1 radiopharmaceuticals

15
1 Radiopharmaceuticals portray physiology, biochemistry, or pathology in the body without causing any physiological effect. They are referred to as radiotracers because they are given in subpharmacological doses that “trace” a particular physiological or pathological process in the body. This chapter presents general principles regarding radio- nuclides and radiopharmaceuticals, their production, radiolabeling, quality assurance, dispensing, and radiation safety. ELEMENTS, RADIONUCLIDES, AND RADIOPHARMACEUTICALS Most radiopharmaceuticals are a combination of a radioac- tive molecule, a radionuclide, that permits external detec- tion and a biologically active molecule or drug that acts as a carrier and determines localization and biodistribution. For a few radiotracers (e.g., radioiodine, gallium, and thal- lium), the radioactive atoms themselves confer the desired localization properties. Both naturally occurring and syn- thetic molecules can potentially be radiolabeled. Different types of atoms are called elements. Different types of nuclei are termed nuclides. An element is charac- terized by its atomic number (Z)—that is, the number of protons in the nucleus. The atomic number specifies the position of the element in the periodic table (Fig. 1-1). A nuclide is characterized by its atomic number and mass number (A)—that is, protons plus neutrons in the nucleus. Nuclides with the same number of protons are called iso- topes and belong to the same element (Box 1-1). Unstable nuclides are called radionuclides. Radionuclides try to become stable by emitting electromagnetic radiation or charged particles during radioactive decay. Radioactivity is the spontaneous emission of radiation given off by radionuclides. Radiopharmaceutical mechanisms of localization impor- tant to clinical practice are listed in Table 1-1. Understand- ing the mechanism and rationale for the use of each agent is critical to understanding the normal and pathological findings demonstrated scintigraphically. Radiopharmaceuticals must be approved by the U.S. Food and Drug Administration (FDA) before they can be commercially produced and used for human clinical or research purposes. Desired Attributes of Radiopharmaceuticals Certain characteristics are desirable for clinically useful radiopharmaceuticals. Radionuclide decay should result in gamma emissions of suitable energy (100-200 keV is ideal for gamma cameras and 511 keV for positron emission tomography [PET]) and sufficient abundance (percent likelihood of emissions per decay) for external detection. It should not contain particulate radiation (e.g., beta emis- sions), which increases patient radiation dose, although beta emissions are suitable for therapeutic radiopharma- ceuticals. The effective half-life should be long enough for only the intended application, usually a few hours. The radionuclide should be carrier-free—that is, it is not contaminated by either stable radionuclides or other radionu- clides of the same element. Carrier material can negatively influence biodistribution and labeling efficiency. It should have high specific activity—that is, radioactivity per unit weight (mCi/mg). A carrier-free radionuclide has the highest specific activity. Technetium-99m most closely matches these desir- able features for the gamma camera and fluorine-18 for PET. The pharmaceutical component should be free of any toxicity or physiological effects. The radiopharmaceutical should not disassociate in vitro or in vivo and should be readily available or easily compounded. The radiopharma- ceutical should rapidly and specifically localize according to the intended application. Background clearance should be rapid, leading to good target-to-background ratios. PRODUCTION OF RADIONUCLIDES Naturally occurring radionuclides (e.g., uranium, actinium, thorium, radium, and radon) are heavy, toxic elements with very long half-lives (>1000 years). They have no clini- cal role in diagnostic nuclear medicine. Radionuclides commonly used clinically are artificially produced by nuclear fission or through the bombardment of stable materials by neutrons or charged particles. Neutron bombardment of enriched uranium-235 results in fission products located in the middle of the atomic chart (Fig. 1-1). Bombardment of medium–atomic-weight nuclides with low-energy neutrons (neutron activation) in a nuclear reactor results in neutron-rich radionuclides. Neutron-rich radionuclides (e.g., iodine-131, xenon-133, CHAPTER 1 Radiopharmaceuticals   Part I Basic Principles

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Page 1: 1 radiopharmaceuticals

Chapter 1

Radiopharmaceuticals  

Part I

Basic Principles

Radiopharmaceuticals portray physiology, biochemistry, or pathology in the body without causing any physiological effect. They are referred to as radiotracers because they are given in subpharmacological doses that “trace” a particular physiological or pathological process in the body.

This chapter presents general principles regarding radio-nuclides and radiopharmaceuticals, their production, radiolabeling, quality assurance, dispensing, and radiation safety.

ELEMENTS, RADIONUCLIDES, AND RADIOPHARMACEUTICALS

Most radiopharmaceuticals are a combination of a radioac-tive molecule, a radionuclide, that permits external detec-tion and a biologically active molecule or drug that acts as a carrier and determines localization and biodistribution. For a few radiotracers (e.g., radioiodine, gallium, and thal-lium), the radioactive atoms themselves confer the desired localization properties. Both naturally occurring and syn-thetic molecules can potentially be radiolabeled.

Different types of atoms are called elements. Different types of nuclei are termed nuclides. An element is charac-terized by its atomic number (Z)—that is, the number of protons in the nucleus. The atomic number specifies the position of the element in the periodic table (Fig. 1-1). A nuclide is characterized by its atomic number and mass number (A)—that is, protons plus neutrons in the nucleus. Nuclides with the same number of protons are called iso-topes and belong to the same element (Box 1-1). Unstable nuclides are called radionuclides. Radionuclides try to become stable by emitting electromagnetic radiation or charged particles during radioactive decay. Radioactivity is the spontaneous emission of radiation given off by radionuclides.

Radiopharmaceutical mechanisms of localization impor-tant to clinical practice are listed in Table 1-1. Understand-ing the mechanism and rationale for the use of each agent is critical to understanding the normal and pathological findings demonstrated scintigraphically.

Radiopharmaceuticals must be approved by the U.S. Food and Drug Administration (FDA) before they can be commercially produced and used for human clinical or research purposes.

1

Desired Attributes of Radiopharmaceuticals

Certain characteristics are desirable for clinically useful radiopharmaceuticals. Radionuclide decay should result in gamma emissions of suitable energy (100-200 keV is ideal for gamma cameras and 511 keV for positron emission tomography [PET]) and sufficient abundance (percent likelihood of emissions per decay) for external detection. It should not contain particulate radiation (e.g., beta emis-sions), which increases patient radiation dose, although beta emissions are suitable for therapeutic radiopharma-ceuticals. The effective half-life should be long enough for only the intended application, usually a few hours.

The radionuclide should be carrier-free—that is, it is not contaminated by either stable radionuclides or other radionu-clides of the same element. Carrier material can negatively influence biodistribution and labeling efficiency. It should have high specific activity—that is, radioactivity per unit weight (mCi/mg). A carrier-free radionuclide has the highest specific activity. Technetium-99m most closely matches these desir-able features for the gamma camera and fluorine-18 for PET.

The pharmaceutical component should be free of any toxicity or physiological effects. The radiopharmaceutical should not disassociate in vitro or in vivo and should be readily available or easily compounded. The radiopharma-ceutical should rapidly and specifically localize according to the intended application. Background clearance should be rapid, leading to good target-to-background ratios.

PRODUCTION OF RADIONUCLIDES

Naturally occurring radionuclides (e.g., uranium, actinium, thorium, radium, and radon) are heavy, toxic elements with very long half-lives (>1000 years). They have no clini-cal role in diagnostic nuclear medicine. Radionuclides commonly used clinically are artificially produced by nuclear fission or through the bombardment of stable materials by neutrons or charged particles.

Neutron bombardment of enriched uranium-235 results in fission products located in the middle of the atomic chart (Fig. 1-1). Bombardment of medium–atomic-weight nuclides with low-energy neutrons (neutron activation) in a nuclear reactor results in neutron-rich radionuclides. Neutron-rich radionuclides (e.g., iodine-131, xenon-133,

Page 2: 1 radiopharmaceuticals

2  Nuclear Medicine: The Requisites

Figure 1-1. Periodic table. Highlighted elements have radionuclides commonly used in nuclear medicine.

chromium-51, and molybdenum-99) generated through fis-sion or neutron activation undergo beta-minus decay. Charged particle bombardment (with protons, deuterons, alpha particles) to a wide variety of target materials in cyclo-trons or other special accelerators produces proton-rich radio-nuclides that will undergo positron decay (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18) or electron capture (e.g., iodine-123, gallium-67, thallium-201, and indium-111).

