CHAPTER 5
SELF-CONTAINED IRRADIATORS

SUMMARY

Self-contained irradiators1 are used mostly for blood irradiation, biomedical and radiation research, and calibration of other devices. Blood banks irradiate selected units of blood to prevent at-risk patients from developing graft-versus-host disease (GVHD), a rare but usually fatal complication of transfusion. Most self-contained irradiators use a radionuclide radiation source, with the vast majority being cesium-137 because of its long half-life, relatively low cost, and relatively modest shielding requirements, which make it possible to place a device in the upper floors of some hospitals and blood banks. Several alternatives to the use of cesium-137 for blood irradiation currently exist, including cobalt-60 sources, which, unlike cesium-137 sources, would be resistant to dispersal, as well as a commercially available x-ray device and existing hospital linacs, which do not contain radionuclide sources. All existing replacements are currently more costly than the current cost of purchasing and operating cesium-137 blood irradiators. In addition, if high-activity glass or pollucite or other ceramic cesium-137 sources were available, then new cesium-137 irradiators could be designed to use them, and some old irradiators could even be retrofitted, depending on the size and shape of the new source pencils. These alternative forms could reduce the devices’ hazard with respect to malevolent uses.

Another kind of self-contained irradiator is a calibration chamber for high-dose-rate radiation detectors used by nuclear power plants and some other facilities. The calibration irradiators typically use about 15 TBq (400 Ci) but some hold as much as 82 TBq (2,200 Ci) of cesium-137. Some of these calibrators are located at nuclear power plant facilities, which are under more stringent security requirements than facilities with only materials licenses, but over 100 are located outside of nuclear power plants. The following sections describe blood irradiation, research irradiation, and calibration laboratories, including what they are needed for and whether replacements are technically feasible.

BLOOD IRRADIATION

Hospitals and blood banks irradiate blood products to prevent transfusion-associated graft-versus-host-disease (GVHD). Transfusion-associated GVHD is a deadly transfusion complication resulting when some donor white blood cells (specifically, T lymphocytes, Figure 5-1)

1

Self-contained irradiators are classified as “Category I” irradiators by the American National Standards Institute (ANSI), ANSI Standard N433.1, Safe Design and Use of Self-Contained, Dry Source Storage Gamma Irradiators (Category I). This is not to be confused with the IAEA Category 1 definition. This ANSI standard defines a Category I irradiator as “[a]n irradiator in which the sealed source(s) is completely contained in a dry container constructed of solid materials, the sealed source(s) is shielded at all times, and human access to the sealed source(s) and the volume(s) undergoing irradiation is not physically possible in its designed configuration.” The dry storage is to distinguish the self-contained irradiators from the large panoramic sterilization irradiators, which are stored in a water pool.



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CHAPTER 5 SELF-CONTAINED IRRADIATORS SUMMARY Self-contained irradiators1 are used mostly for blood irradiation, biomedical and radiation research, and calibration of other devices. Blood banks irradiate selected units of blood to prevent at-risk patients from developing graft-versus-host disease (GVHD), a rare but usually fatal complication of transfusion. Most self-contained irradiators use a radionuclide radiation source, with the vast majority being cesium-137 because of its long half-life, relatively low cost, and relatively modest shielding requirements, which make it possible to place a device in the upper floors of some hospitals and blood banks. Several alternatives to the use of cesium-137 for blood irradiation currently exist, including cobalt-60 sources, which, unlike cesium-137 sources, would be resistant to dispersal, as well as a commercially available x-ray device and existing hospital linacs, which do not contain radionuclide sources. All existing replacements are currently more costly than the current cost of purchasing and operating cesium-137 blood irradiators. In addition, if high-activity glass or pollucite or other ceramic cesium-137 sources were available, then new cesium-137 irradiators could be designed to use them, and some old irradiators could even be retrofitted, depending on the size and shape of the new source pencils. These alternative forms could reduce the devices’ hazard with respect to malevolent uses. Another kind of self-contained irradiator is a calibration chamber for high-dose-rate radiation detectors used by nuclear power plants and some other facilities. The calibration irradiators typically use about 15 TBq (400 Ci) but some hold as much as 82 TBq (2,200 Ci) of cesium-137. Some of these calibrators are located at nuclear power plant facilities, which are under more stringent security requirements than facilities with only materials licenses, but over 100 are located outside of nuclear power plants. The following sections describe blood irradiation, research irradiation, and calibration laboratories, including what they are needed for and whether replacements are technically feasible. BLOOD IRRADIATION Hospitals and blood banks irradiate blood products to prevent transfusion-associated graft-versus-host-disease (GVHD). Transfusion-associated GVHD is a deadly transfusion complication resulting when some donor white blood cells (specifically, T lymphocytes, Figure 5-1) 1 Self-contained irradiators are classified as “Category I” irradiators by the American National Standards Institute (ANSI), ANSI Standard N433.1, Safe Design and Use of Self-Contained, Dry Source Storage Gamma Irradiators (Category I). This is not to be confused with the IAEA Category 1 definition. This ANSI standard defines a Category I irradiator as “[a]n irradiator in which the sealed source(s) is completely contained in a dry container constructed of solid materials, the sealed source(s) is shielded at all times, and human access to the sealed source(s) and the volume(s) undergoing irradiation is not physically possible in its designed configuration.” The dry storage is to distinguish the self-contained irradiators from the large panoramic sterilization irradiators, which are stored in a water pool. 85

