Worker Health Study Summaries

Research on long-term exposure

Beryllium Processors (Beryllium)

1995

Purpose

Before this study began, we knew that people exposed to beryllium may develop two forms of beryllium disease, acute and chronic. These are lung diseases caused by exposure to beryllium. The acute form is a rare pneumonia-like disease that occurs shortly after very high exposures to beryllium. The chronic form may develop many years after being exposed to beryllium. Chronic beryllium disease is described in the fact sheet “Steps to Protect Your Health.”

Our study, however, focused on lung cancer. Some studies had previously linked lung cancer to beryllium exposure. However, this link was uncertain. Thus, we did our study to further examine this issue.

Description

We studied 9,225 workers employed at 7 beryllium processing plants between 1940 and 1969.

We based the study on work records that we got from the companies. We also obtained the death certificates of workers who had died. We counted the number of workers who died from each disease.

Then we calculated the number of deaths from each disease that we would expect to find in the workers, based on how often people die of these diseases in the U.S. population as a whole. If the number of deaths in the workers is higher than the expected number, then workplace exposures may be the cause.

What We Found

We found an increased risk of lung cancer in workers exposed to beryllium at all plants combined. We found 280 deaths, but expected 221.

The lung cancer excess was confined to workers hired in the 1940s and 1950s.

Among workers hired in the 1960s, the risk of lung cancer was noticeably lower than expected. We found 18 deaths from lung cancer and expected about 29.

We examined the effect of smoking and county of residence on lung cancer risk.

We concluded that these factors could not completely explain the increased lung cancer risk.

The study did not address the relationship of lung cancer to the degree of exposure or to specific types of beryllium compounds.

Another NIOSH Beryllium Study

Another NIOSH study, which looked at causes of death among 689 people who were reported to a national beryllium disease registry (the Registry Study), also found increased deaths from lung cancer. (203 people were included in both the workplace and the registry studies).

What Does This Mean?

The authors of the study and many scientists (including the International Agency for Research on Cancer) believe that most of the excess in lung cancer was due to beryllium exposure because:

• Smoking and county of residence did not completely explain the excess.
• Breathing in beryllium compounds causes lung cancer in some animals.
• The highest increase in lung cancer occurred many years after exposure began.

This is what we expected, since it takes a long time for cancers to develop.

Other scientists argue that part or all of the excess may have been due to other factors, including smoking or exposure to acid mists, uranium, and nickel. Chronic beryllium disease and lung cancer may develop many years after the last exposure to beryllium. Thus, you and your doctor should be aware that you might have an increased risk of developing these diseases.

What You Can Do to Protect Your Health

• You should not smoke. Cigarette smoking causes lung cancer and may make chronic beryllium disease worse. For ways to stop smoking, call the American Lung Association at 800-LUNG-USA or the American Cancer Society at 800-227-2345.
• If you have lung or breathing problems that don’t go away, see your doctor. Take the fact sheet For Your Doctor with you.

If you, your doctor, or members of your family have any questions, or would like a copy of the technical reports, call at 800-356-4674.

Why the Study Was Done

The main purpose of the workplace study was to see if exposure to beryllium is associated with lung cancer.

Since inhaling some beryllium compounds caused lung cancer in rats, and may cause it in monkeys, there was concern that it might cause lung cancer in people.

Beryllium is already known to cause chronic beryllium disease, a lung disease.

How the Study Was Done

Study Group

We included 7 plants to make sure we had enough workers in the study.

The study group included all men who had worked for at least 2 days at any of the plants between 1940 and 1970.

Records

This study was done without contacting the individual worker because it was based on records. It included living and deceased workers.

Government records were used to find out which workers had died before 1989. Death certificates reported the cause of death. NIOSH used public records to find out the death rate for certain diseases in the general public.

Comparing Results

We compared how often deaths from specific diseases occurred in beryllium workers to how often they occurred in the general public.

When deaths from specific diseases are more common in beryllium workers than among the general public, beryllium exposure may be the reason.

What the Workplace Study Found

Lung Cancer

Among all workers in the study, there were 280 deaths from lung cancer, where 221 were expected. This means that all workers in the study had about 1¼ times more lung cancer deaths than expected.

Workers hired in the 1940s, when exposures were the highest, had a significant increase in lung cancer. We found 177 deaths, but expected only 125. This was almost 1½ times the normal level.

There were slightly more lung cancer deaths than expected in workers hired in the 1950s, with 85 found and 68 expected. This was about 1¼ times the normal level.