The production source and physical characteristics of commonly used radionuclides in clinical nuclear medicine practice are summarized in Tables 1-2 and 1-3.

RADIONUCLIDE GENERATORS

One of the practical issues faced in nuclear medicine is the desirability of using relatively short-lived agents (i.e., hours rather than days or weeks) and at the same time the need to have radiopharmaceuticals delivered to hospi-tals or clinics from commercial sources. One way around

Box 1-1. Radionuclides and Isotopes

(Protons + Neutrons)(Protons)

AZX 131

53 Iodine

12353 Iodine 127

53 Iodine

An element is characterized by its atomic number (Z).A nuclide is characterized by its mass number (A) and

its atomic number (Z).131I, 123I, and 127I are isotopes of iodine and unstable

radionuclides.127I is stable iodine.

Table 1-1   Mechanisms of Radiopharmaceutical Localization

Mechanism Applications or examples

Compartmental localization Blood pool imaging, direct cystography

Passive diffusion (concentration dependent)

Blood–brain barrier breakdown, glomerular filtration, cisternography

Capillary blockade (physical entrapment)

Perfusion imaging of lungs

Physical leakage from a luminal compartment

Gastrointestinal bleeding, detection of urinary tract or biliary system leakage

Metabolism Glucose, fatty acids

Active transport (active cellular uptake)

Hepatobiliary imaging, renal tubular function, thyroid and adrenal imaging

Chemical bonding and adsorption Skeletal imaging

Cell sequestration Splenic imaging (heat- damaged red blood cells), white blood cells

Receptor binding and storage Adrenal medullary imaging, somatostatin receptor imaging

Phagocytosis Reticuloendothelial system imaging

Antigen-antibody Tumor imaging

Multiple mechanisms

Perfusion and active transport Myocardial imaging

Active transport and metabolism Thyroid uptake and imaging

Active transport and secretion Hepatobiliary imaging, salivary gland imaging

Page 3: 1 radiopharmaceuticals

radiopharmaceuTicals 3

Table 1-2   Physical Characteristics of Single-Photon Radionuclides Used in Clinical Nuclear Medicine

Radionuclide Principal mode of decay Physical half-lifePrincipal photon energy in keV

(abundance) (%) Production method

Mo-99 Beta minus 2.8 days 740 (12), 780 (4) Reactor

Tc-99m Isomeric transition 6 hr 140 (89) Generator (Mo-99)

I-131 Beta minus 8 days 364 (81) Reactor

I-123 Electron capture 13.2 hr 159 (83) Cyclotron

Ga-67 Electron capture 78.3 hr 93 (37), 185 (20), 300 (17), 395 (5) Cyclotron

Tl-201 Electron capture 73.1 hr 69-83 (Hg x-rays), 135 (2.5), 167 (10) Cyclotron

In-111 Electron capture 2.8 days 171 (90), 245 (94) Cyclotron

Xe-127 Electron capture 36 days 172 (26), 203 (7), 375 (17) Cyclotron

Xe-133 Beta minus 5.2 days 81 (37) Reactor

Co-57 Electron capture 272 days 122 (86) Cyclotron

Table 1-3   Positron-Emitting Radionuclides: Physical Characteristics

Radionuclide Physical half-life (min) Positron energy (MeV) Range in soft tissue (mm) Production method

C-11 20 0.96 4.1 Cyclotron

N-13 10 1.19 5.4 Cyclotron

O-15 2 1.73 7.3 Cyclotron

F-18 110 0.635 2.4 Cyclotron

Ga-68 68 1.9 8.1 Generator (Ge-68)

Rb-82 1.3 3.15 15.0 Generator (Sr-82)

this dilemma is the use of radionuclide generator systems. These systems consist of a longer-lived parent and a shorter-lived daughter. With this combination of half-lives, the generator can be shipped from a commercial vendor and the daughter product will still have a useful half-life for clinical applications. Although various generator systems have been developed over the years (Table 1-4), to date, the most important is the Mo-99/Tc-99m system.

Molybdenum-99/Technetium-99m Generator Systems

Mo-99 is produced by the fission of U-235. The product is often referred to as fission moly. The reaction is U-235 (n, fission) → Mo-99. After Mo-99 is produced in the fission reaction, it is chemically purified and passed on to an ion

Table 1-4  Radionuclide Generator Systems and Parent and Daughter Half-Lives

Parent Parent half-life Daughter Daughter half-life

Mo-99 66 hr Tc-99m 6 hr

Rb-81 4.5 hr Kr-81m 13 sec

Ge-68 270 days Ga-68 68 min

Sr-82 25 days Rb-82 1.3 min

exchange column composed of alumina (Al2O3) (Table 1-5). The column is typically adjusted to an acid pH to promote binding. The positive charge of the alumina binds the molybdate ions firmly. The loaded column is placed in a lead container with tubing attached at each end to permit column elution.

Table 1-5  Molybdenum-99/Technetium-99m Generator Systems

Radionuclides Parent (Mo-99) Daughter (Tc-99m)

Half-life 66 hr 6 hr

Mode of decay Beta minus Isomeric transition

Daughter products Tc-99m, Tc-99 Tc-99

Principal photon energies*

740 keV, 780 keV 140 keV (89%)

Generator Function

Composition of ion exchange column

Al2O3

Eluent Normal saline (0.9%)

Time from elution to maximum daughter yield

23 hr

*The decay scheme for Mo-99 is complex, with over 35 gamma rays of differ-ent energies given off. The listed energies are those used in clinical practice for radionuclide purity checks.

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4  Nuclear Medicine: The Requisites

Generator Operation and Yield

The relationship between Mo-99 decay and the ingrowth of Tc-99m is illustrated in Figure 1-2. Maximum buildup of Tc-99m activity occurs at 23 hours after elution. This time point is convenient, especially if sufficient Tc-99m activity is available to accomplish each day’s work. Other-wise, the generator can be eluted, or “milked,” more than once per day. Partial elution is also illustrated in Figure 1-2. Fifty percent of maximum is reached in approximately 4.5 hours, and 75% of maximum is available at 8.5 hours.

Although greatest attention is paid to the rate of Tc-99m buildup, Tc-99m is constantly decaying, with buildup of stable Tc-99 (or “carrier” Tc-99) in the generator. Genera-tors received after commercial shipment or generators that have not been eluted for several days have significant car-rier Tc-99 in the eluate. Because the carrier Tc-99 behaves chemically similarly to Tc-99m, it can compete and adversely affect radiopharmaceutical labeling efficiency. Many labeling procedures require the reduction of Tc-99m from a +7 valence state to a lower valence state. If the elu-ate contains sufficient carrier Tc-99, complete reduction may not occur, resulting in poor labeling and undesired radiochemical contaminants in the final preparation.

Two types of generator systems are available with respect to elution. “Wet” systems, today most commonly used in regional radiopharmacies, come with a reservoir of normal saline (0.9%) (Fig. 1-3). Elution is accomplished by placing a special sterile vacuum vial on the exit or collec-tion port. The vacuum vial is designed to draw the appro-priate amount of saline across the column.

In “dry” systems, common in imaging clinics, a volume-calibrated saline charge is placed on the entry port and a vacuum vial is placed on the collection port (Fig. 1-4). The vacuum draws the saline eluent out of the original vial, across the column, and into the elution vial. Elution vol-umes are in the range of 5 to 20 mL. Elutions can be per-formed for add-on or emergency studies that are required in the course of a day (Fig. 1-2). The amount of Tc-99m activity available from a generator decreases each day as a result of decay of the Mo-99 parent (Fig. 1-2). In practice,

Ingrowth

Maximum activityat 23 hr

Mo-99 decayT1/2 � 2.8 days

Tc-99mT1/2 � 6 hr elution Elution

10

0.2

Rel

ativ

e ac

tivity 0.5

1.0

0.120 30 40

Time (hr)

50 60 70 80

Partialelution

Figure 1-2. Decay curve for Mo-99 and ingrowth curves for Tc-99m. Successive elutions, including a partial elution are illustrated. Relative activity is plotted on a logarithmic scale, accounting for the straight line of Mo-99 decay.

the 2.8-day half-life of Mo-99 allows generators to be used for 2 weeks.

