Radiation Protection Dosimetry Advance Access published May 21, 2015 Radiation Protection Dosimetry (2015), pp. 1–7
doi:10.1093/rpd/ncv346
INTERNAL DOSIMETRY FOR INTAKE OF 18FDG USING SPOT URINE SAMPLE Siwan Noh1, Sol Jeong2, Mijeong An3, Han-Ki Jang4, Tae-Eun Kwon1, Jong Il Lee2, Tai Jin Park4 and Jai-Ki Lee1,* 1 Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Korea 2 Korea Atomic Energy Research Institute, 989-111 Daeduk-daero, Yuseong-gu, Daejeon 305-353, Korea 3 National Institute of Environmental Research, 42 Hwangyeong-ro, Seo-gu, Incheon 404-708, Korea 4 Korean Association for Radiation Application, 77 Seongsuil-ro, Seongdong-gu, Seoul 133-822, Korea
Received 2 February 2015; revised 15 April 2015; accepted 15 April 2015 In nuclear medicine, workers handle unsealed radioactive materials. Among the materials, 18FDG is the most widely used in PET/CT technique. Because of the short half-life of 18F, it is very challenging to monitor internal exposure of nuclear medicine workers using in vitro bioassay. Thus, the authors developed the new in vitro bioassay methodology for short half-life nuclides. In the methodology, spot urine sample is directly used without normalisation to 1-d urine sample and the spot urinary excretion function was newly proposed. In order to estimate the intake and committed dose for workers dealing 18FDG, biokinetic models for FDG was also developed. Using the new methodology and biokinetic model, the in vitro bioassay for workers dealing 18FDG was successfully performed. The authors expect that this methodology will be very useful for internal monitoring of workers who deal short-lived radionuclides in the all field as well as the nuclear medicine field.
INTRODUCTION Nuclear medicine involves handling of radioactive materials that can give rise to internal exposure of staff (http://nucleus.iaea.org/HHW/MedicalPhysics/ NuclearMedicine/RadiationProtection/RadProtWork AndPublic/index.html). Attention has been paid in recent years to radiation protection in nuclear medicine department (1) along with increased use of radiopharmaceuticals, particularly those having short half-life. Presently, 18FDG, an analogue of glucose labelled with radionuclide 18F, is the most widely used radiopharmaceutical in PET/CT technique(2). The 18F has a half-life of 1.8 h and is one of the most typical short-lived radionuclides. Even if 18F has small internal dose coefficients because of its short half-life, non-negligible internal exposures may occur if handling of such radionuclides is frequent or the protection level of working environment is poor. However, individual monitoring of internal exposure to short-lived radionuclides such as 18F could be challenging because the body burden of these nuclides rapidly vanish. Due to this reason, quantitative dosimetry addressing the internal doses from these short-lived radionuclides is often overlooked in most of the nuclear medicine departments. In that, the authors propose an approach applicable to monitoring programme against internal exposure to short-lived radionuclides. In vitro assay of urine samples are often employed for individual monitoring of internal exposure under
hospital settings. In vitro method has several advantages. First, it is inexpensive when compared with the in vivo assay utilising whole-body counters. Second, it can be applied for alpha and beta emitter. Also, the bioassay samples instead of workers themselves can be sent to outside institution for analysis. In the case of urine bioassay, the standard procedures require collection of urine for whole 1 d in order to decrease uncertainty. Since it is very difficult to collect the urine sample for 1 d, however, spot urine samples are commonly used with normalisation using creatinine concentration or specific gravity(3). In the case of the short-lived radionuclides, application of the standard procedures would be greatly challenged because the activity concentration in the urine could go below the minimum detectable activity (MDA) even in 1 d. In this study, therefore, the authors proposed the new in vitro bioassay methodology for short-lived radionuclides such as 18F using the spot urine sample directly. Using the new methodology, the authors performed the bioassay with first spot urine samples for workers dealing 18FDG. MATERIALS AND METHODS Development of methodology using spot urine sample for short-lived radioisotopes In order to estimate the intake activity and committed dose of workers handling 18FDG from in vitro bioassay, the authors developed the new methodology using spot urine sample directly instead of
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*Corresponding author: [email protected]
S. NOH ET AL.
qðtÞ ¼ e½At qð0Þ:
ð1Þ
In this equation, q(t) is the vector including activities in each compartment at any subsequent time t, and q(0) is the initial vector that contains the initial activities in each compartment. The matrix [A] is formed by modifying a transfer rate matrix [R] as in the following equation: aii ¼
N X
r ji ; aij ¼ r ji ;
for i = j;
ð2Þ
j¼1 j=i
where rji is a transfer rate from compartment i to j and composes the matrix [R]. If it is assumed that urinating completely voids the content of urinary bladder, the activities in the urinary bladder compartment at time t after intake of unit activity is equal to the spot urinary excretion function. The activities in the urinary bladder compartment are accumulated from intake time to first urinating time whereas it is assumed that urine in the urinary bladder is constantly eliminated with the rate of 12 d21 to represent the first-order kinetics of the urinary bladder in the conventional bioassay(5). It also can be reasonably assumed that the radionuclide concentration in urine before the intake be zero by virtue of the short half-life of the nuclide considered. Hence, the elapsed time from the previous voiding before the work does not affect the interpretation of monitoring result. For another spot urine sample, other than first sample, spot urinary excretion function can be
calculated by modifying Equation (1) as following equation: qðt tb Þ ¼ e½Aðttb Þ qðtb Þ;
ð3Þ
where q(t 2 tb) is the vector including activities in each compartment at elapsed time from previous urinating time tb to sampling time t. q(tb) is the vector that contains the activities in each compartment at time tb with 0 Bq in the urinary bladder compartment due to the bladder voiding by urinating.