There were noticeably fewer lung cancer deaths than expected in workers hired in the 1960s. We found 18 deaths, but expected 28 or 29.

Other factors which may elevate lung cancer deaths in groups of workers are cigarette smoking and living in an area with a high risk of lung cancer.

NIOSH investigators analyzed smoking data from a beryllium workers’ survey in 1968. This survey found that, at least at that time, beryllium workers were heavier smokers than the general population. This increased smoking was predicted to result in 1 1/8 times more deaths from lung cancer than expected.

Adjustment for county lung cancer rates did not affect the expected number of lung cancer deaths. NIOSH investigators concluded that neither smoking nor geographic location fully explained the lung cancer risk.

Beryllium Disease Registry Results

The increase in lung cancer in beryllium-exposed workers was also seen in another NIOSH study of people who were reported to a national beryllium disease registry.

In that other study, we found 28 lung cancer deaths, but expected 14. Those who developed acute beryllium disease, a form of the disease caused by very high exposures to soluble forms of beryllium, had the highest risk. We saw 17 deaths, but expected only 7 or 8.

Additional Findings of the Workplace Study

Lung Diseases, Including Chronic Beryllium Disease

At all plants combined, we saw an increase in the group of lung diseases that includes chronic beryllium disease. We found 101 deaths, but expected only 68.

Heart Disease

We also saw an increase in heart disease at all plants combined. We saw 1,314 deaths, but expected 1,240. Most of this increase was in heart attacks. This was an unusual finding, but we do not know if it was related to beryllium exposure.

Kidney Disease

Deaths from kidney diseases were 1½ times more common in workers who worked at beryllium processing plants than in the general public. We found 30 deaths, but expected 20.

This is a rare cause of death, and very few workers are likely to die from it.

Since beryllium passes through the kidneys, it is possible that it can damage them. However, this is a new finding. We do not know if this increase is related to beryllium exposure.

Mouth Cancer

We found an increase in mouth and salivary gland cancers at one plant that was not found at other plants. At the one plants we found 9 deaths, but expected only 2 or 3.

This is the first time that an increase in these cancers has been seen in beryllium workers. We do not know what caused this increase.

Mouth and salivary gland cancers are very rare. Only a very few workers developed these cancers.

What the Study Means

This study showed an increase in lung cancer in workers exposed to beryllium.

We believe that the most likely cause of the increase in lung cancer was exposure to beryllium.

Other scientists believe that smoking or exposure to acid mists, uranium, or nickel caused part or all of the increase in lung cancer.

Our study also confirmed that exposure to beryllium can cause lung diseases, especially chronic beryllium disease.

Even employees who worked with beryllium for less than a year may be at risk of developing chronic beryllium disease and lung cancer.

The lung cancer seen in this study generally occurred many years after first exposure to beryllium. Therefore, it is possible that workers will continue to have an increased risk of lung cancer.

Any Questions?

If you, your doctor, or a family member would like more information, call our toll free number: 800-356-4674.

Steps to Protect Your Health

Symptoms of Chronic Beryllium Disease and Lung Cancer

If you have been exposed to beryllium, you may be at increased risk of lung cancer or chronic beryllium disease. Although only a few people will develop these diseases, you may want to know the symptoms.

The main symptoms of chronic beryllium disease are shortness of breath while exercising or walking, cough, fatigue, weight loss, or chest pain.

These symptoms, as well as coughing up blood, may also be symptoms of lung cancer.

Even if you have these symptoms, it may not mean you have a serious illness.

If you have these problems and they do not go away, see your doctor.

If you do not have symptoms, you do not need to make a special trip to the doctor.

Chronic Beryllium Disease

Chronic beryllium disease is a rare disease that only occurs in a small percentage of people who have been exposed to beryllium.

The amount of exposure to beryllium (the dose) plays a role in the development and severity of the disease. However, sensitization (an allergy-type reaction) to beryllium is a major factor. Hence, a small number of people will develop chronic beryllium disease even with minimal beryllium exposure.

Chronic beryllium disease often causes scarring of the lungs. Doctors can sometimes see these scars on chest x-rays. The scars may make it difficult to breathe. A simple breathing test tells your doctor how well your lungs are working.

Although there is no cure for chronic beryllium disease, corticosteroids (not the type used by athletes) can often control the symptoms. However, these drugs have side effects. Thus, they must be used under the care of a doctor.

