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.

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.

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

5 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.

4

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.

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 cases 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

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.

tive reports may be dependent on the difficulties in detection of small amounts of beryllium in biologic material.

The skin test of Curtis," if positive, supplies corroborative evidence of beryllium disease. Because beryllium has been shown to be a sensitizing agent, positive tests may be observed in persons so sensitized but without evidence of beryllium disease. In at least two Registry cases of biopsy-proved beryllium disease (characteristic histopathology and significant beryllium assays) the skin test has been negative.

Pulmonary function studies have shown the basic lung physiological defect to be an impaired diffusion of oxygen from inspired air into the minute pulmonary vasculature. This alveolar-capillary block is shown by increased gradients of oxygen partial pressure across the involved membrane and deficient oxygen content (unsaturation) of the arterial bood. As might be expected with progressive fibrosis, the stiffening of the lung tissue gives rise to ventilatory defects which are not evident early in the disease.

The Neighborhood Cases-The 44 recognized neighborhood cases of beryllium disease constitute a remarkable group in that their case fatality rate (54%) is higher than that in any occupational group. Almost all the patients either lived within the vicinity of a plant discharging air-borne beryllium compounds or came into contact with dust-covered clothes brought home by beryllium workers. Twenty-one of these patients could describe as their only source of exposure residence in the vicinity of such a plant. The high case fatality rate in these patients is probably misleading; there is reason to believe that the milder cases have been largely overlooked or misdiagnosed because of the remote relationship to beryllium-using operations.

On the other hand, it is not inconceivable that some of these people were unusually vulnerable to toxic beryllium compounds. It is furthermore possible that the responsible compounds themselves, by virtue of chemical or physical characteristics, were unusually toxic. Such vulnerability or such characteristics have not been demonstrated.

Pathology The pathology picture of acute beryllium pneumonitis in those few cases examined has been characterized by an acute inflammatory reaction with a fibrinoid alveolar exudate containing numerous mononuclear cells, capillary engorgement, and occasional focal hemorrhagic extravasation. The typical lesion of the chronic disease is a noncaseating pulmonary granuloma the appearance of which is such that there is dispute among experienced pathologists as to whether or not it can be distinguished from the changes seen in sarcoidosis. There is a diffuse septal thickening with interstitial collections of mononuclear and giant cells and amorphous debris. Fibrosis may be minimal or may predominate over the granulomatosis. Improvement of spleen, liver, kidney, lymph nodes, myocardium, and striated muscle has been reported.

The osteosclerosis 13 observed in rats and rabbits following the parenteral injection of beryllium compounds has not stimulated a systematic pathology study of bone in human cases. There have been a few instances of increased bone density in patients, but a review of bone films has not yielded evidence of general osteosclerosis. Neither the osteosarcomas 14 nor the pulmonary tumors observed in certain beryllium-exposed animals have appeared in humans. Experience thus far has revealed only one case each of bronchiogenic and alveolarcell carcinoma in chronic beryllium disease patients.

Correlations between the quantity of tissue beryllium and the extent of tissue alteration have not been established.

Therapy-Although there is as yet no specific therapy for beryllium disease, the introduction of the adrenocorticotrophic hormone (corticotropin, ACTH) and the adrenocortical steroids into clinical medicine has given the physician a potent agent for its control. Prior to their use the treatment of chronic beryllium disease was entirely symptomatic and based upon the use of oxygen and bed rest. The relief offered was transient, and there was no apparent alteration in the course of the disease.

11 Curtis, G. H. Cutaneous Hypersensitivity Due to Beryllium, Arch. Dermat. & Syph. 64:470, 1951.

12 Ferris, B. G., Jr.; Affeldt, J. E.; Kriete, H. A., and Whittenberger, J. L.: Pulmonary Function in Patients with Pulmonary Disease Treated with ACTH, A. M. A. Arch. Ind. Hyg. 3:603, 1951.

13 Scott, J.: The Experimental Production of Tolerance and Osteosclerosis by Repeated Intravenous Injections of Beryllium Sulphate, University of Rochester Atomic Energy Project, UR-125, 1950.

