and frequency of each emission of the radionuclide are known. If we designate E i as the energy of the i th emission, n i is the frequency of that emission. The amount of radiation energy emitted per unit of accu- mulated radioactivity can then be described as D i = 2.13n i E i (6) where E i is in MeV and D i is in (g-rad/mCi-hr). D i is defined as equilib- rium absorbed dose constant of the i th emitter. The energy emitted from the i th emission of the radionuclide in the source organ is a product of the equilibrium absorbed dose constant, D i , and accumulated radioac- tivity, Ã. If a radionuclide deposited in the source organ has more than one emission, the equilibrium absorbed dose constant should be cal- culated for each emission and summated. Total Energy Absorbed by Target Organ, D Due to the distance and attenuation between the source organ and target oranges, only a fraction of the energy emitted by the source organ is absorbed by the target organ. This fraction factor needs to be quantified so that the total absorbed dose by the target organ can be estimated. Absorbed Fraction f The absorbed fraction depends on the geometric relationship of the source and target organ, the emission energy of the radionuclide, and the composition of the source organs, the target organ, and those organs in between. Mathematically, the absorbed fraction of the i th emission of the radionuclide can be expressed as f i (t k ¨ s j ). The energy absorbed by the target organ, t k , from the i th emission of the radionu- clide in source organ, s j , is equal to à j f i (t k ¨ s j )D i . So the total energy absorbed by target organ, t k , from all emissions in the source organ, s j , is (7) Because the absorbed dose is defined as energy absorbed in unit mass, the dose delivered from the source organ, s j , to the target organ, t k , is (8) where à j is the cumulated activity in source organ, s j , and m k is the mass of the target organ, t k . The total dose to the target organ can be obtained by summing the doses from all the source organ of the body: The calculation of absorbed fraction, f, for each penetrating emis- sion, for example, photons, is very complicated, as it is highly depen- dent on the energy of the radiation emission, the geometry between the target and source organs, and the characteristics of the tissue and organ. The range of f is between 0 and 1 from the source organ to target D t rad D ts kk j j () () =¨ ()  . D tsrad A m ts k j j k i k ji i ¨ () () = Ê Ë Á ˆ ¯ ˜ ¨ ()  ˜ fD Energy Absorbed (g - rad) =¨ ()  ˜ .Ats ji k ji i fD 40 Chapter 4 Dosage of Radiopharmaceuticals and Internal Dosimetry organ (target organ can be the source organ itself) for photons with emitting energy >10 keV. When the target organ is the same as the source organ, and electron or photon energy is <10keV, f=1. If the target organ is a different organ, then f=0. This assumes that the source organ will attenuate and absorb within itself the entire radiation energy when the radiation emission is a low-energy photon or a non- penetrating particle, such as an electron. Specific Absorbed Dose Fraction, F Arearrangement of equation 8, gives us (9) The term , is defined as the specific absorbed fraction, F i (t k ¨ s j ). This is the fraction of the i th radiation emitter that is given off by the radionuclide in the source organ, s j , and absorbed, per unit mass, by target organ t k . Equation 9 can then be written as (10) The specific absorbed fraction has been calculated using mathematical phantom models based on different age groups with complex mathe- matical simulations for source-target pairs. The results are a set of com- prehensive tables of specific absorbed fractions for each reference age group. Table 4.1 is an example that was formulated by Oak Ridge National Lab (1). This example involves a 500keV photon, the specific absorbed fraction from the kidney (source organ) to what could be con- sidered the average liver of a 10-year-old (2.35E-2/kg or 2.35E-5/g). A simplified quantity, dose per cumulated activity, or S