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86 RADIATION SOURCE USE AND REPLACEMENT FIGURE 5-1 Scanning electron micrograph of a normal T lymphocyte. SOURCE: Image courtesy of Lawrence Berkeley National Laboratory (Yaris, 2003). attack the recipient’s tissues.2 GVHD can develop either when the recipient’s immune system does not recognize the donor’s foreign white blood cells as different or when the recipient’s immune system is weakened or defective and is unable to contain and eliminate transfused lymphocytes. Chemotherapy or radiotherapy treatments are prescribed for patients with a number of hematological cancers requiring bone marrow or peripheral blood stem cell transplants. Donor T cells that contaminate red cell and platelet units will recognize the recipients’ cells as foreign, proliferate, and mount an immune response against recipient tissues. In approximately 90 percent of the cases, this immune response, or transfusion- associated GVHD, leads to tissue destruction, organ failure, and death (Butch, 1996). To prevent GVHD in transfusion recipients, blood banks typically irradiate red blood cells and platelet components. Irradiation produces ionizations and free radicals that damage genetic material in the white blood cells and inhibit cell division (replication) (Plappert et al., 1995; van Ankeren et al., 1988). T cells require cell division to mount an effective immune response. Therefore, treatment of blood with sufficient ionizing radiation prevents T-cell proliferation and GVHD. Neither red cells nor platelets contain the genetic material for replication, and damage to genetic material in platelets (mitochondrial DNA) does not compromise the platelet's use. Irradiation of blood with a dose of 25 Gy delivered from a blood irradiator or a radiotherapy linear accelerator (linac) to blood containers kills 99.9995 percent (a reduction factor of 200,000) of white blood cells that contaminate red cell products and more than 99.9988 percent (a reduction factor of 80,000) of white blood cells that contaminate platelet products, respectively, so that less than approximately 1/100,000th of the initial white cells are viable. Current guidance from the Food and Drug Administration (FDA) recommends a dose of 25 Gy delivered to the midplane of the blood container with no part of the blood container to receive less than 15 Gy. This dose is sufficient to prevent GVHD and has no impact on platelet properties, shelf life, or in vivo platelet recovery and survival, and minor effects on red cell properties, shelf life, and in vivo circulatory recovery and survival (Butch, 1996). Irradiators are dose mapped once per year, and times for exposure are calculated either once (for cesium-137 sources) or four times (for cobalt-60 sources) per year to ensure that doses delivered to blood products meet these quality control standards (Luban et al., 2000; Moroff and Luban, 1997; Pelszynski et al., 1994). Approximately 10.5 percent of blood components that were produced in the United States (of about 15.5 billion total units prepared) in 2001 were irradiated (Sullivan et al., 2007). It is estimated that only about one-fifth of all irradiated red cell units are produced at centralized 2 T lymphocytes are specialized white blood cells that identify and destroy invading organisms such as bacteria and viruses.

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SELF-CONTAINED IRRADIATORS 87 blood centers; the remaining units are irradiated at hospitals. The higher production of irradiated red cell units by hospitals may be due to the shortened shelf-life of gamma-irradiated red cell products (28 days rather than 42 days). In addition, some physicians are concerned about infusing irradiated units that have been stored for several days or weeks to infants and some adults. This is because irradiated red cells leak potassium at twice the rate of normal red cells and some patients are susceptible to adverse cardiac events from potassium following transfusion. Therefore, in many hospitals, red cell units are irradiated just prior to transfusion. An alternative explanation for high hospital production of irradiated products is that most hospitals already have the equipment for irradiation and thus do not wish to pay fees to blood centers for this service. Much greater than 10 percent of the 10.3 million platelet units produced in 2001 are estimated to have been gamma irradiated (Sullivan et al., 2007). From 2002 to 2004, the use of bone marrow and peripheral blood stem cell transplants increased approximately 8.8 percent annually. In recent years, experimental transplant activity has expanded to include not only patients with hematological cancers, but also those with genetic abnormalities in their hemoglobin (hemaglobinopathies), such as sickle-cell anemia, thalassemia, and autoimmune diseases such as scleroderma, multiple sclerosis, rheumatoid arthritis, juvenile idiopathic arthritis, and systemic lupus erythematosus. Nontransplant patients requiring transfusion, including patients with some congenital immunodeficiencies, immunodeficiencies from viral infection, and low-birthweight or in-utero neonates with immature immune systems, may also require gamma-irradiated blood products (McCullough et al., 2006; van Laar and Tyndal, 2006). Aside from irradiation, there are other ways to inactivate white cells or one can remove them from red cell and platelet components. Investigating these alternatives is, however, difficult to do in the United States because there is an ethical dilemma in conducting a trial to investigate use of an experimental prophylactic treatment to prevent a deadly disease when a well-known, efficacious alternative (irradiation) is readily available.3 The existing alternatives are described below. Cesium Blood Irradiators A simplified design of a typical cesium-137 blood irradiator is shown in the schematic in Figure 5-2, a photograph of a typical blood irradiator is shown in Figure 5-3, and the technical specifications for four irradiators are given in Table 5-1. One to six blood containers (usually bags) are labeled for quality control and placed in a metal canister by an operator who then loads the canister into the irradiator. After automatically shielding the operator from source exposure and simultaneously positioning the canister adjacent to one or more shielded pencil-shaped cesium-137 sources, the irradiator rotates the canister to ensure more uniform gamma-ray exposure of the entire volume of each blood unit. 3 The potential for GVHD depends on the population (it is higher in transplant recipients and in countries where genetic variation is small) and so, selection of the study population would determine the study size. In a more susceptible population, the size of the trial would need to be smaller than in a less susceptible population.

