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 12 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.

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.

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.

That steroid therapy is no "cure" is to be seen in the relapses which may follow premature cessation of treatment. Ferris 15 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 thisdisease 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.

17

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 2μg 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. A.M.A. Arch. Indust. Health 19:169, 1959. 18 Cash, R.; Shapiro, R. I.; Levy, S. H., and Hopkins, S. M. Therapy of Beryllium Poisoning, New England J. Med., to be published.

Chelating Agents in the

Medical supervision of workers requires that those persons with previous beryllium disease, other chronic respiratory illness, or abnormal chest x-ray findings be excluded from beryllium operations. The preplacement examination should include a 14 x 17 chest x-ray film so as to establish a base line against which subsequent changes, if any, can be compared. Routine "berylliosis examinations" have been of little help in the control of beryllium disease, and special examinations are probably indicated only after known overexposures or in the event of clinical complaints or weight loss. The regular annual medical examination is desirable, however, and respiratory illness should be gone over in considerable detail. The determination of vital capacity is of no value in the control of chronic beryllium disease, for a ventilatory defect in this illness is generally not demonstrable until the lung is markedly fibrotic and stiffened. As beryllium disease may be related to a hypersensitivity to the element, and since the beryllium patch test may produce sensitivity or, as has been suggested, disease manifestations in already sensitized persons, it is unwise to use this test in screening procedures.

CONCLUSIONS

It is to be emphasized that beryllium disease is a systemic intoxication and not a pneumoconiosis. The final word regarding its clinical character, course, prognosis and treatment was not been said, and new data are constantly being collected. The diagnosis of beryllium poisoning rests upon the establishment of beryllium exposure, the presence of beryllium in body fluids or tissue, and the demonstration of consistent histopathological findings. The clinical and radiologic pictures are so protean that they, together with the beryllium patch test, supply corroborative rather than diagnostic evidence.

Because of the delay in the onset of beryllium disease after exposure and as a result of the expanding uses of beryllium and its compounds, physicians concerned with occupational etiologies need to remain aware of the causes, course and therapy of this granulomatous man-made disease.

Dr. Hardy's address in Massachusetts General Hospital, Boston 14.

Senator MUSKIE. Our next witness will be Dr. Robert A. Kehoe, of the University of Cincinnati College of Medicine, Cincinnati, Ohio. Dr. Kehoe, we appreciate your coming here this morning and further enlightening the committee.

Dr. KEHOE. Thank you.

Senator MUSKIE. You may proceed.

May I say for the benefit of all of us that you may cover as much of your prepared testimony as you want orally but we will include it all in the record. We don't object to listening to it if you wish to read it all.

STATEMENT OF DR. ROBERT A. KEHOE, UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE, CINCINNATI, OHIO

Dr. KEHOE. First of all I would like to say I appreciate the opportunity of being here. I have no hope whatever of being able to present to your committee other than in terms of documents and published materials, the information that is available on this subject.

I am afraid we would be here the rest of the week if I were to undertake to do this. So that what I shall do is briefly to outline where it appears to me that we stand in this situation at the present time, and refer briefly to the evidence that puts us, in my opinion, in that position; and then refer to you and your committee and its staff the published material on this subject which has been assembled for your use. There is a much longer memorandum that I should not dare to undertake to present here this morning. A series of reproductions of the material that has been issued in various reports, and publications in this country and abroad have been put together for your benefit, primarily because much of it is very difficult to obtain.

64-886-6614

It goes back to 1924 and is not readily available in the journals that exist at the present time. Some of it has actually been lost but for our copies.

Senator MUSKIE. Is it your intent to make this available for the files of the committee?

Dr. KEHOE. That is right. These volumes have been assembled for the purpose of making this information available. Another copy is available if it would be of any interest.

Senator MUSKIE. Would it make interesting night reading?

Dr. KEHOE. Several nights. It would not be a thousand and one, but it would be several.

I would like briefly to state my own position at the present time, if I may.

It is the purpose of this statement to present briefly the salient facts concerning the hygienic aspects of the occurrence and distribution of lead in the environment of citizens of the United States of America, with particular reference to the contribution made by the use of leaded gasoline.

