A team led by Babetta Marrone of Los Alamos' Bioscience Division has devised a new, more accurate blood test to identify workers who are sensitized to beryllium. The researchers also have pinpointed genetic markers that indicate increased risk for a small number of workers who are more likely to develop CBD.
"This significant advance will help create an even stronger safety envelope for our workers who handle beryllium," said DOE Secretary Bill Richardson. "By identifying those workers who are more susceptible to being hurt by beryllium exposure, we can find them appropriate work that does not put them at increased risk. Pushing the science of worker safety is something we must do at the same time that we compensate workers harmed by exposure to beryllium from past practices."
Los Alamos maintains the DOE's capabilities for research and development in beryllium, a unique metal used in nuclear weapons and, in the commercial sector, for telescope mirrors, golf clubs and a host of other applications.
Roughly 3 to 4 percent of all people are at risk for serious illness from working with beryllium, although the risk is higher for some workers such as machinists. If they inhale beryllium metal in powder form, they can become sensitized to beryllium, that is, their immune systems become allergic when beryllium enters their bodies. Beryllium sensitization can be an early sign of Chronic Beryllium Disease, a disabling and sometimes fatal lung condition. CBD symptoms may not appear for more than 10 years after exposure to the metal. No cure is known.
"Sometimes people call beryllium sensitization an allergy, but it's not like ragweed," Marrone said. "The so-called allergic mechanism found in CBD is a cell-mediated immune response, with a delayed reaction to the allergen. A variety of biochemical events at the molecular level contribute to this immune response. Our blood test identifies these molecular events."
The new blood test and the separate test for genetic markers, when used together, will help predict and diagnose CBD, and help to prevent future cases of beryllium disease.
BLOOD TEST CBD is accompanied by an increased sensitization to beryllium, which currently can be detected with a blood test called the Lymphocyte Proliferation Test, or LPT.
However, not everyone who tests positive for beryllium sensitization on the blood test will develop CBD. The psychological impact of testing positive is high, especially because it can take many years to develop CBD after first exposure to beryllium. What is needed is a blood test that better predicts CBD.
Los Alamos' new test, called the Immuno-LPT, takes advantage of the fact that both sensitization and CBD are responses to beryllium by the immune system.
A specific lymphocyte, the T helper or CD4+ cell, is implicated in CBD. Using flow cytometry, a laser-based cell analysis technique developed and refined over many years by Los Alamos, the Immuno-LPT detects proliferation of the CD4+ cells in response to beryllium. The Immuno-LPT shows that people who have CBD typically show a CD4+ cell response to beryllium. However, some people who are sensitized but don't have CBD may have another type of response involving proliferation of T suppressor or CD8+ cells.
"Our results suggest that individuals who have CD4+ cell proliferation in response to beryllium have the greatest likelihood of developing chronic beryllium disease, because their responses match those seen in CBD," Marrone said. "So we think the Immuno-LPT may be more accurate than the current test in predicting whether someone will develop CBD."
Results of initial Immuno-LPT studies are scheduled to be published next week in the journal Toxicology. Authors of the paper are Georgia Farris, Yulin Shou, Robert Habbersett, Hugh Smith and Marrone, all of Los Alamos; Lee Newman, Elizabeth Barker and Lisa Maier of the National Jewish Medical and Research Center in Denver; and Edward Frome of Oak Ridge National Laboratory.
GENETIC MARKERS Scientists have long suspected that a genetic risk factor for CBD makes certain individuals more likely to develop sensitivity and disease when they become exposed to even small amounts of beryllium. Such an effect may explain why CBD is seen in some people with minimal exposure to beryllium, and also why many with high exposure don't develop CBD.
Los Alamos researchers now can locate genetic markers that are present in individuals with CBD but absent in others who don't have the disease.
"Our goal is to identify a panel of markers and the degree of risk associated with each," Marrone said.
Several years ago, researchers discovered tantalizing evidence of a possible genetic marker for susceptibility to chronic beryllium disease, called Glu69. Their discovery couldn't be used to help workers because the marker they identified also occurred frequently in a control population. When projected to the general population, the marker might be present in one in three people who are not susceptible to the disease
"We've been able to pull apart these two populations a lot better," Marrone said.
"We looked more closely at the alleles, the region of the genome around the marker, and we found other contributing genetic factors that help us pinpoint those who are at risk," she said.
For CD4+ cells to proliferate in response to beryllium, the beryllium must be "presented" to them by protein molecules called Human Leukocyte Antigens factors, Marrone said.
Slight differences in the DNA sequence of the gene responsible for making the HLA protein often are found in individuals with CBD. The responsible gene is found in a major histo-compatibility complex region on chromosome 6 that is associated with the immune response.
"Since these differences are inherited, and not caused by beryllium exposure, we could use the genetic markers to identify individuals with greater susceptibility to develop beryllium disease," Marrone explained. "Beryllium workers with greater genetic risk could make more informed decisions about whether they should work with beryllium. They also could be placed on more intensive medical surveillance."
Authors of the initial research paper on the genetic markers, which was published last year in The Journal of Immunology, include Zaolin Wang, Scott White, Michelle Petrovic, Owatha Tatum and Marrone of Los Alamos' Bioscience Division; and Newman and Maier from the National Jewish Medical and Research Center.
Marrone and her colleagues in Los Alamos' Bioscience Division are working with industrial hygienists, physicians, environmental scientists, chemists and health physicists to better understand how beryllium damages the immune system, with the ultimate goal of a cure for beryllium disease. Experts in legal and ethical issues also seek to integrate new information about genetic markers into beryllium medical surveillance practices.
"Our approach is based on what we're learning about the mechanisms that make workers susceptible to beryllium disease," Marrone explained. "If we're interested in preventing beryllium disease, we have to consider all the risk factors. That's the only way that we're going to prevent disease and eliminate CBD in the workplace."
DOE Secretary Richardson recently announced proposed legislation that would compensate current and former workers and contractors who are ill because of beryllium exposure at DOE nuclear facilities. DOE has established its Chronic Beryllium Disease Prevention Program, part of federal law 10 CFR Part 850. Los Alamos, Lawrence Livermore and Lawrence Berkeley national laboratories are working together with the University of California Operations Office and the DOE on a plan to implement the DOE program.
"Los Alamos hopes to integrate the new tests into this implementation plan, which will provide Los Alamos workers with the most advanced technology available for beryllium health surveillance, " Marrone said.
Los Alamos National Laboratory, a multidisciplinary research institution engaged in strategic science on behalf of national security, is operated by Los Alamos National Security, LLC, a team composed of Bechtel National, the University of California, The Babcock & Wilcox Company, and the Washington Division of URS for the Department of Energy's National Nuclear Security Administration.
Los Alamos enhances national security by ensuring the safety and reliability of the U.S. nuclear stockpile, developing technologies to reduce threats from weapons of mass destruction, and solving problems related to energy, environment, infrastructure, health, and global security concerns.