value, has been calculated for the source-target organs for many radionuclides of inter- est. The S value of the source-target organs, pair j and k, is defined as . This is calculated in the conventional units of rad/mCi-hr. Medical Internal Radiation Dose (MIRD) com- mittee pamphlet No. 11 tabulated many of the most commonly used radionuclides for the standard adult phantom (2). Now Equation 10 can be rewritten as D(t k ¨ s j )(rad) = à j S(t k ¨ s j ). (11) The total dose D(t k ) to target organ k is then described as (12) If the accumulated radioactivity in each source organ is known, one can calculate the total dose to the target organ by using the S-value table and summing up the dose delivered to the target organ from each D tASts k j k j j () =¨ ()  ˜ . St s t s k ji k j i i ¨ () =¨ ()  FD. D tsradA t s k jji k j i i ¨ () () =¨ ()  ˜ .FD f i k j k ts m ¨ () D tsradA ts m k jj i k j k i i ¨ () () = ¨ ()  ˜ . f D X. Zhu 41 42 Chapter 4 Dosage of Radiopharmaceuticals and Internal Dosimetry Table 4.1. Specific absorbed fraction of photon energy in kg-1: recommended values for a 10-year-old Source = Energy (MeV) Kidneys Target 0.010 0.015 0.020 0.030 0.0500.100 0.200 0.500 1.000 1.500 2.000 4.000 Adrenals 4.84E - 03 5.22E - 021.29E - 011.57E - 011.06E - 01 7.46E - 02 6.89E - 02 6.69E - 02 6.74E - 02 6.21E - 025.67E - 02 4.40E - 02 UB Wall 0.0 0.0 5.85E - 07 2.95E - 04 2.08E - 03 2.49E - 03 2.91E - 03 3.29E - 03 3.33E - 03 3.23E - 03 3.09E - 03 2.64E - 03 Bone Sur 1.39E - 04 3.49E - 03 1.40E - 02 3.67E - 02 3.90E - 021.90E - 021.06E - 02 8.00E - 03 7.26E - 03 6.82E - 03 6.45E - 03 5.42E - 03 Brain 0.0 0.0 0.0 5.72E - 08 9.29E - 06 5.32E - 05 7.84E - 051.31E - 04 1.91E - 04 2.33E - 04 2.68E - 04 3.65E - 04 Breasts 0.0 0.0 3.85E - 07 7.36E - 04 2.82E - 03 2.59E - 03 3.19E - 03 3.63E - 03 3.53E - 03 3.36E - 03 3.21E - 03 2.82E - 03 St Wall 0.0 2.18E - 051.78E - 03 1.94E - 022.80E - 022.27E - 022.08E - 022.06E - 021.92E - 021.70E - 021.53E - 021.25E - 02 SI Wall 5.55E - 10 1.06E - 04 3.50E - 03 1.77E - 022.70E - 022.20E - 022.06E - 021.90E - 021.73E - 021.62E - 021.52E - 021.25E - 02 ULI Wall 0.0 1.70E - 051.61E - 03 1.43E - 022.70E - 022.13E - 021.76E - 021.79E - 021.64E - 021.54E - 021.45E - 021.17E - 02 LLI Wall 0.0 4.04E - 07 1.18E - 04 2.68E - 03 5.43E - 03 6.63E - 03 6.04E - 03 5.70E - 03 5.63E - 03 5.34E - 03 5.05E - 03 4.27E - 03 Kidneys 5.37E + 00 4.43E + 00 3.21E + 00 1.54E + 00 5.95E - 01 3.46E - 01 3.56E - 01 3.74E - 01 3.54E - 01 3.29E - 01 3.06E - 012.39E - 01 Liver 8.35E - 05 3.55E - 03 1.58E - 02 3.85E - 02 3.75E - 022.74E - 022.49E - 022.35E - 022.19E - 022.04E - 021.91E - 021.62E - 02 Lng Tiss 0.0 5.05E - 06 5.96E - 04 5.35E - 03 9.10E - 03 7.87E - 03 7.35E - 03 6.81E - 03 7.09E - 03 6.34E - 03 5.74E - 03 5.15E - 03 Muscle 3.13E - 03 8.91E - 03 1.43E - 021.59E - 021.16E - 02 8.53E - 03 8.27E - 03 8.39E - 03 8.04E - 03 7.58E - 03 7.14E - 03 5.88E - 03 Ovaries 0.0 1.55E - 08 4.97E - 052.30E - 03 7.47E - 03 8.85E - 03 8.20E - 03 8.49E - 03 7.53E - 03 6.96E - 03 6.66E - 03 6.24E - 03 Pancreas 5.22E - 10 3.99E - 04 1.26E - 02 6.20E - 02 6.58E - 02 4.69E - 02 3.98E - 02 4.04E - 02 3.44E - 02 3.02E - 022.77E - 022.36E - 02 R Marrow 6.38E - 051.33E - 03 4.91E - 03 1.23E - 021.51E - 021.38E - 021.37E - 021.35E - 021.23E - 021.14E - 021.08E - 02 8.81E - 03 Skin 1.14E - 04 7.68E - 04 2.97E - 03 5.28E - 03 4.27E - 03 3.41E - 03 3.68E - 03 4.08E - 03 3.89E - 03 3.94E - 03 3.93E - 03 3.31E - 03 Spleen 2.92E - 03 3.80E - 021.13E - 011.51E - 01 9.95E - 02 6.31E - 025.57E - 025.76E - 025.31E - 02 4.89E - 02 4.55E - 02 3.69E - 02 Testes 0.0 0.0 1.53E - 09 1.76E - 05 3.60E - 04 6.40E - 04 8.50E - 04 1.05E - 03 1.16E - 03 1.18E - 03 1.20E - 03 1.12E - 03 Thymus 0.0 0.0 7.94E - 08 1.13E - 04 7.80E - 04 1.89E - 03 2.30E - 03 2.50E - 03 2.60E - 03 2.64E - 03 2.57E - 03 2.21E - 03 Thyroid 0.0 0.0 1.36E - 10 5.08E - 06 2.18E - 04 6.20E - 04 7.04E - 04 7.71E - 04 8.36E - 04 9.48E - 04 1.01E - 03 9.37E - 04 GB Wall 0.0 3.31E - 05 3.69E - 03 2.55E - 025.26E - 02 3.56E - 03 2.48E - 022.40E - 022.00E - 021.86E - 021.80E - 021.66E - 02 Ht Wall 0.0 2.51E - 08 4.81E - 052.89E - 03 7.30E - 03 8.58E - 03 7.65E - 03 7.51E - 03 7.66E - 03 6.95E - 03 6.32E - 03 5.20E - 03 Uterus 0.0 1.26E - 09 1.72E - 051.78E - 03 6.39E - 03 8.05E - 03 6.87E - 03 6.99E - 03 7.56E - 03 7.10E - 03 6.57E - 03 5.48E - 03 Cristy M, Eckerman KF, Specific absorbed fraction of energy at various ages from internal photon source. IV. Ten-year-old. Oak Ridge National Laboratory Report ORNL/TM-8381:Vol. 4, 1987 Bone Sur: Bone Surface; GBWall: Gall Bladder Wall; Ht Wall: Heart Wall; LLI Wall: Lower Large Intestine Wall; Long Tiss: Lung Tissue; R Marrow: Red Marrow; SI Wall: Small Intestine Wall; St. Wall: Stomach Wall; UB wall: Urinary Bladder Wall; ULI Wall: Upper Large Intestine Wall. X. Zhu 43 source organ. In absence of the S-value tables for other age groups, the S value can be calculated using tabulated F and D values, as discussed earlier. Pediatric Dose Estimate For pediatric patients, radiopharmaceutical dosages are based on a pediatric dosing schedule. There are many different dosing sche- dules. The most common ones are those using body weight or body surface areas as guides to scale the dose. Pediatric dose schedules consider many factors to scale down the dosage from that of adult to child, including organ doses, effective dose, and image quality. However, absorbed radiation dose and effective dose to pediatric patients are not as simple as the dosing schedule. They are not just simple linear scaled-down doses of those for adult patients. As we dis- cussed before, radiation doses to patients depend on geometric and anatomic relationships of source to target organs. Differences in pedi- atric organ size, density, and composition significantly change the geo- metric and anatomic relationships that were established for adult patient (or phantom). Differences of biokinetics, due to age-related dif- ferences in uptakes (e.g., thyroid uptake of iodine), and excretion (e.g., bladder voiding interval), must be considered when estimate radiation doses for pediatric patients. Mathematical phantoms for age groups considering the geometric and anatomic variables have been well developed. They are typically for infants, and 1-, 5-, 10-, and 15-year-olds. Specific absorbed fraction has been calculated and tabulated (e.g., Table 4.1) for each age-specific phantom group. Combined with dose schedule, age-adjusted uptake and excretion parameters, pediatric radiation doses can then be estimated according to Equation 10. Practical Approach to Internal Dose Estimate The estimation of internal dose from a radionuclide in a human is rather a complicated process. Studies of biokinetic models of a partic- ular radiopharmaceutical normally begin through investigations of the model in animals. Modeling data are collected starting with the initial amount of the radiopharmaceutical of interest that is injected into the animal. The percentage of the radionuclide that is taken up by the source organ is determined through imaging. Other pertinent data are collected through assays of blood and urine. These data points are then carefully plotted or fitted to an established mathematical model that describes the biokinetics of the radionuclides in each source organ. Complex regulatory requirements regarding human research subjects dictate that dose estimates in human subjects should con- ducted after successful animal studies. Many radiopharmaceuticals are not directly studied for pediatric applications because of complicated social and ethical issues related to conducting radiation research in children. A wealth of information concerning internal dosimetry for the most commonly used radionuclides in nuclear medicine has been estab- lished and published, including dosimetry data for radionuclides used in positron emission tomography (PET) scanning (3–6). Pediatric dose estimates have also been calculated for different age groups based on adult biokinetics of radiopharmaceuticals and anatomic phantom models. Researchers have observed the differences between pediatric