per year, which is the dose limit for the general public as recommended by the ICRP.
Evaluation of the dose from internal exposure
Excreta from a patient administered the labeled somatostatin analogue flows to a sewage treatment plant primarily as urine, which then flows into a river. After additional treatment, this liquid could be used as potable water. Thus, provisional calculation of the dose from internal exposure assumes that all of the radiation administered to a patient flows into a river. The Yodo River accepts a large quantity of treated effluent, so this water system will be used as a model to evaluate the dose from internal exposure.
-
The average flow of the Yodo River water system is about 4.1 [TL] per year (annual average prior to 1991–1995).
-
Population of the metropolitan Osaka area that obtains potable water from that water system: About 14.02 million (2012) (Osaka Prefecture + Nara Prefecture + Wakayama Prefecture + 1/2 of Hyogo Prefecture) [21].
-
Total population of Japan: About 127.52 million (2012) [21].
-
Population of the metropolitan Osaka area as a proportion of Japan’s total population: 10.99% (0.11).
-
Number of patients with a gastroenteropancreatic neuroendocrine tumor in Japan: 11,642 (number of patients per 100,000 population: 2.69 with a pancreatic neuroendocrine tumor, 6.42 with a gastrointestinal neuroendocrine tumor) [22].
-
Number of such patients with distant metastasis: 1176 (percent with distant metastasis: 19.9% with distant metastasis of a pancreatic endocrine tumor, 6.0% with distant metastasis of a gastrointestinal neuroendocrine tumor) [22].
Assuming that Lu-177-DOTA-TATE will be administered to all of these patients.
-
Number of patients in the metropolitan Osaka area eligible for treatment: 1176 × 0.11 = 129 (calculated with respect to the population).
That said, Fig. 0.11 is with respect to the population of the metropolitan Osaka area. This is assuming that Lu-177-DOTA-TATE is administered to each patient at a dose of 7400 MBq in 4 rounds per year.
-
Level of radioactivity of the total dose of Lu-177-DOTA-TATE administered to patients in the metropolitan Osaka area:
7400 [MBq/administration] × 4 [rounds/patient] × 129 [patients] = 3.82 [TBq]
Here, the entire quantity of Lu-177-DOTA-TATE is assumed to be discharged into the Yodo River water system, where it is entirely in a water-soluble form.
-
Lu-177-DOTA-TATE concentration in the river:3.82 [TBq/] ÷ 4.1 [TL/y] = 0.93 [Bq/L].
That said, 4.1 TL is the average annual flow of the Yodo River water system.
-
Annual intake of Lu-177-DOTA-TATE per member of the general public (assuming 2 L of water for drinking per d) [23]:
0.93 [Bq/L] × 2 [L/d] × 365 [d/y] = 678.90 [Bq/y]
-
In the aforementioned instance, the dose from internal exposure in 1 y:
678.90 [Bq/y] × 5.3 × 10−7 [mSv/Bq] = 0.36 [µSv/y].
However, 5.3 × 10−7 [mSv/Bq] is the effective dose coefficient for ingestion of Lu-177 [24].
0.36 µSv/year is substantially lower than 1 mSv, which is the annual dose limit for the general public. Even if the upper reaches of the Yodo River water system (e.g., Kyoto Prefecture) are contaminated to the same extent, Lu-177-DOTA-TATE would contribute less than 0.1% to the annual dose limit for the general public.
