A primary study on biological behavior of aluminum using ²⁶Al-AMS

A primary study on biological behavior of aluminum using 26 Al-AMS 1 2 first-author 2 3 corresp Correspindingauthor. E-mail address: wangxg@gxu.edu.cn Correspindingauthor. E-mail address: wangxg@gxu.edu.cn wangxg@gxu.edu.cn 2 3 2 3 4 4 4 Guangxi University of Chinese Medicine, Nanning 530001, China Guangxi University of Chinese Medicine, Nanning 530001, China GXU-NAOC Center for Astrophysics and Space Sciences, Department of Physics, Guangxi University, Nanning 530004, China GXU-NAOC Center for Astrophysics and Space Sciences, Department of Physics, Guangxi University, Nanning 530004, China Guangxi Key Laboratory for the Relativistic Astrophysics, Nanning 530004, China Guangxi Key Laboratory for the Relativistic Astrophysics, Nanning 530004, China China Institute of Atomic Energy, Beijing 102413, China China Institute of Atomic Energy, Beijing 102413, China Aluminum is concerned as a possible cause of many diseases. To investigate the long-term Al biokinetics and bioavailability in various kinds of Al-contained medicine and food, an accelerator mass spectrometry (AMS) based on the HI-13 tandem has been established for biological analysis with 26 Al ( T 1/2 = 716 000 yr) as the tracer. In this paper, the animal tracing, sample preparation procedure and 26 Al-AMS measurement are presented. The sample preparation procedure has been simplified. A high sensitivity of 5×10 −15 for 26 Al/ 27 Al has been achieved. Two phases were found before and after a break time ( t b ) for the 26 Al retained in blood and brain, with t b ≈ 8 and 12 hours after the 26 Al tracer injection, respectively. 26 Al Accelerator mass spectrometry Biological tracing 1. Introduction 1 Aluminum is the most abundant metal element in the environment, and is the most common metal element in our life. It is also a trace element in human body, but not the essential one. In medicine, chemical Al-compounds are used as antiseptic, alum, antacid or phosphate binder for dialysis patients with renal failure. On the other hand, Al is concerned as a cause of many diseases (e.g. osteopathy, anemia and encephalopathy) [ 1 1 - 5 5 1-5 ] , if its intake is too much. As shown in Table 1 Table 1 , neither of the radioisotopes is suitable for use as an tracer to study Al biological behavior and bioavailability in animals and human, which had been carried out by employing just the stable isotope 27 Al [ 3 3 ] before 1990. Since the natural level of 27 Al in the environment (~ 0.1g/g) is far greater than that in biological samples (10 −6 –10 −8 g/g), the research on behaviors of Al in animals and human had been obstructed by difficulties in distinguishing the trace amount of Al in biological samples from the environment. 1 1 Isotopes 1 1 25 Al 1 1 26 Al 1 1 27 Al 1 1 28 Al 1 1 29 Al 1 1 T 1/2 1 1 7.2 s 1 1 716,000 yr 1 1 Stable 1 1 2.3 min 1 1 6.6 min Therefore, two tracer approaches are well accepted to study Al biokinetics. One is the use of congeners, such as radioactive 67 Ga, based on similar chemical properties of Al and Ga. However, their chemical reactions in body are different [ 6 6 , 7 7 ] . Another one is the accelerator mass spectrometry (AMS) [ 8 8 - 13 13 8-13 ] , or ultra-sensitivity mass spectrometry, using 26 Al, the only long-life radioisotope of Al ( T 1/2 =716,000 yr), and the only Al isotope being capable of tracing research, but quite difficult, though. The methods for measuring 26 Al include decay counting and conventional mass spectrometry (MS). MS cannot discriminate 26 Al from the 26 Mg isobar, while the decay counting method to detect the trace amount of 26 Al (close to detection limits) is of large uncertainties. Therefore, 26 Al tracer in medical application is