Radiation Dose to Patients from Radiopharmaceuticals: a Compendium of Current Information Related to Frequently Used Substances.

This report provides a compendium of current information relating to radiation dose to patients, including biokinetic models, biokinetic data, dose coefficients for organ and tissue absorbed doses, and effective dose for major radiopharmaceuticals based on the radiation protection guidance given in Publication 60(ICRP, 1991). These data were mainly compiled from Publications 53, 80, and 106(ICRP, 1987, 1998, 2008), and related amendments and corrections. This report also includes new information for 82Rb-chloride, iodide (123I, 124I, 125I, and 131I) and 123I labeled 2ß-carbomethoxy 3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FPCIT).The coefficients tabulated in this publication will be superseded in due course by values calculated using new International Commission on Radiation Units and Measurements/International Commission on Radiological Protection adult and paediatric reference phantoms and Publication 103 methodology (ICRP,2007). The data presented in this report are intended for diagnostic nuclear medicine and not for therapeutic applications.

Development and validation of a GEANT4 radiation transport code for CT dosimetry.

The authors have created a radiation transport code using the GEANT4 Monte Carlo toolkit to simulate pediatric patients undergoing CT examinations. The focus of this paper is to validate their simulation with real-world physical dosimetry measurements using two independent techniques. Exposure measurements were made with a standard 100-mm CT pencil ionization chamber, and absorbed doses were also measured using optically stimulated luminescent (OSL) dosimeters. Measurements were made in air with a standard 16-cm acrylic head phantom and with a standard 32-cm acrylic body phantom. Physical dose measurements determined from the ionization chamber in air for 100 and 120 kVp beam energies were used to derive photon-fluence calibration factors. Both ion chamber and OSL measurement results provide useful comparisons in the validation of the Monte Carlo simulations. It was found that simulated and measured CTDI values were within an overall average of 6% of each other.

Comparison of measured and calculated dose rates near nuclear medicine patients.

Widely used release criteria for patients receiving radiopharmaceuticals (NUREG-1556, Vol. 9, Rev.1, Appendix U) are known to be overly conservative. The authors measured external exposure rates near patients treated with I, Tc, and F and compared the measurements to calculated values using point and line source models. The external exposure dose rates for 231, 11, and 52 patients scanned or treated with I, Tc, and F, respectively, were measured at 0.3 m and 1.0 m shortly after radiopharmaceutical administration. Calculated values were always higher than measured values and suggested the application of "self-shielding factors," as suggested by Siegel et al. in 2002. The self-shielding factors of point and line source models for I at 1 m were 0.60 ± 0.16 and 0.73 ± 0.20, respectively. For Tc patients, the self-shielding factors for point and line source models were 0.44 ± 0.19 and 0.55 ± 0.23, and the values were 0.50 ± 0.09 and 0.60 ± 0.12, respectively, for F (all FDG) patients. Treating patients as unshielded point sources of radiation is clearly inappropriate. In reality, they are volume sources, but treatment of their exposures using a line source model with appropriate self-shielding factors produces a more realistic, but still conservative, approach for managing patient release.

Realistic reference adult and paediatric phantom series for internal and external dosimetry.

A new generation of realistic, image-based anthropomorphic phantoms has been developed based on the reference masses and organ definitions given in the International Commission on Radiological Protection Publication 89. Specific absorbed fractions for internal radiation sources have been calculated for photon and electron sources for many body organs. Values are similar to those from the previous generation of 'stylized' (mathematical equation-based) models, but some differences are seen, particularly at low particle or photon energies, due to the more realistic organ geometries, with organs generally being closer together, and with some touching and overlapping. Extension of this work, to use these phantoms in Monte Carlo radiation transport simulation codes with external radiation sources, is an important area of investigation that should be undertaken.

Image quantification for radiation dose calculations--limitations and uncertainties.