Quality Control

Rigorous quality control is performed before commercial generator shipment; however, each laboratory must per-form quality control steps each time the generator is eluted, to meet various federal and state regulatory guide-lines (Table 1-6).

Radionuclide PurityThe only desired radionuclide in the Mo-99/Tc-99m gen-erator eluate is Tc-99m. Any other radionuclide in the sample is considered a radionuclide impurity and is unde-sirable because it will result in additional radiation expo-sure to the patient without clinical benefit.

The most common radionuclide contaminant in the gen-erator eluate is the parent radionuclide, Mo-99. Tc-99, the daughter product of the isomeric transition of Tc-99m, is also present but is not considered an impurity or contami-nant. Although Tc-99 can be a problem from a chemical standpoint in radiolabeling procedures, it is not a problem from a radiation or health standpoint and is not tested for as a radionuclide impurity. The half-life of Tc-99 is 2.1 × 105 years. It decays to ruthenium-99, which is stable.

The amount of parent Mo-99m in the eluate should be as small as possible, because any contamination by a long-lived radionuclide increases the radiation dose without pro-viding any benefit to the patient. The Nuclear Regulatory Commission (NRC) sets limits on the amount of Mo-99 in the eluate, and this must be tested on each elution. The easiest and most widely used approach is to take advantage of the energetic 740- and 780-keV gamma rays of Mo-99 with dual counting of the specimen. The generator eluate

30-mLevacuated

vial

500-mLreservoir

0.9% saline

Leadshield

Leadshield

Filter

Mo-99bound

toaluminaanion

exchangecolumn

Figure 1-3. Wet radionuclide generator system.

Page 5: 1 radiopharmaceuticals

is placed in a lead container designed so that all of the 140-keV photons of technetium are absorbed but approximately 50% of the more energetic Mo-99 gamma rays can pene-trate. Adjusting the dose calibrator to the Mo-99 setting provides an estimate of the number of microcuries of Mo-99 in the sample. The unshielded sample is then mea-sured on the Tc-99m setting, and a ratio of Mo-99 to Tc-99m activity can be calculated.

The NRC limit is 0.15 μCi of Mo-99 activity per 1 mCi of Tc-99m activity in the administered dose. Because the half-life of Mo-99 is longer than that of Tc-99m, the ratio increases with time. If the initial reading shows near- maximum Mo-99 levels, either the actual dose to be given

Lead shield

Lead shield

30-mLevacuatedvial

Saline

Filter

Mo-99bound

toaluminaanion

exchangecolumn

Figure 1-4. Dry radionuclide generator system.

Table 1-6  Purity Checks: Molybdenum-99/Technetium-99m Generator

Purity checks Problem Standard

Radionuclide purity

Excessive Mo-99 in eluent

<0.15 μCi Mo-99/mCi Tc-99m at time of administration

Chemical purity Al2O3 from generator ion exchange column in elution

<10 μg/mL (fission generator) (aurin tricarboxylic acid spot test)

Radiochemical purity

Reduced oxidation states of Tc-99m (i.e., +4, +5, or +6 instead of +7)

95% of Tc-99m activity should be in +7 oxidation state

radiopharmaceuTicals 5

to the patient should be restudied before administration or the buildup factor should be computed mathemati-cally. From a practical standpoint, the Mo-99 activity may be taken as unchanged and the Tc-99m decay calculated (Table 1-7). Breakthrough is rare but unpredictable. When it does occur, Mo-99 levels can be far higher than the legal limit.

Chemical PurityA routine quality assurance step is to measure the genera-tor eluate for the presence of the column packing material, Al2O3. Colorimetric qualitative spot testing determines if unacceptable levels are present. Excessive aluminum lev-els may interfere with the normal distribution of certain radiopharmaceuticals—for example, increased lung activ-ity with Tc-99m sulfur colloid and liver uptake with Tc-99m methylene diphosphonate (Tc-99m MDP).

Radiochemical PurityWhen Tc-99m is eluted from the generator, its expected valence state is +7, in the chemical form of pertechnetate (TcO−

4). The clinical use of sodium pertechnetate as a radiopharmaceutical and the preparation of Tc-99m –labeled pharmaceuticals from commercial kits are based on the +7 oxidation state. The United States Pharmacopeia (USP) standard for the generator eluate is that 95% or more of Tc-99m activity be in this +7 state. Reduction states at +4, +5, or +6 result in impurities. These reduction states can be detected by thin-layer chromatography. Prob-lems with radiochemical purity of the generator eluate are infrequently encountered but should be considered if kit labeling is poor. Measures of pharmaceutical purity are summarized in Table 1-8.

TECHNETIUM CHEMISTRY AND RADIOPHARMACEUTICAL PREPARATION

Tc-99m is the most commonly used radionuclide because of its ready availability, the favorable energy of its principal

Table 1-7   Physical Decay of Technetium-99m

Time (hr) Fraction remaining

0 1.000

1 0.891

2 0.794

3 0.708

4 0.631

5 0.532

6 0.501

7 0.447

8 0.398

9 0.355

10 0.316

11 0.282

12 0.251

Tc-99m physical half-life = 6.02 hr.

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6  Nuclear Medicine: The Requisites

Table 1-8   Measures of Pharmaceutical Purity

Parameter Definition Example issues

Chemical purity Fraction of wanted vs. unwanted chemical in preparation Amount of alumina breakthrough in Mo-99/Tc-99m generator eluate

Radiochemical purity Fraction of total radioactivity in desired chemical form Amount of bound vs. unbound Tc-99m in Tc-99m diphosphonate

Radionuclide purity Fraction of total radioactivity in the form of desired radionuclide

Ratio of Tc-99m vs. Mo-99 in generator eluate; I-124 in an I-123 preparation

Physical purity Fraction of total pharmaceutical in desired physical form Correct particle size distribution in Tc-99m MAA preparation; absence of particulate contaminates in any a solution

Biological purity Absence of microorganisms and pyrogens Sterile, pyrogen-free preparations

MAA, Macroaggregated albumin.

Table 1-9   Technetium-99m Radiopharmaceuticals

Agent Application

Tc-99m sodium pertechnetate Meckel’s diverticulum detection, salivary and thyroid gland scintigraphy

Tc-99m sulfur colloid Lymphoscintigraphy

Liver/spleen scintigraphy, bone marrow scintigraphy

Tc-99m diphosphonate Skeletal scintigraphy

Tc-99m macroaggregated albumin (MAA) Pulmonary perfusion scintigraphy, liver intraarterial perfusion scintigraphy,

Tc-99m red blood cells Radionuclide ventriculography, gastrointestinal bleeding, hepatic hemangioma

Tc-99m diethylenetriamine-pentaacetic acid (DTPA) Renal dynamic scintigraphy, lung ventilation (aerosol), glomerular filtration rate

Tc-99m mercaptoacetyltriglycine (MAG3) Renal dynamic scintigraphy

Tc-99m dimercaptosuccinic acid (DMSA) Renal cortical scintigraphy

Tc-99m iminodiacetic acid (HIDA) Hepatobiliary scintigraphy

Tc-99m sestamibi (Cardiolite) Myocardial perfusion scintigraphy, breast imaging

Tc-99m tetrofosmin (Myoview) Myocardial perfusion scintigraphy

Tc-99m exametazime (HMPAO) Cerebral perfusion scintigraphy, white blood cell labeling

Tc-99m bicisate (ECD) Cerebral perfusion scintigraphy

ECD, Ethyl cysteinate dimer; HMPAO, hexamethylpropyleneamine oxime.

gamma photon (140 keV), its favorable dosimetry with lack of primary particulate radiations, and its nearly ideal half-life (6 hours) for many clinical imaging studies. How-ever, technetium chemistry is challenging. In most label-ing procedures, technetium must be reduced from the +7 valence state. The reduction is usually accomplished with stannous ion. One exception is the labeling of Tc-99m sul-fur colloid, which requires heating.