If you have chronic beryllium disease or other chronic lung problems, you should ask your doctor to give you a flu shot every fall. You should also make sure that you have been vaccinated against pneumonia.

Lung Cancer

If lung cancer is present, it may also show up on the chest x-ray.

If your doctor suspects cancer, he or she will do other tests.

Mouth Cancer

Mouth cancers can often be detected early by having your dentist examine your mouth. Ask your dentist to check your mouth for cancer at your regular checkup.

Preventing Lung and Mouth Cancer

Smoking causes lung and mouth cancers and may make the symptoms of chronic beryllium disease worse. You should not smoke. Chewing tobacco causes mouth cancer. You should not chew tobacco. Many organizations have programs that can help you quit.

For information on how to stop smoking, call the American Cancer Society at 800-227-2345. They have information on smoking cessation programs in your local area.

They also have free information on the treatment and diagnosis of various cancers. The American Lung Association has programs to help you stop smoking. For information, call them at 800-LUNG-USA. They can also direct you to doctors that treat lung diseases.

Exposure to Beryllium

The Occupational Safety and Health Administration’s permissible exposure limit (PEL) for beryllium exposure is 0.002 mg/cubic meter (2µg/m³) averaged over 8 hrs.

However, because NIOSH believes that beryllium is a potential workplace cancer causing agent, it recommends the lowest possible exposure. The NIOSH recommended exposure limit (REL) is 0.0005 mg/cubic meter (.5µg/m³) for beryllium.

Other Sources of Information

The National Jewish Center for Immunology and Respiratory Medicine in Denver, Colorado does research on chronic beryllium disease.

Their toll free number provides information about lung diseases. If you have questions about chronic beryllium disease or lung cancer, call them at 800-222-LUNG.

For more information on the diagnosis and treatment of cancer, call The National Cancer Institute at 800-4-CANCER.

If you, your doctor, or members of your family have any questions, or would like a copy of the technical reports, call NIOSH at 800-356-4674.

Technical Information for Your Doctor

The National Institute for Occupational Safety and Health (NIOSH) conducted two retrospective cohort mortality studies, a workplace study of employees exposed to beryllium compounds and a registry study of patients who had beryllium disease.

Your patient was a subject of the workplace study. He was employed by a beryllium manufacturer in the past and may continue to be exposed to beryllium. Your patient can provide you with information about his exposure history.

We are providing this fact sheet about beryllium disease to physicians because beryllium disease is rare and may be hard to diagnose. We also include a summary of the study results that may relate to your patient’s health.

Purpose of the Studies

Previous studies that showed a link between beryllium and lung cancer had been criticized for methodologic difficulties. Thus, our studies were designed to re-examine the relationship between beryllium exposure and lung cancer.

Findings of the Two Studies

The workplace study found a modest excess of lung cancer in workers exposed to beryllium after taking smoking habits into consideration. It also found an expected increase in beryllium disease.

The registry study showed that those who had had acute beryllium disease, a form of the disease associated with very high exposures to beryllium, had the highest increase in lung cancer. We believe that the most likely cause of the increase in lung cancer was exposure to beryllium.

Other diseases found in excess in the workplace study were emphysema, heart diseases, including ischemic heart disease and cor pulmonale (a known sequela of beryllium disease), chronic kidney diseases, and oral cancer. The increase in emphysema may have resulted from the misdiagnosis of beryllium disease. We do not know the cause of the increases in heart diseases (other than cor pulmonale), kidney diseases, or oral cancer. The increase in oral cancer was seen only at one plant, where some of the subjects worked. Cor pulmonale and emphysema were also elevated only in one plant.

Beryllium Disease

Beryllium disease occurs in two forms: acute and chronic. The acute form has a short latency period, usually occurs during exposure, is brief in duration, and presents clinically as a type of chemical pneumonitis.

Since the adoption of the Atomic Energy Commission beryllium standard (which later became the Occupational Safety and Health Administration standard) that has reduced exposure, acute beryllium disease is very rare and should not occur unless there is an industrial accident.

However, some patients who have had the acute form later develop the chronic form. This fact sheet focuses on chronic beryllium disease (CBD) which may occur many years after exposure to beryllium has stopped, whether or not the patient has had prior acute beryllium disease.

Chronic beryllium disease occurs from inhalation of beryllium. It is characterized mainly by pulmonary noncaseating granulomas.