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88 RADIATION SOURCE USE AND REPLACEMENT FIGURE 5-2 Diagrams of (A) a configuration of a gamma irradiator using cesium-137 and (B) a configuration of a linac irradiator. The plastic bolus is a container that enhances the dose uniformity in the irradiation configuration shown. SOURCE: Image provided by the committee. FIGURE 5-3 Typical self-shielded blood irradiator and typical 500-ml blood bag and small irradiation canister. SOURCE: Images provided by the committee.

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SELF-CONTAINED IRRADIATORS 89 TABLE 5-1 Comparison of Cesium-137 Irradiators Model Nordion Nordion CIS Shepherd GC 1000 Elite GC 3000 IBL 437C 143 Specification Load (kg/sq m) 1,467 1,886 5,200 Not available Weight (kg) 1,150 1,479 2,150 907 or 1,814 Height (m) 1.55 1.55 1.50 2 Width (m) 0.8 0.8 0.67 0.6 Depth (m) 0.98 0.98 0.650 0.6 Outlet (V) 110 110 100–240 110 Activity (TBq) [Ci] 24.1–107.4 53.7 or 107.4 63–189 42.8–259 [575–2,900] [1,450 or 2,900] [1,700-5,100] [1,155–7,000] Canister (liters) 0.824 2.34 3.8 0.6–3.9 Time to deliver 25 Gy 1.6–7.14 2.56–5 2.8 or more Not available (min) SOURCE: Courtesy of Gammacell® 1000 Elite/3000 Elan (MDS Nordion, 2006); CIS IBL 437C (CIS-US, Inc., 2007); Shepherd 143 adapted from Cook (1996), with additional information from the Sealed Source and Device Registry. An example of a dose map of one canister is given in Figure 5-4. If the dose at the midplane is defined as 100 percent, the dose in any portion of the canister other than the very top and bottom center portion does not typically vary by more than ±20 percent. Exposure times are typically several minutes; irradiators containing higher activity sources have shorter exposure times due to their increased dose rate. An irradiator takes twice as long to deliver a given exposure after the source has decayed through one half-life. Given the 30.2-year half-life of cesium-137, a typical blood irradiator is in service for approximately 30 years before needing to reload the source, or more commonly replace the entire irradiator to maintain a practical exposure time. Because blood irradiators are self-contained (they have built-in shielding), they need not be located in a bunker in the basement of a hospital or blood center. The weights of cesium blood irradiators do, however, require more support than is found in the upper floors of many buildings, in which case the irradiators may need to be located next to a structural support for the building or have additional support installed to spread out the weight. REPLACEMENTS FOR BLOOD IRRADIATORS There are several alternatives to radioactive cesium chloride self-contained irradiators. These include different material forms for cesium-137 sources, cobalt-60 sources, x-ray sources, chemical inactivation, and filtration techniques. Each of these is discussed below. The committee spoke with the major self-contained-irradiator manufacturers and found them reluctant to shift toward replacements for radionuclide radiation sources without some incentives.

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90 RADIATION SOURCE USE AND REPLACEMENT FIGURE 5-4 Typical dose map in a blood irradiation canister. SOURCE: Unpublished data on isodose curve in percentages for Gammacell 1000, provided by the American Red Cross, 2007. Different Material Forms for Cesium-137 Sources Manufacturers of self-contained radionuclide source devices have commented in the committee’s public meetings that the decrease in specific activity from preparing a cesium- containing ceramic would make it impossible to produce current dose rates in existing devices. They have also said that it is likely that new designs of blood irradiators would have to be fashioned to use ceramic or other complexed forms of cesium in a 24- to 100-TBq device. Increasing the number of pencil sources by a factor of two to five would be expected to produce dose rates from cesium pollucite irradiators that are equivalent to existing cesium chloride irradiators. The committee examined several designs of self-contained irradiators, and some of them can accommodate several different source loadings with little change in the rest of the design. This is possible because the shielding is designed for the maximum activity loading and the source holder can accommodate more than one source pencil. If alternative forms of high-activity cesium-137 source can be produced with cesium densities within a factor of two of the current radioactive cesium chloride sources, then at least some of the self- contained irradiator designs could simply switch to the alternative forms by loading two pencils instead of one, with no retrofits required and no degradation in performance. (Regulatory reviews are needed for alternative forms of radioactive material used in current radiation source devices, as noted in Chapter 10.) Cobalt-60 Blood Irradiators Use of blood irradiators containing a radionuclide metal, with limited solubility and considerable resistance to explosive dispersion, would reduce the potential for widespread contamination of large areas if it were used in a radiological dispersal device. There are blood irradiators with the radionuclide metal cobalt-60 instead of the radioactive cesium chloride source. In the late 1980s there was an interruption of fabrication of cesium-137 irradiators because of the closure of a major cesium-137 production facility. During that period, at least one