The actual final oxidation state of technetium in many radiopharmaceuticals is unclear. Some technetium com-pounds are chelates, which involve a complex bond at two or more sites on the ligand. Others are used on the basis of their empirical efficacy without complete knowledge of how technetium is being complexed in the final molecule.

The major Tc-99m–labeled radiopharmaceuticals are summarized in Table 1-9. The details of individual tech-netium radiopharmaceuticals are discussed in the chap-ters on individual organ systems and include key points in preparation and the recognition of in vivo markers of radiopharmaceutical impurities.

Commercial kits contain a reaction vial with the appropri-ate amount of stannous ion (tin), the nonradioactive phar-maceutical to be labeled, and other buffering and stabilizing agents. The vials are flushed with nitrogen to prevent atmo-spheric oxygen interrupting the reaction. The sequence of steps in a sample labeling process is illustrated in Figure 1-5. Sodium pertechnetate is drawn into a syringe and assayed in the dose calibrator. After the Tc-99m activity is confirmed, the sample is added to the reaction vial. The amount of Tc-99m activity added for each product is deter-mined by the number of patient doses desired in the case of a multidose vial, an estimate of the decrease in radioactivity caused by decay between the time of preparation and the estimated time of dosage administration, and the in vitro stability of the product. The completed product is labeled and kept in a special lead-shielded container until it is time to withdraw a sample for administration. Each patient dose is individually assayed before being dispensed.

Excessive oxygen can react directly with the stannous ion, leaving too little reducing power in the kit, which can

Page 7: 1 radiopharmaceuticals

radiopharmaceuTicals 7

Tc-99m as sodium pertechnetatefrom generator eluate

Nitrogen-purgedkit reaction vialwith nonradioactivematerials

A

Tc-99m radiopharmaceuticalready for dispensing

B

Patient dosewithdrawn fromvial

C

Syringe with radiopharmaceuticalfor the patient

Plastic shield toprevent contamination

15 mCi

Dosecalibrator

Patient dose assayedin dose calibrator before it is dispensed

DFigure 1-5. Preparation of a Tc-99m–labeled radiopharmaceutical. A, Tc-99m as sodium pertechnetate is added to the reaction vial. B, Tc-99m radio-pharmaceutical is ready for dispensing. C, The patient dose is withdrawn from the vial. D, Each dose is measured in the dose calibrator before it is dispensed.

result in unwanted free Tc-99m pertechnetate in the prep-aration. A less common problem is radiolysis after kit preparation, also resulting in free pertechnetate. The phe-nomenon is seen when high amounts of Tc-99m activity are used. The kit preparations are usually designed so that multiple doses can be prepared from one reaction vial.

QUALITY ASSURANCE OF TECHNETIUM-99M–LABELED RADIOPHARMACEUTICALS

The difficult nature of technetium chemistry highlights the importance of checking the final product for radiochemical purity, defined as the percentage of the total radioactivity in

a specimen that is in the specified or desired radiochemical form (Table 1-8). For example, if 5% of the Tc-99m activity remains as free pertechnetate in a radiolabeling procedure, the radiochemical purity would be stated as 95%, assuming no other impurities. Each radiopharmaceutical has a spe-cific radiochemical purity to meet USP standards or FDA requirements, typically 90%. Causes of radiochemical impurities include poor initial labeling, radiolysis, decom-position, pH changes, light exposure, or presence of oxidiz-ing or reducing agents.

The usual approach to assay radiochemical purity in vitro is thin-layer chromatography. Radiochromatogra-phy is performed in the same manner as conventional

Page 8: 1 radiopharmaceuticals

8  Nuclear Medicine: The Requisites

chromatography, by spotting a sample of the test material at one end of a strip. A solvent is then selected for which the desired radiochemical and the potential contaminants have known migration patterns, so the strip can be placed in a dose calibrator for counting. The radiolabel provides an easy means for quantitatively measuring the migration patterns.

In vivo radiochemical impurities contribute to back-ground activity or other unwanted localization and degrade image quality. For many agents, the presence of a radio-chemical impurity can be recognized by altered in vivo biodistribution.

For technetium radiopharmaceuticals, the presence of free pertechnetate and insoluble hydrolyzed reduced technetium moieties are tested using instant thin-layer chromatography techniques. For example, using acetone as the solvent, free pertechnetate migrates with the sol-vent front in a paper and thin-layer chromatography sys-tem, whereas Tc-99m diphosphonate and hydrolyzed reduced technetium remain at the origin (Fig. 1-6). For selective testing of hydrolyzed reduced technetium, a silica gel strip is used with saline as the solvent. In this system, both free pertechnetate and Tc-99m diphospho-nate move with the solvent front and hydrolyzed reduced technetium again stays at the origin (see Fig. 1-6). This combination of procedures allows measurement of each of the three components. Chromatography systems have been worked out for each major technetium-labeled radiopharmaceutical.

Chromatographic scanners provide detailed strip chart recording of radioactivity distribution. In practice, the

Figure 1-6. Radiochromatography for quality control of Tc-99m diphos-phonate. The count-activities on the strips are indicated by the numbers beside the strip diagram. The black dot at the bottom of each strip repre-sents the origin. Acceptable (left): 3% of the activity does not migrate with Tc-99m diphosphonate in saline, and 2% migrates as Tc-99m pertechne-tate with the solvent front using methanol: acetone. Thus 5% of the radioactivity is not present at Tc-99m diphosphonate. Unacceptable (right), 5% of the activity is present as impurities (saline chromatogram) and 22% as free pertechnetate (methanol: acetone chromatogram). This radiophar-maceutical is of unacceptable quality and should not be used clinically. The Rf (rate of flow) of a compound is the distance from the center of its activity on the strip to the origin (site of application) divided by the dis-tance from the solvent front to the origin. An Rf of 1 means that the com-pound moves with the solvent front, whereas an Rf of 0 means that the component remains at the origin.

easiest way to perform chromatography is simply to cut the chromatography strip into two pieces that can be counted separately.

SINGLE-PHOTON RADIOPHARMACEUTICALS OTHER THAN TC-99M

Radioiodine I-131 and I-123

I-131 as sodium iodide was the first radiopharmaceutical of importance in clinical nuclear medicine. It was used for physiological studies of the thyroid gland for several years in the late 1940s (Table 1-10). Subsequently, it was used to radiolabel radiopharmaceuticals for scintigraphy, including human serum albumin, MAA, hippuran, and meta-iodo-benzyl-guanidine (MIBG). These radiopharmaceuticals are no longer diagnostically used.

The disadvantages of I-131 include relatively high prin-cipal photon energy (364 keV), long half-life (8 days), and presence of beta particle emissions. However, it is an important radiopharmaceutical for the treatment of hyper-thyroidism and differentiated thyroid cancer.

Whenever possible, I-123 is substituted for I-131 for diagnostic purposes. It has a shorter half-life (13.2 hours) (Table 1-2), and its principal photon energy (159 keV) is better suited to imaging with the gamma camera. It decays by electron capture, and the dosimetry is favorable com-pared with that of I-131. Even in applications in which imaging over a period of several days allows for improved

Table 1-10  Non–Technetium-99m Radiopharmaceuticals for Single-Photon Imaging

Agent Application

Diagnostic

Xe-133 xenon (inert gas) Pulmonary ventilation scintigraphy

Xe-127 xenon (inert gas) Pulmonary ventilation scintigraphy

Kr-81m krypton (inert gas) Pulmonary ventilation scintigraphy

I-123 sodium iodide Thyroid scintigraphy, thyroid uptake function studies

In-111 oxine leukocytes Inflammatory disease and infection detection

I-123 meta-iodo-benzyl- guanidine (MIBG)

Adrenal medullary tumor imaging

In-111 pentetreotide (OctreoScan)

Somatostatin receptor tumor imaging

I-123 ioflupane (DaTscan) Dopamine transporter receptor imaging for Parkinson disease and parkinsonian syndromes

Therapy

I-131 sodium iodide Thyroid cancer scintigraphy; thyroid uptake function studies; treatment of Graves disease, toxic nodule, and thyroid cancer

I-131 tositumomab (Bexxar)

B-cell lymphoma imaging and therapy

In-111 ibritumomab (Zevalin) B-cell lymphoma therapy

Page 9: 1 radiopharmaceuticals

target-to-background ratio and thus making I-131 seem advantageous, I-123 is now increasingly replacing I-131—for example, for whole-body thyroid cancer scans and MIBG imaging. I-123 ioflupane (DaTscan) has recently been approved to confirm or exclude the diagnosis of Par-kinson disease.