very difficult without AMS, which is advantages over MS methods in its high sensitivity, small sample size requirement, free from isobar and molecular ion interferences, and short measurement time. Taking advantages of nomeasurable 26 Al in the environment or in normal biological organisms, the 26 Al-AMS approach, which avoids interference of endogenous Al in studying Al biokinetic and bioavailability, has been carried out in several groups [ 2 2 , 3 3 , 14 14 - 25 25 14-25 ] . Studies with 26 Al-AMS on mice aluminum biokinetic were performed by the groups in Manchester [ 3 3 , 15 15 , 16 16 ] , Orsay [ 17 17 ] , Zurich [ 18 18 ] , Tokyo [ 19 19 ] , Munich-Aachen [ 2 2 ] , and Kentucky [ 20 20 ] . The Manchester and Munich-Aachen groups did studies on human Al biokinetic, too. They found that some Al is retained in the body, most probably within the skeleton and brain. Most of Al that enters the blood is excreted in urine within a few days or weeks. Al bioavailability was estimated in a number of 26 Al-AMS studies, including a model food and biscuit containing acidic SALP [ 20 20 - 24 24 20-24 ] . It was also found that typical human foods have high Al bioavailability, but still, there are Al-contained medicine and food with unknown Al biokinetic and bioavailability. Too much human intake of Al may be retained in skeleton and brain, which may cause osteopathy, anemia and encephalopathy. We need 26 Al-AMS to investigate the long-term Al biokinetics and bioavailability in Al-contained medicine and food in China. In this paper, a 26 Al-AMS tracing method is established and the primary results are presented. 2. Materials and methods 1 2.1 Animals 2 Wistar rats of 2-months old were purchased from Guangxi Medical University, Nanning, China, and fed with standard diet. All animal experiments were performed according to the Guidelines for the Care and Use of Laboratory Animals [ 26 26 ] . The mice were divided into the experimental, control and background groups, with 3 mice in each group. The tracer isotope 26 Al is the laboratory standard kept from 1996 at the AMS lab of China Institute of Atomic Energy (CIAE) AMS. Decay counting method was used to calibrate the 26 Al/ 27 Al ratio. The 26 Al/ 27 Al ratio of AlCl 3 solution for injection was 1.5×10 −9 , with the 26 Al content of 2.5 μg/mL. The solution was prepared by successive dilution of the original standard sample. The three animal groups were treated as follows: 1) Experimental group: The mice are used to inject 26 Al for experimental tracing. 30 mice were divided into 10 subgroups ( n =3) for 10 time scales. The mice were tail mainline injected with 1 mL of 26 AlCl 3 (pH=4.5), and were blood-sampled and euthanized for brain-sampling at 0.5, 2, 4, 8, 16, 48, 72, 96, 120 and 168 h after injection. 2) Control group ( n =3): The mice were injected with 1 mL 27 AlCl 3 solution, for the behavior observation. 3) Background group ( n =3): The mice were injected with 1mL normal saline solution for AMS measurement of the 26 Al as background sample. 2.2 Sample preparation 2 The beam current of 26 AlO − is 20–40 times higher than the 26 Al − , but the number of 26 Mg isobar will become too large to identify 26 Al of ultra-low level. Besides, the particle transmission of single atom is higher than molecular ions. Therefore, a single atomic negative Al − form is adopted in our AMS measurement. Taking advantage of the electric potential of Mg electron affinity is lower than zero, Mg - ions cannot be extracted, but the Al - can, from the AMS multi-cathode source. As the interfere isobar 26 Mg is no longer a problem, a simplified preparation process was developed ( Fig. 1 Fig. 1 ). 