Even individuals with short exposures to beryllium (less than 1 year) may eventually develop CBD. Most studies report an average time between first exposure and onset of symptoms of 10 to 15 years, although some cases do not develop disease for several decades following first exposure.

Diagnostic Criteria for Chronic Beryllium Disease

In 1952, the Beryllium Case Registry, currently inactive, was established as a means of following the effects of beryllium and beryllium disease. This registry consists of persons suspected of having several different forms of beryllium disease, including both acute and chronic beryllium disease.

As a result of observations on many of these cases, the following criteria were developed to identify those cases with chronic beryllium disease:

1. documentation of beryllium exposure,
2. presence of beryllium in body tissues or fluids,
3. evidence of lower respiratory tract disease and a clinical course consistent with chronic beryllium disease,
4. radiographic evidence of pulmonary interstitial fibronodular changes,
5. restrictive or obstructive spirometry or reduced carbon monoxide diffusing capacity, and
6. noncaseating granuloma in lung or lymph node biopsy or pulmonary mononuclear cell infiltrates.

To be included as a registry case, the subject needed to satisfy at least four of the six criteria including at least one of the first two.

While the above criteria may be used for a presumptive diagnosis of CBD, to make a definitive diagnosis of CBD, most clinical experts now require evidence of beryllium hypersensitivity along with histopathology on lung biopsy consistent with beryllium disease, as well as a history of exposure to beryllium.

Beryllium disease may be confused with sarcoidosis or other interstitial lung diseases. Individuals who have had exposure to beryllium should receive a thorough assessment of respiratory symptoms, a chest examination, pulmonary function tests, and chest x ray. Some cases may present with a paucity of symptoms and subtle clinical abnormalities.

Pulmonary Function Tests

Patients with CBD usually have a reduced diffusing capacity, often, but not always, with a restrictive pattern on spirometry. Patients with CBD sometimes develop an obstructive impairment due to peribronchial granuloma formation.

Radiologic Studies

The typical radiographic findings in CBD are diffuse infiltrates often accompanied by bilateral hilar lymphadenopathy. The radiographic infiltrates are granular, nodular, linear, or mixed. Coarse interstitial densities indicative of fibrosis, and in rare cases, hyperlucent areas indicative of emphysema, may be seen.

Beryllium Sensitivity Tests

The beryllium-specific lymphocyte proliferation test (LPT) often referred to as the beryllium-specific lymphocyte transformation test (LTT) in the medical literature, measures the proliferative rate of lymphocytes in the presence of beryllium salts. This test is done on peripheral blood lymphocytes or bronchoalveolar (BAL) lymphocytes and can be used to determine if a patient is sensitized to beryllium.

As with other non-routine laboratory tests performed on living cells, logistical and other issues must be considered in advance for the test to be properly done. However, it is possible to arrange for shipment of cells to one of the few laboratories which currently offer this testing service (listed below).

Limitations of LPT

Blood-LPT on Asymptomatic Patients with Normal Pulmonary Function and Chest X-ray

Studies are underway to evaluate the usefulness of blood LPT as a screening test for asymptomatic persons in a number of worker populations.

Blood-LPT on Symptomatic Patients or Patients with Abnormal X-ray or Pulmonary Function Tests

One group reported 93% sensitivity for the blood-LPT in patients with known CBD. However, another group reported that only 48% of patients with known CBD are positive. Therefore, the interpretation of the test in symptomatic patients is also problematic.

BAL-LPT

The LPT on bronchoalveolar lymphocytes has high sensitivity in symptomatic CBD. However, since it requires lymphocytes from a bronchoalveolar lavage, it is only appropriate for symptomatic patients or asymptomatic patients with abnormal lung function or chest x-ray who are undergoing bronchoscopy for diagnostic purposes. In appropriate clinical situations or research settings, the test may also be indicated for asymptomatic individuals with no radiographic or functional abnormalities who are blood-LPT positive. There are reports of a false positive rate of up to 25% for the BAL-LPT test among beryllium-exposed patients with other lung diseases, and the test may be less sensitive in patients with subclinical disease. False negatives also occur in both the blood and BAL-LPT tests. Some are the result of immunosuppression in patients on corticosteroids. Therefore, this test must be used cautiously.

Some researchers have found lung damage in people exposed to beryllium who are not sensitized to beryllium. They believe that this damage was caused by beryllium exposure. Thus, your patient may have lung damage attributable to beryllium even in the absence of beryllium sensitivity.

