FIGURE 6.-Patient with beryllium poisoning, showing cachexia in chronic beryllium disease (reproduced from Tepper et al." with the permission of the publisher).

Industry must come to see that prompt and prospective studies of populations exposed to potential risks provide early honest answers and prevent the kinds of rumors and confusion that have beset the story of beryllium disease to date. I am speaking to a university community that is accepting more and more of the public-servant view of its activities, so wonderfully exemplified in the life and work of Dr. Alice Hamilton. Alfred North Whitehead points the way to use the great resources of education to finally control man-made disease. I quote from Lucien Price's Dialogues of Whitehead while he was at Harvard: "The college faculties are going to want watching. I am immensely annoyed

43

43 Whitehead, A. N. Dialogues of Alfred North Whitehead, as Recorded by Lucien Price. New York: Mentor, 1956. Pp. 56-57 and 180.

by the smugness of a certain kind of talk which goes on among my colleagues.. the aloofness of the university from practical life; not only the federal and state governments, but even municipal affairs. There is a great function which awaits the American universities, and that is to civilize businesses... It is not enough that they should amass fortunes . . . and then endow a college or a hospital. The motive in amassing the fortune should be in order to use it for a socially constructive end.

"Law has been civilized . . . medicine has been taken out of magic; education has been getting rid of its humbug; and next it is time to teach business its sociological function; for if America is to be civilized, it must be done by the business class, who are in possession of the power and the economic processes. I don't need to tell you that there is a good deal of sniffing on this, the Harvard College and graduate schools side of the Charles River, sniffing at the New Harvard School of Business Administration on the opposite bank. That strikes me as snobbish and unimaginative. If the American universities were up to their job they would be taking business in hand and teaching it ethics and professional standards."

[Journal of Occupational Medicine, April 1959]

BERYLLIUM DISEASE-A REVIEW OF CURRENT KNOWLEDGE

(Harriet L. Hardy, M.D., and Lloyd B. Tepper, M.D., Boston*)

Although there is no dearth of recent literature on beryllium disease and the toxicology of beryllium compounds, a review at this time may be of importance for a variety of reasons to the physician concerned with occupational illness. Fundamental is the fact that the disease continues to be diagnosed in new cases, although the hazardous etiologic exposures were generally concluded more than a decade ago. This delay in the onset of clinical symptoms gives one good reason to believe that other cases are overlooked because such potentially harmful beryllium exposure is not suspected or revealed even on detailed questioning. A review is presented for the additional reason that patients with chronic beryllium disease are not in all instances receiving the active therapy which present knowledge suggests is the best yet available. Furthermore, it appears that the increasing military and industrial demands for beryllium will be accompanied by an increase in the number of workers who may be subjected to possibly hazardous exposures to toxic compounds of this element.

HISTORY

Acute respiratory tract disease due to beryllium compounds was reported as early as 1933 in German workers engaged in the extraction of the metal from its ore, beryl. Two years later Fabroni described a disease in experimental animals exposed to beryllium compounds, and in 1936 Gelman,1 in describing the Russian experience with the disease, recognized its presence in plant watchmen whose posts were more than 100 meters from any beryllium operation. Additional reports from Russia and Germany followed but generally escaped American interest. When considered, the toxicity of beryllium compounnds was largely attributed to the anion involved rather than to the beryllium itself.

In 1941, Massachusetts tuberculosis sanatoria admitted the first fluorescenttube workers disabled by a pulmonary disease which appeared on chest x-ray films as a fine bilateral miliary mottling suggestive of miliary tuberculosis. When this diagnosis had been ruled out, it was felt that these persons had sarcoidosis, although it was considered odd that all 14 patients whose cases had been reported by 1944 had worked in the same industry.

The suspicion that this so-called "Salem sarcoid" was due to exposure to beryllium-containing phosphors was intensified when the late Dr. Leroy U.

*Dr. Hardy is Associate Physician in charge of Occupational Medical Clinic, Massachusetts General Hospital, and Dr. Tepper is Fellow in Occupational Medicine, Department of Preventive Medicine, Harvard Medical School.