Biokinetic model for 18FDG In order to interpret bioassay samples from workers handling 18FDG using the new methodology, a biokinetic model for inhalation and ingestion of FDG is necessary. At present, specific biokinetic model is absent for inhalation and ingestion of FDG. A former study(2) used the ICRP 53(6) model describing the distribution of FDG after intravenous administration, the ICRP 66(7) respiratory model and the gastrointestinal tract model. In this study, the authors used the ICRP 106(8) model, which replaces the ICRP 53 model, the ICRP 66 respiratory model and the ICRP 30 gastrointestinal tract model. In the ICRP 106 model for FDG, the uptake fraction to the brain (0.08) is to be higher than that was given in the ICRP 53 model (0.06). Also, the uptake to the liver and lungs is additionally considered, and the uptake fraction is 0.08 and 0.03, respectively. The authors assumed that the FDG absorbed from respiratory or alimentary tract to blood is distributed to each compartment with a 1 min of half-time. This assumption is based on the ICRP 106 publication, which describes that most of the radiopharmaceutical is cleared rapidly from the circulation with a half-time of ,1 min following intravenous administration. Using the biokinetic model for FDG constructed in this study, the authors evaluated internal dose coefficient, e50 for inhalation and ingestion of 18FDG. Calculation of the internal dose coefficient is divided into two parts: U50 (the number of disintegration at each compartment for 50 y: 18 250 d) and specific effective energy (SEE) calculation. U50 can be calculated as in the following equation(9): U50 ¼ l½A1 ðe½A50 years ½IÞq0 ;
ð4Þ
where l is decay constant if q0 is given in the number of atoms or 8.64` 104 for the number of transformations (d21 Bq21) if q0 is given in becquerel. In the case of the short-lived radioisotopes like 18F, however, the dose of urinary bladder can be underestimated if existing bladder voiding model which assumes that urine is constantly excreted from the urinary bladder
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normalisation to 1-d urine sample. Since the first spot urine after intake generally includes the highest activities of target radionuclide and therefore can decrease an uncertainty, first the authors focused on the first spot urine and then extrapolated to the next urine samples. In this methodology, the authors proposed ‘spot urinary excretion function’ Eus(t) to use spot urine sample directly. If the first spot urine sample after intake is used, this function is defined as the excreted activities in the first spot urine sample at time t after intake of 1 Bq. The spot urinary excretion function is calculated using biokinetic compartment model, which is commonly used in the field of internal dosimetry. In this model, each organ and tissue is considered as independent compartment. The transfer between compartments is described by first-order kinetics with transfer coefficient, r (d21). The activities in each compartment at time t after intake of 1 Bq can be calculated by solving the first-order simultaneous differential equation. In order to solve the equation simply, linear algebra using matrix is commonly used as in the following equation(4):
18
21
FDG INTERNAL DOSIMETRY USING SPOT URINE
In vitro bioassay for 18FDG production facility workers The authors applied the new methodology to in vitro bioassay for workers involved in the production of 18 FDG. Two workers who produce 18FDG in the hospital located in Daejon, South Korea, were the participants in this study and fully informed about the purposes and procedure of the study. The in vitro bioassay for two participants was performed four times with the same procedure. The procedure of the in vitro bioassay for the workers using the new methodology is as follow: (1) (2) (3) (4)
Take the first urine after the work. Record the time of work and urine sampling. Measure mass of the urine sample. Measure activity concentration of the target nuclide (i.e. 18F) in the urine sample as soon as possible. (5) Record the result including the time of measurement. (6) Interpret the result to estimate the intake and the committed doses. In order to measure the activity concentration in the urine sample, gamma spectroscopy was performed. Gamma spectroscopy system used in this study consists of ORTEC GEM30P4-83 HPGe detector with electrical cooling and DSA-1000 (Canberra, USA). Canberra’s Genie-2000 software was used to analyse the peak obtained from annihilation gamma rays. For gamma spectroscopy, a spot urine sample was drawn off cylindrical U8 container. After the activity concentration is measured, intake activity of workers can
Figure 1. Overall procedure of the new methodology using the first spot urine sample.
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with transfer rate of 12 d . Thus, the authors calculated the U50 with the assumption that the urinary bladder is voided every 3.5 h. This period is the reference voiding period of adult described in ICRP publication 89(10). SEE is calculated from multiplying specific absorbed fraction (SAF) by radiation emission yield, radiation energy and radiation weighting factor. Even though SAF should be calculated using reference computational phantoms under ICRP 103(11) dosimetry system, the SAF for all source and target organs is not available yet. For this reason, the authors used SEECAL 2.0 program(12) in which SAF based on MIRD phantom is used when they prepare SEE data for 18F. In internal dosimetry, absorption type in the respiratory tract and fractional absorption, f1 in the alimentary tract are crucial factors. There are three absorption types: F (fast), M (moderate) and S (slow), which is decided by chemical compound of nuclide. Fractional absorption, f1 means the fraction of the ingested amount of the element absorbed to blood in small intestine compartment, which is also decided by chemical compound of nuclide. Since there has been no study to decide absorption type and f1, the authors considered all absorption types and f1 of 1.0, which is the recommended value for all fluorine compounds in ICRP publication 68(13). Activity median aerodynamic diameter (AMAD) was assumed as 5 mm, ICRP reference value for working places. For this reason, the result of dosimetry in this study may show approximate internal exposure level of workers.
S. NOH ET AL.
be calculated as in the following equation: I¼
mu C ; Eus ðtÞ
ð5Þ
where mu is mass of the spot urine sample and C is the measure activity concentration of the target nuclide. Then, committed effective dose of workers is easily calculated from multiplying the intake activity by internal dose coefficient e50. In order to decide Eus(t), intake time should be determined. Based on the IDEAS guideline(14), mid-point of the work time is assumed as the intake time in the absence of knowledge of the exact intake time. If the estimated dose exceeds 1 mSv, however, more likely intake time should be assessed to decrease uncertainty. Since there is no evidence for intake by ingestion, the authors assumed intake pathway as inhalation. Also, intake activities and committed effective doses were estimated for all absorption type because there is no ICRP default value. RESULTS Figure 1 shows the overall procedure of the new methodology for the first spot urine sample developed in this study. As shown in Figure 1, the new methodology consists of three parts: † †
Calculation of spot urinary excretion function. Measurement of total activity in the spot urine sample.
Figure 3. The first spot urinary excretion function for intake of 18FDG.
†
Estimation of intake activity and committed effective dose.
Figure 2 shows the biokinetic model of FDG for inhalation and ingestion, which was developed by combination of the ICRP 106 FDG model, the ICRP 66 respiratory model and the gastrointestinal tract model. Deposition fractions in each respiratory compartment are to be initial value for inhalation, and 1 Bq in the stomach compartment is to be initial value for ingestion. It was assumed that the material in ‘lungs’ compartment transferred from ‘blood’
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Figure 2. The biokinetic model of FDG for inhalation and ingestion.