Quality control of radioiodinated pharmaceuticals is nec-essary to reduce radiation exposure to the thyroid gland. In nonthyroid imaging applications, it is common practice to block the thyroid gland with oral iodine (potassium iodide [SSKI], Lugol solution, or potassium iodide tablets) to pre-vent thyroid accumulation of any iodine present as a radio-chemical impurity or metabolite. Protocols vary, but thyroid blocking medications are started 1 to 12 hours before radiotracer administration in dosages equivalent to at least 100 mg of iodide.

Indium-111

In-111 has proved useful for clinical nuclear medicine (Table 1-10). Its principal photon energies of 172 and 245 keV are favorable, and their abundance is high (>90%). The 2.8-day half-life permits multiple-day sequential imaging. Examples of radiopharmaceuticals include In-111 oxine leukocytes for detection of inflammation and infection and the somatostatin receptor–binding peptide In-111 pentetreotide (OctreoScan) to detect neuroendo-crine tumors.

Thallium-201

Tl-201 became available in the mid-1970s for myocardial scintigraphy. It behaves as a potassium analog, with high net clearance (~85%) in its passage through the myocardial capillary bed, which makes it an excellent marker of regional blood flow to viable myocardium.

The major disadvantage of thallium as a radioactive imaging agent is the absence of an ideal photopeak for imaging. The gamma emissions (135 and 167 keV) occur in low abundance (see Table 1-2). The emitted mercury characteristic x-rays in the range of 69 to 83 keV are acquired, as sometimes are the 167-keV gamma emissions. The ability of the gamma scintillation camera to discrimi-nate scattered events from primary photons is suboptimal at this energy. Because of its poor imaging characteristics, Tc-99m–labeled cardiac perfusion radiopharmaceuticals are used.

Radioactive Inert Gases

Radioactive inert gases are used for pulmonary ventilation imaging. Xe-133 is the most commonly used. Its advantage over Tc-99m–labeled aerosols is better distribution into the lung periphery in patients with chronic obstructive lung disease. A disadvantage is the relatively low energy of its principal photon (81 keV), dictating the performance of ventilation scintigraphy before Tc-99m perfusion scintig-raphy. Because of its poor imaging characteristics and dosimetry issues, Tc-99m–labeled aerosols are more com-monly used. Xe-133 has a 5.2-day half-life, posing radia-tion safety issues answered to some extent by a xenon trap (charcoal).

radiopharmaceuTicals 9

Xenon-127 is theoretically superior to Xe-133 because of its higher photon energies (Table 1-2). Thus the ventila-tion study can be performed after the perfusion scan, lim-ited to the locations of perfusion defects. The high cost of producing Xe-127 and long half-life (36 days) have kept it from wide use.

Krypton-81m has advantages because of its high princi-pal gamma emission (190 keV) and short half-life (13 sec-onds), allowing for postperfusion imaging and multiple-view acquisition without concern for retained activity or radia-tion dose. However, the rubidium-81/kr-81m generator system is expensive and must be replaced daily because of its short half-life.

DUAL PHOTON RADIOPHARMACEUTICALS FOR POSITRON EMISSION TOMOGRAPHY

The physical characteristics of commonly used positron-emitting radionuclides are summarized in Table 1-3. Many radiopharmaceuticals have been described for use with PET (Box 1-2). Carbon, nitrogen, and oxygen are found ubiqui-tously in biological molecules. It is thus theoretically possi-ble to radiolabel almost any molecule of biological interest. F-18 has the advantage of a longer half-life than C-11, N-13, or O-15 and has been used as a label for the glucose analog fluorodeoxyglucose (FDG). F-18 FDG has found wide-spread clinical application in whole-body tumor imaging and, to a lesser extent, imaging of the brain and heart. The uptake of F-18 FDG is a marker of tumor metabolism and viability.

Box 1-2. Positron Emission Tomography Selected Radiopharmaceuticals

PERFUSION AGENTSO-15 waterN-13 ammoniaRb-82 chloride

METABOLIC AGENTSF-18 sodium fluorideFe-18 fluorodeoxyglucoseO-15 oxygenC-11 acetateC-11 palmitateN-13 glutamate

TUMOR AGENTSF-18 fluorodeoxyglucoseC-11 methionineF-18 fluorothymidine

RECEPTOR-BINDING AGENTSC-11 carfentanilC-11 racloprideF-18 fluoro-l-dopa

BLOOD VOLUMEC-11 carbon monoxideGa-68 ethylenediamine tetraacetic acid

AMYLOID-IMAGING AGENTF-18 florbetapir

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10  Nuclear Medicine: The Requisites

Rubidium-82 is available from a generator system with a relatively long-lived parent (strontium-82, T½ = 25 days) (Table 1-4). Like thallium, it is a potassium analog and used for myocardial perfusion imaging. Its availability from a generator system obviates the need for onsite cyclo-tron production. One limitation is the high energy (3.15 MeV) of its positron emissions. This results in a relatively long average path in soft tissue before annihilation, degrad-ing the spatial resolution available with the agent. This feature is shared to a lesser extent by O-15.

F-18 florbetapir was recently approved by the FDA for amyloid brain imaging.

The production of most positron-emitting radionuclides and their subsequent incorporation into PET radiophar-maceuticals is expensive and complex, requiring a cyclo-tron or other special accelerator and relatively elaborate radiochemical-handling equipment. In-house self- contained small cyclotrons with automated chemistry are available but are expensive for most clinical settings. The large, increasing clinical demand and the relatively long 2-hour half-life of F-18 FDG has resulted in its production and distribution by regional radiopharmacies.

DISPENSING RADIOPHARMACEUTICALS

Normal Procedures

General radiation safety procedures should be followed in all laboratories (Box 1-3). The dispensing of

Box 1-3. Radiation Safety Procedures

Wear laboratory coats in areas where radioactive materials are present.

Wear disposable gloves when handling radioactive materials.

Monitor hands and body for radioactive contamina-tion before leaving the area.

Use syringe and vial shields as necessary.Do not eat, drink, smoke, apply cosmetics, or store

food in areas where radioactive material is stored or used.

Wear personnel monitoring devices in areas with radioactive materials.

Never pipette by mouth.Dispose of radioactive waste in designated, labeled,

and properly shielded receptacles located in a secured area.

Label containers, vials, and syringes containing radioactive materials. When not in use, place in shielded containers or behind lead shielding in a secured area.

Store all sealed sources (floods, dose calibrator sources) in shielded containers in a secured area.

Before administering doses to patients, determine and record activity.

Know what steps to take and the person to contact (radiation safety officer) in the event of a radiation accident, improper operation of radiation safety equipment, or theft or loss of licensed material.

radiopharmaceuticals is governed by exacting rules and regulations promulgated by the FDA and NRC, as well as state pharmacy boards and hospital radiation safety com-mittees. Radiopharmaceuticals for clinical use must be approved by the FDA. Radiopharmaceuticals are prescrip-tion drugs that cannot be legally administered without being ordered by an authorized individual. The NRC authorized user and the radiopharmacy are responsible for confirming the appropriateness of the request, ensuring that the correct radiopharmaceutical designated amount is administered to the patient, and keeping records of both the request and documentation of dosage administration.

