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Dose calibrator linearity test: 99mTc versus 18F radioisotopes*

Objective The present study was aimed at evaluating the viability of replacing 18F with 99mTc in dose calibrator linearity testing. Materials and Methods The test was performed with sources of 99mTc (62 GBq) and 18F (12 GBq) whose activities were measured up to values lower than 1 MBq. Ratios and deviations between experimental and theoretical 99mTc and 18F sources activities were calculated and subsequently compared. Results Mean deviations between experimental and theoretical 99mTc and 18F sources activities were 0.56 (± 1.79)% and 0.92 (± 1.19)%, respectively. The mean ratio between activities indicated by the device for the 99mTc source as measured with the equipment pre-calibrated to measure 99mTc and 18F was 3.42 (± 0.06), and for the 18F source this ratio was 3.39 (± 0.05), values considered constant over the measurement time. Conclusion The results of the linearity test using 99mTc were compatible with those obtained with the 18F source, indicating the viability of utilizing both radioisotopes in dose calibrator linearity testing. Such information in association with the high potential of radiation exposure and costs involved in 18F acquisition suggest 99mTc as the element of choice to perform dose calibrator linearity tests in centers that use 18F, without any detriment to the procedure as well as to the quality of the nuclear medicine service.


INTRODUCTION
Dose calibrator is an indispensable equipment in the field of nuclear medicine, and is widely utilized in the measurement of radioisotopes quantities to be administered to patients both in diagnostic and therapeutic procedures. For evaluation and proper maintenance, such an equipment must be routinely submitted to performance tests, particularly the linearity test (1) . Such a test is aimed at evaluating whether the equipment maintains its capability of measuring the radioisotopes activities in different magnitudes, as the quanti-ties utilized in diagnostic and therapeutic procedures may differ by orders of magnitude.
Several studies in the literature indicate the relevance of the linearity test and the technical procedures for its implementation (1)(2)(3)(4) . Such a test is aimed at evaluating the linear response of the equipment produced by different activities of a given radioisotope, from a source with an activity close to the minimum resolution of the measurement system (MBq) to a high activity source (GBq). In practice, generally one starts with a high activity source, which will decrease according to the radioisotope physical decay. Although the linearity test may be performed by utilizing different radioisotopes, technetium-99m ( 99m Tc) has been the element of choice due to its short physical half-life (6 hours), wide availability, low cost and for being the element with higher representativeness at nuclear medicine clinics. On the other hand, the increasing number of clinics dedicated to positron emission tomography, relying mainly on fluoride-18 ( 18 F), has led to questions on the possibility of the utilization of 99m Tc in linearity tests at such clinics, with a view on the high acquisition cost of 18 F. Based on the above mentioned factors, the main objective of the present study is evaluating the use of 99m Tc and 18 F radioisotopes in linearity tests, comparing results and indicating the radioisotope of lowest operational cost for nuclear medicine clinics.

MATERIALS AND METHODS
The linearity test was performed utilizing 99m Tc and 18 F sources in a CRC-25R dose calibrator, serial number 252090 (Capintec Inc., USA) of the Nuclear Medicine Service of Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (Icesp). Such an equipment is based on a pressurized ionization chamber, with suitable characteristics for utilization in the field of nuclear medicine. Previously to linearity tests, precision, accuracy, source geometry tests and daily controls were performed in the dose calibrator, assuring the good quality of the equipment before starting the study.
The initial activity of the 99m Tc source (62 GBq) was obtained by means of 99 Mo/ 99m Tc generator elution process, number 350IP0039, acquired under purchasing procedure from Instituto de Pesquisas Energéticas e Nucleares (Ipen). The 18 F source (initial activity of 12 GBq), lot 131213-0101, was acquired by donation from Ciclotron of Instituto de Radiologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Both sources were in the liquid physical state, with respective volumes of 6.0 mL and 2.5 mL, in glass vials.
The 99m Tc source was measured along five days while the 18 F source was measured along two days, starting from the initial activities of 62 GBq and 12 GBq, respectively, obtaining 13 measurement spots for the 99m Tc source and 10 spots for the 18 F source. The activity considered for each measurement spot corresponded to the arithmetic mean of five measurements. The 99m Tc activity as well as that of 18 F were measured until the activities reached values compatible with the lower resolution of the measurement system, indicated by the manufacturer (~ 1 MBq) and in accordance with the minimum activity to be utilized in the test and indicated by different recommendations (4)(5)(6)(7) .
The method adopted to evaluate dose calibrator response linearity in relation to the variation of the sources activities was the decay method, which consists of measuring the activity of a given source along time, allowing for the plotting of the "activity versus time" curve and the comparison of the experimental activity values with the expected theoretical values for the source at the different measurement times. The calculation of the theoretical activities took into consideration the physical half-life of both 99m Tc (6 hours) and 18 F (1.83 hours) (6) . The acceptable limits for deviation between the theoretical and experimental values were ± 5% and ± 10% in accordance with recommendations from International Atomic Energy Agency (IAEA) and standards of Comissão Nacional de Energia Nuclear (CNEN) (3,4,8) .
Both the 99m Tc and the 18 F sources were measured with the equipment being pre-adjusted for the measurement of 99m Tc sources ( 99m Tc "window") and subsequently for 18 F sources ( 18 F "window"), thus allowing for the comparison of detector response for the same radioactive source when measured at different radioisotope windows.
The acquisition costs of the 99m Tc and 18 F sources necessary for the linearity tests were also estimated.
In the present study, as necessary, some data are presented as mean value ± 1 standard deviation.