Laboratories

If you would like the LPT test done for your patient, contact one of the following centers for instructions on sample collection. The clinic directors are knowledgeable about beryllium disease and can also refer you to specialists.

The National Jewish Center for Immunology and Respiratory Medicine Clinical Immunology Laboratory
1400 Jackson St
Denver, CO 80206
303-398-1344

Specialty Laboratory, Inc.
2211 Michigan Ave.
Santa Monica, CA 90404
310-828-6543

Cleveland Clinic
9500 Euclid Ave.
Cleveland, OH 44195
216-444-2790

The University of Pennsylvania
876 Maloney Building
3400 Spruce Street
Philadelphia, PA 19104
215-662-6479

Another source of information concerning beryllium disease is:

The Occupational/Environmental Health Clinic
Dept of Family Practice
MetroHealth Medical Center
2500 MetroHealth Drive
Cleveland, Ohio 44109-1998
216-778-8087

Beryllium Patch Warning

The beryllium patch test should not be used because of false negatives, induction of beryllium sensitivity, and the possibility of severe anaphylactoid reaction.

Pathology

Pathologic changes in CBD include chronic interstitial pneumonitis with mononuclear cell infiltration and non-caseating granulomas. Non-caseating granulomas have also been found in the lymph nodes, liver, skin, spleen, and other tissues. Varying degrees of fibrosis may be present in different parts of the lung.

Other Tests

Active CBD is typically characterized by lymphocytosis in BAL fluid. Some patients may have one or more of the following: elevated serum IgG, elevated serum IgA, high erythrocyte sedimentation rate, erythrocytosis, hyperuricemia, hypercalcemia, or hypercalciuria.

Treatment

Patients with mild CBD may not need any treatment, but should be clinically followed with periodic assessment of symptoms, chest examination, pulmonary function tests, and chest x-rays. The only available treatment is corticosteroids. Improvements in symptoms, signs, clinical course, and radiographic abnormalities have been seen in some patients treated with corticosteroids. Patients presumptively diagnosed as having CBD without evidence of beryllium sensitization should be examined for possible systemic involvement by sarcoidosis (e.g., uveitis), since misdiagnosis of sarcoidosis as CBD is more likely in these individuals.

In severe CBD, as in any chronic lung disorder, hypoxemia, pulmonary hypertension, and right heart failure may require supportive measures including supplemental oxygen, diuretics, and possibly digitalis.

To prevent respiratory infections, patients should be immunized against influenza and pneumococcal infections, and antibiotic therapy should be administered promptly for suspected bacterial respiratory infections.

Any patient who has CBD or is sensitized to beryllium should be removed from further exposure to beryllium.

Lung Cancer

Strongly encourage smokers to quit. Symptomatic patients should be evaluated. X-ray and sputum cytology have been used for case finding in asymptomatic patients. However, these tests did not lower mortality from lung cancer in screening trials.

The National Cancer Institute (NCI) is planning screening trials to evaluate new techniques for lung cancer screening. If your patient is concerned about lung cancer and may want to participate in a lung cancer screening trial, call the NCI toll free line 800-4-CANCER for further information.

For patients at increased risk of oral cancer, NCI recommends periodic complete oral examinations by a dentist or physician.

If you have any questions or you want a copy of these reports or the cited references, call 800-356-4674. Say you are calling about the beryllium study.

Additional Resources

Ward E, Okun A, Ruder A, et al. (1992). A mortality study of workers at seven beryllium processing plants. American Journal of Industrial Medicine 22:885-904. (Study Report)

Steenland K, Ward E (1991). Lung cancer incidence among patients with beryllium disease: A cohort mortality study Journal of the National Cancer Institute 83:1380-1385.

Sanderson W, Ward E, Steenland K et al. (2001). Lung cancer case-control study of beryllium disease. American Journal of Industrial Medicine 39:133-144.

Sanderson W, Petersen P, Ward E (2001). Estimating historical exposures of workers in a beryllium manufacturing plant. American Journal of Industrial Medicine 39: 145-157.

Sprince NL. Beryllium Disease. id: Occupational Respiratory Diseases. Merchant JA, ed. NIOSH publication no. 86-102, pp 385-399.

Rossman MD, Jones-Williams W. Immunopathogenesis of chronic beryllium disease. In: Beryllium: Biomedical and Environmental Aspects. Rossman MD, Press OP, Powers MB, eds. Williams & Wilkins, Baltimore, MD, pp 121-132.