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No radiation protection reasons for restrictions on 14C urea breath tests in children
1M GUNNARSSON, PhD, 1,2S LEIDE-SVEGBORN, PhD, 3K STENSTRÖM, PhD, 4G SKOG, PhD, 5L-E NILSSON, BSc, 3R HELLBORG, PhD and 1S MATTSSON, PhD
1Department of Radiation Physics, Lund University, Malmö University Hospital, SE-205 02 Malmö
2Department of Laboratory and Imaging Sciences, Malmö University College, Malmö University Hospital, SE- 205 02 Malmö, 3Department of Nuclear Physics, Lund University, Box 118, SE -221 00 Lund, 4Department of Quaternary Geology, Lund University, Tornavägen 13, SE-223 63 Lund and 5Department of Clinical Physiology, Lund University, Malmö University Hospital, SE-205 02 Malmö, Sweden.
 
 
Abstract
Traditional 14C urea breath tests are normally not used for younger children because the radiation exposure is unknown. High sensitivity accelerator mass spectrometry and an ultra-low amount (440 Bq) of 14C urea were therefore used both to diagnose Helicobacter pylori (HP) infection in seven children, age 3-6 years, and to make radiation dose estimates. The activity used was 125 times lower than the amount normally used for older children and 250 times lower than that used for adults. Results were compared with previously reported biokinetic and dosimetric data for adults and older children age 7-14 years. 14C activity concentrations in urine and exhaled air per unit administered activity for younger children (3-6 years) correspond well with those for older children (7-14 years). For a child aged 3-6 years who is HP negative, the urinary bladder wall receives the highest absorbed dose, 0.3 mGy MBq-1. The effective dose is 0.1mSv MBq-1 for the 3-year old child and 0.07 mSv MBq-1 for the 6-year-old child. For two children, the 10 min and 20 min post-14C administration samples of exhaled air showed a significantly higher amount of 14C activity than for the rest of the children, that is 6% and 19% of administered activity exhaled per hour compared with 0.3-0.9% (mean 0.5%) of administered activity exhaled per hour indicating that these two children that is were HP positive. For a 3-year-old HP positive child, absorbed dose to the urinary bladder wall was 0.3 mGy MBq-1 and effective dose per unit of administered acitivity was 0.4 mSv MBq-1. Using 55 kBq, which is a normal amount for older children when liquid scintillation counters are used for measurement, the effective dose will be approximately 6µSv to a 3-year-old HP negative child and 20 µSv to a HP positive child. Thus there is no reason for restrictions on performing a normal 14C urea breath test, even on young children.

The 14C urea breath test is widely used for detecting Helicobacter pylori (HP) infection [1-3] in the stomach. Since it is non-invasive, cheap and easy to perform with standard liquid scintillation counters (LSCs), the test has become very popular. However, owing to the long physical half-life of 14C 5730 years) and uncertainties in the biokinetics, there are generally restrictions on performing the 14C urea breath test on small children and other sensitive groups, such as pregnant or breast-feeding women. We have previously shown that, for older children aged 7-14 years, dose values per unit of administered activity are similar to those for adults [4].

To detect HP infection and to study the biokinetics of 14C urea in younger children, aged 3-6 years, we have used accelerator mass spectrometry (AMS) [5,6] for the breath test instead of LSCs. Use of AMS makes it possible to reduce administered activity to less than 1% of the activity used in connection with measurements with the LSC technique. As an alternative to the 14C urea test, non-radioactive 13C urea has been promoted [7], mainly on the basis of radiation safety aspects. The use of 13C presupposes access to a mass spectrometer, normally not available in a hospital. Moreover, the signal/background ratio for the 13C method is considerably lower than for the 14C method. Thus the 14C alternative is better, both from an analytical and economic point of view. Therefore in case of 14C use, the question of radiation exposure to the patient is critical.

The aims of the present study were two-fold. First, to use the AMS technique and an ultra-low amount of 14C urea to diagnose HP infection, and second, to determine whether there are significant differences between the biokinetics and dosimetry for small children, aged 3-6 years, compared with the previously studied group of adults and children aged 7-14 years.
 
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Material and methods
Subjects
Seven paediatric patients aged 3-6 years were referred to the Department of Nuclear Medicine at Malmö University Hospital for a 14C urea breath test. As no reliable radiation dose estimates were available for this age group, the investigation was carried out with an ultra-low amount of 14C urea and the exhaled air was analysed with a high sensitivity AMS technique. Following overnight fasting, patients were given 440 Bq 14C urea (Code CFA 41; Amersham Pharmacia Biotech, Uppsala, Sweden) orally in 125 ml water containing 200 mg of non-labeled urea. To reduce possible contamination from urease-producing bacteria in the mouth, subjects brushed their teeth and rinsed their mouths with some help from parents / medical staff before administration. Thus study was approved by the Ethics Committee at Lund University and the Regional Radiation Protection Committee.
 