18
FDG INTERNAL DOSIMETRY USING SPOT URINE
Table 1. The first spot urinary excretion functions for intake of 18FDG. Inhalation (AMAD ¼ 5 mm)
Time (min) Type F
Type M
Type S
f1 ¼ 1.0
1.59` 1023 7.15` 1023 1.34` 1022 1.85` 1022 2.25` 1022 2.54` 1022 2.74` 1022 2.89` 1022 2.98` 1022 3.03` 1022 3.05` 1022 3.04` 1022 3.01` 1022 2.96` 1022 2.90` 1022 2.83` 1022 2.74` 1022 2.66` 1022 2.56` 1022 2.47` 1022 2.37` 1022 2.27` 1022 2.17` 1022 2.07` 1022 1.98` 1022 1.88` 1022 1.79` 1022 1.70` 1022 1.62` 1022 1.53` 1022 1.45` 1022 1.38` 1022 1.30` 1022 1.23` 1022 1.16` 1022 1.10` 1022 1.04` 1022 9.79` 1023 9.24` 1023 8.71` 1023 8.21` 1023 7.74` 1023 7.29` 1023 6.87` 1023 6.47` 1023 6.09` 1023 5.73` 1023 5.39` 1023 5.07` 1023 4.77` 1023 4.49` 1023 4.22` 1023 3.97` 1023 3.73` 1023 3.51` 1023 3.30` 1023
1.85` 1024 1.13` 1023 2.85` 1023 5.08` 1023 7.54` 1023 9.96` 1023 1.22` 1022 1.42` 1022 1.58` 1022 1.72` 1022 1.82` 1022 1.89` 1022 1.95` 1022 1.98` 1022 1.99` 1022 1.98` 1022 1.96` 1022 1.93` 1022 1.90` 1022 1.85` 1022 1.80` 1022 1.74` 1022 1.69` 1022 1.62` 1022 1.56` 1022 1.50` 1022 1.43` 1022 1.37` 1022 1.31` 1022 1.25` 1022 1.19` 1022 1.13` 1022 1.07` 1022 1.02` 1022 9.66` 1023 9.16` 1023 8.67` 1023 8.20` 1023 7.76` 1023 7.33` 1023 6.93` 1023 6.54` 1023 6.17` 1023 5.82` 1023 5.49` 1023 5.18` 1023 4.88` 1023 4.60` 1023 4.33` 1023 4.08` 1023 3.84` 1023 3.62` 1023 3.40` 1023 3.20` 1023 3.01` 1023 2.83` 1023
3.05` 1025 4.66` 1024 1.69` 1023 3.61` 1023 5.89` 1023 8.27` 1023 1.05` 1022 1.25` 1022 1.43` 1022 1.57` 1022 1.68` 1022 1.77` 1022 1.83` 1022 1.87` 1022 1.89` 1022 1.89` 1022 1.88` 1022 1.86` 1022 1.82` 1022 1.78` 1022 1.74` 1022 1.69` 1022 1.63` 1022 1.57` 1022 1.52` 1022 1.46` 1022 1.40` 1022 1.33` 1022 1.28` 1022 1.22` 1022 1.16` 1022 1.10` 1022 1.05` 1022 9.95` 1023 9.44` 1023 8.95` 1023 8.48` 1023 8.03` 1023 7.59` 1023 7.18` 1023 6.78` 1023 6.41` 1023 6.05` 1023 5.71` 1023 5.38` 1023 5.08` 1023 4.79` 1023 4.51` 1023 4.25` 1023 4.00` 1023 3.77` 1023 3.55` 1023 3.34` 1023 3.14` 1023 2.96` 1023 2.78` 1023
5.42` 1024 4.16` 1023 1.04` 1022 1.75` 1022 2.46` 1022 3.09` 1022 3.63` 1022 4.08` 1022 4.44` 1022 4.72` 1022 4.92` 1022 5.05` 1022 5.13` 1022 5.15` 1022 5.14` 1022 5.09` 1022 5.01` 1022 4.91` 1022 4.79` 1022 4.65` 1022 4.50` 1022 4.35` 1022 4.19` 1022 4.02` 1022 3.86` 1022 3.69` 1022 3.53` 1022 3.37` 1022 3.21` 1022 3.05` 1022 2.90` 1022 2.75` 1022 2.61` 1022 2.48` 1022 2.35` 1022 2.22` 1022 2.10` 1022 1.99` 1022 1.88` 1022 1.77` 1022 1.67` 1022 1.58` 1022 1.49` 1022 1.40` 1022 1.32` 1022 1.25` 1022 1.17` 1022 1.10` 1022 1.04` 1022 9.79` 1023 9.21` 1023 8.67` 1023 8.15` 1023 7.67` 1023 7.21` 1023 6.78` 1023 Continued
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10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300 310 320 330 340 350 360 370 380 390 400 410 420 430 440 450 460 470 480 490 500 510 520 530 540 550 560
Ingestion
S. NOH ET AL. Table 1. Continued Inhalation (AMAD ¼ 5 mm)
Time (min) Type F
Type M
Type S
f1 ¼ 1.0
3.10` 1023 2.91` 1023 2.74` 1023 2.57` 1023 2.42` 1023 2.27` 1023 2.13` 1023 2.00` 1023 1.88` 1023 1.77` 1023 1.66` 1023 1.56` 1023 1.47` 1023 1.38` 1023 1.29` 1023 1.21` 1023
2.67` 1023 2.51` 1023 2.36` 1023 2.22` 1023 2.08` 1023 1.96` 1023 1.84` 1023 1.73` 1023 1.63` 1023 1.53` 1023 1.44` 1023 1.35` 1023 1.27` 1023 1.19` 1023 1.12` 1023 1.05` 1023
2.62` 1023 2.46` 1023 2.32` 1023 2.18` 1023 2.05` 1023 1.92` 1023 1.81` 1023 1.70` 1023 1.60` 1023 1.50` 1023 1.41` 1023 1.33` 1023 1.25` 1023 1.17` 1023 1.10` 1023 1.03` 1023
6.38` 1023 5.99` 1023 5.64` 1023 5.30` 1023 4.98` 1023 4.68` 1023 4.40` 1023 4.13` 1023 3.88` 1023 3.65` 1023 3.43` 1023 3.22` 1023 3.02` 1023 2.84` 1023 2.67` 1023 2.50` 1023
Table 2. Internal dose coefficients for intake of 18FDG (Sv Bq21). Inhalation (AMAD ¼ 5mm)
Ingestion Type M
Type S
f1 ¼ 1.0
8.86` 10211
9.24` 10211
5.05` 10211
Type F 5.46` 10211
Table 3. The work information and measurement result for the first spot urine samples. No. 1. 2. 3. 4.
