Home » Estimation of radiation dose from ingested tritium in humans by administration of deuterium-labelled compounds and food

Estimation of radiation dose from ingested tritium in humans by administration of deuterium-labelled compounds and food

D/H ratios in urine and 13C/12C ratios in breath

D2O and D-labelled glucose were administered once to volunteers, orally, while D-labelled alanine and D-labelled palmitic acid were administered once daily for four successive days. The D/H ratios in urine, after the administration of D2O and D-labelled glucose, are shown in Fig. 2, and those of D-labelled alanine and D-labelled palmitic acid are shown in Fig. 3. Boiled green soybean, which was cultivated hydroponically in 20{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} D2O solution, was administered as D-labelled soybean on weekdays, for 2 weeks, and the subsequent D/H ratios in urine are shown in Fig. 4. It is noteworthy that, in all figures showing D/H ratios in urine, the ratios are shown as increments above the background values measured before administration, and are normalised to the same dosage per body weight (1 g D per 70 kg). After the administration of D2O and D-labelled glucose, the D/H ratios increased and then decreased, within two exponential components, in 2 of 3 male volunteers and 2 of 6 female volunteers in the D2O group, and in 3 of 5 males and 1 of 5 female volunteers in the glucose group. However, the second component was not detected for the rest of the volunteers because of the rapid decrease in the ratios to below the limit (90{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} upper confidence limit of the background fluctuation of urine samples from each volunteer obtained before the administration) to cut off data and any subsequent data. The D/H ratios in urine, during the administration of D-labelled alanine, palmitic acid, and soybean, increased at each time point (Fig. 5). After the peak of the last administration, the ratios decreased exponentially within one or both components (Figs. 3, 4) similarly to changes observed in volunteers administered with D2O and D-labelled glucose. For the volunteers with D-labelled glucose, alanine, and palmitic acid, the 13C-labelled compounds were administered simultaneously. The excess of the 13C/12C ratios in breath, above the background ratio, were normalised to the same dosage per body weight (1 g13C per 70 kg), and are shown in Fig. 6. The 13C/12C ratios of alanine and palmitic acid showed steep peaks, in contrast to the gradual increase in D/H ratios for volunteers given these compounds. The half-life of FWT is significantly higher than the reported half-life of carbon dioxide measured by intravenous injection of 14C-bicarbonate (5 min)28. The difference between the D/H and 13C/12C ratios was considered to be due to the difference in the metabolisms of HDO and 13CO2, because the metabolic degradation rates of D-labelled and 13C-labelled compounds were considered the same until they degraded into inorganic molecules. The degradation ratio for OBT and organic carbon is assumed as the same by the ICRP5.

Figure 2

D/H ratios in urine after single oral administration of D2O and D-labelled glucose. The ratio was normalized to the same dosage per body weight (1 g D per 70 kg). Lines were fitted using models shown in Fig. 1. Data below the 90{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} upper confidence limit of the background fluctuation for each volunteer, and the subsequent data after elimination from the fit, are shown by crosses. Each colour represents a different volunteer.

Figure 3
figure3

D/H ratios in urine, after oral administration of D-labelled alanine and palmitic acid, over four successive days. The ratio was normalized to the same dosage per body weight (1 g D per 70 kg). Lines were fitted using models shown in Fig. 1. Data below the 90{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} upper confidence limit of the background fluctuation for each volunteer, and the subsequent data after elimination from the fit, are shown by crosses. Each colour represents a different volunteer.

Figure 4
figure4

D/H ratios in urine, after oral administration of D-labelled soybean for 2 weeks, except for Saturday and Sunday. The ratio was normalized to the same dosage per body weight (1 g D per 70 kg). Lines were fitted using models shown in Fig. 1. Data below the 90{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} upper confidence limit of the background fluctuation for each volunteer, and the subsequent data after elimination from the fit, are shown by crosses. Each colour represents a different volunteer.