biokinetic models and those of an adult, especially in regard to infants, and so improvements in dosimetry data for pediatric patients continue. The Annals of International Commission on Radiological Protection (ICRP) Publication 53 provides biokinetic models and lists radiation doses to patients from the most commonly used radiopharmaceuticals in nuclear medicine (7). ICRP Publication 80 recalculated 19 of the most frequently used radiopharmaceuticals from ICRP 53 and added 10 more new radiopharmaceuticals (8). Tables 4.2 to 4.4 are absorbed-dose tables of several radiopharmaceuticals used for PET imaging, adapted from ICRP80. 44 Chapter 4 Dosage of Radiopharmaceuticals and Internal Dosimetry Table 4.2. Absorbed dose of 18 F-FDG (2-fluoro-2-deoxy-D-glucose) Absorbed dose per unit activity administered 18 F 109.77min (mGy/MBq) Organ Adult 15 years 10 years 5 years 1 year Adrenals 1.2E - 021.5E - 022.4E - 02 3.8E - 02 7.2E - 02 Bladder 1.6E - 012.1E - 012.8E - 01 3.2E - 015.9E - 01 Bone surfaces 1.1E - 021.4E - 022.2E - 02 3.5E - 02 6.6E - 02 Brain 2.8E - 022.8E - 02 3.0E - 02 3.4E - 02 4.8E - 02 Breast 8.6E - 03 1.1E - 021.8E - 022.9E - 025.6E - 02 Gall bladder 1.2E - 021.5E - 022.3E - 02 3.5E - 02 6.6E - 02 GI-tract Stomach 1. 1E - 021.4E - 022.2E - 02 3.6E - 02 6.8E - 02 SI 1.3E - 021.7E - 022.7E - 02 4.1E - 02 7.7E - 02 Colon 1.3E - 021.7E - 022.7E - 02 4.0E - 02 7.4E - 02 (ULI 1.2E - 021.6E - 022.5E - 02 3.9E - 02 7.2E - 02) (LLI 1.5E - 021.9E - 022.9E - 02 4.2E - 02 7.6E - 02) Heart 6.2E - 02 8.1E - 021.2E - 012.0E - 01 3.5E - 01 Kidneys 2.1E - 022.5E - 02 3.6E - 025.4E - 02 9.6E - 02 Liver 1.1E - 021.4E - 022.2E - 02 3.7E - 02 7.0E - 02 Lungs 1.0E - 021.4E - 022.1E - 02 3.4E - 02 6.5E - 02 Muscles 1.1E - 021.4E - 022.1E - 02 3.4E - 02 6.5E - 02 Oesophagus 1.1E - 021.5E - 022.2E - 02 3.5E - 02 6.8E - 02 Ovaries 1.5E - 022.0E - 02 3.0E - 02 4.4E - 02 8.2E - 02 Pancreas 1.2E - 021.6E - 022.5E - 02 4.0E - 02 7.6E - 02 Red marrow 1.1E - 021.4E - 022.2E - 02 3.2E - 02 6.1E - 02 Skin 8.0E - 03 1.0E - 021.6E - 022.7E - 025.2E - 02 Spleen 1.1E - 021.4E - 022.2E - 02 3.6E - 02 6.9E - 02 Testes 1.2E - 021.6E - 022.6E - 02 3.8E - 02 7.3E - 02 Thymus 1.1E - 021.5E - 022.2E - 02 3.5E - 02 6.8E - 02 Thyroid 1.0E - 021.3E - 022.1E - 02 3.5E - 02 6.8E - 02 Uterus 2.1E - 022.6E - 02 3.9E - 025.5E - 021.0E - 01 Remaining organs 1.1E - 021.4E - 022.2E - 02 3.4E - 02 6.3E - 02 Effective dose 1.9E - 022.5E - 02 3.6E - 025.0E - 02 9.5E - 02 (mSv/MBq) Source: ICRP Publication 80 Radiation Dose to Patients from Radiopharmaceutical. Annals of ICRP 1998;28(3):10–49, with permission from the ICRP. X. Zhu 45 Table 4.3. Absorbed dose [methyl- 11 C]thymidine Absorbed dose per unit activity administered 11 C 20.38min (mGy/MBq) Organ Adult 15 years 10 years 5 years 1 year Adrenals 2.9E - 03 3.7E - 03 5.8E - 03 9.3E - 03 1.7E - 02 Bladder 2.3E - 03 2.7E - 03 4.3E - 03 7.1E - 03 1.3E - 02 Bone surfaces 2.4E - 03 3.0E - 03 4.7E - 03 7.6E - 03 1.5E - 02 Brain 1.9E - 03 2.4E - 03 4.0E - 03 6.7E - 03 1.3E - 02 Breast 1.8E - 03 2.3E - 03 3.6E - 03 5.9E - 03 1.1E - 02 Gall bladder 2.8E - 03 3.4E - 03 5.2E - 03 7.9E - 03 1.5E - 02 GI-tract Stomach 2.4E - 03 2.9E - 03 4.6E - 03 7.3E - 03 1.4E - 02 SI 2.4E - 03 3.1E - 03 4.9E - 03 7.8E - 03 1.5E - 02 Colon 2.4E - 03 2.9E - 03 4.7E - 03 7.4E - 03 1.4E - 02 (ULI 2.4E - 03 3.0E - 03 4.8E - 03 7.7E - 03 1.4E - 02) (LLI 2.3E - 03 2.7E - 03 4.5E - 03 7.1E - 03 1.3E - 02) Heart 3.4E - 03 4.3E - 03 6.8E - 03 1.1E - 022.0E - 02 Kidneys 1.1E - 021.3E - 021.9E - 022.8E - 025.1E - 02 Liver 5.2E - 03 6.8E - 03 1.0E - 021.6E - 022.9E - 02 Lungs 3.0E - 03 3.9E - 03 6.2E - 03 9.9E - 021.9E - 02 Muscles 2.1E - 03 2.6E - 03 4.1E - 03 6.6E - 03 1.3E - 02 Oesophagus 2.2E - 03 2.8E - 03 4.3E - 03 6.9E - 03 1.3E - 02 Ovaries 2.4E - 03 3.0E - 03 4.8E - 03 7.6E - 03 1.4E - 02 Pancreas 2.7E - 03 3.4E - 03 5.3E - 03 8.3E - 03 1.6E - 02 Red marrow 2.5E - 03 3.1E - 03 4.8E - 03 7.6E - 03 1.4E - 02 Skin 1.7E - 03 2.1E - 03 3.4E - 03 5.6E - 03 1.1E - 02 Spleen 3.0E - 03 3.7E - 03 5.9E - 03 9.6E - 03 1.8E - 02 