RESULTS
Successive measurements of the 99m Tc and 18 F sources have experimentally demonstrated the variation of their activities over time as result of the radioactive decay process. All the experimental measurements and the ratios between such measurements are presented on Table1, and the trend lines for the obtained values can be observed on Figures 1, 3, 5 and 6. The deviation value presented on the table corresponds to the deviation between the experimental activity value acquired by means of the dose calibrator and that estimated for the source by means of calculation for the same time span.
Because of the good precision of the equipment, the standard deviation presented in each measurement series corresponded to approximately 1% of the mean value for that set of measurements.
It is important to emphasize that the experimental activities indicated on the table and figures represent the mean value of a series of five measurements, but the measurements standard deviation (approximately 1% of the mean value) was not indicated in order not to impair or confuse the visual analysis of the charts and table. Figures 2 and 4 represent the characteristic charts of the linearity test, indicating the relationship between the experi-mental and theoretical values of the 99m Tc and 18 F activities as a function of time, as well as the lower and upper acceptable limits for the test in accordance with the IAEA recommendations and CNEN standards.
The mean deviation between the experimental and theoretical activities for the 99m Tc and 18 F sources were, respectively, 1.10 (± 2.57)% and 1.45 (± 2.02)% and the maximum values observed were 7.47% for the 99m Tc source and 6.24% for the 18 F source, both values located at the lower resolution limit of the measurement system (< 1 MBq). For activity levels greater than the lower resolution limit of the system, the mean values of the deviations were 0.56 (± 1.79)% for the 99m Tc source and 0.92 (± 1.19)% for the 18 F source, indicating an excellent quality of the system in the measurement of different activity quantities of a same radioisotope.
The adjustment of an exponential function of the y = a + be λt and λ = 0.693/T 1/2physical types, for the experimental data for the 99m Tc and 18 F sources allowed for the calculation of the physical half-life for both elements, whose values were, respectively, 5.949 (± 0.002) hours and 1.816 (± 0.007) hour with a difference of less than 1% from values reported in the literature (6) . The mean ratio between the activities indicated by the equipment for the 99m Tc source when measured at the respective 99m Tc and 18 F windows was 3.42 (± 0.06) while for the 18 F source was 3.39 (± 0.05). Such ratios were considered constant throughout the entire measurement period (Table 1) implying the possibility of utilization of both ra-dioisotopes in the linearity test, independently from the window utilized to measure the source, as the linearity test aims at evaluating the equipment response in the measurement of different activity quantities, whose response should be linear in the interval between the lower and upper limits of activity utilized at the nuclear medicine clinic on a daily basis (4) .
As regards costs, the acquisition cost of a 99 Mo/ 99m Tc generator with 6.75 GBq (250 mCi) for the performance of

DISCUSSION
The electric current generated at an ionization chamber-based dose calibrator, which is proportional to the activity, is related both to the quantity of radioactive atoms existing at a given sample and to the photons energy released during the disintegration process. The same electric current per activity unit (pA/MBq -picoampere per MBq) may be obtained from different radioisotopes, a fact that hinders the identification of the radioisotope by the dose calibrator during the measurement process. Thus, in order to obtain a reliable reading from the dose calibrator it is necessary to enter correction factors for the electric current proportional to the radioisotope to be measured, and that is automatically obtained by means of the radioisotope selector that exists in the equipment. Generally, the correction factors between a given radioisotope and another are constant, taking as a ref-