Figure 5
figure5

D/H ratios in urine after the oral administration of D-labelled alanine, palmitic acid, and soybean for 4, 4, and 14 days, respectively; all panels are the enlargement of the same data shown in Figs. 3 and 4. The ratio was normalized to the same dosage per body weight (1 g D per 70 kg). Lines were fitted using a model shown in Fig. 1. Each colour represents a different volunteer. D-labelled alanine and palmitic acid were administered over four successive days. D-labelled soybean was administered daily for 2 weeks, except for Saturday and Sunday.

Figure 6
figure6

13C/12C in breath after the oral administration of 13C -labelled glucose, alanine, and palmitic acid. Each colour represents a different volunteer. 13C -labelled alanine and palmitic acid were administered over four successive days. 13C -labelled glucose soybean was administered once at day 0.

Biokinetics of deuterium ingested as D2O

We developed metabolic models to analyse the data obtained from each volunteer administered D-labelled compounds or food. The structure of these models is shown in Fig. 1. The parameter values in the metabolic model for each volunteer were determined by the least squares method, and are summarised in Tables 1, 2, 3, 4 and 5.

Table 1 Estimated parameters of HDO model for each D2O administered volunteer.
Table 2 Estimated parameters of OBD model for each volunteer administered with D-labelled glucose.
Table 3 Estimated parameters of OBD model for each volunteer administered with D-labelled alanine.
Table 4 Estimated parameters of OBD model for each volunteer administered with D-labelled palmitic acid.
Table 5 Estimated parameters of OBD model for each volunteer administered with D-labelled soybean.

The mean half-lives and standard deviations for the free water deuterium (FWD) compartment of the HDO models, as estimated from the data of D2O-administered males (n = 3), females (n = 6), and the combined group of volunteers, were 10 ± 2, 10 ± 3, and 10 ± 3 days, respectively (Fig. 7). These values were comparable to the reported half-lives of the FWT described above and to the value given by the ICRP OBT model. These results support the assumption that the biokinetics of OBD are equivalent to that of OBT.

Figure 7
figure7

Biokinetic parameters of the OBD metabolic models. The model structure is shown in Fig. 1. Half-lives of FWD, the half-life of deuterium (D) in free water D (FWD) compartment among volunteers of each group; d1, distribution factor to FWD; d2, distribution factor to OBD compartment; blue, male volunteers; green, female volunteers; grey, all volunteers. Error bar shows the standard deviation among volunteers in each group. *The values obtained from 13C-labelled compound administration experiments31. In those case, the ratios of the first and the second component of the exponential decrease in 13C/12C ratios in breath corresponded to d1 and d2, respectively.

The half-lives of the OBD compartment in the HDO models were estimated using data from 1 of 3 male and 3 of 6 female D2O-administered volunteers. The second component of the exponential decrease was not observed in the remaining volunteers in the group. The values obtained varied from 44 to 107 days. Balonov et al. studied the metabolism of HTO after its injection, inhalation, and ingestion, and reported that the second component of HTO decreased with a half-life ranging from 39 to 76 days29. Trivedi et al. (1997) reported a longer half-life, ranging from 58 to 104 days, in urine from workers exposed to HTO30. Our results are comparable to these, although the longer half-lives of the second component were considered to be affected by the observation period.

Half-lives of the FWD compartment in the OBD models

The half-lives of the FWD compartment in the OBD models estimated using data from volunteers administered with D-labelled glucose (n = 11), alanine (n = 6), palmitic acid (n = 9), and soybean (n = 7), were 10 ± 2, 10 ± 1, 11 ± 3, and 11 ± 3 days, respectively (Fig. 7). The difference between male and female volunteers was not significant (p > 0.05) for either compound or food. The mean half-life of FWD for each compound and food did not vary significantly (p > 0.05). Values were approximately comparable to half-lives of the fast-decreasing component, reported from experiments administering HTO6,7,8,9,10,11,12,13 and OBT20 described above, and the value used in the ICRP OBT model5. These results indicate that the half-lives of FWD in the OBD models were independent of the metabolic degradation rates of ingested compounds and foods, and corresponded to the half-life of FWD in each volunteer.