Intake time
Sampling time
Sample mass (g)
10:25 7:27 6:05 6:40
13:50 11:30 10:45 10:00
81 234 106 224
18
F concentration (Bq g21)
MDA (Bq g21)
1.472+0.0270 0.138+0.00700 0.163+0.0140 0.277+0.0178
0.0465 0.0270 0.0580 0.0396
Table 4. Estimated intake and committed effective dose using the first spot urine samples. No.
1. 2. 3. 4.
Estimated intake (Bq)
Committed effective dose (mSv)
Inhalation (Type F)
Inhalation (Type M)
Inhalation (Type S)
Inhalation (Type F)
Inhalation (Type M)
Inhalation (Type S)
4931+90 1579+80 1015+87 2515+162
6530+120 2012+102 1260+108 3352+215
6772+124 2074+105 1294+111 3480+224
0.269+0.00491 0.0862+0.00437 0.0554+0.00475 0.137+0.00885
0.579+0.0106 0.178+0.00904 0.112+0.00957 0.297+0.0190
0.626+0.0115 0.192+0.00970 0.120+0.0103 0.322+0.0207
compartment does not absorbed into blood compartment again. Using the biokinetic model of FDG, the first spot urinary excretion functions for inhalation and ingestion were calculated from Equation (1). Figure 3
shows the first spot urinary excretion functions, and Table 1 provides the value of the functions for every 10 min up to 12 h. Table 2 presents the internal dose coefficient e50 for inhalation and ingestion of 18FDG. The internal dose
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570 580 590 600 610 620 630 640 650 660 670 680 690 700 710 720
Ingestion
18
FDG INTERNAL DOSIMETRY USING SPOT URINE
coefficients for inhalation are provided for absorption type of F, M and S, and the coefficient for ingestion is provided for fractional absorption f1 of 1.0. Table 3 shows the information needed for bioassay and measurement results. It was assumed that only acute intake occurs and the predicted intake is midpoint of the production work. From the data in Table 3, intake activity and committed effective dose of the workers were estimated for inhalation and ingestion both as shown in Table 4. As shown in Table 4, internal exposure level of the workers is not interpreted to be significant even if absorption type is assumed as Type S.
In this study, the authors performed the in vitro bioassay for the workers dealing 18FDG using spot urine samples. Since 18F has very short half-life (1.83 h), the authors developed the new in vitro bioassay methodology using spot urine sample directly without normalisation to the 1-d urine sample. In the methodology, the spot urinary excretion function, Eus(t) was newly proposed instead of daily urinary excretion functions. Also, the biokinetic model of FDG for inhalation and ingestion was also constructed and implemented in the calculation of Eus(t) for intake of 18FDG. The methodology developed in this study can be applied for all short-lived radionuclides including 18 F. Therefore, the authors expect that this methodology will be very useful for internal monitoring of workers who deal short-lived radionuclides in the all field as well as the nuclear medicine field. FUNDING This study was supported by Nuclear Research and Development Program of the Nuclear Safety and Security Commission (NSSC). REFERENCES 1. Ho, W. Y., Wong, K. K., Leung, Y. L., Cheng, K. C. and Ho, F. T. H. Radiation doses to staff in a nuclear medicine department. Hong Kong J. Radiol. 5, 24–28 (2002).
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CONCLUSION
2. Oliveira, C. M., Lima, F. F., de Oliveira, M. L., da Silva, T. V., Dantas, A. L., Dantas, B. M., Alonso, T. C. and da Silva, T. A. Evaluation of a technique for in vivo internal monitoring of 18F within a Brazilian laboratory network. Radiat. Prot. Dosim. 153(1), 100– 105 (2013). 3. Doerfel, H. et al. General guidelines for the estimation of committed effective dose from incorporation monitoring data (Research Center Karlsruhe, Karlsruhe) (2006). ISSN 0947-8620. 4. Birchall, A. and James, A. C. A microcomputer algorithm for solving first-order compartment models involving recycling. Health Phys. 56(6), 857–868 (1989). 5. International Commission on Radiological Protection. Individual monitoring for internal exposure of workers. (1997). ICRP Publication 78. Ann. ICRP. 27(3– 4). 6. International Commission on Radiological Protection. Radiation dose to patients from radiopharmaceuticals. (1988). ICRP Publication 53. Ann. ICRP 18(1–4). 7. International Commission on Radiological Protection. Human respiratory tract model for radiological protection. (1994). ICRP Publication 66. Ann. ICRP 24(1– 3). 8. International Commission on Radiological Protection. Radiation dose to patients from radiopharmaceuticals-addendum 3 to ICRP publication 53. (2008). ICRP Publication 106. Ann. ICRP 38(1– 2). 9. Polig, E. Modeling the distribution and dosimetry of internal emitters: a review of mathematical procedures using matrix methods. Health Phys. 81(5), 492–501 (2001). 10. International Commission on Radiological Protection. Basic anatomical and physiological data for use in radiological protection reference values. (2002). ICRP Publication 89. Ann. ICRP 32(3–4). 11. International Commission on Radiological Protection. The 2007 recommendations of the International Commission on Radiological Protection. (2007). ICRP Publication 103. Ann. ICRP 37(2– 4). 12. Oak Ridge National Laboratory. RSICC computer code collection-SEECAL 2.0. CCC-620 (Oak Ridge National Laboratory, Oak Ridge, TN) (1995). 13. International Commission on Radiological Protection. Dose coefficients for intakes of radionuclides by workers. (1994). ICRP Publication 68. Ann. ICRP 24(4). 14. Castellani, C. M., Marsh, J. W., Hurtgen, C., Blanchardon, E., Berard, P., Giussani, A. and Lopez, M. A. IDEAS guidelines (version 2) for the estimation of committed doses from incorporation monitoring data. (2013). EURADOS Report 2013-01.
