July 2011
Volume 52, Issue 8
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Retina  |   July 2011
PET/CT Imaging of I-124–Radiolabeled Bevacizumab and Ranibizumab after Intravitreal Injection in a Rabbit Model
Author Affiliations & Notes
  • John B. Christoforidis
    From the Departments of Ophthalmology and
  • Michelle M. Carlton
    Radiology, Ohio State University College of Medicine, Columbus, Ohio.
  • Michael V. Knopp
    Radiology, Ohio State University College of Medicine, Columbus, Ohio.
  • George H. Hinkle
    Radiology, Ohio State University College of Medicine, Columbus, Ohio.
  • Corresponding author: John Christoforidis, Department of Ophthalmology, Ohio State University College of Medicine, 915 Olentangy River Road, Columbus, OH 43210; jbchristo@hotmail.com
Investigative Ophthalmology & Visual Science July 2011, Vol.52, 5899-5903. doi:10.1167/iovs.10-6862
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      John B. Christoforidis, Michelle M. Carlton, Michael V. Knopp, George H. Hinkle; PET/CT Imaging of I-124–Radiolabeled Bevacizumab and Ranibizumab after Intravitreal Injection in a Rabbit Model. Invest. Ophthalmol. Vis. Sci. 2011;52(8):5899-5903. doi: 10.1167/iovs.10-6862.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose.: To determine whether bevacizumab and ranibizumab remain confined within the vitreous cavity after intravitreal injection and to determine the pharmacokinetic properties of these agents within the vitreous cavity.

Methods.: Radiolabeling with I-124 was completed using a modified Iodogen method. After testing for radiochemical purity, three anesthetized Dutch-belted rabbits underwent intravitreal injection with I-124 bevacizumab, and three underwent it with I-124 ranibizumab. All rabbits were imaged with a Micro PET-CT scanner on days 0, 2, 5, 7, 14, 21, 28, and 35.

Results.: The intravitreally placed radiolabeled agents were found to be contained within the vitreous cavity for the duration of the study with no extravasation into the central nervous system or elsewhere. I-124 bevacizumab was detectable until day 28, whereas I-124 ranibizumab was detectable until day 21. The kinetic model appears to represent a two-compartment model, and the average retention times for bevacizumab and ranibizumab after correction for radioactive decay were found to be 4.2 days and 2.8 days, respectively.

Conclusions.: There was no significant escape of bevacizumab and ranibizumab from the vitreous cavity after intravitreal injection. After correction for radioactive decay, both agents remained detectable until 28 and 21 days, respectively, with retention properties that validated those methods reported in previous studies.