Testes 2.0E - 03 2.5E - 03 3.9E - 03 6.2E - 03 1.2E - 02 Thymus 2.2E - 03 2.8E - 03 4.3E - 03 6.9E - 03 1.3E - 02 Thyroid 2.3E - 03 2.9E - 03 4.7E - 03 7.8E - 03 1.5E - 02 Uterus 2.4E - 03 3.0E - 03 4.8E - 03 7.6E - 03 1.4E - 02 Remaining organs 2.1E - 03 2.6E - 03 4.2E - 03 6.8E - 03 1.3E - 02 Effective dose 2.7E - 03 3.4E - 03 5 .3E - 03 8.4E - 03 1.6E - 02 (mSv/MBq) Source: ICRP Publication 80 Radiation Dose to Patients from Radiopharmaceutical. Annals of ICRP 1998;28(3):10–49, with permission from the ICRP. Table 4.4. Absorbed dose 15 O-abeled water Absorbed dose per unit activity administered 15 O 2.04min (mGy/MBq) Organ Adult 15 years 10 years 5 years 1 year Adrenals 1.4E - 03 2.2E - 03 3.1E - 03 4.3E - 03 6.6E - 03 Bladder 2.6E - 04 3.1E - 04 5.0E - 04 8.4E - 04 1.5E - 03 Bone surfaces 6.2E - 04 8.0E - 04 1.3E - 03 2.3E - 03 5.5E - 03 Brain 1.3E - 03 1.3E - 03 1.4E - 03 1.6E - 03 2.2E - 03 Breast 2.8E - 04 3.5E - 04 6.0E - 04 9.9E - 04 2.0E - 03 Gall bladder 4.5E - 04 5.5E - 04 8.6E - 04 1.4E - 03 2.7E - 03 GI-tract Stomach 7.8E - 04 2.2E - 03 3.1E - 03 5.3E - 03 1.2E - 02 SI 1.3E - 03 1.7E - 03 3.0E - 03 5.0E - 03 9.9E - 03 Colon 1.0E - 03 2.1E - 03 3.7E - 03 6.2E - 03 1.2E - 02 (ULI 1.0E - 03 2.1E - 03 3.7E - 03 6.2E - 03 1.2E - 02) (LLI 1.1E - 03 2.1E - 03 3.7E - 03 6.2E - 03 1.2E - 02) Heart 1.9E - 03 2.4E - 03 3.8E - 03 6.0E - 03 1.1E - 02 Kidneys 1.7E - 03 2.1E - 03 3.0E - 03 4.5E - 03 8.1E - 03 References 1. Cristy M, Eckerman KF. Specific absorbed fraction of energy at various ages from internal photon source. IV. Ten-year-old. Oak Ridge National Labora- tory Report ORNL/TM-8381, vol. 4, 1987. 2. Snyder WS, Ford MR, Warner GG, et al. “S” absorbed dose per unit cumu- lated activity. Nm/MIRD Pamphlet No. 11. New York: Society of Nuclear Medicine, 1975. 3. Ruotsalainen U, S uhonen-Polvi H, Eronen E, et al. Estimated radiation dose to the newborn in FDG-PET studies. J Nucl Med 1996;37:387–393. 4.Hays MT, Watson EE, Stabin M, et al. MIRD dose estimate report No. 19: radiation absorbed dose estimates from 18F-FDG. J Nucl Med 2002;43:210– 214. 5. Sorenson JA, Phelps ME. Physics in Nuclear Medicine. New York: Harcourt Brace Jovanovich, 1987. 6. Stabin MG, Stabbs JB, Toohey RE, et al. Radiation Dose for Radiopharma- ceuticals, NEREG/CR. Radiation Internal Dose Center, Oak Ridge Institute of Science and Education, 1996. 7. ICRP Publication 53, Radiation Dose to Patient from Radiopharmaceutucal, Annals of ICRP, vol. 18, pp. 1–4. New York: Elsevier, 1988. 8. ICRP Publication 80, Radiation Dose to Patients from Radiopharmaceutical, Annals of ICRP, vol. 28, p. 3. New York: Elsevier, 1998. 46 Chapter 4 Dosage of Radiopharmaceuticals and Internal Dosimetry Table 4.4. Absorbed dose 15 O-abeled water (Continued) Absorbed dose per unit activity administered 15 O 2.04min (mGy/MBq) Organ Adult 15 years 10 years 5 years 1 year Liver 1.6E - 03 2.1E - 03 3.2E - 03 4.8E - 03 9.3E - 03 Lungs 1.6E - 03 2.4E - 03 3.4E - 03 5.2E - 03 1.0E - 02 Muscles 2.9E - 04 3.7E - 04 6.1E - 04 1.0E - 03 2.0E - 03 Oesophagus 3.3E - 04 4.2E - 04 6.7E - 04 1.1E - 03 2.1E - 03 Ovaries 8.5E - 04 1.1E - 03 1.8E - 03 2.8E - 03 5.8E - 03 Pancreas 1.4E - 03 2.0E - 03 4.2E - 03 5.4E - 03 1.2E - 02 Red marrow 8.5E - 04 9.7E - 04 1.6E - 03 3.0E - 03 6.1E - 03 Skin 2.5E - 04 3.1E - 04 5.2E - 04 8.8E - 04 1.8E - 03 Spleen 1 .6E - 03 2.3E - 03 3.7E - 03 5.8E - 03 1.1E - 02 Testes 7.4E - 04 9.3E - 04 1.5E - 03 2.6E - 03 5.1E - 03 Thymus 3.3E - 04 4.2E - 04 6.7E - 04 1.1E - 03 2.1E - 03 Thyroid 1.5E - 03 2.5E - 03 3.8E - 03 8.5E - 03 1.6E - 02 Uterus 3.5E - 04 4.4E - 04 7.2E - 04 1.2E - 03 2.3E - 03 Remaining organs 4.0E - 04 5.6E - 04 9.4E - 04 1.7E - 03 2.9E - 03 Effective dose 9.3E - 04 1.4E - 03 2.3E - 03 3.8E - 03 7.7E - 03 (mSv/MBq) Source: ICRP Publication 80 Radiation Dose to Patients from Radiopharmaceutical. Annals of ICRP 1998;28(3):10–49, with permission from the ICRP. 5 Pediatric PET Research Regulations Geoffrey Levine Good intentions are necessary, but not sufficient, to conduct pediatric positron emission tomography (PET) research. This chapter provides direction to guide the process of conducting PET research in children. Code of Federal Regulations (CFR) When the executive rule-making voice of the government speaks, it does so officially through the Code of Federal Regulations (1). These are not the laws, per se, but rather the nitty gritty rules necessary to carry out the laws that are made by Congress. For example, Congress may pass a law to provide for a safe drug supply; the executive branch (e.g., the Food and Drug Administration, FDA) carries out the intent of the law and writes the rules (e.g., “Intravenous products shall be sterile and pyrogen-free”). Reading 21 CFR (Title 21 of the CFR, where the FDArules are located) is about as exciting as reading the telephone book or the Inter- nal Revenue Service regulations for preparing tax returns (until you come to that one paragraph that appears to justify your objective), but it is necessary. The judicial system interprets the regulations and may enforce compliance. Each agency of the executive branch of the gov- ernment or each specific purpose for a set of regulations has a partic- ular location. Title 10, for example, is where one finds radiation safety and safe use of radiopharmaceutical use in humans. Table 5.1 provides an example of several other locations within the CFR that may be of interest to the reader (3). In addition to the CFR, the various agencies issue letters, guidelines, interpretations, descriptions of courses, com- ments, request for comments, etc., in an effort to communicate with the public and research investigators, among others. And, like cement, the rules become more solidified with time. Occasionally, the book is opened for a rewrite, providing a glimpse into the “mind” of the gov- ernment. One such opportunity appeared on November 16, 2004, in an open meeting at the FDAheadquarters in which an update of the Radioactive Drug Research Committee (RDRC) regulations was being 47 48 Chapter 5Pediatric PET Research Regulations Table 5.1. Some additional examples of codified federal policy 07 CFR Part 1C Department of Agriculture 10 CFR Part 35 Human Use of Radiopharmaceuticals 10 CFR Part 745 Department of Energy 15 CFR Part 27 Department of Commerce 16 CFR Part 1028 Consumer Product Safety Commission 21 CFR Part 361.1 Radiopharmaceutical Use in Humans 40 CFR Part 26 Environmental Protection Agency 45 C FR Part 46 Public Welfare, Protection of Human Subjects 45 CFR Part 690 National Science Foundation Note:There are source documents, regulations, amendments to regulations, Web sites, parts, subparts, preliminary documents for review, rewrites, updates, clarifications, and numerous other forms of communication. Source: Data from ref. 2. considered (4). The regulations will be examined shortly, particularly as they relate to PET research in children. Table 5.2 provides a resource list to facilitate communication (4,5,14). Pathways Allowed by the Federal Regulatory System There are three major routes to conduct research that are allowed by the federal regulatory system: (1) an investigational new drug (IND) application, (2) a physician-sponsored IND, and (3) the RDRC mecha- nism (6–8,15–21). The full IND approach is the one taken by drug manufacturers who intend to obtain FDA approval to market a pharmaceutical to the general public, usually for commercial purposes. The manufacturer conducts physical, chemical, and biologic studies in vitro and then in animals prior to studies in humans (clinical trials, phases I, II, III described below), followed by postmarketing studies (phase IV), post–new drug approval. The pharmaceutical house has sufficient talent, expertise, and staff in its regulatory and medical departments to know how to proceed on its own. Asecond pathway is the physician-sponsored IND, which usually involves studies with more than 30 subjects, can be conducted at one or multiple sites, and can involve agents that are new entities, new routes of administration, new dosage forms for existing or new drugs, new populations (including