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SELF-CONTAINED IRRADIATORS 91 supplier of blood irradiators developed cobalt-60 blood product irradiators. Unlike the cesium- 137 blood irradiators in which radioactive pencil source(s) are positioned on one side or in a U shape around a central, rotating canister on a turntable, the cobalt-60 irradiator had multiple fixed sources arranged around a central cavity into which the canister was lowered. These units were stocked with sufficient cobalt-60 that reloading of the radionuclide was not required for 10 to 15 years. Cobalt-60, with its more energetic gamma emission, requires an approximately fourfold increase in the mass of lead shielding compared to cesium-137 for the same activity source. A cobalt-60 source gives a much higher dose rate to the object being irradiated than does a cesium-137 source of the same activity, so a lower activity cobalt source can be used, even if the irradiator is loaded with extra activity to compensate somewhat for cobalt-60's faster decay rate. As a result, the cobalt-60 irradiator units (mainly their shields) weighed only about twice as much as most cesium-137 blood irradiators; a device weighed approximately 2,700 kg. Because the weight required bottom-floor installation in most buildings and because its shortened useful life (15 instead of 30 years) made operation more costly, very few of these irradiators were sold to blood banks and hospitals. However, the use of cobalt may still be viable in many cases. Currently, 31 cobalt-60 blood irradiators are reported to be located in the United States. X-ray Irradiators An x-ray blood irradiator originally developed and distributed by Rad Source Technologies, Inc. (Alpharetta, GA), the RS 3000, received Food and Drug Administration approval for use and has been available as an alternative to cesium-137 and cobalt-60 irradiators since August 1999. The device, which is similar in size and lower in weight than cesium-137 blood irradiators, utilizes 160-kVp x rays and can irradiate up to 2–3 units of red cells, depending on the bag manufacturer, with 25–37.6 Gy in approximately 5 minutes (Table 5-2). In one side-by-side study, similar lymphocyte inactivation and red cell potassium release were observed in red cell units treated with this x-ray device compared to units treated with the same dose of cesium-137-generated gamma rays (Janatpour et al., 2005). X-ray–treated red cells exhibited an enhanced degree of hemolysis (breakdown of red blood cells) during storage compared to cesium-137 gamma-ray–treated units; however, these differences were small and not clinically significant. There are reports that the early RS 3000 irradiators suffered from reliability and service- related problems. In May 2002, the company issued a voluntary nationwide recall of all 20 of its installed RS 3000 blood irradiators to complete a cooling system retrofit to prevent overheating and failure. During the retrofit or failure of the irradiator, some users were forced to send blood units to other institutions for irradiation with radionuclide sources. In 2003, the company licensed its x-ray blood irradiator to Nordion, who markets the device as the Raycell®. Because of the history of x-ray device breakdown and the critical nature of providing irradiated blood to patients, there are concerns among some in the blood bank community that radionuclide “backups” of x- ray devices are needed at institutions to be available during times of x-ray device failures. The Raycell® has achieved a small but growing market penetration. By October 2006, MDS Nordion estimated that there were approximately 100 Raycell® units in operation (United States, Sweden, Germany, France, Italy). Approximately 80 additional x-ray blood irradiators developed primarily by two other foreign manufacturers are in use outside the United States. Costs of purchasing a Raycell® are roughly comparable to purchasing cesium-137 irradiators, based on user information provided to the committee. Direct operating costs would be expected to be somewhat larger than those of a radionuclide blood irradiator because of the increased costs of electricity in the x-ray device and increased need for service and part replacement. A maximum electricity cost of less than $0.18 for irradiating three units of blood

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92 RADIATION SOURCE USE AND REPLACEMENT can be estimated by utilizing the stated voltage specification, maximum amperage, 5–minute irradiation time (Table 5-2) and assuming $0.12/kWhr for electricity costs. A course for training service personnel for installation and maintenance of the Raycell®, including x-ray tube replacement and alignment, high-voltage generator replacement, and dosimetry is offered by MDS Nordion and listed as Can$1,500. However, service needs for a failed instrument are urgent, the complexity of required preventive maintenance is much greater than for radionuclide sources and beyond the abilities of many blood bank staff, and the need to maintain good manufacturing practice conditions lead users to purchase an annual maintenance and service agreement for the device. The current cost of an agreement is approximately $10,600 per device per annum, and costs are expected to increase as instruments age. Thus, over a 30-year period, or the expected lifetime of a cesium-137 blood irradiator, use of the Raycell® x-ray device instead of the radionuclide irradiator is expected to incur at least $318,000 in additional service and maintenance costs. The cost of these services therefore increases the cost of irradiating blood by 177% over the purchase cost ($180,000, as reported by MDS Nordion) of a new cesium-137 irradiator, which are reliable in the field and require less complex maintenance. The committee contacted some organizations that currently own and operate Raycell® devices, and despite this additional cost, they were actually considering purchasing more of the x-ray devices rather than the gamma irradiators. One factor may be that a blood irradiator processes many blood units over its lifetime, so the cost difference on a per-unit basis could be relatively small. In addition, the costs of disposal or retirement of an existing cesium-137 blood irradiator that an owner would incur with a transition to x-ray irradiators is estimated by manufacturers (MDS Nordion, JL Shepherd & Associates) to be $35,000 to $40,000. These costs are primarily for transportation of sources. There is currently no disposal facility available for civilian high- activity cesium sources in the United States. The only options for disposition of an unwanted source are to return the source to the manufacturer for recycling or to request that the source be taken by the National Nuclear Security Administration’s Offsite Source Recovery Project (OSRP), which stores the sources free of charge to the companies. Therefore, the actual cost to the country of disposal of high-activity cesium-137 devices is currently unknown. Further, companies and users that rely on continued take-back practices of other companies, and even from the OSRP, are taking risks in light of the potential for shifts in business practices and the sometimes shaky federal funding for the OSRP. TABLE 5-2 Features of the Raycell® Irradiator X-ray potential 160 kV Weight 710 kg 2 Floor loading 1,115 kg/m Canister dimensions 6 in. × 4 in. (diameter × depth) (15 cm × 9.5 cm), 1.68 liters Unit dimensions 59.45 in. (151 cm) high, 44.63 in. (114 cm) wide, 21.75 in. (56 cm) deep Utility requirements 200–240 V ac, 50/60 Hz single phase, 60 A maximum, 380–440 V ac, 50/60 Hz three phase, 40 A maximum Water flow rate and pressure 2.6 gpm (10 L/min) 50–70 psi (345–483 kPa) Time to deliver 25 Gy (min) ~5 SOURCE: Courtesy of MDS Nordion (2006).