The use of agents that suppress vascular endothelial growth factor (VEGF) has become the standard of care for treatment of the exudative form of age-related macular degeneration (AMD). Bevacizumab (Avastin; Genentech, San Francisco, CA; Roche, Basel, Switzerland) is widely used on an off-label basis in the treatment of neovascular AMD. In addition, ranibizumab (Lucentis; Genentech, San Francisco, CA; Roche, Basel, Switzerland) has recently been approved by the US Food and Drug Administration for the treatment of macular edema secondary to central and branch retinal vein occlusion. Both ranibizumab and bevacizumab are widely used off-label for the treatment of diabetic macular edema in the United States. In clinical practice they are injected intravitreally at a frequency no sooner than every 4 weeks for ranibizumab and every 4 to 6 weeks for bevacizumab. 
Intravitreal injection of anti-VEGF agents is the most commonly performed procedure in the treatment of the retina. Systemic side effects have been described with the use of both agents. Ranibizumab has been associated with an increased risk for nonocular hemorrhages (ecchymoses, gastrointestinal hemorrhages, hematoma, vaginal hemorrhages, subdural hematomas), most notably stroke. 1,2 It may be that the treated population is at increased risk for stroke and that patients with a history of stroke appear to be more susceptible. 3 5 Although the systemic use of bevacizumab has been associated with multiple systemic side effects, including hypertension, proteinuria, wound healing complications, GI perforation, nonocular hemorrhages, and thromboembolic events, these effects have not been systematically studied with intravitreal use and await validation in upcoming clinical trials. 6 9  
A clinical question that often arises is whether anti-VEGF agents actually remain within the vitreous cavity after intravitreal placement. It remains uncertain whether significant escape occurs from the vitreous cavity into the systemic circulation or into the central nervous system through the optic nerve that may account for systemic side effects. Furthermore, it is unclear whether these agents actually remain in the vitreous cavity for the duration of the 4- to 6-week treatment interval. Previous pharmacokinetic studies on animal models to determine the intravitreal duration and half-lives of these agents have relied primarily on serial immunoassay measurements from different animals at different time intervals after intravitreal injection rather than serial measurements over time from the same animals. 10 13 In this study, we performed serial PK measurements on the same animal. 
The use of positron emission tomography (PET)/computed tomography (CT) offers a novel approach to directly and noninvasively visualize these radiolabeled anti-VEGF agents in the vitreous cavity and to determine their pharmacokinetic properties. PET is a nuclear medicine imaging technique that produces a three-dimensional image of a functional process within the body. It detects pairs of gamma rays that are emitted by a positron-emitting radionuclide. Biologically active molecules can then be detected by labeling with a positron-emitting radionuclide such as I-124. Images of radionuclide concentrations are then reconstructed three-dimensionally by computer analysis. The coregistration of PET and CT scans allows for the two scans to be performed in immediate sequence, enabling precise correlation of functional and anatomic imaging during the same scan session. 
The goals of our project using PET/CT to image intravitreally placed I-124–radiolabeled bevacizumab and ranibizumab in a rabbit model were threefold: first, to determine whether intravitreally placed anti-VEGF agents remain within the vitreous cavity after injection; second, to study the pharmacokinetic properties of these two agents by sequential ocular imaging of the animals over time; third, to further validate our serial methods by studying agents with well-known half-lives. 
Materials and Methods
Radiolabeling of bevacizumab and ranibizumab with I-124 (IBA Molecular, Dulles, VA) was completed using a modified Iodogen method, described previously by Zou ET al. 14 Radiochemical purity for I-124–labeled bevacizumab and I-124–labeled ranibizumab was found to be 95% and 98%, respectively. 
All treatments were conducted in agreement with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research. All experimental protocols were approved, and the procedures followed were in accordance with the ethical standards of the Institutional Animal Care and Use Committee at The Ohio State University. Six male Dutch-belted rabbits (Myrtle's Rabbitry, Thompsons Station, TN) weighing 1.5 to 1.8 kg each were used for this study. The rabbits were anesthetized with intramuscularly placed xylazine (0.1–0.2 mL; 5 mg/mL) and ketamine hydrochloride (1.7 mL; 100 mg/mL). Intravitreal injection consisting of 0.5 mg/0.05 mL I-124–labeled ranibizumab or 1.25 mg/0.05 mL I-124–labeled bevacizumab was placed 1 mm posterior to the limbus of the left eye in three rabbits for each of the two agents. 
The anesthetized rabbits were then lightly secured to the scanner bed with elastic socks or gauze for the purpose of imaging. The animals were imaged for 10 minutes in the micro-PET/CT (Inveon; Siemens Preclinical, Knoxville, TN), followed by an attenuation scan for 15 minutes. Micro-PET scans each resulted in a reconstructed volume with an effective pixel size of 0.78 mm. Micro-CT had an effective pixel size of 0.099 mm. The scans were performed on days 0, 2, 5, 7 and then weekly. Imaging was discontinued 1 week after the radiolabeled agent was undetectable, which occurred on day 28 for ranibizumab and on day 35 for bevacizumab. After the last imaging session, the anesthetized rabbits were euthanatized by intravenous injection of 3 mL saturated KCl. 
The radioactive units, in becquerels per milliliter, obtained at each time point were modified with a correction factor to account for radioactive decay of I-124. Resultant measurements were used to formulate the retention curves and to calculate the intravitreal half-lives of each agent. The half-life of each agent was calculated using the following formula for first-order kinetics:   where T1/2 is the half-life, T is the elapsed time, AmtB is the beginning amount, and AmtE is the ending amount. 
Results
Escape from the Vitreous Cavity
In all six rabbits, I-124 bevacizumab and I-124 ranibizumab were not detectable outside the vitreous cavity and the thyroid for the length of the study after intravitreal injection. None of the eyes developed evidence of endophthalmitis, uveitis, cataract, or other adverse events during the study. The two montages illustrate serial images for each agent over time (Figs. 1, 2). Radioactive emission was set at a range of 10% to 75% for all the figures to eliminate noise and to provide for a consistent range of emission for all the figures. Although there was discernible anatomic localization within the eye at lower emission thresholds, background noise levels were increased. 
Figure 1.
 