Radiation dose calculations in nuclear medicine depend on quantification of activity via planar and/or tomographic imaging methods. However, both methods have inherent limitations, and the accuracy of activity estimates varies with object size, background levels, and other variables. The goal of this study was to evaluate the limitations of quantitative imaging with planar and single photon emission computed tomography (SPECT) approaches, with a focus on activity quantification for use in calculating absorbed dose estimates for normal organs and tumors. To do this we studied a series of phantoms of varying complexity of geometry, with three radionuclides whose decay schemes varied from simple to complex. Four aqueous concentrations of 99mTc, ¹³¹I, and ¹¹¹In (74, 185, 370, and 740 kBq mL⁻¹) were placed in spheres of four different sizes in a water-filled phantom, with three different levels of activity in the surrounding water. Planar and SPECT images of the phantoms were obtained on a modern SPECT/computed tomography (CT) system. These radionuclides and concentration/background studies were repeated using a cardiac phantom and a modified torso phantom with liver and "tumor" regions containing the radionuclide concentrations and with the same varying background levels. Planar quantification was performed using the geometric mean approach, with attenuation correction (AC), and with and without scatter corrections (SC and NSC). SPECT images were reconstructed using attenuation maps (AM) for AC; scatter windows were used to perform SC during image reconstruction. For spherical sources with corrected data, good accuracy was observed (generally within ±10% of known values) for the largest sphere (11.5 mL) and for both planar and SPECT methods with 99mTc and ¹³¹I, but were poorest and deviated from known values for smaller objects, most notably for ¹¹¹In. SPECT quantification was affected by the partial volume effect in smaller objects and generally showed larger errors than the planar results in these cases for all radionuclides. For the cardiac phantom, results were the most accurate of all of the experiments for all radionuclides. Background subtraction was an important factor influencing these results. The contribution of scattered photons was important in quantification with ¹³¹I; if scatter was not accounted for, activity tended to be overestimated using planar quantification methods. For the torso phantom experiments, results show a clear underestimation of activity when compared to previous experiment with spherical sources for all radionuclides. Despite some variations that were observed as the level of background increased, the SPECT results were more consistent across different activity concentrations. Planar or SPECT quantification on state-of-the-art gamma cameras with appropriate quantitative processing can provide accuracies of better than 10% for large objects and modest target-to-background concentrations; however when smaller objects are used, in the presence of higher background, and for nuclides with more complex decay schemes, SPECT quantification methods generally produce better results.

Review of standards of protection for pregnant workers and their offspring.

The recommendations of the International Commission on Radiological Protection and the IAEA Basic Safety Standards (BSS) make clear that the embryo and fetus should be regarded as a member of the public when considering the protection of female workers who are or may be pregnant. The BSS note that the embryo and fetus should be 'afforded the same broad level of protection as required for members of the public'. Similar guidance is included in national legislation in a number of countries. On the basis of a review of such guidance, it was concluded that although the recommendations provided in the BSS are in general agreement with the international consensus on approaches to the protection of pregnant workers and their offspring, more specific supporting guidance is needed. The IAEA is preparing a technical document that extends and clarifies previous advice and considers the practical application of the advice for workers in different types of workplace, for which important potential routes of exposure for the pregnant worker have been identified. This action is being carried out under the framework of the International Action Plan for Occupational Radiation Protection.

Influence of total-body mass on the scaling of S-factors for patient-specific, blood-based red-marrow dosimetry.

To perform patient-specific, blood-based red-marrow dosimetry, dose conversion factors (the S factors in the MIRD formalism) have to be scaled by patients' organ masses. The dose to red marrow includes both self-dose and cross-irradiation contributions. Linear mass scaling for the self-irradiation term only is usually applied as a first approximation, whereas the cross-irradiation term is considered to be mass independent. Recently, the need of a mass scaling correction on both terms, not necessarily linear and dependent on the radionuclide, has been highlighted in the literature. S-factors taking into account different mass adjustments of organs are available in the OLINDA/EXM code. In this paper, a general algorithm able to fit the mass-dependent factors S(rm<--tb) and S(rm<--rm) is suggested and included in a more general equation for red-marrow dose calculation. Moreover, parameters to be considered specifically for therapeutic radionuclides such as (131)I, (90)Y and 177Lu are reported. The red-marrow doses calculated by the traditional and new algorithms are compared for (131)I in ablation therapy (14 pts), 177Lu- (13 pts) and (90)Y- (11 pts) peptide therapy for neuroendocrine tumours, and (90)Y-Zevalin therapy for NHL (21 pts). The range of differences observed is as follows: -36% to -10% for (131)I ablation, -22% to 5% for 177Lu-DOTATATE, -9% to 11% for (90)Y-DOTATOC and -8% to 6% for (90)Y-Zevalin. All differences are mostly due to the activity in the remainder of the body contributing to cross-irradiation. This paper quantifies the influence of mass scaling adjustment on usually applied therapies and shows how to derive the appropriate parameters for other radionuclides and radiopharmaceuticals.