children) or disease states, new indica- tions, etc. The physician or other qualified investigator (with a physi- cian as co-investigator) is usually medical center or hospital based and will be required to fill out FDAforms 1571, 1572, and 1573 among pos- sibly others. This process of how to compile, assemble, complete and submit the physician-sponsored IND has been reviewed broadly and in detail elsewhere (15). A third pathway is the RDRC approach. Using this mechanism, the FDA delegates authority to a local committee to approve research studies (usually up to 30 patients, although the number can be higher under certain circumstances, for example, if FDAform 2915 is com- pleted). The composition of the membership of that committee has FDA prior approval. Authority is given by this committee to investi- gators to conduct only phase I and phase II clinical trials, meeting very strict and specific criteria (see below). Under no circumstances are the results from such studies to be used to make clinical decisions for any of the participants in the study until the study is completed and the data are analyzed. In theory, the findings are investigational and remain unproven at this point. It is possible that approved clinical methods used to validate the research finding may be clinically helpful or of benefit to a study participant. For example, the findings from a computed tomography (CT) scan used to study the metabolism and distribution of a new diagnostic radiopharmaceutical such as a radio- labeled monoclonal antibody that was designed to locate a tumor, may find their way to the patient’s or subject’s medical record, but not infor- mation provided by the radiolabeled monoclonal antibody. This RDRC G. Levine 49 Table 5.2. Selected reference sites and sources relative to pediatric PET research Food and Drug Administration (December, 2004) Main telephone number 1-888-INFO-FDA E-mail http://www.FDA.gov Drug information telephone number 1-301-827-4570 Pediatric Drug Development (PDD) 1-301-594-PEDS (7337) E-mail Pdit@cder.FDA.gov Division of Drug Imaging and DMIRPD, RDRC Drug Program Radiopharmaceutical Drug Products (DMIRPD) E-mail http://www.FDA. gov/cder/ regulatory/RDRC/default.htm. Radioactive Drug Research Program Address Food and Drug Administration Center for Drug Evaluation and Research Division of Medical Imaging and Radiopharmaceutical Drug Products HFD-160 Parklawn Building, Room 18R-45 5600 Fishers Lane Rockville, MD 20852 Attention: RDRC Team Director Geor ge Mills, MD Senior manager Capt. Richard Fejka, USPHS, RPh, BCNP Clinical trials Government http://www.Clinicaltrials.gov United Healthcare Foundation http://www.Unitedhealth- carefoundation.org/emb.html Books Kowalsky RJ, Falen SW. Radiopharmaceuticals in Nuclear Pharmacy, 2nd ed. Available from the American Pharmaceutical and Nuclear Medicine Association, Washington, D.C. http://www.pharmacist.com/store/cfm Clinical evidence by the evidence-based update on more tha n 1000 medical conditions including clinical trials. British Medical Journal. Free of charge to healthcare professionals. http://www.unitedhealthcarefoundation.org/Emb.html Legislative Information Gateway to the Congressional Record and Congressional Committee Information. http://thomas.loc.gov Source: Data from refs. 4–13. [...]... the research (21 CFR 50. 52) (5) References 1 Best Pharmaceuticals for Children Act Public Law 10 7-1 09 In: 115 Stat 107th Congress 20 02: 1408–1 424 2 Pediatric Research Equity Act of 20 03 Public Law 10 8-1 55 In: 117 Stat 108th Congress 20 03:1936–1943 3 Roberts R, Rodriguez W, Murphy D, Crescenzi T Pediatric drug labeling: improving the safety and efficacy of pediatric therapies JAMA 20 03 ;29 0(7): 905–911... cancer risks from diagnostic radiology Pediatr Radiol 20 02; 32( 10):700–706 13 Pierce DA, Preston DL Radiation-related cancer risks at low doses among atomic bomb survivors Radiat Res 20 00;154 (2) :178–186 14 Brenner DJ Estimating cancer risks from pediatric CT: going from the qualitative to the quantitative Pediatr Radiol 20 