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Radiation Protection Dosimetry Advance Access published online on January 24, 2009
Radiation Protection Dosimetry, doi:10.1093/rpd/ncn318
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© The Author 2009. Published by Oxford University Press. All rights reserved
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access version of this article for non-commercial purposes provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a derivative work this must be clearly indicated. For commercial re-use, please contact journals.permissions@oxfordjournals.org

EFFICACY OF ORAL AND INTRAPERITONEAL ADMINISTRATION OF CBMIDA FOR REMOVING URANIUM IN RATS AFTER PARENTERAL INJECTIONS OF DEPLETED URANIUM

S. Fukuda1,*, M. Ikeda1, M. Nakamura1, X. Yan2 and Y. Xie2

1 Research Center for Radiation Emergency Medicine, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan
2 Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, People's Republic of China

* Corresponding author: s_Fukuda{at}nirs.go.jp

Received September 24, 2008, amended December 9, 2008, accepted December 14, 2008


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

The efficacy of oral administration of the chelating agent catechol-3,6-bis(methyleiminodiacetic acid) (CBMIDA) for removing uranium from rats after intraperitoneal (i.p.) and intramuscular (i.m.) injections of depleted uranium (DU) was examined and the results with those by the i.p. injection of CBMIDA were compared. In Experiment 1, after a single i.p. injection of 8 mg kg–1 of DU of rat's body weight, 35 8-week-old male rats were divided into seven groups consisting of five rats each. Three groups were administered with CBMIDA 240, 720 or 1200 mg kg–1 of rat's body weight orally once a day, and three other groups received an i.p. injection of 240, 480 or 720 mg kg–1 CBMIDA for 3 d, starting 30 min after DU injection on the first day. One DU group received no CBMIDA. The remaining five intact rats were used as a control group. Rats were killed 6 d after DU injection. In Experiment 2, the 35 male rats that received a single i.m. injection of 8 mg kg–1 DU were divided into seven groups, and the rats of each group received the same doses of CBMIDA on the same schedules of treatment as those described in Experiment 1. The results obtained in Experiment 1 indicated that orally administered CBMIDA significantly increased the excretion of uranium at doses of 720 and 1200 mg kg–1 and decreased uranium concentrations, particularly in the kidney, at all the doses tested, and the effects were almost equal to those of the i.p. injection. The lack of increases in creatinine and blood urea nitrogen in serum indicated that CBMIDA is efficacious in preventing the renal dysfunction caused by uranium. In Experiment 2, oral administration of CBMIDA significantly increased uranium excretion and significantly decreased uranium concentrations, particularly in the kidneys, at all the doses tested, and the effects were almost equal to those of the i.p. injection. However, these effects of CBMIDA on the i.m.-injected DU were lower than those of the i.p.-injected DU in Experiment 1. These results indicated that oral administration of CBMIDA has almost the same efficacy as that administered by the parenteral route. Additional study is necessary to obtain satisfactory effects for the clinical use of CBMIDA, particularly for wounds contaminated accidentally with uranium.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Depleted uranium (DU) can affect human health via chemical and radiation toxic actions(1–3). Uranium uptake might induce damage to the kidneys and bones mainly by the chemical action, by the intake of more than 2 mg kg–1 uranium(4,5) or the deposition of 3 µg g–1 uranium in the kidney(6,7). Also, a small amount of uranium may harm the health of individuals chronically exposed to a uranium-polluted environment(8,9) or those with embedded shrapnel from a DU bomb(10–12).

Uptake of uranium can occur by inhalation or ingestion or via wounds. In a radiation accident, uranium can enter the blood through wounds or transdermally via acid burn(13,14). Factors that affect the behaviour and excretion of uranium after the intake in wounds(15) include the depth of the wound and the chemical form of the uranium. Uranium, free uranyl UO2+2, in acid solution is one of the chemical forms that can enter the body; it is present during the treatment of uranium employed for producing nuclear fuel. It is beneficial to test this chemical form of uranium when attempting to clarify not only the uranium's toxicity but also the effects of a chelating agent.