Image montage illustrating clearance patterns of I-124 bevacizumab within the vitreous cavity in a rabbit model. The agent is still discernible on day 21 but not detectable on day 28. Range of acquisition of radioactive emission was 10% to 75%.
Figure 1.
 
Image montage illustrating clearance patterns of I-124 bevacizumab within the vitreous cavity in a rabbit model. The agent is still discernible on day 21 but not detectable on day 28. Range of acquisition of radioactive emission was 10% to 75%.
Figure 2.
 
Image montage illustrating clearance pattern of I-124 ranibizumab within the vitreous cavity over time in a rabbit model. The agent is still discernible on day 14 but not detectable on day 21. A phantom containing I-124 ranibizumab in a tuberculin syringe is easily discerned on day 28 (arrow), indicating that the lack of positron emission in the vitreous cavity was due to ranibizumab clearance rather than to I-124 decay. Range of acquisition of radioactive emission was 10% to 75%.
Figure 2.
 
Image montage illustrating clearance pattern of I-124 ranibizumab within the vitreous cavity over time in a rabbit model. The agent is still discernible on day 14 but not detectable on day 21. A phantom containing I-124 ranibizumab in a tuberculin syringe is easily discerned on day 28 (arrow), indicating that the lack of positron emission in the vitreous cavity was due to ranibizumab clearance rather than to I-124 decay. Range of acquisition of radioactive emission was 10% to 75%.
Ranibizumab and bevacizumab were visible until days 14 and 21 and detectable until day 21 and 28, respectively. Any further detection beyond these days was compatible with background noise. Intravitreal levels of radioactivity, in becquerels per milliliter, are listed for each rabbit in Table 1. Accumulation of I-124 in the thyroid gland was visible at lower emission thresholds (Fig. 3). For both agents, I-124 was not visible in the thyroid on day 0, peaked on day 2 and was last detectable on day 14 for five rabbits (Table 2). The sixth rabbit had the highest intravitreal I-124 levels on day 0, and I-124 remained detectable in the thyroid until day 21. 
Table 1.
 
Intravitreal Radioactivity Levels (Bq/mL)
Table 1.
 
Intravitreal Radioactivity Levels (Bq/mL)
Day Bev 1 Bev 2 Bev 3 Ran 1 Ran 2 Ran 3
0 175370.0 205250.0 178970.0 167730.0 116000.0 164540.0
2 84861.5 106740.0 89862.3 89780.3 50111.7 69510.8
5 31247.2 38312.8 33722.5 21029.2 14030.5 19604.7
7 15523.8 19824.4 17006.6 5933.5 5946.1 8350.8
14 1549.1 1929.9 1695.3 470.6 275.7 454.5
21 174.5 44.3 161.4 31.6 16.7 31.1
28 17.2 23.8 15.9 4.9 8.2 9.1
35 7.6 5.1 9.1
Figure 3.
 
I-124 accumulation in the thyroid gland at day 7 (arrow). Range of acquisition of radioactive emission was set between 2% and 25% to allow for lower levels of detection.
Figure 3.
 
I-124 accumulation in the thyroid gland at day 7 (arrow). Range of acquisition of radioactive emission was set between 2% and 25% to allow for lower levels of detection.
Table 2.
 
Thyroid Radioactivity Levels (Bq/mL)
Table 2.
 
Thyroid Radioactivity Levels (Bq/mL)
Day Bev 1 Bev 2 Bev 3 Ran 1 Ran 2 Ran 3
2 429.4 490.6 351.3 475.0 410.0 464.9
5 311.4 388.5 272.8 321.0 416.0 367.6
7 224.0 323.4 217.3 207.1 297.1 294.4
14 77.2 113.8 71.1 43.5 71.8 59.1
21 33.6
Pharmacokinetic Properties
Resultant clearance patterns were consistent within each of the two agent groups (Fig. 4). I-124 ranibizumab could be imaged on day 28 as a phantom in a syringe though it was not detectable in the vitreous cavity at this time (Fig. 2). For each agent the absorption appeared to fit a two-compartment model with an initial rapid distribution phase until day 5, followed by a slower elimination phase. The average intravitreal half-lives for bevacizumab and ranibizumab after adjustment for radioactive I-124 decay were calculated to be 4.02 (± 0.137) and 2.71 (± 0.056) days, respectively, for the initial distribution phase and 4.27 (± 0.157) and 2.82 (± 0.089) days, respectively, for the elimination phase. The overall average intravitreal half-lives of bevacizumab and ranibizumab were 4.22 (± 0.124) and 2.81 (± 0.083) days, respectively. These values were in agreement with previous works by others. 10 13  
Figure 4.
 