1) The blood/brain samples were decomposed with 10 mL of concentrated nitric acid at 80°C for 24 h in a Teflon-sealed vessel 2) After cooling, 15 mg of 27 AlCl 3 were added in the sample solution as a carrier, and then heat at 140°C for 4 h in a Teflon-sealed vessel inserted in a stainless steel botter. 3) After cooling, the blood samples were centrifuged and Al-contained solution samples will be obtained. 4) Add NaOH solution to the Al-containing sample solution, and carefully adjust the solution to PH7–8. Al(OH) 3 sediment can be formed at pH=7–8, while a very few of Mg(OH) 2 can be formed at this pH value. Therefore, the most of 26 Mg, isobar of our interesting isotope 26 Al, could be eliminated in this step. 5) Al(OH) 3 sediment was obtained via centrifugation, and then converted to Al 2 O 3 at 1000°C for 2h. In the AMS measurement, each sample was mixed with an equal mass of pure silver powder for improving thermal and electric conductivity, and pressed into a sample holder of a 40-sample NEC MC-SNICS ion source. 2.3 Analysis of 26 Al by accelerator mass spectrometry 2 The number of 26 Al was measured with the AMS at CIAE ( Fig.2 Fig.2 ). Since its installation in 1989, 26 Al, 36 Cl, 41 Ca, 55 Fe, 64 Gu, 79 Se, 99 Tc, 129 I, 151 Sm, 182 Hf, 236 U and 237 Np have been measured for applications in biomedicine, nuclear physics, nuclear astrophysics and environmental science [ 11 11 , 27 27 - 36 36 27-36 ] . Fig. 2 Fig. 2 shows schematically the AMS system based on an HI-13 Tandem accelerator. This work was carried out on AMS Beamline 1. The AMS Beamline 2 was for AMS research of medium-heavy mass nuclides.. Single atomic ions of Al − from the ion source are selected by the low energy magnetic analysis system for injection into HI-13Tandem accelerator, typically with 40 nA beam current at the lower energy Faraday cup (LEFC). The Al − ions are pre-accelerated to 110 keV in the low energy system, and to 7 MeV by the first column of the tandem accelerator. The negative ions are stripped by a 3 μg/cm 2 thick carbon foil, and the position ions are further accelerated in the second column by the terminal voltage. A 90° double-focusing analyzing magnet was used to select ions 26 Al 7+ , with energy of 56.1 MeV. According to theoretical simulation of the charge stripping, the charge state 7+ at 7 MV has a large fraction of ~34%. The 26 Al 7+ ion beams are transported to the AMS Beamline 1 and detection system, with a switching magnet and 15° electrostatic deflector. The analyzer magnet, switching magnet, electrostatic analyzer and other beam optical elements are adjusted to obtain optimal 26 Al 7+ beam line. Since no interference of 26 Mg isobar, a Si(Au) surface barrier detector is used to record the number and energy of the 26 Al 7+ . The 27 Al beam current is record by the LEFC in low energy system, and the 26 Al/ 27 Al isotope ratios can be obtained. In this study, each sample was measured at least three times. All isotope ratios were normalized by 26 Al/ 27 Al standards sample. 3. Results 1 3.1 26 Al-AMS based on extracting Al - ions 2 Typically, the beam current of 27 Al − is ~40 nA at LEFC. The ions extracting is stable ( Fig.3 Fig.3 ), which is crucial for measurement precision. Typical current is lower than that at UTTAC and SUERC [ 37 37 , 38 38 ] , because of mainly the low electron affinity of Al, and the not-so-good ion source and low energy system, caused by a low vacuum problem at that time. However, this did not have much effect on this work. The preparation of biological sample is a key step in the tracing experiment. As shown Fig. 3 Fig. 3 , beam current of the prepared Al 2 O 3 sample is over 40 nA, and it is larger than that of commercial sample. The overall particle transmission between the low energy injection system and the detection system is ~3%. Fig .4(a) Fig .4(a) is the 56.1 MeV 26 Al 7+ ion spectra of the background sample prepared with the same sample preparation procedure. It demonstrates that there were no interference isotopes in our measurement. The combination of our sample preparation procedure and extraction of single atomic negative Al − from the ion source, the 26 Mg isobar is highly suppressed. Fig. 4(b) Fig. 4(b) is spectra of the blood sample, and it can be sure that the peak at 56.1 MeV is the counts of 26 Al 7+ ions. The simplicity preparation procedure can satisfy the biological tracing requirement. We used the blank sample (commercial Al 2 O 3 and our background sample) to test the AMS system. The sensitivity is good, with the 26 Al/ 27 Al ratio of lower than 5×10 −15 . 3.2 Al biological behavior in blood 2 In this work to establish the 26 Al-AMS method for biological tracing, the 26 Al/ 27 Al ratio, instead of the 26 Al concentration, is used. The 26 Al concentration can be got from 26 Al = ( 26 Al/ 27 Al) ratio× 27 Al concentration, which can be measured by spectrophotometry. The data of 26 Al/ 27 Al ratios in blood are shown in Fig.5 Fig.5 . Because of limit in beam time of the tandem accelerator, we measured the blood samples of six time points (0.5, 2, 8, 16, 48, 168 h). The data could be fitted with a nonlinear function: <math display="block" id="M1"><mrow><msup><mrow/><mrow><mn>26</mn></mrow></msup><mtext>Al</mtext><msup><mo>/</mo><mrow><mn>27</mn></mrow></msup><mtext>Al</mtext><mo>=</mo><mn>1.63</mn><mo>×</mo><msup><mrow><mn>10</mn></mrow><mrow><mo>−</mo><mn>10</mn></mrow></msup><msup><mi>t</mi><mrow><mo>−</mo><mo stretchy="false">(</mo><mn>1.588</mn><mo>±</mo><mn>0.355</mn><mo stretchy="false">)</mo></mrow></msup><mo>.</mo></mrow></math> The decrease index is similar with the result of Priest et al . [ 3 3 ] , who found that the Al concentration ( A Al ) in the blood after injection varied in a function of time as A Al = 0.206 t −1.250 . We also found, as shown in Fig. 5 Fig. 5 , that the data also can be well fitted by a two-component function of time, <math display="block" id="M2"><mrow><msup><mrow/><mrow><mn>26</mn></mrow></msup><mtext>Al</mtext><msup><mo>/</mo><mrow><mn>27</mn></mrow></msup><mtext>Al</mtext><mo>=</mo><mn>1.85</mn><mo>×</mo><msup><mrow><mn>10</mn></mrow><mrow><mo>−</mo><mn>11</mn></mrow></msup><mrow><mo>[</mo><mrow><msup><mrow><mrow><mo>(</mo><mrow><mi>t</mi><mo>/</mo><msub><mi>t</mi><mtext>b</mtext></msub></mrow><mo>)</mo></mrow></mrow><mrow><mo>−</mo><mo stretchy="false">(</mo><mn>0.457</mn><mo>±</mo><mn>0.121</mn><mo stretchy="false">)</mo></mrow></msup><mo>+</mo><mtext> </mtext><msup><mrow><mrow><mo>(</mo><mrow><mi>t</mi><mo>/</mo><msub><mi>t</mi><mtext>b</mtext></msub></mrow><mo>)</mo></mrow></mrow><mrow><mo>−</mo><mo stretchy="false">(</mo><mn>2.921</mn><mo>±</mo><mn>0.195</mn><mo stretchy="false">)</mo></mrow></msup></mrow><mo>]</mo></mrow><mo>,</mo></mrow></math> where the t b ≈8 h is break time, and the exponents −(0.457±0.121) and −(2.921±0.195) denote respectively the time before and after t b ,, corresponding to the slow and fast decrease phase. 3.3 Al biological behavior in brain 2 Brain samples of five time points (2,16,48,72 and 168 h) were measured. The 26 Al/ 27 Al results are shown in Fig. 6 Fig. 6 . It can be seen that the brain 26 Al/ 27 Al ratio went up quickly in 16 h after the Al injection. It retained stable in the first week, with a nonlinear function of 26 Al / 27 Al =1.41×10 −13 t −(0.142±0.136) . Also, the data could be well fitted by a two-component function of time, as shown in Fig.6 Fig.6 , <math