02; 32( 4) :22 8 22 3; discussion 42 44 15 Brenner DJ, Doll R, Goodhead DT, et al Cancer... Mozley PD, et al Biodistribution and imaging with ( 123 )I-ADAM: a serotonin transporter imaging agent J Nucl Med 20 04; 45(5):834–841 10 Seltzer MA, Jahan SA, Sparks R, et al Radiation dose estimates in humans for (11)C-acetate whole-body PET J Nucl Med 20 04;45(7): 123 3– 123 6 11 Herzog P, Rieger CT Risk of cancer from diagnostic x-rays Lancet 20 04;363(9406):340–341 12 Hall EJ Lessons we have learned from... PA, July 15, 20 04 http://ohrp.sosphs.dhhs.gov/humansubjects/ guidance/45cfr46.htm 22 COX -2 inhibitors under scrutiny in wake of Rofecoxib withdrawal APhA Drug Info Line 20 04;1 2 23 Food and Drug Administration Modernization Act of 1997 Title 21 Section 121 Positron emission tomography http://www.fda.gov/cder/ regulatory /Pet/ petlaw.html 24 Radiopharmaceuticals for positron emission tomography-compounding... pediatric indication is for localization of seizure foci in epilepsy The recommended dose of 2. 6 mCi would result in an estimated absorbed radiation dose to the urinary bladder (as the organ with the highest exposure across all age groups) of 11 .2 rem in a newborn (3.4 kg), 4.4 rem in a 1-year-old (9.8 kg), 2. 4 rem in a 5-year-old (19 kg), 1.6 rem in a 10-year-old ( 32 kg), and 1.0 rem in a 15-year-old... 20 03;85(1):15 22 18 Cohen BL Cancer risk from low-level radiation AJR 20 02; 179(5):1137–1143 19 Frush DP, Donnelly LF, Rosen NS Computed tomography and radiation risks: what pediatric health care providers should know Pediatrics 20 03; 1 12( 4):951–957 20 Charron M, Lentle BC Is it really this simple? Pediatr Radiol 20 03; 33(11):811–814; author reply 5–7 21 de Gonzalez AB, Darby S Risk of cancer from diagnostic x-rays:... Chapter 823 US Pharmacopeia 20 /National Formulary 25 , 20 02 25 Update—new fludeoxyglucose F-18 injection PET drug approved in less than 6 months http://fda.gov/cder/regulatory /pet/ Fludeoxyglucose htm 26 Swanson DP Radioactive drug research committee/human use subcommittee meeting minutes University of Pittsburgh Pittsburgh, PA, November 17, 20 04 6 Issues in the Institutional Review Board Review of PET Scan... of 18F-FDG within these dosage guidelines would not require an IND application (assuming all of the conditions of 21 CFR 3 12. 2 are met), even for other pediatric indications However, an IND would be required for all other PET drugs The requirement for an IND application as part of pediatric PET drug development creates both a regulatory and financial burden It is unlikely that 21 CFR 3 12 and 21 CFR... to successful treatment by partial pancreatectomy J Pediatr Surg 20 04;39(3): 27 0 27 5 30 Stabin MG, Gelfand MJ Dosimetry of pediatric nuclear medicine procedures Q J Nucl Med 1998; 42( 2):93–1 12 31 Royal HD Radiation Dose Limits for Adult Subjects 20 04 http://www fda.gov/cder/meeting/clinicalResearch/royal1.ppt 32 Gelfand MJ Pediatric Nuclear Medicine and the RDRC Regulations 20 04 http://www.fda.gov/cder/meeting/clinicalResearch/gelfand.ppt... Industry Cambridge: Cambridge University Press, 20 05 27 Ross LF Do healthy children deserve greater protection in medical research? [see comment] J Pediatr 20 03;1 42( 2):108–1 12 28 Fekete CN, de Lonlay P, Jaubert F, Rahier J, Brunelle F, Saudubray JM The surgical management of congenital hyperinsulinemic hypoglycemia in infancy J Pediatr Surg 20 04;39(3) :26 7 26 9 29 Adzick NS, Thornton PS, Stanley CA, Kaye . 1.2E - 021 .6E - 022 .5E - 02 4.0E - 02 7.6E - 02 Red marrow 1.1E - 021 .4E - 022 .2E - 02 3.2E - 02 6.1E - 02 Skin 8.0E - 03 1.0E - 021 .6E - 022 .7E - 025 .2E - 02 Spleen 1.1E - 021 .4E - 022 .2E - 02. 022 .7E - 02 4.1E - 02 7.7E - 02 Colon 1.3E - 021 .7E - 022 .7E - 02 4.0E - 02 7.4E - 02 (ULI 1.2E - 021 .6E - 022 .5E - 02 3.9E - 02 7.2E - 02) (LLI 1.5E - 021 .9E - 022 .9E - 02 4.2E - 02 7.6E - 02) Heart. 6.2E - 02 8.1E - 021 .2E - 0 12. 0E - 01 3.5E - 01 Kidneys 2. 1E - 022 .5E - 02 3.6E - 025 .4E - 02 9.6E - 02 Liver 1.1E - 021 .4E - 022 .2E - 02 3.7E - 02 7.0E - 02 Lungs 1.0E - 021 .4E - 022 .1E - 02