From the Massachusetts General Hospital. Some of the work reported was supported by a grant from the National Institutes of Health, Research Grants Division (No. 3812), and some by the Division of Biology and Medicine of the Atomic Energy Commission.

1 Gelman, J. G.: Poisoning by Vapors of Beryllium Oxyfluoride, J. Indust. Hyg. & Toxicol. 18:371, 1936.

2 Shipman, T. L.: History of the Beryllium Problem, in Pneumoconiosis, edited by A. J. Vorwald, New York, Paul B. Hoeber, Inc. (medical book department of Harper & Brothers), 1950, Chap. 1.

Gardner recognized its similarity to the illness in six foundry workers about whom he had been consulted as early as 1938. A subsequent investigation revealed that the involved foundry had been working with beryllium-copper alloys since 1932.

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In 1945, Van Ordstrand and his associates described their five-year experience with an acute yet transient pneumonitis in Ohio workers engaged in extracting beryllium from beryl. One year later Hardy and Tabershaw reported in detail the Massachusetts experience with chronic disease in fluorescent-lamp workers. Since then, illness of an acute ("Ohio") or chronic ("Massachusetts") form has been reported from a variety of industries; beryllium and its compounds have been the common denominator among them.

As of Jan. 1, 1959, the Beryllium Registry at the Massachusetts General Hosptial, Boston, has accepted 604 cases of beryllium disease from the larger number of suspected cases submitted. Of these 604 cases, 61% have been of the chronic illness. Previously unrecognized cases, though few in number, continue to be reported.

USES OF BERYLLIUM

The physician is hindered in diagnosing chronic beryllium disease by the fact that worker-patient frequently does not know the nature of the materials with which he or those around him have worked. Furthermore, this work exposure may have terminated more than a decade prior to the onset of current clinical symptoms.

Toxic beryllium exposure must be considered when a variety of occupational histories are related (Table). Although there have been no reports of beryllium disease in miners of the ore, beryl, which contains from 2% to 12% beryllium, the subsequent extraction process has been frequently implicated in the disease. The manufacture of fluorescent tubes constituted a second major source of toxic exposure in that phosphors used from 1938 to 1949 often contained from 2% to 14% beryllium, generally as zinc-manganese-beryllium silicate. This hazardous use of beryllium was discontinued in 1949 by mutual agreement of the manufacturers. No such self-regulation has applied to the "neon" sign producers, many of whom operate small backyard or garage "factories" and who may freely obtain and process beryllium oxide in the preparation of phosphors.

Any operation in which beryllium alloy particles fine enough to reach the lower respiratory tract are generated is potentially hazardous. Chronic beryllium disease has been reported in two cases when this element constituted not more than 2% of a copper alloy.5

Beryllium is used in windows of x-ray tubes because it is easily penetrated by the rays and is stable at high temperatures. It is also employed in nuclear energy projects, since it readily yields neutrons under alpha particle bombardment. The oxide is a superior refractory ceramic and finds use in crucibles and special refractory bricks. Beryllium disease has been reported in each of these industries.

Because of its lightness, rigidity, and resistance to heat, beryllium is today finding use in structural parts of high-velocity space vehicles. The oxide may be used in heat-resistant ceramic nose-cones. Though this defense production is carried on under strict industrial hygiene supervision, the physician caring for the involved workers must remain alert for evidence of beryllium disease, which, fortunately, has not been observed.

It is to be emphasized that typists, clerks, engineers, and janitors, though they do not directly use beryllium, may be affected because of atmospheric contamination. Furthermore, neighborhood atmospheric contamination or berylliumcontaining dusts brought home on work clothes may lead to disease in persons remote from any plant.

3 Van Ordstrand, H. S.; Hughes. R.; DeNardi, J. M., and Carmody, M. G.: Beryllium Poisoning, J. A. M. A. 129:1084, 1945.

4 Hardy, H. L., and Tabershaw, I. R.: Delayed Chemical Pneumonitis Occurring in Workers Exposed to Beryllium Compounds, J. Indust. Hyg. & Toxicol. 28:197, 1946.