display="block" id="M3"><mrow><msup><mrow/><mrow><mn>26</mn></mrow></msup><mtext>Al</mtext><msup><mo>/</mo><mrow><mn>27</mn></mrow></msup><mtext>Al</mtext><mo>=</mo><mn>1.10</mn><mo>×</mo><msup><mrow><mn>10</mn></mrow><mrow><mo>−</mo><mn>13</mn></mrow></msup><mrow><mo>[</mo><mrow><msup><mrow><mrow><mo>(</mo><mrow><mi>t</mi><mo>/</mo><msub><mi>t</mi><mtext>b</mtext></msub></mrow><mo>)</mo></mrow></mrow><mrow><mo stretchy="false">(</mo><mn>1.620</mn><mo>±</mo><mn>0.125</mn><mo stretchy="false">)</mo></mrow></msup><mo>+</mo><mtext> </mtext><msup><mrow><mrow><mo>(</mo><mrow><mi>t</mi><mo>/</mo><msub><mi>t</mi><mtext>b</mtext></msub></mrow><mo>)</mo></mrow></mrow><mrow><mo>−</mo><mo stretchy="false">(</mo><mn>0.142</mn><mo>±</mo><mn>0.136</mn></mrow></msup></mrow><mo>]</mo></mrow><mo> </mo><mo> </mo><mo>,</mo></mrow></math> where the t b ≈12 h is the break time. The Al content in brain increased before t b with an increase index of 1.620±0.125,corresponding to the slow decrease phase of the blood sample ( Fig.5 Fig.5 ). After the Al came into the brain, it would decrease slowly, with a decrease index of −(0.142±0.136). If the Al intake continues, the Al accumulated in brain would cause many kinds of diseases. 4. Conclusion 1 In conclusion, a 26 Al-AMS tracing method including the animal tracing, sample preparation and AMS measurement have been established on the HI-13 tandem accelerator. The sample preparation procedure is simplified, and easy to achieve. By extracted single atomic negative Al - from ion source, taking advantage of the lack of any isobaric interference, a high sensitivity of lower than 5×10 -15 for 26 Al/ 27 Al has been achieved. We found that the 26 Al / 27 Al ratio in blood and brain behaved as a two-component function of time. The blood 6 Al / 27 Al ratios show a low and a fast decrease phase before and after a break time t b (about 8 hours post injection), with a decrease index −(0.457±0.121) and −(2.921±0.195), respectively. These two phases are related to the fast increase and slow decrease phase in the brain 6 Al / 27 Al ratios, before and after a time t b time (about 12 hours post injection), with the index (1.620±0.125）and −(0.142±0.136). After the time t b , the Al in the brain decreased very slowly. If the Al intake continues, the Al accumulation in the brain will cause many kinds of diseases. Further experiments are needed to prove the Al biological behavior. References A. C. Alfrey , G. R. LeGendre , W. D. Kaehny , The dialysis encephalopathy syndrome — possible aluminum intoxication . N Engl J Med , 294 : 184 - 188 ( 1976 ). DOI: 10.1056/NEJM197601222940402 http://doi.org/10.1056/NEJM197601222940402 The dialysis encephalopathy syndrome — possible aluminum intoxication Ch. Hohl , P. Gerisch , G. 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Nucl Instrum Meth B , 361 : 39 - 42 ( 2015 ), DOI: 10.1016/j.nimb.2015.03.064 http://doi.org/10.1016/j.nimb.2015.03.064 Decadal 10Be, 26Al and 36Cl QA measurements on the SUERC 5 MV accelerator mass spectrometer We thank Prof. Zheng Zou-Wen from Guangxi University of Chinese Medicine for the help in the animal tracing experiments. 10.1007/s41365-016-0065-y Supported by National Natural Science Foundation of China (No. 41166002), Guangxi Natural Science Foundation (No. 2012GXNSFBA053004, 2013GXNSFFA019001) and Guangxi New Century Education Project (No.2013JGZ100) . 2015-04-13 2015-08-27 2015-09-28 2016-05-06 2016-06-20 2021-04-11 © China Science Publishing & Media Ltd. (Science Press), Shanghai Institute of Applied Physics, the Chinese Academy of Sciences, ChineseNuclear Society and Springer Nature Singapore Pte Ltd. 2016 This is a post-peer-review, pre-copyedit version of an article published in Nuclear Science and Techniques. The final authenticated version is available online at: http://dx.doi.org/10.1007/s41365-016-0065-y http://dx.doi.org/10.1007/s41365-016-0065-y . 2016 Nuclear Science and Techniques 03 27