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SELF-CONTAINED IRRADIATORS 93 Use of the Raycell® instead of a radionuclide blood irradiator would be expected to have reduced indirect operating costs, because x-ray devices are not subject to the increased security controls required by the U.S. Nuclear Regulatory Commission (U.S. NRC) for gamma irradiators and other Category 1 and 2 devices (see Chapter 3), and also may have fewer other regulatory burdens because the device contains no radionuclides. However, not all savings in security costs would necessarily be realized if for example, the facility has other reasons to employ security personnel. Other kilovoltage sources will soon enter the market, produced by manufacturers of research irradiators. See the section below on Research Irradiators. Electron-Beam Irradiators Electron beams have been used to sterilize food and low-density medical products (Kunstad, 2001) in devices similar to large-scale x-ray irradiators but lacking high-density targets used to generate x-rays. Because electron-beam irradiators do not need to perform the inefficient conversion of electron to x-ray energy, they do not waste 90 to 95 percent of the electrical power needed to supply these devices. In beam generators, 5 or 10 MeV electrons directly bombard the product to be sterilized as it is passed through the beam. For food products with a density of approximately 1 g/cm3, electron penetration is limited to approximately 5 cm. Based on the fact that blood products have densities similar to those of food products, it is expected that only one blood product thickness (about 2 to 4 cm) could be irradiated at a time. No electron-beam irradiators have been used to routinely treat blood products to prevent GVHD, although the doses necessary for prevention of GVHD are roughly 1,000-fold less than those needed to sterilize other types of products. An electron-beam food irradiator has capital equipment costs up to $3.5 million, with a large cost associated with the waveguide of the instrument. With high capital costs, one could consider shipping blood products to a centralized electron-beam irradiator. However, it is not feasible to have centralized electron-beam irradiation of blood. Blood products typically are irradiated “on demand.” The short 5-day shelf life of platelet products, in particular, would not permit adequate shipping time, “in queue” time as other materials are irradiated, and processing time necessary to send units to centralized irradiation facility. The development of small on-demand electron-beam devices specifically designed for blood irradiation has not been explored, and its development, as the state of the art exists today, would be hampered by the high cost of the instrument and in particular the cost of the waveguide. To be competitive with radionuclide blood irradiators, an e-beam instrument would have to be developed that could be marketed for approximately $200,000 per device. Very low energy electron sources up to 150 kVp have been developed in this price range, but the penetration of such low energy electrons is insufficient to be of use in this application. Linacs Linacs that are routinely used for radiotherapy of cancer patients have also been successfully used for blood irradiation (Moroff and Luban, 1997). With their high dose rates, large radiation field (up 40 cm × 40 cm) and x-ray energies capable of delivering a uniform dose in a 25-cm-thick volume when opposed beams are used, many units of blood can be simultaneously irradiated within a 5- to 10-minute period. Because their capital costs are already supported by radiotherapy departments, and patient use is usually limited to the daytime hours, evening use of linacs for blood irradiation is feasible. Irradiation would need to be carried out by a trained radiation therapist or physicist, rather than blood bank staff, so operating costs may be greater than those associated with gamma irradiation of blood using a radionuclide source. The