Before any material is dispensed, quality assurance mea-sures should be carried out. These are described earlier in this chapter for the Mo-99/Tc-99m generator system and Tc-99m–labeled radiopharmaceuticals. For other agents, the package insert or protocol for formulation and dispens-ing should be consulted for radiochromatography or other quality control steps that must be performed before dos-age administration. Good practice dictates that quality control should always be performed, even when not legally required. Every dose should be physically inspected for any particulate or foreign material (e.g., rubber from the tops of multidose injection vials) before administration. Each dose administered to a patient must be assayed in a dose calibrator. The administered activity should be within ±20% of the prescription request.

Special Considerations

Pregnancy and LactationThe possibility of pregnancy should be considered for every woman of childbearing age referred to the nuclear medicine service for a diagnostic or therapeutic procedure. Pregnancy alone is not an absolute contraindication to per-forming a nuclear medicine study. For example, pulmo-nary embolism is encountered in pregnant women and is associated with potential serious morbidity and mortality. Thus the risk-to-benefit ratio of ventilation-perfusion scintigraphy is high and considered an acceptable proce-dure in this circumstance. The radiation dosage is kept to a minimum. Tc-99m MAA does not cross the placenta, but xenon does. Radioiodine also crosses the placenta. The fetal thyroid develops the capacity to concentrate radioio-dine at 10 to 12 weeks of gestation, and cretinism caused by in utero exposure to therapeutic I-131 may occur.

Women who are lactating and breastfeeding require special attention. The need to suspend breastfeeding is determined by the half-life of the radionuclide and the degree to which it is secreted in breast milk. Radioiodine is secreted by the breast, and breastfeeding should be terminated altogether after the administration of I-131. NRC regulations stipulate that the patient must receive verbal and written instructions to that effect. For I-123, breastfeeding could safely be resumed after 2 days. For Tc-99m agents, 12 to 24 hours is sufficient. Further recommendations regarding breastfeeding for various radiopharmaceuticals are listed in Table 1-11.

Dosage Selection for Pediatric PatientsVarious approaches have been used for scaling down the radiopharmaceutical dose administered to children. There is no perfect way to do this because of the differential rate

Page 11: 1 radiopharmaceuticals

of maturation of body organs and the changing ratio of dif-ferent body compartments to body weight. Empirically, body surface area correlates better than body weight for dosage selection. Various formulas and nomograms have been developed.

An approximation based on body weight uses the formula:

Pediatric dose =Patient weight (kg)

70 kg× Adult dose

Another alternative is the use of Webster’s rule:

Pediatric dose =Age in years + 1Age in years + 7

Adult dose×

This formula is not useful for infants. Moreover, in some cases a calculated dose may not be adequate to obtain a diagnostically useful study and physician judgment must be used. For example, a newborn infant with suspected biliary atresia may require 24-hour delayed Tc-99m HIDA imaging, which is not feasible if the dose is too low. There-fore a minimum dose for each radiopharmaceutical should be established.

The concept As Low As Reasonably Achievable (ALARA) has always been a basic tenet in nuclear medicine regard-ing the administered dose. This concept has been recently reemphasized for pediatric diagnostic imaging. It has been restated as the lowest absorbed radiation dose that is consistent with quality imaging. Expert consensus recommendations for pediatric administered doses are listed in Table 1-12.

Nuclear Regulatory Commission and Agreement StatesThe NRC regulates all reactor by-product materials with regard to use and disposal, radiation safety of personnel using them, and the public. Certain states, termed Agree-ment States, have entered into regulatory agreements with the NRC that give them the authority to license and inspect by-products, sources, or special nuclear material used or possessed within their borders. Currently more

table 1-11  Recommendations for Radiopharmaceuticals Excreted in Breast Milk

Radiopharmaceutical

Administered activity mCi

(MBq)Counseling

adivsed

Withhold breast-feeding

Ga-67 citrate 5.0 (185) Yes Cessation

I-131 sodium iodide 0.02 (0.7) Yes Cessation

I-123 sodium iodide 0.4 (14.8) Yes 48 hr

I-123 MIBG 10 (370.0) Yes 48 hr

Tl-201 3 (111) Yes 96 hr

In-111 leukocytes 5 (185) Yes 48 hr

Tc-99m MAA 4 (148) Yes 12 hr

Tc-99m red blood cells 20 (740) Yes 12 hr

Tc-99m pertechnetate 5 (185) Yes 4 hr

Modified with permission from Stabin MG, Breitz HB. Breast milk excretion of radiopharmaceuticals: mechanisms, findings, and radiation dosimetry. J Nucl Med. 2000;41:863-873.MAA, Macroaggregated albumin; MIBG, meta-iodo-benzyl-guanidine.

RadiophaRmaceuticals  11

than 40 states are Agreement States, and the number is growing. These states agree to set regulations at least as strict as those of the NRC, but they may have stricter rules.

Authorized UserAn Authorized User is a person with documented training and experience in the safe handling and use of radioactive materials for medical use who is authorized to order, receive, store, and administer radiopharmaceuticals. Two general paths exist for becoming an authorized user: certi-fication by specialty board or training and work experi-ence. The NRC has defined requirements for becoming an authorized user based on the type of use for the radio-pharmaceutical—uptake and dilution, imaging and local-ization, and therapy (Box 1-4). Once Authorized User eligible status is achieved, the candidate can apply to bod-ies such as the hospital Radiation Safety Committee and the Radiation Safety Officer to become an authorized user with a radioactive materials license.

Medical EventThe NRC defines a medical event as a radiopharmaceutical dose administration involving the wrong patient, wrong radiopharmaceutical, wrong route of administration, or administered dose differing from the prescribed dose when the effective dose equivalent to the patient exceeds 5 rem to the whole body or 50 rem to any individual organ (Box 1-5). The definition and procedures for handling mis-administrations of radiopharmaceuticals are set out in the

table 1-12  Consensus Recommendations for Administered Activities in Children

Radiopharmaceutical

Recommended administered

activity mCi/kg (MBq/kg)

Minimum activity

mCi (MBq)

Maximum activity

mCi (MBq)

I-123 MIBG 0.14 (5.2) 1.0 (37) 10 (370)

Tc-99m MDP 0.25 (9.3) 1.0 (37)

F-18 FDG

Body

Brain

0.10-0.14 (3.7-5.2)

0.10 (3.7)

1.0 (37)

Tc-99m DMSA 0.05 (1.85) 0.5 (18.5)

Tc-99m MAG3 0.10 (3.7) 4.0 (148) 4 (148)

Tc-99m HIDA 0.05 (1.85) 0.5 (18.5)

Tc-99m MAA 0.07 (2.59) 0.4 (14.8)

Tc-99m pertechnetate 0.05 (1.85) 0.25 (9.25)

F-18 sodium fluoride

Tc-99m (cystography)

Tc-99m SC (liquid GE)

Tc-99m SC (solid GE)

(GE, gastric emptying)

0.06 (2.22) 0.5 (18.5)

0.25 (9.25)

0.25 (9.25)

1.0 (≤37)

1.0 (37)

0.5 (18.5)

Modified from Gelfand MJ, Parisi MT, Treves ST; Pediatric Nuclear Medicine Dose Reduction Workgroup. Pediatric radiopharmaceutical administered doses: 2010 North American consensus guidelines. J Nucl Med. 2011;52(2):318-322.DMSA, Dimercaptosuccinic acid; FDG, fluorodeoxyglucose; GE, ; HIDA, hepa-tobiliary iminodiacetic acid; MAA, macroaggregated albumin; MDP, methylene diphosphonate; MIBG, meta-iodo-benzyl-guanidine; SC, .

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12  Nuclear Medicine: The Requisites

Code of Federal Regulations (10 CFR-35); however, the ter-minology was changed in 2002. What was previously called a misadministration is now called a medical event. Many of the prior misadministrations no longer have to be reported to the NRC or state.

Medical events are extremely unlikely to occur as a result of any diagnostic nuclear medicine procedure. Most will be related to radioiodine I-131. However, when a med-ical event is recognized, regulations for reporting the event and management of the patient must be followed. The details are determined in part by the kind of material involved and amount of the adverse exposure of the patient. All medical events must be reported to the radia-tion safety officer, regulatory agency, referring physician, and affected patient. Complete records on each event must be retained and available for NRC review for 10 years.