14 Dutra. F. R., and Largent, E. J.: Osteosarcoma Induced by Beryllium Oxide, Am. J. Path. 26:197, 1950.

The introduction in 1950 of corticotropin and shortly thereafter of the adrenal steroids has been accompanied by both subjective and objective clinical improvement in patients with chronic beryllium disease. Pulmonary alveolar-capillary oxygen gradients have diminished under this therapy, and there have been almost spectacular restorations of myocardial compensation in cases with evidence of well-established cor pulmonale.

Previously abnormal serum protein distributions and urinary calcium levels have become normal in studied cases of beryllium poisoning with adequate steroid treatment.

Chest roentgenograms in at least two instances have shown complete clearing which persists when therapy is stopped; more frequently definite abnormalities, though usually lessened, do persist. A curious phenomenon has been observed following the institution of corticoid therapy in some patients in that their chest films clear markedly, then regress almost to the pretreatment status, and subsequently show varying degrees of improvement, though all this while the patient has made steady clinical gain without correlation with the fluctuating x-ray picture.

15

That steroid therapy is no "cure" is to be seen in the relapses which may follow premature cessation of treatment. Ferris " has made the somewhat discouraging observation that, in spite of continued steroid therapy, the alveolarcapillary oxygen gradient may begin to creep upward again after a period of definite improvement with reduction in the gradient. Long-term steroid therapy, in some cases longer than five years, has been required because of the persistence of signs and symptoms of beryllium intoxication.

If there is objective evidence of disturbed body functions in beryllium disease, the evidence is adequate that steroid therapy represents the best presently known course of action. Though well-known risks accompany the use of steroids, the risks associated with neglected or undertreated chronic beryllium disease are greater by far. Reported steroid side-effects in this disease have been limited to rare gastritis without demonstrable ulceration and a few instances of transient glycosuria. Seeler 16 has reported that the only deaths from this disease in steroid-treated patients have occurred when the disease was far advanced at the institution of this therapy. The currently reported maintenance prednisone dosages are generally within the range of 15 to 20 mg daily.

When intoxicated, oxygen may be used freely in these patients, for it is not dangerous as it is in emphysema or other diseases of alveolar hypoventilation. Arterial carbon dioxide tension is normal or even reduced in chronic beryllium disease.

The need for effective and safe specific therapy in beryllium intoxication is reflected in recent studies of chelating agents. Aurintricarboxylic acid, an effective agent in experimental acute intravenous beryllium poisoning, continues to be evaluated." More recently Cash and his associates have reported an increased urinary excretion of beryllium in chronically poisoned patients when either trisodium monohydrogen EDTA or calcium-disodium EDTA is administered. The side-effects and clinical usefulness of these materials remains to be more completely evaluated.

Prevention-Prevention of beryllium disease lies in the control of atmospheric contamination by particles of toxic respirable material. The substitution of halophosphates for beryllium-containing phosphors was a major step in this direction.

When the element cannot be excluded from essential operations, control becomes dependent upon industrial hygiene engineering and medical supervision of workers. On the basis of animal studies and known human experience, the value of 2ug per cubic meter of air has been suggested as safe for longterm exposure. There have been no reports of disease at this level of exposure during the 10 years it has been used. In-plant control must not be achieved at the cost of neighborhood contamination; careful recovery of toxic materials and appropriate stack design are essential.

15 Ferris, B. G., Jr.: Pulmonary Function in Patients with Beryllium Intoxication, A.M.A. Arch. Indust. Health 19:146, 1959.

16 Seeler. A. O.: Treatment of Chronic Beryllium Poisoning, A.M.A. Arch. Indust. Health 19:164. 1959. 17 Schubert, J., and Rosenthal, M. W.: Chemical Approaches to the Treatment of Beryllium Poisoning. 4.M.A. Arch. Indust. Health 19:169, 1959.

Chelating Agents in the

18 Cash, R. Shapiro, R. I.; Levy, S. H., and Hopkins, S. M. Therapy of Beryllium Poisoning, New England J. Med., to be published.