doi:10.1093/rpd/ncv346
INTERNAL DOSIMETRY FOR INTAKE OF 18FDG USING SPOT URINE SAMPLE Siwan Noh1, Sol Jeong2, Mijeong An3, Han-Ki Jang4, Tae-Eun Kwon1, Jong Il Lee2, Tai Jin Park4 and Jai-Ki Lee1,* 1 Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 133-791, Korea 2 Korea Atomic Energy Research Institute, 989-111 Daeduk-daero, Yuseong-gu, Daejeon 305-353, Korea 3 National Institute of Environmental Research, 42 Hwangyeong-ro, Seo-gu, Incheon 404-708, Korea 4 Korean Association for Radiation Application, 77 Seongsuil-ro, Seongdong-gu, Seoul 133-822, Korea
Received 2 February 2015; revised 15 April 2015; accepted 15 April 2015 In nuclear medicine, workers handle unsealed radioactive materials. Among the materials, 18FDG is the most widely used in PET/CT technique. Because of the short half-life of 18F, it is very challenging to monitor internal exposure of nuclear medicine workers using in vitro bioassay. Thus, the authors developed the new in vitro bioassay methodology for short half-life nuclides. In the methodology, spot urine sample is directly used without normalisation to 1-d urine sample and the spot urinary excretion function was newly proposed. In order to estimate the intake and committed dose for workers dealing 18FDG, biokinetic models for FDG was also developed. Using the new methodology and biokinetic model, the in vitro bioassay for workers dealing 18FDG was successfully performed. The authors expect that this methodology will be very useful for internal monitoring of workers who deal short-lived radionuclides in the all field as well as the nuclear medicine field.
INTRODUCTION Nuclear medicine involves handling of radioactive materials that can give rise to internal exposure of staff (http://nucleus.iaea.org/HHW/MedicalPhysics/ NuclearMedicine/RadiationProtection/RadProtWork AndPublic/index.html). Attention has been paid in recent years to radiation protection in nuclear medicine department (1) along with increased use of radiopharmaceuticals, particularly those having short half-life. Presently, 18FDG, an analogue of glucose labelled with radionuclide 18F, is the most widely used radiopharmaceutical in PET/CT technique(2). The 18F has a half-life of 1.8 h and is one of the most typical short-lived radionuclides. Even if 18F has small internal dose coefficients because of its short half-life, non-negligible internal exposures may occur if handling of such radionuclides is frequent or the protection level of working environment is poor. However, individual monitoring of internal exposure to short-lived radionuclides such as 18F could be challenging because the body burden of these nuclides rapidly vanish. Due to this reason, quantitative dosimetry addressing the internal doses from these short-lived radionuclides is often overlooked in most of the nuclear medicine departments. In that, the authors propose an approach applicable to monitoring programme against internal exposure to short-lived radionuclides. In vitro assay of urine samples are often employed for individual monitoring of internal exposure under
hospital settings. In vitro method has several advantages. First, it is inexpensive when compared with the in vivo assay utilising whole-body counters. Second, it can be applied for alpha and beta emitter. Also, the bioassay samples instead of workers themselves can be sent to outside institution for analysis. In the case of urine bioassay, the standard procedures require collection of urine for whole 1 d in order to decrease uncertainty. Since it is very difficult to collect the urine sample for 1 d, however, spot urine samples are commonly used with normalisation using creatinine concentration or specific gravity(3). In the case of the short-lived radionuclides, application of the standard procedures would be greatly challenged because the activity concentration in the urine could go below the minimum detectable activity (MDA) even in 1 d. In this study, therefore, the authors proposed the new in vitro bioassay methodology for short-lived radionuclides such as 18F using the spot urine sample directly. Using the new methodology, the authors performed the bioassay with first spot urine samples for workers dealing 18FDG. MATERIALS AND METHODS Development of methodology using spot urine sample for short-lived radioisotopes In order to estimate the intake activity and committed dose of workers handling 18FDG from in vitro bioassay, the authors developed the new methodology using spot urine sample directly instead of
# The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
Downloaded from http://rpd.oxfordjournals.org/ at New York University on November 13, 2015
*Corresponding author: [email protected]
S. NOH ET AL.
qðtÞ ¼ e½At qð0Þ:
ð1Þ
In this equation, q(t) is the vector including activities in each compartment at any subsequent time t, and q(0) is the initial vector that contains the initial activities in each compartment. The matrix [A] is formed by modifying a transfer rate matrix [R] as in the following equation: aii ¼
N X
r ji ; aij ¼ r ji ;
for i = j;
ð2Þ
j¼1 j=i
where rji is a transfer rate from compartment i to j and composes the matrix [R]. If it is assumed that urinating completely voids the content of urinary bladder, the activities in the urinary bladder compartment at time t after intake of unit activity is equal to the spot urinary excretion function. The activities in the urinary bladder compartment are accumulated from intake time to first urinating time whereas it is assumed that urine in the urinary bladder is constantly eliminated with the rate of 12 d21 to represent the first-order kinetics of the urinary bladder in the conventional bioassay(5). It also can be reasonably assumed that the radionuclide concentration in urine before the intake be zero by virtue of the short half-life of the nuclide considered. Hence, the elapsed time from the previous voiding before the work does not affect the interpretation of monitoring result. For another spot urine sample, other than first sample, spot urinary excretion function can be
calculated by modifying Equation (1) as following equation: qðt tb Þ ¼ e½Aðttb Þ qðtb Þ;
ð3Þ
where q(t 2 tb) is the vector including activities in each compartment at elapsed time from previous urinating time tb to sampling time t. q(tb) is the vector that contains the activities in each compartment at time tb with 0 Bq in the urinary bladder compartment due to the bladder voiding by urinating.