Graph demonstrating clearance curves for the two I-124–labeled agents. The units are corrected for I-124 radioactive decay. Dashed curves: radioactive counts of individual rabbits; solid curves: average radioactive counts for each agent. The curves are consistent with each of the two groups, and bevacizumab is cleared more slowly than ranibizumab. I-124 bevacizumab remains detectable until day 28, whereas I-124 ranibizumab is detectable until day 21.
Figure 4.
 
Graph demonstrating clearance curves for the two I-124–labeled agents. The units are corrected for I-124 radioactive decay. Dashed curves: radioactive counts of individual rabbits; solid curves: average radioactive counts for each agent. The curves are consistent with each of the two groups, and bevacizumab is cleared more slowly than ranibizumab. I-124 bevacizumab remains detectable until day 28, whereas I-124 ranibizumab is detectable until day 21.
Discussion
In this study, integrated PET/CT imaging was used to visualize I-124–labeled ranibizumab and bevacizumab in the vitreous cavity after intravitreal injection. There was no evidence of escape of bevacizumab and ranibizumab from the vitreous cavity, though iodine was found to be sequestered in the thyroid gland. The measured intravitreal radioactive emission from these agents allowed us to determine the pharmacokinetic properties of these proteins while in the vitreous cavity. The novelty of integrated PET/CT imaging compared with previous immunoassay methods for the determination of pharmacokinetic properties of intravitreally placed agents lies in its ability to directly and noninvasively visualize the labeled agent and to serially follow the same subject over time. 
Concerns have been raised that intravitreal ranibizumab and systemic bevacizumab may predispose patients to stroke and nonocular hemorrhages. 1,2,6 9 We found no evidence of escape of these agents into the central nervous system or elsewhere in any of the subjects during the length of the study that could account for these side effects. Once the anti-VEGF agent is absorbed into the bloodstream, I-124 decouples from its substrate and is sequestered in the thyroid gland. We found these levels to be low and not detectable after day 14 in 5 of 6 rabbits. Hematogenous spread is below PET/CT resolution thresholds and cannot be excluded based on our findings. We were, unfortunately, not able to directly measure ranibizumab or bevacizumab in the bloodstream because the methodology was not available at our institution or at any of our referral laboratories. 
The agents remained detectable only in the vitreous cavity until day 28 (bevacizumab) and day 21 (ranibizumab). The phantom containing ranibizumab was easily detectable at day 28, indicating that the lack of positron emission from the vitreous cavity at this time was likely due to the absorption of ranibizumab rather than to the radioactive decay of I-124. The duration of both agents in the vitreous cavity was found to be significantly less than the 4- to 6-week treatment interval typically used in clinical practice. The significance of this finding is uncertain because the physiologic effects of these agents may remain active after they are no longer detectable by PET imaging. Klettner and Roider have demonstrated that VEGF suppression lasted longer than the persistence of VEGF inhibitors in porcine RPE cell cultures treated with bevacizumab and ranibizumab. 15 It may be that additional pathways of VEGF suppression, such as cellular internalization of these agents or postinhibition VEGF receptor feedback mechanisms, remain to be elucidated. 
The half-lives for ranibizumab and bevacizumab in our study (2.8 and 4.2 days, respectively) were found to compare favorably with previously reported findings using immunoassay techniques. Using a rabbit model, Bakri et al. 10,11 found half-lives in the vitreous cavity to be 3.2 days for ranibizumab and 4.32 days for bevacizumab. Kim et al. 12 found the half-life of rituximab, a 145-kDa agent similar in size to bevacizumab, to be 4.7 days. 12 In primates after bilateral intravitreal injection (0.5 mg), Gaudreault et al. 13 found half-lives to be 3.2 in ranibizumab and 5.6 days in a 148-kDa anti-VEGF agent (rhuMab) that is similar in size to bevacizumab. The findings in our model indicate the presence of a two-compartment pharmacokinetic decay model similar to that previously described by Zhu et al., 15 with an initial rapid distribution phase to day 5, followed by a subsequent slower elimination phase. 