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94 RADIATION SOURCE USE AND REPLACEMENT Indiana Blood Center, which uses an x-ray irradiator to irradiate blood for several hospitals, told the committee that it charges $55 per unit for irradiation services that otherwise would be done using the hospital’s in-house linacs for irradiation. Further, blood irradiation by a hospital department other than the blood bank may be inconvenient because of the need to accommodate the radiation oncology schedule. In addition, the high capital costs of acquiring linacs would be prohibitive for use at nonhospital blood centers. Hospital-based linacs could serve as a viable backup if a blood irradiator became dysfunctional, and in some circumstances, could replace cesium-137 based hospital blood irradiators. Nonirradiation Approaches Leukoreduction Filters to diminish white cell levels in red cell and platelet units by a factor of 1,000 to 100,000 (3 log10 to 5 log10) are currently available and are routinely used in a majority of cellular blood products. In theory, a reduction in donor leukocyte counts would be expected to protect against GVHD. However, several cases have been reported documenting the occurrence of GVHD despite leukoreduction with previous generation filters that were not as efficient at removing lymphocytes as are current filters (Garcia Gala et al., 1993; Hayashi et al., 1993; Heim et al., 1992). Because of these reports, filtration of blood with the current generation of filters generally is not considered by physicians to be effective prophylaxis against GVHD, although it is actually unknown whether current high-efficiency (5 log10) filters might be an effective substitute for gamma irradiation. Even if 5 log10 leukoreduction could be demonstrated to prevent GVHD, filter breakthough, or filtrations in which the substrates fail to retain the necessary amount of leukocytes to diminish white cell levels by a factor of 1,000 to 1000,000, of leukocytes is estimated to occur at a frequency of 1 in 500. Whether the extent of breakthrough would be sufficient to promote a GVHD reaction is also unknown. Pathogen Reduction Techniques Several methods to inactivate viruses and bacteria in blood components have also shown promise in inactivating white cells at levels that may be useful in prophylaxis against GVHD. All the techniques involve the use of nucleic acid damaging agents. Two existing techniques utilize ultraviolet A (UVA) light to induce photochemical reactions in the agents that attach themselves to nucleic acids critical to reproduction of viruses, bacteria, parasites, and white cells. Amotosalen (S-59), developed by Cerus Corporation, is a synthetic psoralen that inactivates pathogens through such phototreatment. Following phototreatment, platelets containing amotosalen and photoproducts are transferred to a container with a resin designed to reduce the concentration of drug and photoproducts. Studies with amotosalen and UVA light have demonstrated pathogen reduction and inactivation of human white cells comparable to and greater than that achieved in irradiation (a factor of 250,000 reduction in viable white blood cells) (Grass et al., 1998). This technique has been effective in an animal model and three small clinical trials in Europe (Corash and Lin, 2004; Grass et al., 1998). Cerus is licensed in Europe for sale of their amotosalen and UVA light irradiation system for treatment of apheresis platelet units and buffy-coat platelet pools. Costs of the system are estimated to be $80 to $100 per unit. In a system under development by Gambro BCT Corporation, riboflavin (vitamin B2) is used with UVA light treatment to inactivate viruses, bacteria, parasites, and white cells in apheresis and buffy-coat-derived platelet components (Hardwick et al., 2004; Ennever and

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SELF-CONTAINED IRRADIATORS 95 Speck, 1981). Because riboflavin is a substance that is generally recognized as safe4 and the phototreatment product, lumichrome, is not considered to be toxic, riboflavin and photoproducts are not removed in any post-phototreatment step (Ennever and Speck, 1981). A study suggests that this technique may be effective for inhibition of lymphocyte proliferation (Fast et al., 2006). The study demonstrated inactivation of white blood cells up to the limit of detection of the assays used, which is a factor of about 100. A more sensitive assay would be needed to demonstrate whether this method is effective in preventing GVHD, which requires orders of magnitude greater reduction. Phototreatment with both amotosalen and riboflavin result in a smaller fraction of treated platelet products being retained and recirculated in the body compared with using gamma irradiation (AuBuchon et al., 2005; McCullough et al., 2004; Snyder et al., 2004). Thus, both phototreatment alternatives would require the use of more treated platelets than does gamma irradiation. Because of high UV absorbtion in red blood cells, these approaches have not been used for whole blood. Cerus Corporation has also developed a DNA-specific alkylating agent, S-303, to inactivate viruses, bacteria, and parasites in red cell components. Although there are no published data reporting inactivation of white cells, it is anticipated that S-303 will be effective on white cells based on robust inactivation of bacteria and viruses, which have nucleic acid target cross sections that are 10–10,000 times smaller than those of mammalian cells. S-303 also reacts with nucleic acids, but without the UVA light trigger. S-303 is designed to break down in blood to reduce the genotoxicity (mutagenicity and potential carcinogenicity) and general toxicity of the compound, and is used with reduced glutathione, a so-called quencher, to reduce reactivity of S-303 with the red cell membrane. Following incubation of red cells with S-303 for 24 hours at room temperature, red cells containing the S-303 reaction product are transferred to a container with a resin designed to reduce the concentration of either S-303 or its reaction product, although based on its lifetime of approximately 20 minutes none is expected to remain. In Phase I and II clinical trials, the 24-hour recovery and survival of red cells that have been treated with S-303, stored for 35 days, and infused into normal autologous donors is comparable with that of normal donors receiving autologous untreated and similarly stored red cells (Hambleton et al., 1999; Cook et al., 1998). However, in a Phase III chronic transfusion study, three patients developed antibodies to S-303–treated red cells (Benjamin et al., 2005). In addition, in vitro studies on compounds with structures similar to S-303 demonstrated alkylations to proteins, including residual alkylations to the red cell surface despite the addition of reduced glutathione to prevent red cell modification (Cook and Stassinopoulos, 1998; Creech and O'Connell, 1981; Lauffer et al., 1979). A new methodology has been developed to reduce the amount of S-303 reacting with the red cell surface. Further development of S-303 will require repeating clinical studies with revised protocols to prevent red cell surface modifications. RESEARCH IRRADIATORS Research irradiators are used to expose biologic and nonbiologic materials to radiation of various types in order to evaluate the response of target materials to various doses, dose rates, and energies of the applied radiation source. Such units are used in a limited way in 4 Note that "generally recognized as safe" (GRAS) is a technical term: "under sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act (the Act), any substance that is intentionally added to food is a food additive, that is subject to premarket review and approval by FDA, unless the substance is generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of its intended use, or unless the use of the substance is otherwise excluded from the definition of a food additive" (FDA, 2004).