Biokinetic model for 18FDG In order to interpret bioassay samples from workers handling 18FDG using the new methodology, a biokinetic model for inhalation and ingestion of FDG is necessary. At present, specific biokinetic model is absent for inhalation and ingestion of FDG. A former study(2) used the ICRP 53(6) model describing the distribution of FDG after intravenous administration, the ICRP 66(7) respiratory model and the gastrointestinal tract model. In this study, the authors used the ICRP 106(8) model, which replaces the ICRP 53 model, the ICRP 66 respiratory model and the ICRP 30 gastrointestinal tract model. In the ICRP 106 model for FDG, the uptake fraction to the brain (0.08) is to be higher than that was given in the ICRP 53 model (0.06). Also, the uptake to the liver and lungs is additionally considered, and the uptake fraction is 0.08 and 0.03, respectively. The authors assumed that the FDG absorbed from respiratory or alimentary tract to blood is distributed to each compartment with a 1 min of half-time. This assumption is based on the ICRP 106 publication, which describes that most of the radiopharmaceutical is cleared rapidly from the circulation with a half-time of ,1 min following intravenous administration. Using the biokinetic model for FDG constructed in this study, the authors evaluated internal dose coefficient, e50 for inhalation and ingestion of 18FDG. Calculation of the internal dose coefficient is divided into two parts: U50 (the number of disintegration at each compartment for 50 y: 18 250 d) and specific effective energy (SEE) calculation. U50 can be calculated as in the following equation(9): U50 ¼ l½A1 ðe½A50 years ½IÞq0 ;
ð4Þ
where l is decay constant if q0 is given in the number of atoms or 8.64` 104 for the number of transformations (d21 Bq21) if q0 is given in becquerel. In the case of the short-lived radioisotopes like 18F, however, the dose of urinary bladder can be underestimated if existing bladder voiding model which assumes that urine is constantly excreted from the urinary bladder
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normalisation to 1-d urine sample. Since the first spot urine after intake generally includes the highest activities of target radionuclide and therefore can decrease an uncertainty, first the authors focused on the first spot urine and then extrapolated to the next urine samples. In this methodology, the authors proposed ‘spot urinary excretion function’ Eus(t) to use spot urine sample directly. If the first spot urine sample after intake is used, this function is defined as the excreted activities in the first spot urine sample at time t after intake of 1 Bq. The spot urinary excretion function is calculated using biokinetic compartment model, which is commonly used in the field of internal dosimetry. In this model, each organ and tissue is considered as independent compartment. The transfer between compartments is described by first-order kinetics with transfer coefficient, r (d21). The activities in each compartment at time t after intake of 1 Bq can be calculated by solving the first-order simultaneous differential equation. In order to solve the equation simply, linear algebra using matrix is commonly used as in the following equation(4):
18
21
FDG INTERNAL DOSIMETRY USING SPOT URINE
In vitro bioassay for 18FDG production facility workers The authors applied the new methodology to in vitro bioassay for workers involved in the production of 18 FDG. Two workers who produce 18FDG in the hospital located in Daejon, South Korea, were the participants in this study and fully informed about the purposes and procedure of the study. The in vitro bioassay for two participants was performed four times with the same procedure. The procedure of the in vitro bioassay for the workers using the new methodology is as follow: (1) (2) (3) (4)
Take the first urine after the work. Record the time of work and urine sampling. Measure mass of the urine sample. Measure activity concentration of the target nuclide (i.e. 18F) in the urine sample as soon as possible. (5) Record the result including the time of measurement. (6) Interpret the result to estimate the intake and the committed doses. In order to measure the activity concentration in the urine sample, gamma spectroscopy was performed. Gamma spectroscopy system used in this study consists of ORTEC GEM30P4-83 HPGe detector with electrical cooling and DSA-1000 (Canberra, USA). Canberra’s Genie-2000 software was used to analyse the peak obtained from annihilation gamma rays. For gamma spectroscopy, a spot urine sample was drawn off cylindrical U8 container. After the activity concentration is measured, intake activity of workers can
Figure 1. Overall procedure of the new methodology using the first spot urine sample.
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with transfer rate of 12 d . Thus, the authors calculated the U50 with the assumption that the urinary bladder is voided every 3.5 h. This period is the reference voiding period of adult described in ICRP publication 89(10). SEE is calculated from multiplying specific absorbed fraction (SAF) by radiation emission yield, radiation energy and radiation weighting factor. Even though SAF should be calculated using reference computational phantoms under ICRP 103(11) dosimetry system, the SAF for all source and target organs is not available yet. For this reason, the authors used SEECAL 2.0 program(12) in which SAF based on MIRD phantom is used when they prepare SEE data for 18F. In internal dosimetry, absorption type in the respiratory tract and fractional absorption, f1 in the alimentary tract are crucial factors. There are three absorption types: F (fast), M (moderate) and S (slow), which is decided by chemical compound of nuclide. Fractional absorption, f1 means the fraction of the ingested amount of the element absorbed to blood in small intestine compartment, which is also decided by chemical compound of nuclide. Since there has been no study to decide absorption type and f1, the authors considered all absorption types and f1 of 1.0, which is the recommended value for all fluorine compounds in ICRP publication 68(13). Activity median aerodynamic diameter (AMAD) was assumed as 5 mm, ICRP reference value for working places. For this reason, the result of dosimetry in this study may show approximate internal exposure level of workers.
S. NOH ET AL.
be calculated as in the following equation: I¼
mu C ; Eus ðtÞ
ð5Þ
where mu is mass of the spot urine sample and C is the measure activity concentration of the target nuclide. Then, committed effective dose of workers is easily calculated from multiplying the intake activity by internal dose coefficient e50. In order to decide Eus(t), intake time should be determined. Based on the IDEAS guideline(14), mid-point of the work time is assumed as the intake time in the absence of knowledge of the exact intake time. If the estimated dose exceeds 1 mSv, however, more likely intake time should be assessed to decrease uncertainty. Since there is no evidence for intake by ingestion, the authors assumed intake pathway as inhalation. Also, intake activities and committed effective doses were estimated for all absorption type because there is no ICRP default value. RESULTS Figure 1 shows the overall procedure of the new methodology for the first spot urine sample developed in this study. As shown in Figure 1, the new methodology consists of three parts: † †
Calculation of spot urinary excretion function. Measurement of total activity in the spot urine sample.
Figure 3. The first spot urinary excretion function for intake of 18FDG.
†
Estimation of intake activity and committed effective dose.
Figure 2 shows the biokinetic model of FDG for inhalation and ingestion, which was developed by combination of the ICRP 106 FDG model, the ICRP 66 respiratory model and the gastrointestinal tract model. Deposition fractions in each respiratory compartment are to be initial value for inhalation, and 1 Bq in the stomach compartment is to be initial value for ingestion. It was assumed that the material in ‘lungs’ compartment transferred from ‘blood’
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Figure 2. The biokinetic model of FDG for inhalation and ingestion.
