Technetium: Nuclear Medicine’s Crisis

Aging nuclear reactors often struggle to stay on line, a fact that’s just as true for small research reactors as it is for massive power plants. So it shouldn’t have been surprising that during 2008, 2009 and 2010, Canada’s National Research Universal reactor in Chalk River, Ontario, and the High Flux Reactor in Petten, Netherlands, both suffered a lot of downtime. In May 2009, a heavy-water leak at NRU shuttered the facility for 15 months, while cooling system leaks and repairs kept HFR from operating from August 2008 to February 2009, another month in 2009 and six more in 2010.

Those outages might have been mere footnotes in the recent history of the nuclear industry. But the Canadian and Dutch reactors happen to be the principal sources of technetium-99m, the most widely used radioactive isotope in medicine, and their troubles led to an acute global shortage of the element that began in 2009. Karen Gulenchyn, chief of nuclear medicine and molecular imaging for the hospitals of Hamilton, Ontario, was at the sharp end of the crisis. She remembers a time of frantic triage: swapping patients’ appointments, running clinics on weekends, replacing state-of-the-art tests with less effective alternatives.

Technetium is a staple of imaging for diagnosing and monitoring several life-threatening conditions. In cardiology, it’s used to investigate complaints of acute chest pain. Bone scans to detect cancer are another major application, and for pediatric patients in particular, potential alternatives often can’t be used, because they would expose children to excessive radiation. Confirming breast cancers is still another use for which the medical isotope is well suited.

Gulenchyn, testifying about the technetium shortage to the Canadian Parliament in June 2009, described the impact. She said that it had led to limitations in diagnostic testing, a crucial part of a process that begins with a patient complaint, is followed by a history and physical examination, and culminates in diagnosis and treatment. Removing a vital link in that chain reduced certainty about what might be wrong with a particular patient and could result in misdiagnosis—possibly with fatal consequences. “Did people die? Probably,” she says.

Eventually, both reactors were back in business, and supplies of technetium returned to normal. But those days of crisis could return. Even if the reactors don’t suffer additional unplanned downtime, they’re both nearing the end of their useful lives. NRU will cease production by 2016, and HFR around 2020. And with conventional sources of technetium already under pressure, a collision between politics, business and science is forcing a shake-up in the way this essential isotope is made, and in the path it takes to hospitals and outside imaging centers. They have just a few years to secure new sources of technetium before serious shortages begin to bite once more. “I’m nervous about the relatively short time period,” says Vasken Dilsizian, chief of nuclear medicine at the University of Maryland Medical Center in Baltimore. “The process has to move faster.”

Technetium was discovered in 1937, born in a particle accelerator at the University of California, Berkeley. It was the first man-made element, and the isotope technetium-99m was created the following year. Technetium-99m emits gamma rays—similar to diagnostic X-rays—that are detected with a gamma camera. An injection of the isotope can produce real-time images of a beating heart, reveal the presence of bone diseases and even help guide a cancer surgeon’s scalpel. Every year, physicians in the United States use technetium in almost 20 million medical tests, and every one of them is a race against time. With a half-life of just six hours, batches of radioactive technetium dwindle to nothing within days. So the tests rely on a complex supply chain starting at a handful of nuclear reactors around the world that make molybdenum-99, a longer-lived precursor to technetium-99m.

The reactors’ neutrons batter uranium targets, breaking apart nuclei to form a kaleidoscope of daughter isotopes that include about 6% molybdenum-99. Its half-life of 66 hours provides just enough time to extract it from the reactors, separate it from the other radioisotopes and load it into generator units that are shipped to hospitals around the world. As the molybdenum inside the generator decays, it produces a steady stream of technetium-99m that can be “milked” from the device. Combined with molecules that target specific parts of the body, the technetium can illuminate organs, certain types of tissue and physiological processes.

That supply chain, with different companies involved at each stage, has been in place for decades. But now it is “fragile and economically unsustainable,” says Ron Cameron, head of the Nuclear Development Division of the Organisation for Economic Co-operation and Development. About two-thirds of the world’s molybdenum-99 comes from the NRU and HFR reactors. Almost all of the rest originates in a few reactors elsewhere in Europe, South Africa and Australia. The OECD predicts that without new production capacity, demand for molybdenum-99 could outstrip supply within just a few years, between 2016 and 2019.