I am a physician, at present professor emeritus of occupational medicine in the department of environmental health in the college of medicine, University of Cincinnati. I have been a teacher and professor on the faculty of the college of medicine in the department of pathology, first, in physiology, and later and longer director of Kettering Laboratory, which has been concerned with industrial medicine and industrial hygiene from its founding in 1930 until my retirement in 1965.

It still continues. From 1948 until 1965 I was the director of the department of preventive medicine and occupational health, the latter being the area in which the Kettering Laboratory is engaged. I was also the chief medical consultant, with the title and corporate responsibilities of medical director of Ethyl Corp. from 1925 until I retired at the end of 1958, this having been imperative in the early years because I was the only person who was familiar with the toxicology of tetraethyl lead and with the occupational hazards associated with its manufacture and distribution. I continued in this capacity, while maintaining my work in the university.

The impression has existed in certain circles that little information is available on this subject, especially as to matters that relate to the safety of the public.

The fact is, however, that no other hygienic problem in the field of air pollution has been investigated so intensively, over such a prolonged period of time, and with such definitive results. This is not to claim that there are no significant voids in the available information, nor that all of the ultimate answers are at hand.

Nevertheless, it is clear that this specific set of problems has been brought to such a point of understanding, in relation to the public health, as to remove it from the realm of urgency and to consign it into that group of hygienic problems on which a watchful and effective surveillance should be kept. A considerable measure of assurance for the future may also be derived from the fact that methods of surveillance have been developed, over the years of investigation, which are characterized by a high degree of technical precision and physiological relevance.

Senator MUSKIE. Is it fair to say, Dr. Kehoe, that what you have just said is at variance with the position taken by the Public Health Service and the position taken by Dr. Hardy this morning, as to the state of knowledge that we ought to have before reaching final conclusions?

Dr. KEHOE. Not precisely, no, sir. I would simply say that in developing the information on this subject, I have had a greater responsibility than any other person in this country. Since 1924, I and my associates have undertaken to answer the question that relates specifically to the public health.

Our interest has been broader, I may say, more extensive, in the field of industrial health, in which the problem is more serious than it is in the field of the public health. But, with respect to the findings in the field of the public health, I would say, at this point, that we are in the best position that we have been at any time in the 35-year period since leaded gasoline was introduced on the American market.

With respect to the information that is necessary to answer the questions that are available, they are not all answered and there are still investigations to do. But I repeat that the situation is in no sense urgent.

Senator MUSKIE. With respect to this sentence in your testimony "No other hygienic problem in the field of air pollution has been investigated so intensively over such a long period of time and with such definitive results."-is it your intention that that statement apply to industrial exposure to the problem, rather than to the exposure of the general public to lead in the atmosphere?

Dr. KEHOE. Not at all, sir.

The industrial exposure is with us, it is a hazard. Lead poisoning in industry is still one of the most frequent occupational diseases with which we are presented in this country despite the fact that we know how to prevent it.

The question with respect to the public has been from the very start, from 1923 on, hypothetical, a potential risk which we have been undertaking to measure by every means which we can get at, and the evidence at the present time is better than it has been at any time that this is not a present hazard.

Senator MUSKIE. May I ask a further question on this? The Bureau of Mines and the American Petroleum Institute have just entered into a contract involving $480,000 of American Petroleum Institute money to conduct research in this field. Is that in your judgment a reflection of concern or simply routine?

Dr. KEHOE. Not with respect to lead. The concern here is with other aspects of the use of petroleum hydrocarbon fuels, which do present us with a series of problems some of which are unsolved.

Senator MUSKIE. I understood the contract does relate to lead.

Dr. KEHOE. It relates both to leaded and unleaded gasoline, with the idea of establishing whether the lead introduces an additional factor in the behavior of the hydrocarbons. There is no question however about the factor of risk of a sort from the petroleum hydrocarbons. The question at issue here which is being carried out along with the general investigation is whether lead enters into this problem and in any way affects the matter disadvantageously.