 
Samples of exhaled air
Samples of exhaled air were taken prior to and 10 min, 20 min, 24 h and 120 h after administration of 14C urea. Results from the 10 min and 20 min measurements were used clinically to evaluate whether the patient was HP positive or not. All breath samples were collected in glass vials, containing 1.25 g sodium hydroxide, on a solid support (Ascarite; Thomas Scientific, Swedesboro, NJ). The sample preparation and AMS procedure used at the AMS facility in the Pelletron laboratory in Lund have been described in detail earlier [8]. =

The amount of 14C exhaled was determined assuming a basal endogenous carbon dioxide (CO2) production of 20 mmol per kg body weight per hour [9, 10]. The amount of 14C exhaled per hour and unit of administered activity was plotted as a function of time after administration of 14C urea for all patients. A 20 min sample with a normalized 14C activity > 2.2% of administered activity exhaled per hour was considered to indicate that the patient was HP positive. For comparison, results from eight older children from earlier studies [4] were also used. As there was an interest in limiting the number of samples for younger children, no samples were taken in the period between 20 min and 24 h after 14C urea administration. In the analysis the activity as a function of time was compared for small children, with the more complete time-activity curves obtained for older children. Multi-exponential functions were iteratively fitted to each curve using a non-linear least squares regression algorithm. Finally, these curves were analytically integrated to yield the total fraction excreted vie exhaled air.
 
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Samples of urine
Urine samples were collected prior to approximately 30 min after and 24 h and 120 h after administration of 14C urea. Urine was collected in plastic bottles and stored at -180C before analysis with both AMS and LSC techniques. Before the urine was analysed with AMS, the CO2, was extracted and converted into graphite [11, 12]. For LSC measurements, 1 ml urine was added to 18 ml scintillation liquid (Optiphase Hisafe; Wallac Oy, Turku, Finland) and duplicate samples were measured for 30 min in a LSC (1414 Guardian; Wallac Oy, Turku, Finland). The 24 h post-administration urinary excretion was calculated using a normalized urinary excretion rate of 25ml per kg body weight per day [9].
 
 
Kinetic and dosimetric models
The biokinetic model used for dosimetric calculations consists of two parts, a urea model and a CO2 / bicarbonate model [13]. These models have previously been described in detail [4]. Most administered 14C urea is excreted through the kidneys, most likely as intact 14C urea. The residence times in the kidneys and urinary bladder were calculated according to the International Commission on Radiological Protection (ICRP) [14], with bladder voiding intervals taken from ICRP Publication 56 [15]. A minor quantity of the administered 14C urea is broken down to ammonia and CO2 and was treated according to the ICRP CO2 / bicarbonate model [13]. Input parameters in the CO2 / bicarbonate model, which differ between younger and older children, are bone turnover rate and relationship between the fraction of cortical and trabecular bone in the skeleton. Bone turnover rates were taken from ICRP Publication 70[16]. 60% of the bone mass was assumed to be cortical bone and 40% trabecular bone for 3-6 year old children [16].

Voiding time used in the calculation of cumulated activity in the urinary bladder also differs between younger and older children [14].

In domestic model, source organs were the stomach, urinary bladder, cortical bone, trabecular bone and remaining tissues. Residence times obtained from the compartment model were used to estimate absorbed doses with the Medical Internal Radiation Dose (MIRD) technique using the MIRDOSE 3.1 software package (Oak Ridge Associate Universities, Oak Ridge, TN) [17]. Organ doses and effective dose were calculated according to ICRP Publications 60 and 67 [18, 19]. Residence times, absorbed dose and effective dose were calculated for a 3 –year-old HP negative child (body weight approximately 15 kg) and for a 6-year-old HP negative child (body weight approximately 20kg) using biological half-time and fractions obtained for older children [4].
 