There were several limitations to this study. First, the number of animals studied per agent was small; it was limited to six each day because of the large amount of time necessary to prepare and image each rabbit. Despite this, serial measurements were obtained at multiple time points (six or seven) for each animal. Previous pharmacokinetic studies with immunoassay methods have used larger numbers of animals to determine intravitreal anti-VEGF agent levels. However, each time point in these studies represented a separate animal, and between one and four measurements were obtained at each time point. 10 13 Second, serum levels of bevacizumab and ranibizumab to correlate with intravitreal levels could not be obtained at our institution or at any of our referral laboratories. Third, it is uncertain whether decoupling of I-124 occurs from the agent substrate while in the vitreous cavity. Additionally, decoupling would be expected to reduce the intravitreal levels of the anti-VEGF agents; they are not known to be metabolized while in the vitreous cavity, and decoupling would be expected to occur once the labeled agent is absorbed into the bloodstream. Fourth, the use of a rabbit model has several inherent constraints. The vitreous cavity and serum compartment is significantly smaller than that of humans (approximately 1.5 mL vs. 4.5 mL), thereby increasing the ocular drug concentration compared with that in the clinical setting. The half-lives of bevacizumab and ranibizumab have been found to be longer in humans than in rabbits, possibly because the larger vitreous volume results in lower concentrations of agent and increased diffusion times (increased distance with lower diffusion gradient) to the circulation, where it is thought to be cleared from the eye. 16,17 Rabbits also have a smaller serum compartment than humans, increasing systemic exposure compared with humans. Further studies are warranted to continue investigation of this method, particularly in an animal model of choroidal neovascularization. Performing studies in more animals and in larger eyes would also be of use and could provide increased resolution- and agent-concentration gradients. 
In conclusion, PET/CT imaging of intravitreally placed I-124 ranibizumab and I-124 bevacizumab revealed no evidence of significant escape from the vitreous cavity into the central nervous system or elsewhere in a rabbit model. In addition, the intravitreal pharmacokinetic properties of these agents appear to be consistent with those described in previous reports using different techniques. Our described methodology may offer a novel approach for studying the anatomic and pharmacokinetic properties of novel intravitreally placed therapeutic agents with all measurements in one animal. 
Footnotes
 Disclosure: J.B. Christoforidis, None; M.M. Carlton, None; M.V. Knopp, None; G.H. Hinkle, None
The authors thank Jeanne Greene and Stephanie Lewis, DVM, for their veterinary guidance and support throughout the study. 
References
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Ueta T Yanagi Y Tamaki Y Yamaguchi T . Ranibizumab and stroke. Ophthalmology. 2010;117:1860. [CrossRef] [PubMed]
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Bakri SJ Snyder MR Reid JM Pulido JS Ezzat MK Singh RJ . Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology. 2007;114:2179–2182. [CrossRef] [PubMed]
Kim H Csaky KG Chan CC . The pharmacokinetics of rituximab following an intravitreal injection. Exp Eye Res. 2006;82:760–762. [CrossRef] [PubMed]
Gaudreault J Fei D Rusit J . Preclinical pharmacokinetics of ranibizumab after a single intravitreal administration. Invest Ophthalmol Vis Sci. 2005;46:726–733. [CrossRef] [PubMed]
Zou P Povoski SP Hall NC . 124I-HuCC49deltaCH2 for TAG-72 antigen-directed positron emission tomography (PET) imaging of LS174T colon adenocarcinoma tumor implants in xenograft mice: preliminary results. World J Surg Oncol. 2010;8:65. [CrossRef] [PubMed]
Alexa Klettner Johann Roider . Comparison of bevacizumab, ranibizumab, and pegaptanib in vitro: efficiency and possible additional pathways. Invest Ophthalmol Vis Sci. 2008;49:4523–4527. [CrossRef] [PubMed]
Zhu Q Ziemssen F Henke-Fahle S . Vitreous levels of bevacizumab and vascular endothelial growth factor-α in patients with choroidal neovascularization. Ophthalmology. 2008;115:1750–1755. [CrossRef] [PubMed]
Krohne TU Eter N Holz FG Meyer CH . Intraocular pharmacokinetics of bevacizumab after a single intravitreal injection in humans. Am J Ophthlamol. 2008;146:508–512. [CrossRef]
Figure 1.
 