Adverse Reactions to Diagnostic RadiopharmaceuticalsAdverse reactions to radiopharmaceuticals are extremely rare because the pharmaceutical is formulated in a sub-pharmacological dose that should not cause a physiologi-cal effect. When they occur, they are usually mild and rarely fatal. Of concern is the possibility of reactions caused by the development of human antimouse anti-bodies (HAMA) after repeated exposure to radiolabeled antibody imaging agents. This has been a factor in the FDA’s slow approval for radiolabeled antibodies. Tc-99m fanolesomab (NeutroSPEC) had approval withdrawn as a

Box 1-4. Nuclear Regulatory Commission 10 CFR Part 35: Medical Use of By-Product Material

35.190 Training for uptake, dilution, and excretion studies

35.290 Training for imaging and localization studies35.390 Training for any therapy requiring a written

directive35.392 I-131 ≤33 mCi35.394 I-131 >33 mCi35.396 Parental administration of a beta emitter

Box 1-5. Annual Dose Limits for Radiation Exposure (Nuclear Regulatory Commission Regulations)

ADULT OCCUPATIONAL5 rem (0.05 Sv) total effective dose equivalent50 rem (0.5 Sv) to any organ or tissue or extremity15 rems (0.15 Sv) to the lens of the eye

MINORS (<18 YEARS OF AGE) OCCUPATIONAL10% of those for adult workers

EMBRYO/FETUS OCCUPATIONAL0.5 rem (5 mSv) during pregnancy

MEMBERS OF THE PUBLIC0.1 rem (1 mSv)2 mrem (0.02 mSv) in any hour (average)

result of possible serious adverse effects. In-111 capro-mab pendetide (ProstaScint) and In-111 and Y-90 ibritu-momab (Zevalin) and I-131 tositumomab (Bexxar) have proved safe.

RADIATION ACCIDENTS (SPILLS)

In a busy nuclear medicine practice, accidental spills of radioactive material invariably occur. The spills are divided into minor and major categories, depending on the radio-nuclide and the amount spilled. For I-131, incidents involving less than 1 mCi are considered minor; spills more than that are considered major. For Tc-99m, Tl-201, and Ga-67, a major spill is considered to be more than 100 mCi.

The basic principles of responding to both kinds of spills are the same (Box 1-6). For minor spills, people in the area are warned that the spill has occurred. Attempts are made to prevent the spread of the spilled material. Absorbent paper is used to cover the spilled material. Minor spills can be cleaned up using soap and water, disposable gloves, and remote handling devices. All contaminated material, including gloves and other objects, should be disposed of in designated bags. The area should be continually sur-veyed until the reading from a Geiger-Müller (GM) survey meter is at background levels. All personnel involved should also be monitored, including hands, shoes, and clothing. The spill must be reported to the institution’s radiation safety officer.

For major spills, the area is cleared immediately. Attempts are made to prevent further spread with absor-bent pads, and, if possible, the radioactivity is shielded. The room is sealed off, and the radiation safety officer is notified immediately. The radiation safety officer typically directs further response—for example, when and how to proceed with cleanup and decontamination.

In dealing with both minor and major spills, an attempt is made to keep radiation exposure of patients, hospital staff, and the environment to a minimum. The radiation safety officer must restrict access to the area until it is safe for patients and personnel. However, no absolute guide-lines exist to provide a definitive approach to every spill.

Box 1-6. Procedure for Radioactive Spill

1. Notify all persons in the area that a spill has occurred.

2. Prevent the spread of contamination by isolating the area and covering the spill (absorbent paper).

3. If clothing is contaminated, remove and place in plastic bag.

4. If an individual is contaminated, rinse contami-nated region with lukewarm water and wash with soap.

5. Notify the radiation safety officer. 6. Wear gloves, disposable laboratory coat, and

booties to clean up spill with absorbent paper. 7. Put all contaminated absorbent paper in labeled

radioactive waste container. 8. Check the area or contaminated individual with

appropriate radiation survey meter.

Page 13: 1 radiopharmaceuticals

Each laboratory is responsible for developing its own set of written procedures. The radiation safety officer must restrict access to the area until it is safe for patients and personnel.

QUALITY CONTROL IN THE NUCLEAR PHARMACY

Selected quality control procedures for Tc-99m–labeled radiopharmaceuticals and for Mo-99/Tc-99m generator systems are described earlier in this chapter. Consider-ations of radiochemical and radionuclide purity also apply to other single-photon agents and positron radiopharma-ceuticals (see Table 1-8). Radiochemical purity is impor-tant for radioiodinated agents because of the potential for uptake of free radioiodine by the thyroid gland if the radio-label disassociates from the carrier molecule. Other quality control procedures are aimed at ensuring the sterility and apyrogenicity of administered radiopharmaceuticals. Qual-ity control monitoring of the dose calibrator performance is important to ensure that administered doses are within prescribed amounts.

Sterility and Pyrogen Testing

Sterility implies the absence of living organisms (see Table 1-8). Apyrogenicity implies the absence of metabolic prod-ucts such as endotoxins. Because many radiopharmaceuti-cals are prepared just before use, definitive testing before they are administered to the patient is impractical, which doubles the need for careful aseptic technique in the nuclear pharmacy.

Autoclaving is a well-known means of sterilization of prep-aration vials and other utensils and materials, but it is not useful for radiopharmaceuticals. When terminal sterilization is required, various membrane filtration methods are used. Special filters with pore diameters smaller than microorgan-isms have been developed for this purpose. A filter pore size of 0.22 μm is necessary to sterilize a solution. It traps bacte-ria, including small organisms such as Pseudomonas.

Sterility testing standards have been defined by the USP. Standard media, including thioglycollate and soy-bean-casein digest media, are used for different categories of microorganisms, including aerobic and anaerobic bacte-ria and fungi.

Pyrogens are protein or polysaccharide metabolites of microorganisms or other contaminating substances that cause febrile reactions (see Table 1-8). They can be pres-ent even in sterile preparations. The typical clinical syn-drome is fever, chills, joint pain, and headache developing minutes to a few hours after injection. The USP test for pyrogen testing uses limulus amebocyte lysate. It is based on the observation that amebocyte lysate preparations from the blood of horseshoe crabs become opaque in the presence of pyrogens.

Radiopharmaceutical Dose CalibratorsThe dose calibrator is an important instrument in the radiopharmacy and is subject to quality control require-ments. Four basic measurements are included: accuracy, linearity, precision or constancy, and geometry. All of these tests must be performed at installation and after repair.

radiopharmaceuTicals 13

AccuracyAccuracy is measured by using reference standard sources obtained from the National Institute of Standards and Tech-nology. The test is performed annually, and two different radioactive sources are used. If the measured activity in the dose calibrator varies from the standard or theoretical activ-ity by more than 10%, the device must be recalibrated.

LinearityThe linearity test is designed to determine the response of the calibrator over a range of measured activities. A com-mon approach is to take a sample of Tc-99m pertechnetate and sequentially measure it during radioactive decay. Because the change in activity with time is a definable physical parameter, any deviation in the observed assay value indicates equipment malfunction and nonlinearity. An alternative approach is to use precalibrated lead attenu-ators with sequential measurements of the same speci-men. This test is performed quarterly.

Precision or ConstancyThe precision, or constancy, test measures the dose calibra-tor’s ability to measure the same specimen over time. A long-lived standard such as barium-133 (356 keV, T½ 10.7 years), cesium-137 (662 keV, T½ 30 years), or cobalt-57 (122 kev, T½ 271 days) is used. The test is performed daily, and results should be within 10% of the reference standard value.

GeometryThe geometric test is performed during acceptance testing of the dose calibrator. The issue is that the same amount of radioactivity contained in different volumes of sample can result in different measured or observed radioactivities. For a given dose calibrator, if readings vary by more than 10% from one volume to another, correction factors are cal-culated. For convenience, the correction factors are based on the most commonly measured volume of material, which is typically determined from day-to-day clinical use of the dose calibrator.