Normal organ radiation dosimetry and associated uncertainties in nuclear medicine, with emphasis on iodine-131.

In many medical applications involving the administration of iodine-131 ((131)I) in the form of iodide (I(-)), most of the dose is delivered to the thyroid gland. To reliably estimate the thyroid absorbed dose, the following data are required: the thyroid gland size (i.e. mass), the fractional uptake of (131)I by the thyroid, the spatial distribution of (131)I within the thyroid, and the length of time (131)I is retained in the thyroid before it is released back to blood, distributed in other organs and tissues, and excreted from the body. Estimation of absorbed dose to nonthyroid tissues likewise requires knowledge of the time course of activity in each organ. Such data are rarely available, however, and therefore dose calculations are generally based on reference models. The MIRD and ICRP have published metabolic models and have calculated absorbed doses per unit intake for many nuclides and radioactive pharmaceuticals. Given the activity taken into the body, one can use such models and make reasonable calculations for average organ doses. When normal retention and excretion pathways are altered, the baseline models need to be modified, and the resulting organ dose estimates are subject to larger errors. This paper describes the historical evolution of radioactive isotopes in medical diagnosis and therapy. We nonmathematically summarize the methods used in current practice to estimate absorbed dose and summarize some of the risk data that have emerged from medical studies of patients with special attention to dose and effects observed in those who received (131)I-iodide in diagnosis and/or therapy.

Specific absorbed fractions for internal photon emitters calculated for a tomographic model of a pregnant woman.

Specific absorbed fractions are essential for calculation of radiation dose from internal emitters. Existing specific absorbed fractions for pregnant women were calculated using the stylized models; in this work, a partial-body tomographic model for a pregnant woman was constructed from a rare set of CT images. Based on this tomographic model, the Monte Carlo code, EGS4-VLSI, was used to derive specific absorbed fractions. Monoenergetic, isotropic photon emitters from 15 keV to 4 MeV were distributed in different source organs, and doses were calculated to many target regions in the body. Even though the results showed general agreement with previous studies for higher energies, significant differences were also found, especially for lower energies. The main reasons for the differences are due to the variation of mass, geometry, and organ distances, and they demonstrate the influence of more realistic body models on dose calculations.

Developments in the internal dosimetry of radiopharmaceuticals.

Various radionuclides are used in nuclear medicine in different diagnostic and therapeutic procedures. Recently, interest has grown in therapeutic agents for some interesting applications in nuclear medicine. Internal dose models and methods in use for many years are well established, and can give radiation doses to stylised models representing reference individuals. Kinetic analyses need to be carefully planned, and dose conversion factors that are most similar to the subject in question should be chosen, which can then be tailored somewhat to be more patient-specific. Internal dose calculations, however, are currently not relevant in patient management in internal emitter therapy, as they are not sufficiently accurate or detailed to guide clinical decision-making, and as calculated doses have historically not been well correlated with observed effects on tissues. Great strides are being made at many centres regarding the use of patient image data to construct individualised voxel-based models for more detailed and patient-specific dose calculations, and new findings are encouraging regarding improvement of internal dose models to provide better correlations of dose and effect. These recent advances make it likely that the relevance will soon change to be more similar to that of external beam treatment planning.

Retrospective study of the iodine-131 contamination of workers in the radiopharmaceutical industry.

A dose reconstruction study was performed for personnel occupationally exposed to 131I in radiopharmaceutical production, during the years 1981 to 1994, with the objective of estimating committed effective doses and critically reviewing the main causes of their exposures. The workers were selected from a group responsible for the production, labelling and distribution of all radiopharmaceutical material in Brazil. Best estimates of intakes and doses were derived from the examination of the individual monitoring records and the reports from the radiation protection supervisor, complemented by interviews with the workers and with radiation protection officers. Over this time period workers had chronic as well as acute intakes of 131I. Committed effective doses were found to be dependent on the task performed by the worker and the site of operation and inversely correlated with the amounts of iodine handled. Intakes in general were a consequence of inadequate radiation protection control.

Internal dosimetry for radiation therapy in coronary arteries.