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96 RADIATION SOURCE USE AND REPLACEMENT materials research and extensively in radiobiologic research. They are used to evaluate electronics components and satellite components as well. Radiobiologic research involves either the exposure of bacterial, yeast, or mammalian cells to graded doses of radiation in order to evaluate response or the exposure of whole animals or portions of live animals in order to evaluate the response versus dose. Biologic exposure may also be a tool to enable other studies to be done, such as causing immunosupression so that transplantation may be evaluated. Research irradiation has been done with two primary types of irradiators: beam units located in a shielded room and self- contained irradiators with built-in shielding. The beam units are similar to radiotherapy cesium or cobalt units but are located in a shielded room in a research laboratory. They will deliver dose rates of 1 to 3 Gy/min at 50- to 80-cm distance. Self-contained units are housed in a dedicated room in a laboratory (see Figure 5-5). Often some of the units will be located inside an animal facility to allow irradiation of pathogen- free mice without removing them from the protected clean facility. The self-contained units have a cavity large enough to allow placement of partial body shields for small animals and dose-rate modifying shields. Units must deliver dose rates of 1 to 10 Gy/min to a cavity of 4 to 10 liters in size. Ideally the energy is high enough to make the effect similar in relative biologic effectiveness (RBE) to x-rays of 1 MeV or higher in energy, so that RBE corrections do not need to be made. These units can be loaded with cesium-137 or cobalt-60. Required shielding is two times thicker for cobalt units. Research irradiation facilities designed to study biological effects from continuous low- dose-rate exposure over periods of days, weeks, or more are not feasible using conventional x- ray machines or accelerators. No current compact x-ray sources can operate continuously and steadily for such long time periods. Worker hazards are minimal with these units as long as adequate door and source location interlocks are functional and shielding is of adequate thickness. Cost of the units depends on the cavity size, the radionuclide used, and the dose rate desired. Prices range from $150,000 to $500,000. In addition, one must consider the cost of security for the sources and cost of disposal of the sources when decayed or no longer used. Security must prevent access to the unit and removal of the sources. In June 2006, the U.S. NRC and the Agreement States imposed increased controls on irradiators that contain more than threshold quantities of radioactive material (see Chapter 3). Typically, research irradiators are located in facilities that have additional security, particularly if located in animal care units where security is in place for reasons unrelated to the irradiator. FIGURE 5-5 Research irradiators from two different manufacturers. SOURCE: Images provided by the committee.

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SELF-CONTAINED IRRADIATORS 97 Replacement Technologies Prior to the wide availability of radionuclde irradiators, x-ray sources were widely utilized in research applications. Usually a kilovoltage (200–300 kVp) radiotherapy unit is used in a shielded room or located in a shielding box. In some cases for cell irradiation, units with energy as low as 50 kVp are employed. These units provide dose rates of 0.5 to 1.5 Gy/min depending on the target-to-surface distance. Some of these units are still in use. Currently at least two companies market modern kilovoltage systems for specimen irradiation. Precision X-ray, Inc., sells a series of x-ray irradiators ranging in energy from 160 kVp to 320 kVp with an exposure chamber large enough for some animals. Units have been sold to over 30 institutions, some having up to 5 units each. Output ranges from 100 to 3 Gy/min depending on filtration and source-to-surface distance (see Figure 5-6a). Another company, Rad Source Technologies, Inc., has developed a center-filament x-ray tube that irradiates 360 degrees around the tube. This new tube has a cylindrical gold target that will be used in a new type of specimen and blood irradiator that Rad Source reports will be capable of up to 450 Gy/min with multiple tubes and rotating specimen chambers (see Figure 5-6b). As discussed previously, Rad Source Technologies developed the Raycell® now produced by MDS Nordion. These types of devices have the advantage of large fields of irradiation and the freedom from radionuclides and their security and disposal costs. These standard kilovoltage units are reliable, often lasting 30 years. Tube life is estimated at 10 years, and replacement cost is about $18,000. The Rad source unit tube can be returned to the factory and a new filament installed in the tube. Costs of these units range from $120,000 to $150,000, higher for the very high output devices. Both of these companies plan dedicated blood irradiation systems to be marketed in the near future. The disadvantage of such units in radiobiologic research is the kilovoltage x-ray energy which exhibits an increased RBE, although one can correct for this. Megavoltage linacs can also be used, usually nights and weekends in the radiotherapy department. (a) (b) FIGURE 5-6 X-ray research irradiators from (a) Precision X-ray (X-RAD 320) and (b) Rad Source Technologies (RS 2500). SOURCE: Images courtesy of (a) Precision X-ray, Inc., and (b) Rad Source Technologies, Inc.