Sneddon, I. B.: Berylliosis: A Case Report, Brit. M. J. 1:1448, 1955.

Operations incriminated in beryllium disease

Beryllium extraction operations

Fluorescent lamp phosphor manufacturing

Flourescent lamp manufacturing

Fluorescent lamp salvage

"Neon" sign manufacturing

Beryllium metallurgical operations

Beryllium alloy manufacturing

Fabrication and machining with beryllium alloys

Beryllium oxide ceramic manufacturing

X-ray and radio tube manufacturing

Atomic energy projects

CLINICAL BERYLLIUM DISEASE

The clinical syndromes associated with toxic beryllium exposure can be readily divided into two categories: acute and chronic. Though they can be separated in terms of a duration of less than and more than one year, respectively, the dissimilarity between the two groups is evident in the clinical pictures presented, although these themselves vary widely. The acute illness may progress to the chronic form with or without additional exposure, but this course has been definitely documented in only 28 patients.

Acute Beryllium Disease-Acute beryllium disease, most frequently related to intense but brief toxic exposure, consists of variable upper or lower respiratory tract irritation, dermatitis, and/or conjunctivitis. The respiratory tract symptoms range from a mild nasopharyngitis or tracheobronchitis to a severe chemical pneumonitis with a case fatality rate of about 10%. The pneumonitis has usually appeared within 72 hours after heavy exposure, but an insidious form may be delayed for several weeks after a less intense but prolonged exposure. There is a rarely productive cough, anorexia, progressive dyspnea, and chest pain or tightness. Cyanosis, diffuse pulmonary rales, and less commonly, pleural rubs may be found. Bilateral haziness, patchy infiltrations, or nodular densities on chest x-rays appear within three weeks after the onset of symptoms, and such changes have been known to persist as long as one year. These persisting x-ray changes have been observed in patients with the mildest of respiratory symptoms. In acute beryllium intoxication clinical recovery is usually rapid, within weeks, though the insidious form has been known to last several months.

Beryllium dermatitis may be one of three types: a contact dermatitis, a localized dremal ulceration, or a subcutaneous granuloma. The contact dermatitis is described as an edematous, papulovesicular, pruritic eruption occurring on the exposed skin surfaces. Ulceration develops only after a particle of a toxic beryllium-containing substance is introduced into an abrasion or laceration. Healing is not readily achieved without the removal of the offending particle by curettage. Cuts with fluorescent tubes may produce subcutaneous granulomata with the histological features of skin sarcoidosis when a beryllium-containing phosphor is introduced into the skin. Such granulomata may not appear for as long as four years following a cut, which, itself, promptly heals. Wide surgical excision of a granuloma results in complete healing.

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Chronic Beryllium Disease-Chronic beryllium disease was described in 1946 by Hardy and Tabershaw under the diagnostic title of delayed chemical pneumonitis. Since that time 384 cases with 121 deaths (31%) have been reported to the Beryllium Registry. Its clinical character differs from that of the acute disease in that it is of longer duration, may progress in spite of the cessation of toxic exposure, may have widespread systemic manifestations, and may not appear until an "incubation period" of up to 15 years has elapsed. About 70% of the cases in the Registry, however, have shown evidence of clinical disease within five years of the termination of exposure.

Grier, R. S.; Nash, P., and Freiman, D. G.: Skin Lesions in Persons Exposed to Beryllium Compounds. J. Indust. Hyg. & Toxicol. 30:228, 1948. 7 Lederer, H. E., and Savage, J.: Beryllium Granuloma of the Skin, Brit. J. Indust. Med. 11:45, 1954.

Such exposure has in most cases exceeded two years' duration, but chronic illness has apparently followed an exposure of less than six hours. Commonly the disease has been precipitated or, if already manifest, exacerbated by stresses such as pregnancy, surgery, or viral respiratory infections or by the inhalation of irritant fumes other than toxic beryllium compounds.