Chelation therapy is a unique method to increase the excretion of uranium from the body. Many chelating agents have been examined in animal studies over the years to determine their efficacies in removing uranium(5,16–23). It has been demonstrated that catechol-3,6-bis(methyleiminodiacetic acid) (CBMIDA) has the greatest efficacy for removing uranium when it is administered intramuscularly(5,17). There are various conditions to obtain the beneficial effects of chelating agents in a clinical setting, such as the administration routes, dose and timing after intake of DU. Oral administration of a chelating agent has the advantages that after the chelating agent can be taken quickly after the intake of uranium in an accident, and the affected person can continue to take it for a long term without the pain caused by the parenteral administration routes. No side effects were found with the oral administration of CBMIDA(18,24). However, the disadvantage of oral administration of a chelating agent is the low gastro-intestinal absorption rate.

This study was carried out to examine the effects of CBMIDA by oral administration following intraperitoneally injected DU, as a simulated model of how uranium transfers rapidly into blood and deposits in the body, and intramuscularly injected DU, as a simulated model of wounds in which uranium transfers slowly from the DU-injected site.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
DU nitrate consisting of 99.696% 238U, 0.299% 235U and 0.005% 234U was distilled in water, and the pH was adjusted to 1.0 by sodium bicarbonate. The administration volume of the solution was 0.02 ml kg–1 of the body weight of the test rats. CBMIDA (Figure 1) was dissolved in distilled water with sodium bicarbonate, and the pH was adjusted to 6.8 = Various concentrations of CBMIDA were prepared to administer 240, 480, 720 and 1200 mg kg–1 of rat's body weight. Their molar rates of CBMIDA to the dose (8 mg kg–1) of uranium were 17.6, 35.2, 52.8 and 88.0 times, respectively. Male Wistar (WM/MsNrs) rats, 8 weeks old, weighing 187 ± 5 g, were used after they were acclimatised for a few days in a metabolic cage used for the experiments.


Figure 1
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  		Figure 1. Chemical structure of catechol-3,6-bis(methyleiminodiacetic acid).

 
Experiment 1: efficacy of CBMIDA against intraperitoneally injected DU
Forty rats were divided into eight groups of five rats each. Rats in seven of the groups were injected intraperitoneally with 8 mg kg–1 DU. Thereafter, three groups were administered orally once a day with 240, 720 or 1200 mg kg–1 CBMIDA by an oesophageal sound, and three other groups were injected intraperitoneally with 240, 480 or 720 mg kg–1 CBMIDA for 3 d. The administration of chelating agent began 30 min after DU injection on the first day. One DU-injected group received no CBMIDA treatment. Five intact rats were kept as a control group.

The rats were kept individually in a metabolic glass cage, and their body weights and intake of food and water were measured daily until the end of the experiment. The urine and the faeces were each gathered at 1, 2, 3 and 6 d, and the animals were killed 6 d after DU injection. The urine from the bladder and blood from a vena cava posterior were obtained under anaesthesia consisting of a combination of ketamine hydrochloride and xylazine hydrochloride. The kidneys, the liver and the femurs were dissected to measure the concentration of uranium.

Experiment 2: efficacy of CBMIDA against intramuscularly injected DU
After a single intramuscular (i.m.) injection of the same dose of DU as in Experiment 1 into the right femoral muscles of rats, the animals were divided into seven groups of five rats each. Rats in six of the groups received the same doses on the same schedules as the oral and intraperitoneal (i.p.) CBMIDA treatments of Experiment 1. One group received no CBMIDA treatment. The measurement of body weight, food and water intake and excretions of urine and faeces were carried out on the same schedules as those in Experiment 1. Rats were killed at 6 d after DU injection. The blood, the urine, the kidneys, the liver, the left femur and the right femoral muscles where DU was injected were obtained.

