Occupational Respiratory Diseases: Asbestos Associated Disease
by Dr. Irving J. Selikoff
In 1906, H. Montague Murray, a physician at Charing Cross Hospital, London, testified at an inquiry of a British governmental commission into occupational disability compensation that he had seen a man in 1898, very short of breath, who had worked in an asbestos factory. The man's lungs were badly scarred at autopsy. Murray considered that the workroom dust produced the scarring. He also predicted that, since the possibility was known, such cases would be unlikely in the future. With this sanguine projection, the committee did not see the need to provide compensation.
Perhaps because the death was recorded in a governmental commission hearing, it did not arouse medical concern, nor did other scattered references in the United States, Great Britain, Germany, Italy, and France. It was not until 1924, when Cooke published a clear-cut case of a woman who died with pulmonary fibrosis after working for 20 years in an asbestos textile factory, that attention was attracted to the disease potential ofthe dust. Even then, because tuberculosis might have produced this scarring, there were misgivings. Identification of other cases, in which tuberculosis could not have explained the findings, resulted in the entity being accepted. Cooke named the condition pulmonary asbestosis. in line with the broad category of "pocumokonioses" introduced by Zenker 60 years earlier. There followed a series of clinical, epidemiologic, and industrial hygiene studies in Britain by Merewether, Burton Wood, ElIman, Gloyne, and others.
In the United States in 1918, Holfman of the Prudential Insurance Company referred to the adverse health experience of asbestos workers. (He stated that the company would not issue life policies for asbestos workers). Radiologic changes in the lungs of asbestos workers were also described in 1918. However, additional studies were not undertaken until after the British reports. A series of papers in the first half of the 1930s demonstrated the frequent occurrence of fibrotic lung disease among workers in asbestos textile plants. These clinical reports were followed by two industry-wide studies. In the first, undertaken at the request of the asbestos industry by the Metropolitan Life Insurance Company, Lanza and his colleagues reported in 1935 that two-thirds of the x-ray films of 126 persons selected more or less at random among those having more than 3 years of employment in the industry were not normal. Dreessen et al reported in 1938 on findings among 511 employees in asbestos tex tile plants. Unfortunately, many were relatively newly hired, and the investigation omitted many who had left for disability or for other reasons (Lynch and Aycr of the USPHS have written that prior to the survey ". . . the plants discharged ISO workers suspected of having asbestosis")," and there was limited opportunity to see what happened after the passage of time.
The delay in identifying the disease potential of asbestos was sharply disadvantageous, and points a lesson now sensed by many as we consider the introduction of other agents into industry and society. It allowed, in the period 1890-1930, the integration of the use of asbestos products in many areas of industry and consumer products. The "magic mineral" has many highly desirable properties: it is resistant to wear, noncombustible, and its fibrous nature and flexibility make it useful as reinforce ment in products as diverse as asbestos cement and plastics. The availability of several types of asbestos (chrysotile, amosite, crocidolite. anthophyllite) permitted the selection of fibers for specific purposes. Asbestos became woven into the fabric of industrial civilization. In a sense, the Toxic Substances Control Act, which went into effect in the United States on January I, 1977, mandating pretesting, is meant to prevent this from happening again with the growing number of chemicals being introduced into commerce.
As with asbestosis, so also there was considerable delay in recognizing the carcinogenic potential of asbestos. Attention was first called to this possibility in 1935 when Lynch and Smith and Gloyne reported lung cancer associated with asbestos exposure. Additional case reports followed in Great Britain, the United States, and Germany. Nordmaon went so far as to call these the "occupational cancer of asbestos workers." Collection of these scattered case reports in literature reviews, especially those of Hueper, attracted further attention, and this was augmented by an uncomfortable set of statistics contained in the Annual Report of the Chief Inspector of Factories of Great Britain for 1946. Here, all cases known to the Inspectorate to have died with asbestosis from the first recorded case in 1924, were reviewed. More than 13% had had lung cancer. At that time in Great Britain, approximately 1% of deaths would have been expected to be of lung cancer. Further, 8% of deaths among women were associated with lung cancer (women constituted a major part of the workforce in asbestos textile plants), a striking finding in view of the fact that relatively few women died with lung cancer at that time.
Some were reluctant to accept the validity of these observations and their implications, pointing to the absence of population-based studies. In 1955, Doll reported that among a group of men employed for 20 or more years, with asbestos, the risk of lung cancer was increased tenfold. This study was a germinal one in the history of asbestos disease; it incorporated observation of defined populations; it demonstrated long periods of latency; and it enumerated all relevant causes of death. Even so, Braun and Truan, in a study for the Quebec Asbestos Mining Association, concluded in 1958 that there was no cancer risk.
In the early 1960s, additional population-based studies provided extensive new evidence. Mancuso and Coulter confirmed Doll's findings in a United States factory. More ominously, a strikingly increased death rate of lung cancer was observed among a group of users of asbestos products, insulation workers. The number of workers employed in the mining and milling of asbestos, or in the manufacture of asbestos products, was relatively small; the number of people who then used these products was much larger.