Distribution ratios (d
1) to the FWD compartment in the OBD models

The mean distribution ratios (d1) for glucose, to the FWD compartment, determined in males (n = 5), females (n = 6), and in the combined group, were 70 ± 31{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}, 90 ± 11{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}, and 81 ± 23{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}, respectively (Fig. 7). In a previous study, the biokinetics of organic carbon were investigated using 13C-labelled compounds, including the administering of 13C-labelled glucose to males and females, and 13C-labelled palmitic acid to male volunteers31. The ratios reported from this previous study were approximately equivalent to ours: male, 58 ± 16{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}; female, 85 ± 7{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}; and all, 71 ± 15{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} (Fig. 7).

The mean distribution ratios (d1) determined from the data in male (n = 5) and female (n = 4) volunteers in the palmitic acid group were 47 ± 3{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} and 33 ± 8{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}, respectively. The ratio for male was comparable to the ratio found for male volunteers treated with 13C-labelled palmitic acid (49 ± 17{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}) in the previous paper (Fig. 7). These results exhibit the same metabolic rate for each compound, independent of the isotope label used. The difference in the distribution ratios between male and female volunteers administered palmitic acid was significant (p < 0.01). The ratio of body fat to body weight in a healthy Japanese aging from 20 to 29 years is larger in females (28.4 ± 7.0{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}) than that in males (18.7 ± 6.6{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d})32. The cause of the smaller d1 value in female volunteers was presumed to be the larger transfer ratio to body fat due to the larger mass of body fat compared with that for male volunteers. Melintescu et al. have estimated significantly larger retention of tritium from OBT intake for females than for males due to the higher adipose mass in their physiologically based multicompartment model33. Our results were consistent with their estimations.

The mean distribution ratios (d1) to the FWD compartment, estimated from the data in D-labelled alanine-administered male (n = 3) and female (n = 3) volunteers were 81 ± 14{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} and 100 ± 0{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}, respectively. The metabolism differs between amino acids. From previous experiments involving the administration of 13C-labelled compounds, the mean distribution ratios of amino acids were obtained from male and female volunteers as follows: glutamic acid, 64 ± 9{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} and 63 ± 45{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}, respectively; glycine, 36 ± 4{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} and 40 ± 1{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}, respectively; phenylalanine, 31 ± 3{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} and 40 ± 4{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}, respectively; and leucine, 45 ± 6{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}, obtained from male volunteers only31. Our data for alanine gave much larger ratios than these amino acids (p < 0.01).

Using the d1 of glucose, alanine, and palmitic acid described above, the d1 of soybean was estimated to be a weighted mean of these ratios according to the nutritional balance of green soybean, in the assumption that these compounds represent carbohydrates, proteins, and lipids, respectively. The estimated distribution ratio (d1) for soybean based on these compounds (73 ± 8{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}) was greater than that obtained by the D-labelled soybean administration experiment (58 ± 9{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}). The reason for the difference was presumed to be the representativeness of alanine and palmitic acid as amino acid and lipid. The ratio of alanine was greater than the ratios of other amino acids, as described above, and the ratio of palmitic acid was greater than the reported ratio of unsaturated fatty acids obtained by the 13C-labelled experiment in a previous paper as follows: oleic acid, 35 ± 11{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}; linoleic acid, 29 ± 12{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}31. Our estimation of ratio (53 ± 7{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}) improved when we additionally considered the ratios obtained by the 13C-labelled compound administration experiments (see “Methods”).

The procedure used to estimate the distribution ratio of soybean, which utilised the ratios of various compounds estimated by both D- and 13C-labelled compound administration experiments, was applied to the estimation of dietary reference intakes, to validate the ratio in the ICRP model. The ratios calculated for reference intakes in Japan34 and the United States35, with a relatively high carbohydrate and high fat content, respectively, were 68 ± 15{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} and 66 ± 14{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}. These values were slightly higher than those in the ICRP model were (50{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}). The estimated dose coefficients, from the ICRP model, when the ratio of 50{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} is replaced by the ratios of 68{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} and 66{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}, were 3.3 × 10–11 and 3.4 × 10–11 Sv Bq−1, respectively. These values are slightly smaller than the dose coefficient used in the ICRP model (4.2 × 10–11 Sv Bq−1), and suggest that the ratio of 50{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} adopted by the ICRP was cautious.