Radioactivity measurement of uranium
The urine, the faeces and the organs were incinerated at 700°C for 24 h in a crucible. The ash material was dissolved in a 10% nitric acid solution. Subsequently, the solution was poured into a counting vial with a scintillator. The alpha activity of uranium in the vial was measured for 30 min by spectrometry using an alpha liquid scintillation counter (Beckman Instruments, Inc., Model LS5801). The recovery and counting efficiency were confirmed based on the total activity measured in the solution with the DU by alpha spectrometry. The limit of detectable activity of uranium is 0.05 Bq, equivalent to 0.05% of the injected DU.

Serum and urinary biochemical parameters
Glutamic pyruvic transaminase (GPT), glutamic oxalate transaminase (GOT), alkalinephosphatase (ALP), glucose, blood urea nitrogen (BUN), creatinine (Cre) and N-acethyl-D-glucosaminidase (NAG) and Cre in the urine indicating the NAG/Cre rate were measured by an autoanalyzer (Express Plus, Bayer, USA).

Statistical analysis
Statistical analyses were performed by the Mann–Whitney test and Student's t-test using Stat-View 4.5 (Abacus Concepts, Inc., Berkeley, CA, USA). A p-value below 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
Experiment 1
The mean body weights of rats in the DU and CBMIDA groups did not increase or decrease slightly except for a maximum 4% of the pre-values in the i.p.-240 mg kg–1 and oral-1200 mg kg–1 CBMIDA groups 1 d after DU injection, and weights then increased close to the level of the control group at 4 d. The intake of food decreased in all of the i.p.-CBMIDA groups for the first day, but thereafter returned to a level close to that of the control group. The intake of water did not change significantly compared with that of the control groups except the increases for the first 2 d in the DU group.

The uranium excretion rates of the injected dose in the DU group were 4% in the urine and 20% in the faeces for 1 d after DU injection, but thereafter both values decreased rapidly. Those for 6 d were 6% in the urine and 21% in the faeces (Table 1). In the CBMIDA groups, urinary excretion rates in the i.p.-720 mg kg–1 and all of the oral groups deceased significantly, while the faecal excretion rates increased significantly in the i.p.-720 mg kg–1 and oral-720 and -1200 mg kg–1 CBMIDA groups. The total amounts of uranium excreted for 6 d increased significantly in the i.p.-240 and -720 mg kg–1, and oral-720 and -1200 mg kg–1 groups compared with that in the DU group (Figure 2). There are correlations between the doses of CBMIDA and the amounts of uranium excreted, presenting a straight line by the method of least squares (correlation coefficient; r = 0.9629 for i.p. administration, and r = 0.9859 for oral administration). The uranium concentrations decreased significantly in the liver in all of the CBMIDA groups, in the kidney in all of the CBMIDA groups and in the femur of the i.p.-480 and -720 mg kg–1 CBMIDA groups (Table 2). In the results of serum and urinary examinations (Table 3), especially noteworthy was the lack of an increase in the Cre and BUN in all of the CBMIDA groups except for the level of BUN in the oral-240 mg kg–1 CBMIDA group. At the same time, the NAG/Cre increased, although there were large differences due to large individual variations.


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  		Table 1. Urinary and faecal uranium excretion rates (%) of the injected dose for 6 d after the i.p. injection of DU and the CBMIDA treatment in Experiment 1.

 


Figure 2
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  		Figure 2. Comparison of total excretion rates of uranium injected intraperitoneally and intramuscularly by the different administration routes of CBMIDA in Experiments 1 and 2. Values are presented as mean ±SD as shown in Tables 1 and 4. *Significantly different from the values of DU groups (p < 0.05). IP, intraperitoneal injection; Or, oral administration.

 


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  		Table 2. Uranium concentration rate (%) of the injected dose in the organs 6 d after the intraperitoneal injection of DU and the CBMIDA treatment in Experiment 1.