18
FDG INTERNAL DOSIMETRY USING SPOT URINE
Table 1. The first spot urinary excretion functions for intake of 18FDG. Inhalation (AMAD ¼ 5 mm)
Time (min) Type F
Type M
Type S
f1 ¼ 1.0
1.59` 1023 7.15` 1023 1.34` 1022 1.85` 1022 2.25` 1022 2.54` 1022 2.74` 1022 2.89` 1022 2.98` 1022 3.03` 1022 3.05` 1022 3.04` 1022 3.01` 1022 2.96` 1022 2.90` 1022 2.83` 1022 2.74` 1022 2.66` 1022 2.56` 1022 2.47` 1022 2.37` 1022 2.27` 1022 2.17` 1022 2.07` 1022 1.98` 1022 1.88` 1022 1.79` 1022 1.70` 1022 1.62` 1022 1.53` 1022 1.45` 1022 1.38` 1022 1.30` 1022 1.23` 1022 1.16` 1022 1.10` 1022 1.04` 1022 9.79` 1023 9.24` 1023 8.71` 1023 8.21` 1023 7.74` 1023 7.29` 1023 6.87` 1023 6.47` 1023 6.09` 1023 5.73` 1023 5.39` 1023 5.07` 1023 4.77` 1023 4.49` 1023 4.22` 1023 3.97` 1023 3.73` 1023 3.51` 1023 3.30` 1023
1.85` 1024 1.13` 1023 2.85` 1023 5.08` 1023 7.54` 1023 9.96` 1023 1.22` 1022 1.42` 1022 1.58` 1022 1.72` 1022 1.82` 1022 1.89` 1022 1.95` 1022 1.98` 1022 1.99` 1022 1.98` 1022 1.96` 1022 1.93` 1022 1.90` 1022 1.85` 1022 1.80` 1022 1.74` 1022 1.69` 1022 1.62` 1022 1.56` 1022 1.50` 1022 1.43` 1022 1.37` 1022 1.31` 1022 1.25` 1022 1.19` 1022 1.13` 1022 1.07` 1022 1.02` 1022 9.66` 1023 9.16` 1023 8.67` 1023 8.20` 1023 7.76` 1023 7.33` 1023 6.93` 1023 6.54` 1023 6.17` 1023 5.82` 1023 5.49` 1023 5.18` 1023 4.88` 1023 4.60` 1023 4.33` 1023 4.08` 1023 3.84` 1023 3.62` 1023 3.40` 1023 3.20` 1023 3.01` 1023 2.83` 1023
3.05` 1025 4.66` 1024 1.69` 1023 3.61` 1023 5.89` 1023 8.27` 1023 1.05` 1022 1.25` 1022 1.43` 1022 1.57` 1022 1.68` 1022 1.77` 1022 1.83` 1022 1.87` 1022 1.89` 1022 1.89` 1022 1.88` 1022 1.86` 1022 1.82` 1022 1.78` 1022 1.74` 1022 1.69` 1022 1.63` 1022 1.57` 1022 1.52` 1022 1.46` 1022 1.40` 1022 1.33` 1022 1.28` 1022 1.22` 1022 1.16` 1022 1.10` 1022 1.05` 1022 9.95` 1023 9.44` 1023 8.95` 1023 8.48` 1023 8.03` 1023 7.59` 1023 7.18` 1023 6.78` 1023 6.41` 1023 6.05` 1023 5.71` 1023 5.38` 1023 5.08` 1023 4.79` 1023 4.51` 1023 4.25` 1023 4.00` 1023 3.77` 1023 3.55` 1023 3.34` 1023 3.14` 1023 2.96` 1023 2.78` 1023
5.42` 1024 4.16` 1023 1.04` 1022 1.75` 1022 2.46` 1022 3.09` 1022 3.63` 1022 4.08` 1022 4.44` 1022 4.72` 1022 4.92` 1022 5.05` 1022 5.13` 1022 5.15` 1022 5.14` 1022 5.09` 1022 5.01` 1022 4.91` 1022 4.79` 1022 4.65` 1022 4.50` 1022 4.35` 1022 4.19` 1022 4.02` 1022 3.86` 1022 3.69` 1022 3.53` 1022 3.37` 1022 3.21` 1022 3.05` 1022 2.90` 1022 2.75` 1022 2.61` 1022 2.48` 1022 2.35` 1022 2.22` 1022 2.10` 1022 1.99` 1022 1.88` 1022 1.77` 1022 1.67` 1022 1.58` 1022 1.49` 1022 1.40` 1022 1.32` 1022 1.25` 1022 1.17` 1022 1.10` 1022 1.04` 1022 9.79` 1023 9.21` 1023 8.67` 1023 8.15` 1023 7.67` 1023 7.21` 1023 6.78` 1023 Continued
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10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230 240 250 260 270 280 290 300 310 320 330 340 350 360 370 380 390 400 410 420 430 440 450 460 470 480 490 500 510 520 530 540 550 560
Ingestion
S. NOH ET AL. Table 1. Continued Inhalation (AMAD ¼ 5 mm)
Time (min) Type F
Type M
Type S
f1 ¼ 1.0
3.10` 1023 2.91` 1023 2.74` 1023 2.57` 1023 2.42` 1023 2.27` 1023 2.13` 1023 2.00` 1023 1.88` 1023 1.77` 1023 1.66` 1023 1.56` 1023 1.47` 1023 1.38` 1023 1.29` 1023 1.21` 1023
2.67` 1023 2.51` 1023 2.36` 1023 2.22` 1023 2.08` 1023 1.96` 1023 1.84` 1023 1.73` 1023 1.63` 1023 1.53` 1023 1.44` 1023 1.35` 1023 1.27` 1023 1.19` 1023 1.12` 1023 1.05` 1023
2.62` 1023 2.46` 1023 2.32` 1023 2.18` 1023 2.05` 1023 1.92` 1023 1.81` 1023 1.70` 1023 1.60` 1023 1.50` 1023 1.41` 1023 1.33` 1023 1.25` 1023 1.17` 1023 1.10` 1023 1.03` 1023
6.38` 1023 5.99` 1023 5.64` 1023 5.30` 1023 4.98` 1023 4.68` 1023 4.40` 1023 4.13` 1023 3.88` 1023 3.65` 1023 3.43` 1023 3.22` 1023 3.02` 1023 2.84` 1023 2.67` 1023 2.50` 1023
Table 2. Internal dose coefficients for intake of 18FDG (Sv Bq21). Inhalation (AMAD ¼ 5mm)
Ingestion Type M
Type S
f1 ¼ 1.0
8.86` 10211
9.24` 10211
5.05` 10211
Type F 5.46` 10211
Table 3. The work information and measurement result for the first spot urine samples. No. 1. 2. 3. 4.