Acute myocardial infarction, which occurs because of the occlusion of one or more coronary arteries, is the most common form of cardiovascular disease. Balloon angioplasty is often used to treat coronary artery occlusion and is less invasive than surgery involving revascularisation of the myocardium, thus promising a better quality of life for patients. Unfortunately, the rate of re-stenosis after balloon angioplasty is high (approximately 30-50% within the first year after treatment). Intravascular radiation therapy has been used with several types of radiation source, and researchers have observed some success in decreasing the rate of re-stenosis. In this paper theoretical radiation dose distributions for monoenergetic electrons (with discrete energies) and photons are calculated for blood vessels of diameter 1.5, 3.0 and 4.5 mm with balloon and wire sources using the radiation transport code MCNP4B. Stent sources employing 32P are also simulated. Advantages and disadvantages of the radionuclides and source geometries are discussed, as well as issues regarding possible benefits to the patients.

Evolution and status of bone and marrow dose models.

Investigations at the University of Leeds under the direction of F.W. Spiers in the early 1960s through the late 1970s established the first comprehensive assessment of marrow dose conversion factors (DCFs) for beta-emitting radionuclides within the volume or on the surface of trabecular bone. These DCFs were subsequently used in deriving radionuclide S values for skeletal tissues published in MIRD Pamphlet No. 11. Eckerman re-evaluated this work and extended the methods of Spiers to radionuclides within the marrow to provide DCFs for fifteen skeletal regions in computational models representing individuals of six different ages. These results were used in the MIRDOSE3 software. Bouchet et al. used updated information on regional bone and marrow masses, as well as 3D electron transport techniques, to derive radionuclide S values in skeletal regions of the adult. Although these two efforts are similar in most regards, the models differ in three respects in: (1) the definition of the red marrow region, (2) the definition of a surface source of activity, and (3) the assumption applied in transporting electrons through the trabecular endosteum. In this study, a review of chord-based skeletal models is given, followed by a description of the differences in the Eckerman and Bouchet et al. transport models. Finally, new data from NMR microscopy and radiation transport in trabecular bone is applied to address item (1) above. Dose conversion factors from MIRD 11, the Eckerman model, the Bouchet et al. model, and a revised model are compared for several radionuclides important to internal emitter therapy.

A voxel-based head-and-neck phantom built from tomographic colored images.

Recent progress in computer speed and medical imaging has made possible the development of a new family of anthropomorphic models, based on a volume elements (voxels) approach to phantom design. Such phantoms can represent details of the anatomical structures of the human body more realistically. Tomographic images (CT or MRI) contain the basic information for the construction of voxel-based phantoms. Use of voxel-based phantoms has its most significant application in the planning of individual patients therapy. To be implemented, results must be obtained in a reasonably short period of time. The segmentation of organs and tissues is a critical step in this process. This article presents a new approach in the construction of voxel-based phantoms that was implemented to simplify the segmentation process of organs and tissues, reducing the time used in this procedure. A voxel-based head and neck phantom, called MCvoxEL, was built using this new approach. The volumes and masses of the segmented organs and tissues were compared with data published by other investigators.

A theoretical model for prescription of the patient-specific therapeutic activity for radioiodine therapy of Graves' disease.

A fundamental function of the thyroid is to extract iodine from the blood, synthesize it into thyroid hormones, and release it into the circulation under feedback control by pituitary-secreted hormones. This capability of the thyroid, termed as functionality, can in principle be related to the severity of hyperthyroidism in individual patients. In this paper the uptake and release of 131I by the thyroid following the administration of 131I therapy for Graves' disease has been theoretically studied. The kinetics of iodine in the thyroid and blood have been evaluated using a two-compartment model. This simplified model appears to be adequate for dosimetry purposes and allows one to correlate levels of increased thyroid functionality (hyperthyroidism) with clinically measurable kinetic parameters. An expression has been derived for the rate of change of thyroid mass following therapy; this has the same form as an empirical relationship described in an earlier work. A method is presented for calculation of the amount of radioiodine activity to be administered to individual patients in order to achieve the desired final functionality of the gland. The activity to be administered is based on measurements of 131I kinetics after the administration of a 'low-activity' (1850 kBq) tracer for treatment planning.

Vascular-targeted radioimmunotherapy with the alpha-particle emitter 211At.