Comprehensive evaluation of the doses from external and internal exposure
The doses from external (Table 7) and internal exposure (“Evaluation of the dose from internal exposure”) for caregivers and the general public were comprehensively evaluated when patients were administered the labeled somatostatin analogue at a dose of 7400 MBq (max. dose) in up to four rounds of treatment per year (as part of internal radiotherapy with the labeled somatostatin analogue) and released 24 h after administration of each round of treatment. The results of that evaluation are as follows:
$${\text{Caregivers }}1.40{\text{ }}\left[ {{\text{mSv}}} \right]{\text{ }}+{\text{ }}0.36{\text{ }}\left[ {\mu {\text{Sv}}} \right]{\text{ }}={\text{ }}1.40{\text{ }}\left[ {{\text{mSv}}} \right].$$
$${\text{General public }}0.70{\text{ }}\left[ {{\text{mSv}}} \right]{\text{ }}+{\text{ }}0.36{\text{ }}\left[ {\mu {\text{Sv}}} \right]{\text{ }}={\text{ }}0.70{\text{ }}\left[ {{\text{mSv}}} \right].$$
The exposure dose for caregivers was provisionally calculated to be 1.40 [mSv], and that for the general public 0.70 [mSv]. These doses meet the criteria for a reduced dose for both caregivers and the general public.
Criteria for release of a patient administered the labeled somatostatin analogue from a room for patients undergoing the therapy
When a patient has been administered, the labeled somatostatin analogue (7400 MBq) to treat a neuroendocrine tumor, the conditions indicated in (1) and (2) below must be met for the patient to be released from a room for patients undergoing radiation therapy.
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1)
Over 24 h after administration of the labeled somatostatin analogue.
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2)
During release, a radiation-measuring device will be used to measure the 1-cm dose equivalent rate at a distance of 1 m from the surface of the patient’s body, and the 1-cm dose equivalent rate does not exceed 10 µSv/h.
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3)
In addition to 1) and 2), if any of the following circumstances exist in the home after discharge, admission of the patient to a room for patients undergoing radiation therapy 48 h after administration must be considered.
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If the patient lives with highly radiosensitive infants and children (under the age of 15) or pregnant women.
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If the patient is unable to sleep at least 2 m away from individuals in the same household (preferably in a separate room).
-
If the patient is incontinent and he or she requires a diaper or urinary catheter.
-
If the patient must use the same form of public transportation for 2 h or longer upon discharge.
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4)
A patient to whom the labeled somatostatin analogue has been administered should be admitted to a room for patients undergoing radiation therapy. Rooms for patients undergoing radiation therapy are stipulated in Article 30, Section 12 of the Ordinance for Enforcement of the Medical Services Act. In addition, rooms for patients to whom the labeled somatostatin analogue has been administered must be rooms where “appropriate safeguards and steps to prevent contamination” are taken as stipulated in Article 30, Section 15 of the Ordinance for Enforcement of the Medical Services Act. The administrator of a hospital or other medical facility must manage and utilize those rooms in accordance with the criteria in the addenda to this Manual on proper use of a labeled somatostatin analogue.
-
5)
Records related to 1) to 4) will be kept in a format as specified by this Manual on proper use of a labeled somatostatin analogue or addenda and those records will be retained for a given period.
Precautions for patients and their families
After administration of the labeled somatostatin analogue, minute levels of radiation may be present in bodily fluids (principally blood), urine, and feces. Most of the labeled somatostatin analogue that is not taken up by a tumor will be eliminated by the kidneys and urinary tract. It was reported that a relatively high level of radiation is detected in urine for up to 48 h after administration, and so the precautions described in “Precautions in the week following administration of the labeled somatostatin analogue (first week after administration of a labeled somatostatin analogue)” to “Radiation safety management for a patient wearing a diaper or using a urinary catheter” must be explained to patients and their family members (caregivers) in writing prior to administration, and their assent must be obtained.
Precautions in the week following administration of the labeled somatostatin analogue (1st week after administration of a labeled somatostatin analogue)
Precautions with regard to routine activities:
-
①
If a patient loses blood, that blood will be wiped up with toilet paper and flushed down the toilet.
-
②
When there is any potential for coming into contact with a patient’s urine or feces and when coming into contact with clothing contaminated by a patient’s urine or feces, disposable latex gloves will be worn.
-
③
When a patient’s bodily fluids such as blood come into contact with the hands or skin, the contaminated site will be immediately washed with soap.