HFR and NRU are research reactors, used primarily to test nuclear fuels, processes and equipment. Their operators had long regarded molybdenum-99 production as a sideline, and sold it at cost. But that practice not only failed to cover the expense of establishing and running the reactors, or to help fund their replacements; it also kept molybdenum-99 prices artificially low, discouraging commercial providers from establishing alternative sources.

The United States has not had a domestic source of molybdenum-99 since 1989, when a radioactive leak shuttered the country’s only commercial facility. Yet it consumes about half of global production. Once Canada’s NRU reactor closes, the country could be completely dependent on imports flown in from overseas. Even if existing research reactors in Europe or Australia increase their capacity, the United States would be far too vulnerable to breakdowns at any of those sources, argues Robert Atcher, director of the National Isotope Development Center and professor of pharmacy at Los Alamos National Laboratory. “We have to establish a production capacity in the United States to ensure we have the medical isotopes we need,” Atcher says.

Further complicating things, the world’s few molybdenum-producing reactors are losing access to their preferred starting material: targets that contain more than 20% of the isotope uranium-235. Natural uranium contains less than 1% of this isotope, so enrichment is essential to create the targets. But highly enriched uranium (HEU) can also put the bang in nuclear weapons. The United States has long been the sole supplier of HEU to the reactors, but in recent years it has been pressing hard to stop—part of a broader strategy to reduce the risk of nuclear proliferation. The American Medical Isotope Production Act, signed into law by President Obama in January, calls for ceasing all HEU exports by 2020. Yet the law also promises to take steps to ensure the supply of medical isotopes.

Last year, as part of an international effort to limit nuclear proliferation, France, Belgium and the Netherlands agreed to switch to low-enriched uranium for medical isotope production by the end of 2015. But that process is much less efficient—reactors’ yields are expected to drop, and the process will also produce more radioactive waste, both of which will raise costs. “No matter what happens, the price of molybdenum-99 will go up,” predicts Atcher.

Cardiology investigations account for half of all U.S. technetium use, racking up about nine million procedures each year. Many of those are myocardial perfusion studies that track how blood flows through heart muscle—a standard way to investigate unexplained chest pains. Those are particularly useful when they’re combined with single photon emission computed tomography to create a three-dimensional image of the organ.

Until the late 1980s, most heart imaging relied on radioactive thallium-201, but the isotope’s long half-life (73 hours) meant that patients received more radiation than they would from technetium. Using less thallium-201 can cut the exposure, but it also produces fuzzier images, especially in overweight patients. Technetium’s shorter half-life means there can be injections with up to 10 times the initial radioactivity of thallium that produce sharper pictures yet give patients a lower overall dose.

During the 2009 shortage, though, many imaging centers simply had to “turn the clock back and use thallium,” says Dilsizian. In other cases, physicians had to fall back on conventional angiograms, which is an invasive procedure that involves injecting a contrast agent through a catheter to the heart.

Positron emission tomography is another alternative to technetium, but only about 50 of the thousand or so PET scanning centers in the United States are geared up to use it for cardiology, says Dilsizian. PET scans are also much more expensive.

The two companies responsible for supplying technetium generators to U.S. hospitals say they have been working hard to find alternative sources of molybdenum-99. Mallinckrodt Pharmaceuticals of Hazelwood, Mo., extracts and processes most of its own molybdenum-99 at a facility in the Netherlands, sourced largely from HFR, but some of its technetium generators also contain molybdenum-99 made at NRU. Lantheus Medical Imaging in Billerica, Mass., traditionally got all of its molybdenum-99 from health science company Nordion in Ottawa, which extracts and processes the isotope from the NRU reactor. But over the past few years, Lantheus has established new supply deals with reactors in South Africa, Europe and Australia, and aims to eliminate its reliance on NRU by October 2016.

Meanwhile, the U.S. National Nuclear Security Administration set up cooperation agreements with four companies to develop a domestic molybdenum-99 supply that does not require highly enriched uranium. But the largest two companies—GE Hitachi and Babcock and Wilcox—have since shelved their plans, saying their processes aren’t economically viable in the current market. That has left the field wide open for two minnows, both based in Madison, Wis., and provisionally backed by almost $25 million apiece from the NNSA. NorthStar Medical Radioisotopes and the Subcritical Hybrid Intense Neutron Emitter (SHINE) project both are developing innovative production methods from scratch.