Results and Discussion
14C activity in the samples of exhaled air taken 20 min after administration of 14C urea are given in Figure 1. This shows that two patients exhaled significantly more 14C than the others, and these two were considered to be HP positive. The rest of the younger children were considered HP negative. All the older children were considered HP negative according to a standard breath test performed with 55 kBq 14C and liquid scintillation counting [4]. The 14C concentrations in urine and exhaled air, normalized to the activity administered to the patient, are shown in Figures 2 and 3. AMS results show that for younger children, no 14C could be detected in exhaled air taken 5 days post administration. This agrees well with results for older children. This was also the case for the 14C urea found in urine and measured with the LSC. However, for three of the younger children, small amounts of 14C above normal background level of 0.258 ± 0.008 (standard deviation) Bq g-1 carbon could still be detected in the urine with AMS 5 days post administration (0.041, 0.066 and 0.083 Bq g-1 C). Values for younger children are almost the same as those for older children. Therefore, we consider it reasonable to use biological half-times and fractions obtained for older children when calculating absorbed doses to younger children. For a HP positive 3-year-old child, absorbed doses were estimated assuming the fraction excreted in exhaled air to be 65% [13].

The urinary bladder wall received the highest absorbed dose, 0.3mGy MBq-1 for both a 3-year-old and 6-year-old HP negative child (Table 1). For the 3-year-old HP positive child, absorbed dose to the urinary bladder wall was also 0.3 mGy MBq-1. Effective dose was 0.1mSv MBq-1 for a 3-year-old HP negative child and 0.07 mSv MBq-1 for a 6-year-old HP negative child. For the 3-year-old HP positive child, effective dose was 0.4mSv MBq-1. In addition to the uncertainties in the assumption that biokinetic data are the same for younger children as for older children, there are uncertainties in the determination of the fraction of 14C excreted in urine and via exhaled air owing to uncertainties in estimating 24-h urinary production rate and endogenous CO2 production. This has previously been discussed by Leide-Svegborn et al [4]. Absorbed dose to the urinary bladder wall is dependent on urinary bladder volume and voiding time. The absorbed dose given in Table 1 is based on a voiding period depending on the age of the child, e.g. 2.0 h for a 3-year-old child. Absorbed dose and effective dose are higher for a HP positive patient than for a HP negative patient owing to the fact that there is a larger fraction entering the CO2/bicarbonate pool in the first case. Accordingly, remaining tissues get a higher cumulated activity and absorbed dose will be higher for all organs.
 
Figure 1. 14C activity in exhaled air, given as percentage of administered 14C urea activity per hour, in samples taken 20 min after administration and measured with accelerator mass spectrometry. A normalized 14C activity >2.2% of administered activity per hour indicates that the patient is Helicobacter pylori (HP) positive. YCh, younger children (3-6 years); Ch, older children (> 7 years).
 
Figure 2. Fractional excretion of 14C in exhaled air as a function of time after administration of 14C urea. Lines correspond to the curves fitted to the data for older children (>7 years) and symbols to those of younger children (3-6 years).
 
Figure 3. Fractional excretion of 14C in urine as a function of time after administration of 14C urea. Lines correspond to the curves fitted to the data for older children (> 7 years) and symbols to those of younger children (3-6 years).
 
Table1. Mean absorbed does (mGy MBq-1) to various organs and tissues and effective dose (mSv MBq-1) from 14C urea to Helicobacter pylori (HP) negative children aged 3 years and 6 years and HP positive children aged 3 years.
 
  HP negative HP positive
  3-year-olds
(~15 kg)
 6-year-olds
(~20kg)
 3-year-olds
(~15 kg)
Mean absorbed dose      
Urinary bladder 0.34 0.26 0.32
Stomach 0.08 0.05 0.24
Bone surfaces 0.09 0.07 0.45
Other organsa 0.09 0.07 0.38
Effective dose 0.10 0.07 0.38
 
a Other organs include adrenals, brain, breasts, gall bladder, small intestine, colon, heart, kidneys, liver, lungs, muscles, oesophagus, ovaries, pancreas, red marrow, skin, spleen, testes, thymus, thyroid and uterus.
 
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Conclusion
The highly sensitive AMS technique has provided the possibility of carrying out 14C urea breath tests on young children, investigations that were not previously considered acceptable, and has also enabled investigation of the biokinetics and dosimetry of 14C in these children. This study has shown that radiation exposure to children is low. Using 55 kBq 14C urea, which is a usual amount for older children when measurements of 14CO2 are performed with liquid scintillation counting, the effective dose to a 3-year-old HP positive child will be approximately 20 µSv, and 6 µSv in the case of a HP negative child, which is of the same magnitude as a few days of natural background radiation. Thus there are no radiation protection reasons for restrictions on performing a normal 14C urea breath test on young, 3-6-year-old children.
 
 
Acknowledgements

Thanks are due to Professor Bertil Nosslin and Ola Thorsson, MD for helpful discussion of the work.

 
 
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