RECEIVING RADIOACTIVE PACKAGES

Packages containing radioactive materials must be labeled according to the amount of measured activity at the sur-face and at 1 m (Table 1-13). Packaging is required to pass rigorous durability testing: drop test, corner drop test, compression, and water spray for 30 minutes. The U.S. Department of Transportation sets guidelines for regula-tions concerning not only package labeling but also trans-port rules concerning air and truck shipments. Placards are required on all sides of any truck carrying packages in the Level III Yellow label category.

Table 1-13  Survey Limits for Radioactive Material Package Receipt

Test Exposure Limits

Surface survey <200 mR/hr

Activity at 1 m <10 mR/hr

Wipe test 6600 dpm/300 cm2

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14  Nuclear Medicine: The Requisites

Once a radioactive package has been received, it must be monitored for contamination within 3 hours from deliv-ery during normal working hours or within 3 hours of the beginning of the next working day. An inspection is first done, looking for signs of damage or leakage. Then an external survey is performed with a GM counter at the sur-face and at 1 m. Finally, a wipe test is performed, swabbing 300 cm2 of the surface with absorbent paper and counting in a scintillation counter. The sender must be notified of any package exceeding limits (Table 1-14), and records of the survey must be kept, including date, name of the per-son performing the survey, survey readings, manufacturer, lot number, type of product and amount, and time of calibration.

RADIATION DOSIMETRY

The amount of radioactivity that can be administered for scintigraphic procedures performed in clinical nuclear medi-cine is limited by the amount of radiation exposure received

Table 1-14   Radioactive Package Labeling Categories

Exposure

Label category Surface (mR/hr) At 1 m (mR/hr)

I White <0.5 —

II Yellow >0.5 to ≤50 <1

III Yellow >50 to ≤200 >1 to ≤10

Not Allowed >200 >10

by the patient. The patient radiation exposure is determined by the percent localization of the administered dose in each organ of the body, the time course of retention in each organ, and the size and relative distribution of the organs in the body. This information is obtained from biodistribution and pharmacokinetic studies during the development and regu-latory approval process for a new radiopharmaceutical. For each radiopharmaceutical, estimates of radiation absorbed doses are made as part of the approval process and contained in the package insert (Table 1-15).

The radiation absorbed dose (rads) to any organ in the body depends on biological factors (percent uptake, bio-logical half-life) and physical factors (amount and nature of emitted radiations from the radionuclide). One rad is equal to the absorption of 100 ergs per gram of tissue. The for-mula for calculating the radiation absorbed dose is:

D (rk ← rh) = Ãb S (rk ← rh)

The formula states that the absorbed dose in a region k resulting from activity from a source region b is equal to the cumulative radioactivity given in microcurie-hours in the source region (Ã) times the mean absorbed dose per unit of cumulative activity in rads per microcurie-hour (S). The cumulative activity is determined from experimental mea-surements of uptake and retention in the different source regions. The mean absorbed dose per unit of cumulative activity is based on physical measurements and is deter-mined by radiations emanating from the radionuclide.

The total absorbed dose to a region or organ is the sum from all source regions around it and from activity within the target organ. For example, a calculation of the absorbed dose to the myocardium in a Tc-99m tetrofosmin scan must

Table 1-15   Radiation Doses From Common Diagnostic Nuclear Medicine Procedures

Radionuclide (rem) Agent Activity (mCi) Highest dose (rads) (organ) Effective dose equivalent (rem)

F-18 FDG 10 5.9 (bladder) 0.7

Ga-67 Citrate 5 11.8 (bone surface) 1.9

Tc-99m HIDA 5 2.0 (gallbladder) 0.3

HMPAO 20 2.5 (kidneys) 0.7

MAA 4 1.0 (lungs) 0.2

MDP 20 4.7 (bone surface) 0.4

MAG3 20 8.1 (bladder wall) 0.5

Sestamibi 20 2.7 (gallbladder) 0.7

Tetrofosmin 20 2.7 (gallbladder) 0.6

Sulfur colloid 8 2.2 (spleen) 0.3

In-111 Leukocytes 0.5 10.9 (spleen) 1.2

I-123 Sodium iodide (25% uptake) 0.2 2.6 (thyroid) 0.2

I-123 MIBG 10.0 0.1 (liver) 0.07

Xe-133 Inert gas 15 0.06 (lungs) 0.04

Tl-201 Chloride 3 4.6 (thyroid) 1.2

Data from Siegel JA: Guide for Diagnostic Nuclear Medicine and Radiopharmaceutical Therapy. Reston, VA, Society of Nuclear Medicine, 2004.SI conversion: 1 rem = 0.01 Sv; 1 mCi = 37 MBq.FDG, Fluorodeoxyglucose; HIDA, hepatobiliary iminodiacetic acid; HMPAO, hexamethylpropyleneamine oxime; MAA, macroaggregated albumin; MDP, methylene diphos-phonate; MIBG, meta-iodo-benzyl-guanidine.

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take into account contributions from radioactivity localiz-ing in the myocardium and from radioactivity in the lung, blood, liver, intestines, kidneys, and general background soft tissues. The percentage uptake and the biological behavior are different in each of those tissues. The amount of radiation reaching the myocardium is also different, depending on the geometry of the source organ and its dis-tance from the heart. The formula is applied for each source region, and the individual contributions are summed.

Factors that affect dosimetry include the amount of activity administered originally, the biodistribution in one patient versus another, the route of administration, the rate of elimination, the size of the patient, and the pres-ence of pathological processes. For example, for radiophar-maceuticals cleared by the kidney, radiation exposure is greater in patients with renal failure. Another example is the differing percentage uptakes of radioiodine in the thy-roid depending on whether a patient is hyperthyroid, euthyroid, or hypothyroid.

The radiation absorbed dose (rads or Gray) does not describe the biological effects of different types of radia-tion. The equivalent dose (rem or Sievert) relates the absorbed dose in human tissue to the effective biological damage of the radiation. Not all radiation has the same bio-logical effect, even for the same amount of absorbed dose. To determine the equivalent dose, the absorbed dose (rads or Gray) must be multiplied by a quality factor unique to the type of incident radiation.

radiopharmaceuTicals 15

Effective dose is calculated by multiplying actual organ doses by “risk weighting factors” that give each organ’s relative radiosensitivity to developing cancer and adding up the total of all the numbers, which is the effective whole-body dose or just effective dose. These weighting factors are designed so that this effective dose represents the dose that the total body could receive (uniformly) that would give the same cancer risk as various organs getting different doses. The effective dose can be used to com-pare radiation doses of various imaging modalities.

Estimates of radiation-absorbed dose for each major radiopharmaceutical are provided in tabular form in the specific organ system chapters.

SuggeSted Reading

Cherry SR, Sorenson JA, Phelps ME. Physics in Nuclear Medicine. 3rd ed. Philadelphia: W.B. Saunders; 2003.

Christian PE, Waterstram-Rich KM, eds. Nuclear Medicine and PET/CT: Technology and Techniques. 7th ed. St. Louis: Mosby; 2012.

Fahey FH, Treves ST, Adelstein SJ. Minimizing and communicating radiation risk in pediatric nuclear medicine. J Nucl Med. 2011;52(8):1240-1251.

Gelfand MJ, Parisi MT, Treves ST. Pediatric Nuclear Medicine Dose Reduction Workgroup. Pediatric radiopharmaceutical administered doses: 2010 North American consensus guidelines. J Nucl Med. 2011;52(2):318-322.

Mettler FA, Huda W, Yoshizumi TT, Mahesh M. Effective doses in radiology and diagnostic nuclear medicine: a catalog. Radiology. 2008;248(1):254-263.

Saha GB. Fundamentals of Nuclear Pharmacy. 6th ed. New York: Springer; 2010.Siegel JA. Guide for Diagnostic Nuclear Medicine and Radiopharmaceutical Therapy.

Reston, VA: Society of Nuclear Medicine; 2004.Stabin MG, Breitz HB. Breast milk excretion of radiopharmaceuticals: mecha-

nisms, findings, and radiation dosimetry. J Nucl Med. 2000;41(5):863-873.