 


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  		Table 3. Results of serum and urinary constituents measurement in each group in Experiment 1.

 
Experiment 2
The body weights of all the rats of the DU and CBMIDA groups decreased 5–10% of the pre-values 1 d after DU injection. Thereafter, the body weights in the DU and oral-240 mg kg–1 CBMIDA groups continued to decrease slowly but then increased in the i.p.-480 and -720 mg kg–1, and oral-1200 mg kg–1 CBIDA groups, and did not increase in the i.p.-240 and oral-720 mg kg–1 CBMIDA groups. Food intake in all of the CBMIDA groups decreased remarkably for 1 d, but then increased in all groups except the DU and i.p.-240 mg kg–1 CBMIDA groups. Water intake in all of the CBMIDA groups except the oral-1200 mg kg–1 group decreased for 1 d and then increased, but that in the DU group continued to increase after DU injection.

The urinary uranium excretion rates of the injected dose in the DU-injection group were similar to the excretion rate in the faeces (Table 4, Figure 2). The uranium excretion rates for 6 d increased significantly in all of the CBMIDA groups compared with that in the DU group, due to the significant increases in the urine. The uranium concentrations decreased significantly in the liver of the i.p.-CBMIDA groups, in the kidneys of all of the CBMIDA groups, in the femur of the i.p.-480, oral-720 and -1200 mg kg–1 groups and in the muscle of all of the CBMIDA groups except the 720 mg kg–1 group (Table 5). Most of the measured items in the serum and urinary examinations changed significantly from those of the control group, although significant differences were not clear due to the large individual variations (Table 6).


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  		Table 4. DU excretion rates (%) of the injected dose in rats to which DU was injected intramuscularly and treated with CBMIDA s in Experiment 2.

 


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  		Table 5. Uranium concentration rate (%) of the injected dose in the organs 6 d after the intraperitoneal injection of DU and the CBMIDA treatment in Experiment 2.

 


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  		Table 6. Results of serum and urinary constituents measurement in each group in Experiment 2.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
In the DU groups of Experiments 1 and 2, there were large differences in faecal excretion rates of uranium, because the intraperitoneally injected uranium was excreted at a markedly higher rate than that administered by i.m. injection on the first day after DU injection. This might be caused by the differences in administration routes of uranium; the uranium after i.p. injection transferred into the blood more quickly from the injected site, and the concentration in the blood was higher than it was following the i.m. injection. After entry into the blood, uranium combines with various constituents such as transferrin, and thereafter it is distributed to the whole body(25). Unlike the case with faecal excretion, there were no differences in the uranium excreted in the urine and retained in the kidney, regardless of the administration routes. This may indicate that the mass of uranium passing through the kidneys may be limited by the preliminary function of the kidneys and/or may be due to the damages induced by uranium. Therefore, the uranium might be excreted more in the digestive tract via the liver than in the urine when DU is injected intraperitoneally. The urinary and faecal excretion rates of uranium in this experiment were different from the results of other reports, and this may have been caused by the actions of bicarbonate that was used to control the pH of the solution of dissolved DU and CBMIDA; the urinary excretion of uranium is equal to that in faeces when bicarbonate is administered(22), and HCO3– affects the chemical form and behaviour of uranium(18,21).

Following the oral administration of CBMIDA in Experiment 1, the total excretion rates of uranium increased in a dose-dependent fashion, significantly with the doses of 720 and 1200 mg kg–1 in rats to which DU was injected intraperitoneally, and the oral effects were almost equal to those of i.p. administration. No significant increase in the excretion of uranium by the oral-240 mg kg–1 CBMIDA was obtained. In this experimental protocol, the oral-480 mg kg–1 CBMIDA has not set, based on the reason why the gastro-intestinal absorption rate of chelating agent is generally low. So, the oral dose of CBMIDA that may have the same excretion effect as that obtained by the i.p.-480 mg kg–1 CBMIDA, by using the dose–excretion curve of uranium, was 430 mg kg–1. Furthermore, the oral CBMIDA at all the tested doses could reduce the retention rate of uranium, particularly in the kidney, and resulted in an equivalent decrease in total retention rates in organs to those obtained by the i.p.-480 and -720 mg kg–1 CBMIDA administration. Therefore, the oral dose of 480 mg kg–1 CBMIDA is estimated to have an efficacy similar to that of i.p. injection, based on the results that there are no differences in the effects between the oral and i.p. administration.