NorthStar plans to pay the University of Missouri Research Reactor in Columbia, Mo., to irradiate targets of natural molybdenum with neutrons, converting molybdenum-98 to molybdenum-99. The company hopes to begin production in early 2014 and projects that it could meet about 10% of U.S. need. Switching to targets enriched in molybdenum-98—a much more efficient way of making molybdenum-99—the following year could raise that figure to 50%, says James Harvey, chief scientific officer of NorthStar. “We’ll be the first producer of molybdenum-99 in the United States in 25 years,” he says, noting that the company also hopes to build a $194 million facility in Beloit, Wis., that would use an alternative method to produce molybdenum-99 (by spraying gamma rays at molybdenum-100 to knock a neutron out of each nucleus) and could enable NorthStar to meet the entire U.S. appetite for the isotope.

But the molybdenum from both processes has fewer molybdenum-99 atoms in the mix, and the company has had to develop a new form of generator, dubbed TechneGen, to extract sufficient doses of technetium. Harvey hopes to get Food and Drug Administration approval for the system toward the end of this year—which would allow the company to extract molybdenum-99, distribute the generators to hospitals and other imaging centers, and then retrieve them to recycle leftover molybdenum. That would drastically simplify the technetium supply chain, offering potential savings.

Just 10 minutes away from NorthStar’s offices, Greg Piefer believes he has found a very different solution to the potential technetium shortage. In 2005, he founded Phoenix Nuclear Labs, and in 2010 he spun out a new company—SHINE Medical Technologies—to make molybdenum-99 by beaming neutrons at a target of low-enriched uranium in solution. There’s a working prototype of the system, and the company plans to build eight accelerators in an $85 million plant in Janesville, Wis., enough to meet about two-thirds of U.S. demand.

Because its process uses enriched uranium (albeit low enrichment), SHINE’s main hurdle is to get approval from the U.S. Nuclear Regulatory Commission, which could come by the end of 2014, and, at the earliest, the Janesville plant could be finished a year later. The company is in discussions with supply chain participants around the world (including Lantheus and Mallinckrodt) to distribute the molybdenum-99 it would produce, with shipments beginning as early as the end of 2016.

Canada, meanwhile, is trying to shore up its own domestic supply of molybdenum and technetium. In February, the government announced more than $21 million in funding for three projects that could take over from NRU. The Prairie Isotope Production Enterprise in Manitoba is developing a linear accelerator technology that’s similar to NorthStar’s, while the other two, led by the University of Alberta and the TRIUMF particle physics facility in Vancouver, rely on cyclotron particle accelerators that already make short-lived isotopes for PET scanning. (All would circumvent the need for enriched uranium in the harvesting of technetium.)

The cyclotrons at Alberta’s and TRIUMF’s facilities accelerate protons and smash them into molybdenum-100 targets to make technetium directly. But its six-hour half-life limits the area that a single cyclotron could serve. Paul Schaffer, head of nuclear medicine at TRIUMF, estimates that they could ship technetium to the remote town of Prince George, some 480 miles away, in about one half-life. About 20 to 24 cyclotrons would be needed to supply all of Canada’s major hospitals in this way, Schaffer says. He notes that 18 cyclotrons are currently installed or nearing completion in the country, most of which can produce technetium “on some level.”

TRIUMF still needs to conduct clinical trials using its technetium, and once it has begun supplying hospitals, the system would have to be rolled out at other cyclotrons across the country. “I don’t think anyone in Canada thinks there’ll be a huge amount of technetium being made that way by 2016,” says Gulenchyn.

In the coming year, it should become clear whether the global changes to the technetium supply chain are all happening quickly enough to avert a crisis. “By 2016, we’ll know how many producers have switched over to LEU, and how that has affected their supply,” says Cameron. It will also give the wild cards—NorthStar and SHINE—time to prove their mettle.

But Dilsizian argues that the U.S. government should be doing more to ensure that physicians have the medical isotopes they need before the 2016 crunch. “That’s not a long time away,” he warns. One option is for the FDA to fast-track any applications to approve new technetium sources or new PET radiotracers, he suggests, just as it might for an urgently needed cancer drug, for example. “This has been an issue for a long time and it seems like you have to get to last-minute urgency before things happen,” he says.

Others are already steeling themselves for the worst. “Am I confident there’ll be enough?” asks Gulenchyn. “No.”

Originally published in Proto, focusing on the promise of biomedicine, published by Massachusetts General Hospital.

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