Image montage illustrating clearance patterns of I-124 bevacizumab within the vitreous cavity in a rabbit model. The agent is still discernible on day 21 but not detectable on day 28. Range of acquisition of radioactive emission was 10% to 75%.
Figure 1.
 
Image montage illustrating clearance patterns of I-124 bevacizumab within the vitreous cavity in a rabbit model. The agent is still discernible on day 21 but not detectable on day 28. Range of acquisition of radioactive emission was 10% to 75%.
Figure 2.
 
Image montage illustrating clearance pattern of I-124 ranibizumab within the vitreous cavity over time in a rabbit model. The agent is still discernible on day 14 but not detectable on day 21. A phantom containing I-124 ranibizumab in a tuberculin syringe is easily discerned on day 28 (arrow), indicating that the lack of positron emission in the vitreous cavity was due to ranibizumab clearance rather than to I-124 decay. Range of acquisition of radioactive emission was 10% to 75%.
Figure 2.
 
Image montage illustrating clearance pattern of I-124 ranibizumab within the vitreous cavity over time in a rabbit model. The agent is still discernible on day 14 but not detectable on day 21. A phantom containing I-124 ranibizumab in a tuberculin syringe is easily discerned on day 28 (arrow), indicating that the lack of positron emission in the vitreous cavity was due to ranibizumab clearance rather than to I-124 decay. Range of acquisition of radioactive emission was 10% to 75%.
Figure 3.
 
I-124 accumulation in the thyroid gland at day 7 (arrow). Range of acquisition of radioactive emission was set between 2% and 25% to allow for lower levels of detection.
Figure 3.
 
I-124 accumulation in the thyroid gland at day 7 (arrow). Range of acquisition of radioactive emission was set between 2% and 25% to allow for lower levels of detection.
Figure 4.
 
Graph demonstrating clearance curves for the two I-124–labeled agents. The units are corrected for I-124 radioactive decay. Dashed curves: radioactive counts of individual rabbits; solid curves: average radioactive counts for each agent. The curves are consistent with each of the two groups, and bevacizumab is cleared more slowly than ranibizumab. I-124 bevacizumab remains detectable until day 28, whereas I-124 ranibizumab is detectable until day 21.
Figure 4.
 
Graph demonstrating clearance curves for the two I-124–labeled agents. The units are corrected for I-124 radioactive decay. Dashed curves: radioactive counts of individual rabbits; solid curves: average radioactive counts for each agent. The curves are consistent with each of the two groups, and bevacizumab is cleared more slowly than ranibizumab. I-124 bevacizumab remains detectable until day 28, whereas I-124 ranibizumab is detectable until day 21.
Table 1.
 
Intravitreal Radioactivity Levels (Bq/mL)
Table 1.
 
Intravitreal Radioactivity Levels (Bq/mL)
Day Bev 1 Bev 2 Bev 3 Ran 1 Ran 2 Ran 3
0 175370.0 205250.0 178970.0 167730.0 116000.0 164540.0
2 84861.5 106740.0 89862.3 89780.3 50111.7 69510.8
5 31247.2 38312.8 33722.5 21029.2 14030.5 19604.7
7 15523.8 19824.4 17006.6 5933.5 5946.1 8350.8
14 1549.1 1929.9 1695.3 470.6 275.7 454.5
21 174.5 44.3 161.4 31.6 16.7 31.1
28 17.2 23.8 15.9 4.9 8.2 9.1
35 7.6 5.1 9.1
Table 2.
 
Thyroid Radioactivity Levels (Bq/mL)
Table 2.
 
Thyroid Radioactivity Levels (Bq/mL)
Day Bev 1 Bev 2 Bev 3 Ran 1 Ran 2 Ran 3
2 429.4 490.6 351.3 475.0 410.0 464.9
5 311.4 388.5 272.8 321.0 416.0 367.6
7 224.0 323.4 217.3 207.1 297.1 294.4
14 77.2 113.8 71.1 43.5 71.8 59.1
21 33.6
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