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98 RADIATION SOURCE USE AND REPLACEMENT It is possible to design higher energy x-ray units with high output that could be employed for this purpose (see Chapter 4). Such units could replace radionuclide units and would require more shielding and be more expensive than the kilovoltage units discussed above. All of the cesium research irradiators could be replaced by cobalt-60 units, the sources for which are readily available and have potentially higher output and larger fields of irradiation. Because cobalt sources need more frequent source replacement, the acquisition, transportation, and source replacement costs would be higher for operation, but disposal of spent sources is available. They could also be replaced with kilovoltage x-ray units similar to those described above or with small linacs in shielded rooms. CALIBRATION SYSTEMS Calibration systems use high-activity radiation sources (approximately 15 to 82 TBq [400 to 2,200 Ci]) to produce radiation fields of known intensity for calibration of radiation monitoring equipment and dosimeters, whereby the equipment and dosimeters can be evaluated for accurate operation. A source of measured activity is required to calibrate instruments and dosimeters to accepted standards. Figure 5-7 shows a diagram and a photograph of a typical gamma-beam calibration source. The system usually consists of radioactive sources, radiation shielding, a mechanism for positioning the source, and a track or internal chamber for positioning the items to be calibrated. Modern calibration systems may contain a computer controller and safety systems, such as video monitoring, radiation monitors, warning lights and indicators, and a safety interlock system. Although calibration systems may contain different sources for the calibration of gamma, neutron, and beta monitoring equipment and dosimeters, the typical Category 2 sources used for calibration of beta/gamma survey instruments and dosimeters are strontium- 90, cesium-137, and cobalt-60. The U.S. NRC Interim Inventory (2007a) reports 104 calibration irradiators using Category 2 sources in the United States, in addition to calibration irradiators at nuclear power plants. These are primarily located in commercial and government calibration facilities and state regulatory agencies. Additional security is required at most of these facilities because of other nuclear material or radioactive sources that are used at the facilities or for other reasons. Replacement of the cesium chloride sources could be made with glass or pollucite forms of cesium since very high specific activity is not required. According to contemporary national and international radiation dosimetry protocols, Primary Standards Dosimetry Laboratories (PSDLs) and Accredited Dosimetry Calibration Laboratories (ADCLs) are required to provide users’ ionization chambers with calibration coefficients obtained in cobalt-60 gamma-ray beams. Therefore, PSDLs and ADCLs incorporate cobalt-60 irradiators, usually decommissioned clinical teletherapy machines, with cobalt-60 teletherapy sources with an activity of 50 to 370 TBq (1,500 Ci to 10,000 Ci). In the United States, the National Institute of Standards and Technology (NIST) in Washington, D.C., serves as the primary radiation dosimetry laboratory, and there are three accredited dosimetry calibration laboratories.

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SELF-CONTAINED IRRADIATORS 99 FIGURE 5-7 Typical gamma calibrator configuration for survey instrument calibration. SOURCE: Image provided by Hopewell Designs, Inc. (2007). SUMMARY AND FINDINGS In most (and perhaps all) applications discussed in this chapter, radioactive cesium chloride can be replaced by (1) less hazardous forms of radioactive cesium, (2) radioactive cobalt, or (3) nonradionuclide alternatives. However, not all of these alternatives are available now, and all are currently more expensive than radioactive cesium chloride for the users. Use of the more robust but lower specific activity cesium-137 source matrixes may require redesign of some self-contained irradiators, although others might be able to use the new sources without retrofit or any significant change in performance. Finding: In most (and perhaps all) applications, radioactive cesium chloride can be replaced by (1) less hazardous forms of radioactive cesium, (2) radioactive cobalt, or (3) nonradionuclide alternatives. However, not all of these alternatives are available now, and all are currently more expensive than radioactive cesium chloride for the users. Some alternatives to radioactive cesium chloride include radioactive cesium glass and a mineral form (pollucite) loaded with radioactive cesium (described in Chapter 2). These alternative material forms use the same cesium-137 as radioactive cesium chloride; thus, the gamma rays and the half-life are identical, but the specific activity of these sources is smaller and the pollucite is more difficult to fabricate, especially for high-activity sources. The committee judges that none of the current applications of high-activity cesium sources about which it was informed requires the higher specific activity afforded by cesium chloride. Accommodating the larger volume needed to achieve the same source activity would require redesign of some (not all) devices. High-activity cesium sources are not, however, available in these alternative material forms today, and making them available may require the cesium source producer (the Production Association Mayak in Russia) to modify its production process. Cobalt-60 may be substituted for radioactive cesium chloride for many applications (see the discussion in this chapter, on Cobalt-60 Blood Irradiators), although as much as twice the shielding thickness may be required for a source that achieves the same dose rate, and the

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100 RADIATION SOURCE USE AND REPLACEMENT half-life of cobalt-60 is shorter (5.3 years for cobalt-60 versus 30 years for cesium-137) thus lowering significantly the useful lifetime of the source. Shielding challenges can be addressed in part by switching from lead shields to more effective tungsten or depleted uranium shielding, but tungsten shielding is more expensive than lead and manufacturing depleted uranium shielding is a very specialized, expensive operation. The shorter useful lifetime of radiation sources requires that they be replaced periodically, which entails transportation of a fresh source and, in some cases, the used source, with the attendant risks associated with source transportation. X-ray generators are already commercially available as substitutes for applications that do not require gamma rays with the definite energies emitted by cesium-137, and cobalt-60. x- ray tubes can be expensive and require more maintenance than radioactive sources for periodic calibration and replacement. There is new innovation in x-ray irradiators by at least two companies and more replacements for radionuclide radiation sources could come with some incentives.