Time (h)
Radioactive source: 99m Tc Mean ratio: 3.42 ± 0.06 99m Tc / 18 F activities ratio erence the radioisotopes utilized by the manufacturer in the initial calibration of the equipment, such as the 60 Co and 137 Cs (2) radioisotopes.
Usually, the linearity test provides good results within acceptable parameters, provided the characteristics of the measurement system, such as good precision, accuracy and daily constancy testing are properly maintained. In the present study, the tests were carried out with 99m Tc and 18 F sources and in both cases the excellent quality of the equipment was independently demonstrated by measuring different activity quantities from radioisotopes with quite distinctive energies, namely 141 keV ( 99m Tc) and 0.511 MeV ( 18 F) (6) (Figures 2  and 4).
The practically constant ratio between the activities indicated by the equipment for a same source measured at different windows (Table 1; Figures 5 and 6) allows for the demonstration that the utilization of a single radioisotope, for example, 99m Tc, could be enough for the performance of the linearity test, independently from the utilization of 18 F, either exclusively or not, by the nuclear medicine clinic. Conceptually, the response from a dose calibrator is considered to be linear whenever the measured response/estimated response ratio or deviation remains constant along time, a fact that was experimentally demonstrated in the present study (Table 1) (5) .
Additionally, the linearity test evaluates the ionization chamber's saturation characteristics, as well as the electrometer linearity in the electric current measurement. Therefore, the linearity test is not directly linked to the utilized radioisotope, but rather to the amount of electrical loads generated during the measurement process. Thus, the linearity test could be performed with different radioisotopes provided the electric current interval, proportional to the activity interval to be tested are within the limits applied at the nuclear medicine clinic. Such information is very important and useful for those clinics operating exclusively with positron emitters, as is the case of 18 F.
The AAPM Report No. 181 (5) has indicated that the elements of choice for performance of linearity tests have been 99m Tc and 18 F, considering that routine tests with all available radioisotopes are not practicable. There is also evidence that there is a lack of consensus on the activities to be utilized in the test, a situation where some entities recommend the performance of tests with activities within the interval where the dose calibrator will be utilized, while others such as IAEA recommend the test to be initiated with the maximum activity administered to the patients in the clinic routine, although all of the entities are in agreement that the minimum activity to be tested should approach the resolution values of the measurement system (~ 1 MBq) (5) . However, one should consider the fact that not every measured activity will be administered to patients, such as, for example, the activities that will be stored as liquid radioactive waste and, in this particular case, the correct measurement of the activity is a very important factor impacting the storage time span of such waste.
The difference in costs for the performance of the linearity test either by utilizing 99m Tc or the 18 F radioisotopes is very significant, reaching a 40% difference between the two radioisotopes.
A viable option for further reduction in costs would be the supply of de 99m Tc activities by the radioisotope purveyors with the single and exclusive purpose of being utilized for linearity testing. In this context, an inquiry to Ipen for the supply of a 13.5 GBq (500 mCi) 99m Tc activity resulted in a cost lower than that of a generator, or even free of any cost, depending on favorable logistics, thus sharply impacting the cost of the linearity test. It is also important to emphasize that the utilization of 99m Tc sources instead of 18 F sources implies a reduction in the potential occupational and Figure 6. Ratio between activity values indicated by the dose calibrator for a 18 F source as measured in the 99m Tc and 18 F windows. environmental exposure, as a 18 F source presents a dose potential 10 times higher than that of a 99m Tc source with the same activity, namely, 135.1 µGy/GBq.m 2 .h and 14.1 µGy/ GBq.m 2 .h, respectively (9) .
The present study demonstrated the possibility of optimizing dose calibrators linearity testing, drawing the attention of investigators and regulatory agents towards a careful evaluation of the present data, as the dissemination of such information might translate into cost reduction for both private and public health services, without impairing the continuous development of the quality of services rendered to society.

CONCLUSION
The physical characteristics of the dose calibrator utilized in the present study allow for the indication that the results obtained in the linearity tests with 99m Tc can be validated for the utilization of 18 F. Such a result extrapolation, presumably extensible to other apparatuses of similar configuration and in satisfactory conditions of utilization, in association with the high exposure potential and acquisition cost of 18 F, suggest that 99m Tc could be utilized for linearity tests in clinics that utilize 18 F, without impairing the procedure as well as the assurance of the nuclear medicine service quality.