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Unmasking the mysteries of chronic beryllium disease

New tests identify sensitivity, genetic susceptibility

Beryllium is a unique lightweight metal used in nuclear weapons and, in the commercial sector, for telescope mirrors, golf clubs and a variety of other applications. While solid beryllium and beryllium alloys are safe, fine particulate beryllium is hazardous if inhaled.

In certain individuals, breathing microscopic beryllium particles can lead to Chronic Beryllium Disease (CBD), sometimes called berylliosis. CBD is a long-duration, allergic-type lung response that can make the sufferer abnormally weak and is sometimes fatal.

Research into beryllium health effects in the Bioscience Division at Los Alamos National Laboratory center on identifying worker sensitivity and increased risk caused by genetic factors. Only a small percentage of people exposed to beryllium become sensitized to it, meaning they experience an immune-system reaction to exposure. In addition, it appears that not everyone who is sensitized develops CBD.

A team led by Bioscience Division researcher Babs Marrone has devised an improved Lymphocyte Proliferation Test, or LPT, a blood test that can identify sensitized individuals. The researchers also have found genetic markers that indicate increased susceptibility.

The new test, called the Immuno-LPT, takes advantage of the fact that both sensitization and CBD are immune-system responses. Using flow cytometry, a laser-based, cell-analysis technique developed at Los Alamos, researchers can detect a proliferation of a specific white blood cell, or lymphocyte, known as aCD4+cell, that forms in response to beryllium. Results suggest that because CD4+ cell proliferation in people sensitized to beryllium matches the response in people who have CBD, the Immuno-LPT may be quite accurate in predicting the development of CBD.

Because some individuals develop sensitivity and disease when exposed to only miniscule amounts of beryllium, while others with high levels of exposure never get sensitized or develop CBD, scientists wondered if there could be a genetic risk factor.

"Our research has shown that the majority of individuals with CBD, or with a CD4+ response to beryllium, have rare variations of a gene on chromosome 6 containing what is known as a 'Glu69' marker," said Marrone. "We looked closely at the variations around the marker, and we found other contributing genetic factors that help us pinpoint those who are at increased risk."

Because these genetic differences are inherited and not caused by beryllium exposure, researchers could use the genetic markers to identify individuals with greater susceptibility to develop beryllium disease.

All genetic-marker information must be kept confidential, said Marrone. And taking the test must be the decision of the workersówith their informed consent. Given that, the Lab would like to offer the genetic-marker test to more than 3,000 current and former Lab employees who either worked with beryllium or may have had incidental exposure.

Ethical and legal issues must be carefully considered in any genetic testing program, either at the Lab or in industry, according to Marrone. "We want to get the best possible information to the workers so that they can then make informed decisions about their work situation," she said. "At the same time, we must ensure that information from genetic testing does not lead to any kind of discrimination."

Marrone and her colleagues continue to work with industrial hygienists, physicians, environmental scientists, chemists and health physicists to understand better 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.



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