Although the disease may be rarely asymptomatic and evidenced only by abnormalities on chest x-ray films, it frequently involves several organ systems. The respiratory tract is involved at some time in the course of the disease, generally with a pneumonitis causing dyspnea, a usually nonproductive cough, and pleuritic pain. With this picture may be seen tachypnea at rest, cyanosis, and digital clubbing, although auscultatory chest signs may be minimal, transitory, or patchy. Bronchospasm is not typical. With progressive pulmonary disease pulmonary hypertension with resultant cor pulmonale and myocardial decompensation may complicate the picture.

The disease may involve the liver, producing enlargement and laboratory evidence of hepatic dysfunction. The spleen may also be enlarged. There is biopsy and autopsy evidence of granulomatous involvement of these organs, the kidneys, lymph nodes, myocardium, and striated muscle. Convulsions, hyperactive reflexes, and extensor plantar reflexes in conjunction with radiographic evidence of a space-occupying cerebral lesion have been observed in two cases of chronic beryllium disease. Granulomatous changes in the central nervous system therefore have been suspected, although the opportunity for pathology examination in these eases has been denied.

8

Substantial weight loss may be dramatic at the onset of beryllium disease and in a group of beryllium-exposed workers has been used as an indication of beryllium effect. Negative nitrogen balance was described by Waterhouse as a part of beryllium disease. A markedly disturbed serum protein distribution with an elevation of gamma globulin is frequently observed. A negative calcium balance unrelated to steroid therapy or immobilization and disuse has also been observed, and some 10% of the patients chronic with disease have developed renal stones. Hypercalciuria has been demonstrated in many of these patients and in others without stone.

Evanescent beryllium-containing skin nodules having the characteristics of sarcoidosis have been observed, and in at least one case under steroid therapy the reappearance of these nodules on three occasions has heralded the recrudescence of pulmonary symptoms. Other patients have described migratory joint symptoms similar to those of rheumatoid arthritis. These complaints have been ameliorated with salicylates or adrenal corticosteroids.

Spontaneous pneumothorax has been a complication in about 12% of the patients with chronic disease and has been the immediate cause of death in at least two of them.

As far as is known, the occular, parotid, tonsillar, and cystic bone changes of sarcoidosis are not seen in chronic beryllium disease."

The chest x-ray findings in this disease are not specific, and wide variations have been observed. A unique "sandstorm" has been described 10 in early chronic pulmonary disease, but the commoner diffuse, bilateral, miliary nodulation may be easily interpreted to be tuberculosis, sarcoidosis, carcinomatosis, pulmonary mycosis, or another miliary pulmonary disease. Emphysematous blebs or a pneumothorax may be seen, and hilar exaggeration is common.

Tuberculosis in patients with chronic beryllium disease has been conspicuously rare, particularly in view of widespread steroid therapy and hospitalization in tuberculosis sanatoria. Not more than four persons have been reported with active pulmonary tuberculosis, although a fourth of the patients with chronic disease have positive tuberculin reactions. Cancer has been similarly

rare.

In those cases in which the diagnosis of chronic beryllium disease remains uncertain on clinical or epidemiological grounds, quantitative assays for tissue beryllium have been helpful. Some students of this disease, however, have accepted the diagnosis even in the face of negative tissue assays. Such nega

8 Waterhouse, C.; Keutmann, E. H.; Howland, J. W., and Brure, R. A.: Metabolic and Cardio-Respiratory Studies on Patients with Beryllium Granulomatosis, University of Rochester Atomic Energy Project, UR-101, 1949.

Hardy, H. L. Differential Diagnosis Between Beryllium Poisoning and Sarcoidosis. Am. Rev. Tuberc., 74:885, 1956.

10 Wilson, S. A. Delayed Chemical Pneumonitis or Diffuse Granulomatosis of the Lungs due to Beryllium, Radiology 50:770, 1948.