Astatine-211, an alpha-particle emitter, was employed in a model system for vascular-targeted radioimmunotherapy of small tumors in mouse lung to compare its performance relative to other radioisotopes in the same system. Astatine-211 was coupled to the lung blood vessel-targeting monoclonal antibody 201B with N-succinimidyl N-(4-[211At]astatophenethyl) succinamate linker. Biodistribution data showed that the conjugate delivered 211At to the lung (260-418% ID/g), where it remained with a biological half-time of about 30 h. BALB/c mice bearing about 100 lung tumor colonies of EMT-6 cells, each about 2000 cells in size, were treated with 211At-labeled monoclonal antibody 201B. The administered activity of 185 kBq per animal extended the life span of treated mice over untreated controls. Injections of 370 kBq, corresponding to an absorbed dose of 25-40 Gy, were necessary to eradicate all of the lung tumors. Mice receiving 740 kBq of 211At-labeled monoclonal antibody 201B developed pulmonary fibrosis 3-4 months after treatment, as did mice treated with 3700 kBq of the alpha-particle emitter 213Bi-labeled monoclonal antibody 201B in previous work. Animals that were injected with 211At bound to untargeted IgG or to glycine, as control agents, also demonstrated therapeutic effects relative to untreated controls. Control groups that received untargeted 211At required about twice as much administered activity for effective therapy as did groups with lung-targeted radioisotope. These results were not consistent with radioisotope biodistribution and dosimetry calculations that indicated that lung-targeted 211At should be at least 10-fold more efficient for lung colony therapy than 211At bound to nontargeting controls. The data showed that 211At is useful for vascular-targeted radioimmunotherapy because lung tumor colonies were eradicated in the mice. Work in this model system demonstrates that vascular targeting of alpha-particle emitters is an efficient therapy for small perivascular tumors and may be applicable to human disease when specific targeting agents are identified.

Photon specific absorbed fractions calculated in the trunk of an adult male voxel-based phantom.

A new approach for calculating internal dose estimates was developed through the use of a more realistic computational model of the human body. The study demonstrates the capability of building a patient-specific phantom with voxel-based data for the simulation of radiation transport and energy deposition using Monte Carlo methods such as the MCNP-4B code. MCNP-4B was used to calculate absorbed fractions for photons in a voxel-based phantom, and values were compared to reference values from traditional phantoms used for many years. Results obtained in general agreed well with previous values, but considerable differences were found in some cases due to two major causes; differences in the organ masses between the phantoms and the occurrence of organ overlap in the voxel-based phantom (which is not well modeled in the mathematical phantoms). These new techniques offer promise of developing a new generation of more realistic phantoms for internal, as well as external, dose assessment. The principal area of implementation in internal dose assessment should be the development of patient-specific dose estimates in nuclear medicine therapy, such as radioimmunotherapy (RIT). However, as new voxel-based phantoms for different individuals can be developed, they may also be used with the techniques developed here to derive new absorbed fractions and replace the traditional values usedfor other applications in internal and external dose assessment, which have been based on mathematical constructs that are not always very representative of real human organs.

Study of the correlation between administered activity and radiation committed dose to the thyroid in 131I therapy of Graves' disease.

Substantial reduction in the thyroid volume (up to 70-80%) after 131I therapy of Graves' disease has been demonstrated and reported in the literature. Recently a mathematical model of thyroid mass reduction during the first month after therapy has been developed and a new algorithm for the radiation committed dose calculation has been proposed. Reduction of the thyroid mass and the radiation committed dose to the gland depend on a parameter k, defined for each subject. The calculation of k allows the prediction of the activity to administer, depending on the radiation committed dose chosen by the physician. In this paper a method for calculating k is proposed. The calculated values of k are compared to values derived from measurements of the changes in thyroid mass in twenty-six patients treated by 131I for Graves' disease. The radiation committed dose to the thyroid can be predicted within 21%, and the radioiodine activity to administer to the patient can be predicted within 22% using the calculated values of k. The thyroid volume reduction during the first month after therapy administration can be also predicted with good accuracy using the calculated values of k. The radiation committed dose and the radioiodine activity to administer were calculated using a new, very simple algorithm. A comparison between the values calculated by this new algorithm and the old, classical Marinelli-Quimby algorithm shows that the new method is more accurate.