Intake time
Sampling time
Sample mass (g)
10:25 7:27 6:05 6:40
13:50 11:30 10:45 10:00
81 234 106 224
18
F concentration (Bq g21)
MDA (Bq g21)
1.472+0.0270 0.138+0.00700 0.163+0.0140 0.277+0.0178
0.0465 0.0270 0.0580 0.0396
Table 4. Estimated intake and committed effective dose using the first spot urine samples. No.
1. 2. 3. 4.
Estimated intake (Bq)
Committed effective dose (mSv)
Inhalation (Type F)
Inhalation (Type M)
Inhalation (Type S)
Inhalation (Type F)
Inhalation (Type M)
Inhalation (Type S)
4931+90 1579+80 1015+87 2515+162
6530+120 2012+102 1260+108 3352+215
6772+124 2074+105 1294+111 3480+224
0.269+0.00491 0.0862+0.00437 0.0554+0.00475 0.137+0.00885
0.579+0.0106 0.178+0.00904 0.112+0.00957 0.297+0.0190
0.626+0.0115 0.192+0.00970 0.120+0.0103 0.322+0.0207
compartment does not absorbed into blood compartment again. Using the biokinetic model of FDG, the first spot urinary excretion functions for inhalation and ingestion were calculated from Equation (1). Figure 3
shows the first spot urinary excretion functions, and Table 1 provides the value of the functions for every 10 min up to 12 h. Table 2 presents the internal dose coefficient e50 for inhalation and ingestion of 18FDG. The internal dose
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570 580 590 600 610 620 630 640 650 660 670 680 690 700 710 720
Ingestion
18
FDG INTERNAL DOSIMETRY USING SPOT URINE
coefficients for inhalation are provided for absorption type of F, M and S, and the coefficient for ingestion is provided for fractional absorption f1 of 1.0. Table 3 shows the information needed for bioassay and measurement results. It was assumed that only acute intake occurs and the predicted intake is midpoint of the production work. From the data in Table 3, intake activity and committed effective dose of the workers were estimated for inhalation and ingestion both as shown in Table 4. As shown in Table 4, internal exposure level of the workers is not interpreted to be significant even if absorption type is assumed as Type S.
In this study, the authors performed the in vitro bioassay for the workers dealing 18FDG using spot urine samples. Since 18F has very short half-life (1.83 h), the authors developed the new in vitro bioassay methodology using spot urine sample directly without normalisation to the 1-d urine sample. In the methodology, the spot urinary excretion function, Eus(t) was newly proposed instead of daily urinary excretion functions. Also, the biokinetic model of FDG for inhalation and ingestion was also constructed and implemented in the calculation of Eus(t) for intake of 18FDG. The methodology developed in this study can be applied for all short-lived radionuclides including 18 F. Therefore, the authors expect that this methodology will be very useful for internal monitoring of workers who deal short-lived radionuclides in the all field as well as the nuclear medicine field. FUNDING This study was supported by Nuclear Research and Development Program of the Nuclear Safety and Security Commission (NSSC). REFERENCES 1. Ho, W. Y., Wong, K. K., Leung, Y. L., Cheng, K. C. and Ho, F. T. H. Radiation doses to staff in a nuclear medicine department. Hong Kong J. Radiol. 5, 24–28 (2002).
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CONCLUSION
2. Oliveira, C. M., Lima, F. F., de Oliveira, M. L., da Silva, T. V., Dantas, A. L., Dantas, B. M., Alonso, T. C. and da Silva, T. A. Evaluation of a technique for in vivo internal monitoring of 18F within a Brazilian laboratory network. Radiat. Prot. Dosim. 153(1), 100– 105 (2013). 3. Doerfel, H. et al. General guidelines for the estimation of committed effective dose from incorporation monitoring data (Research Center Karlsruhe, Karlsruhe) (2006). ISSN 0947-8620. 4. Birchall, A. and James, A. C. A microcomputer algorithm for solving first-order compartment models involving recycling. Health Phys. 56(6), 857–868 (1989). 5. International Commission on Radiological Protection. Individual monitoring for internal exposure of workers. (1997). ICRP Publication 78. Ann. ICRP. 27(3– 4). 6. International Commission on Radiological Protection. Radiation dose to patients from radiopharmaceuticals. (1988). ICRP Publication 53. Ann. ICRP 18(1–4). 7. International Commission on Radiological Protection. Human respiratory tract model for radiological protection. (1994). ICRP Publication 66. Ann. ICRP 24(1– 3). 8. International Commission on Radiological Protection. Radiation dose to patients from radiopharmaceuticals-addendum 3 to ICRP publication 53. (2008). ICRP Publication 106. Ann. ICRP 38(1– 2). 9. Polig, E. Modeling the distribution and dosimetry of internal emitters: a review of mathematical procedures using matrix methods. Health Phys. 81(5), 492–501 (2001). 10. International Commission on Radiological Protection. Basic anatomical and physiological data for use in radiological protection reference values. (2002). ICRP Publication 89. Ann. ICRP 32(3–4). 11. International Commission on Radiological Protection. The 2007 recommendations of the International Commission on Radiological Protection. (2007). ICRP Publication 103. Ann. ICRP 37(2– 4). 12. Oak Ridge National Laboratory. RSICC computer code collection-SEECAL 2.0. CCC-620 (Oak Ridge National Laboratory, Oak Ridge, TN) (1995). 13. International Commission on Radiological Protection. Dose coefficients for intakes of radionuclides by workers. (1994). ICRP Publication 68. Ann. ICRP 24(4). 14. Castellani, C. M., Marsh, J. W., Hurtgen, C., Blanchardon, E., Berard, P., Giussani, A. and Lopez, M. A. IDEAS guidelines (version 2) for the estimation of committed doses from incorporation monitoring data. (2013). EURADOS Report 2013-01.