The purposes of chelation therapy include not only an increase of uranium excretion and a reduction of uranium retention in the body but also the prevention of harmful damage to the entire body. In the results of serum and urinary examination (Table 2), we noted that the creatine and BUN in serum did not increase significantly in the oral-CBMIDA groups except the 240 mg kg–1 group, although NAG/Cre increased significantly. This might indicate that oral CBMIDA as well as i.p. CBMIDA is efficacious in preventing the kidney dysfunction induced by uranium, although the efficacy may not be complete. However, the increased GPT, GOT, ALP and glucose indicated that uranium induces damages in the bones and the liver(4,26,27) and neither oral nor i.p. CBMIDA could prevent the damages to these organs. The first possible explanation for this is the dose used in this study. Namely, the 8 mg kg–1 DU used to clarify the effects of CBMIDA can clearly induce acute and severe damages before bringing death during 5–7 d after the i.m. injection in rats(5). As a result, the rapid elevation of uranium concentration in our experiments might have induced dysfunction in the liver and the bones beyond the effects of CBMIDA. The second reason might be related to the timing of CBMIDA administration after DU injection. In the results obtained in Experiment 1, noteworthy is the fact that the oral CBMIDA has the beneficial efficacy equivalent to that of i.p. administration, and the significant effects were obtained even if CBMIDA was administered 30 min after uranium injection. These results may indicate that orally administered CBMIDA is absorbed rapidly in the gastro-intestine and elevates the concentration in blood to the level that induces efficacy similar to that caused by i.p. injection.

In an accident, the actual route of uranium intake might be via wounds rather than entry directly into the veins. In the results of Experiment 2, the oral administration of CBMIDA, as well as that by i.p. administration, significantly increased the excretion of uranium in the urine. However, the urinary excretion rates were much lower than that in faeces in Experiment 1. Besides, the faecal excretion rate did not increase by either the oral or i.p. administration routes of CBMIDA. As a result, the total amounts of excreted uranium after the i.m. injection of uranium were lower than that by i.p. injection in Experiment 1 (Figure 2). This might have been because, judging from the differences between the retention rate (about 96%) in the DU-injected site (muscles) and the excreted rates (12.4%) in the DU group (Table 4), uranium might transfer slowly and in smaller amounts from the injected muscles. Therefore, particularly in a short time after the injection, the free uranyl might change rapidly to various complex structures that cannot combine with CBMIDA, because the chemical form of uranium changes according to the pH(28). Indeed, CBMIDA had no uranium removal effect when the uranium was dissolved in a solution with pH 7(17). Also, the chelating action of CBMIDA might be inhibited by the combination of uranium with the constituents in the body(25). Therefore, to resolve these disadvantages and obtain the beneficial effects of CBMIDA by oral administration, it will be important to examine the timing of CBMIDA administration in the future.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
The results of Experiments 1 and 2 indicated that the oral administration of CBMIDA is efficacious in causing a significant excretion of uranium and in reducing the retention of uranium, particularly in the kidney, at almost the same levels as that of i.p. injection in rats to which DU was injected intraperitoneally and intramuscularly. However, the effect of CBMIDA on the i.m.-injected DU, as a wounds model, was lower than that on the i.p.-injected DU, probably due to the transfer rate of uranium from the injected site, the chemical forms of the uranium in the body after intake and the timing of administration of CBMIDA. Therefore, further study is necessary to obtain satisfactory effects for clinical use of CBMIDA.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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