The distribution ratio in the D-labelled soybean administration experiment (48 ± 16{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}) was approximately comparable to the distribution ratio to the FWT compartment in the ICRP model. In rats, the cumulative excretion of tritium in urine, during continuous feeding on tritiated rice, was greater than that shown in tritiated soybean15. Obtaining such data in humans for other major foods may help to support the ratio used in the ICRP model.

Half-lives of the OBD compartment in OBD models

The second component of the exponential decrease was not observed in some volunteers in the glucose and alanine groups (Figs. 2, 3). The distribution ratios d1 in the OBD models of glucose and alanine were 81 ± 23{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d} and 90 ± 13{431c92db2ef93c421a350be785d244bd702e2c73a34f2b6f60cd8fd62b61507d}, respectively. In those volunteers, the second component seemed to be below the background fluctuation, since most of the administered OBD was considered to be immediately degraded to FWD. Further studies are necessary to clarify the half-lives of OBT, for such molecules.

The second component was observed in almost all volunteers in the palmitic acid and soybean groups, except for one female volunteer in the soybean group. The half-life of the OBD compartment was calculated from k1 in each volunteer. The half-lives varied markedly among volunteers, as follows: males treated with palmitic acid, 80–405 days; females treated with palmitic acid, 52–294 days; and males treated with soybean, 20–311 days. Since (in all but one case in each group) the ratios were above the background fluctuation throughout the experimental period, the reason for the difference seemed to be due to the higher variability among individuals in the half-life of OBT, instead of errors derived from experimental detection limits. Longer half-lives, of several hundred days, have been reported in studies on urine from clock dial painters exposed to tritiated luminous compounds36. Taylor, in 2003, proposed a dosimetry model involving a third component with a half-life of 350 days37. The ICRP also adopted a second OBT compartment, with a longer half-life of 365 days, in its model for workers4. This work first provided the half-lives of the second component, estimated for OBT in major nutritional molecules and foods, including half-lives of several hundred days in some volunteers. These results suggest the necessity for a long half-life compartment in dosimetry models for OBT.

Estimation of committed effective doses for palmitic acid and soybean

The committed effective doses from 1 Bq of tritium were estimated by the OBD models of males and females in the palmitic acid group and males in the soybean group. The values varied from 4.2 × 10–11 to 3.5 × 10–10 Sv Bq−1, 3.2 × 10–11–2.9 × 10–10 Sv Bq−1 and 1.9 × 10–11–1.8 × 10–10 Sv Bq−1, among respective groups. The recovery ratios of Rr (d1 + d2) in the palmitic acid and soybean groups were 0.81 ± 0.16 and 0.90 ± 0.10, respectively. Since the committed effective doses from the unrecovered fraction were not included in the estimates, the true values would be higher. The values for palmitic acid and soybean were higher than the dose coefficient used by the ICRP, for members of the public (4.2 × 10–11 Sv Bq−1). In rats, cumulative residual amounts of OBT, after the administration of tritiated fatty acids, were higher than those from glucose were17, and that from soybean was higher than that from rice and wheat, which mainly consisted of carbohydrate15. In humans, the estimated committed effective dose from 1 Bq of 14C in fatty acids was greater than that from glucose31. This work provides the first estimates of the committed effective dose from OBT in major nutritional molecules and food. They were, however, considered compound and ingredient specific. In our study, since the committed effective doses for glucose and alanine were not obtained, due to the lack of reliable d2 and k1 in the OBD models, we could not find the effective dose for a reference diet by the weighted mean of each nutrient molecule. Therefore, further study is necessary to validate the recommended dose coefficient of the ICRP, by obtaining comprehensive data regarding the metabolism of OBT for various nutrient molecules and foods, such as proteins, carbohydrates, and grains.