-
④
Sexual intercourse is prohibited.
-
⑤
Individuals living with a patient should be separated from the patient to the extent possible. A distance of at least 1 m should be maintained. When together for a prolonged period, a distance of 2 m or more should be maintained. Contact with infants and pregnant women will be minimized.
-
⑥
Sleeping with someone else in the same bed will be avoided. A patient should sleep at least 2 m away. If possible, the patient should sleep in a separate room.
-
⑦
The patient will bathe last. After bathing, the bathtub will be cleaned and washed with a brush and cleaning agent.
-
⑧
Outings in public settings (e.g. public transportation, supermarket, shopping centers, movie theaters, restaurants, and sport venues) should be avoided to the extent possible.
When traveling by public transportation, the patient should be separate from other travelers (a distance of 1 m or greater). Travel time in the same vehicle will be reduced so that the patient does not spend more than 6 h on the same form of public transportation. When traveling by taxi, the patient will sit as far away from the driver as possible and travel time with the same driver will be reduced.
Precautions with regard to handling laundry:
-
①
Clothing worn by a patient administered the labeled somatostatin analogue will be washed separately from the clothing of other individuals, and not at the same time. In addition, bed linens and undergarments soiled with blood or urine will be prepared for washing.
Precautions with regard to urination, defecation, or vomiting:
-
①
Male patients will urinate while seated.
-
②
When feces or urine soil the toilet or floor, that material will be wiped up with toilet paper and flushed down the toilet.
-
③
A toilet will be flushed about two times after use.
-
④
Hands will be washed and cleaned with soap after urination or defecation.
-
⑤
Hands and skin that come into contact with a patient’s bodily fluids (e.g. blood), excreta, or vomitus will be cleaned and washed with soap.
Precautions in the 3 months after administration of the labeled somatostatin analogue (first 3 months after administration of a labeled somatostatin analogue)
Precautions with regard to routine activities:
-
①
When a patient is using facilities that detect radiation to prevent terrorism overseas (national borders, airports, etc.), the patient will carry proof of treatment such as a medical certificate.
Precautions in the 6 months after administration of the labeled somatostatin analogue (first 6 months after administration of a labeled somatostatin analogue)
Precautions with regard to routine activities:
-
①
Female patients will avoid becoming pregnant or nursing and male patients will use condoms.
Precautions for patients after administration of the labeled somatostatin analogue
After administration, the labeled somatostatin analogue will quickly be excreted in the urine, and the level of residual radioactivity in the body is reported to decrease to about 30% of the original dose within 24 h of administration and to about 20% of that dose within 48 of administration [14].
Radiation safety management for a patient wearing a diaper or using a urinary catheter
The following precautions must be taken by a patient who is wearing a diaper or using a urinary catheter soon after administration (in principle, 1 week).
When handling a diaper, urinary catheter, or urine collection bag, disposable gloves will be worn, i.e., the same precautions as are followed to prevent biohazards will be taken.
Precautions when wearing a diaper or using a urinary catheter (at home or in the hospital):
-
①
Vinyl sheets should be used by an incontinent patient who is wearing a diaper.
-
②
When a patient is still using a urinary catheter despite being released from a room for patients undergoing radiation therapy, the urine in a urine collection bag will be disposed of in the toilet and the toilet will be flushed twice. After handling, hands will be washed and cleaned.
-
③
A catheter or urine collection bag will be replaced prior to the discharge of an inpatient.
Precautions during disposal of a diaper or urinary catheter:
-
①
A diaper worn by a patient at home will be placed in a plastic bag and the bag will be closed so that the contents do not leak. The bag will be disposed of as ordinary garbage.
-
②
When disposing of infectious waste such as diapers at a hospital, refer to Handling the Diapers of Patients who have been Administered a Radiopharmaceutical (Guidelines for Medical Personnel Working in Nuclear Medicine) (March 2001, 1st ed., March 2004, 2nd ed.) [25].