As with asbestosis, there had been a decades-long lag between initial identification of the problem of lung cancer and full acceptance of its importance and the need for control.
The same was true for mesothelioma. This neoplasm, very uncommon in the past (perhaps 1 in 1000 or 1 in 10,000 deaths) began to be reported in scattered case summaries in the 1940s and 1950s. Both pleural mesothelioma and peritoneal mesothelioma were noted. We might have had the same 30-year delay in associating these neoplasms with prior asbestos exposure had it not been for the observations of Wagner and his colleagues, who reported in 1960 on 47 cases of mesothelioma seen in the previous 5 years; this at a time when most major medical centers in the world would have found it unusual to see one or two.
Wagner's cases all came from a part of South Africa in which there were many small asbestos (erocidolite) workings. Inquiry had been made about the prior occupation and residence of the cases, often from surviving kin or others who could have known of their earlier lives. Most were found to have had potential exposure to asbestos decades before. Some had played as children on the mounds of tailings near asbestos mills; one had lived by a road along which asbestos had been brought to a mill. There was no population base against which to judge the incidence of the observed cases, and the histories of exposure were anecdotal and circumstantial, but it was difficult to ignore the claimed association, and the previous case reports took on new significance. Statistical and population-based data soon confirmed Wagner's suggestions, and ever since, the appearance of mesothelioma has been a signal to search for prior asbestos exposure. In one recent series, 69 of 70 consecutive patients with pleural mesothelioma had had asbestos exposure, and there was some question about the seventieth.
Other neoplasms have been found to be associated with prior asbestos exposure. In 1964, gastrointestinal cancer was identified, and increased incidence of cancer of the larynx, oropharyox, and kidney has also been noted. Cancer of the lung and mesothelioma remain the more important, in terms of frequency and mortality risk. Other nonmalignant complications have been reported, including benign asbestotic pleural effusion and Caplan's syndrome, an association of rheumatoid arthritis and pocumoconiosis. However, asbestosis remains by far the most important nonmalignant change.
The term asbestos is given to naturally occurring fibrous minerals, a pragmatic definition. By common consent, it is limited to naturally occurring, commercial, fibrous minerals of the serpentine or amphibole series. Fibrous forms of other minerals, such as wollastonite, fibrous brucite, or fibrous forms of calcite or gypsum, are not included. The name, therefore, has a commercial, industrial derivation. Chrysotile (white asbestos) is the sole representative of the serpentine suhdivision, while crocidolite (bIue asbestos), amosite, anthcphyllite, and actinolite-tremolite are amphiboles. Amosite tends to be brown, because of its iron content. Amphiboles are major constituents in rock formations throughout the worId, but fibrous forms rarely occur in deposits that can be economically developed.
Chrysotile, on the other hand, is not a common rock-forming mineral but does occur in a number of large deposits, particularly in Canada and the Soviet Union. Amosite is largely found in South Africa (its name derives from "Asbestos Mining Organization of South Africa"). Commercial deposits of anthophyllite are found in Finland, Bulgaria, and the United States. A large number of other minerals may be found in physical admixture with asbestos fibers as the ores are mined and cannot be removed by simple cleaning processes. These may affect the usefulness of the product and also the biologic potential.
The essential characteristic of all asbestos minerals is their fibrous nature. Gross fibers are visible to the naked eye, but these are really bundles of much finer fibrils, with diameters in the Angstrom range, visible only by electron microscopy. This fact underlies many public health approaches to the asbestos problem, since when the fibers are large and not yet separated into their component fibrils, they can be seen with the optical microscope. The Occupational Safety and Health Administration regulations call for counting fibers 5 to 100 microns in length. Once comminuted to fibril dimensions, they can no longer be seen with the optical microscope. The electron microscopes that would be needed are not readily available to state and federal regulatory agencies. Consequently, we have a numerical standard for exposure at work sites where the fibers can be counted, but none for environmental circumstances. The Environmental Protection Agency's current standard restricts industry to "no visible emissions."
The fibers visible to the naked eye are also too large to enter the lung; generally, those greater than 5 microns in diameter cannot penetrate into the finer recesses of the lung. That is one reason why comparatively few fibers large enough to be visible by optical microscopy are seen in lungs of people cxposed to asbestos. A second, probably more important, reason is that when fibers small enough to enter are inhaled, they are further split into their component fibrils, 350A or so in diameter in the case of chrysotile and somewhat larger with amosite or crocidolite. This makes for diagnostic difficulty in the pathology laboratory; the optical microscope is generally used, and fibrils in the lung are much too fine to be visible. Individuals may die of asbestosis, yet virtually no fibers be found on routine examination of the lung. However, when ashed, myriads of very fine fibrils may be seen. Asbestos bodies are an other matter; these are fibers that become coated intra-cellularly, in viva, with an iron-rich gel of distinctive appearance; such coating generally occurs only on the thicker and longer fibers. Asbestos bodies are not an index of the presence or absence of disease; merely, that asbestos has been inhaled and that the tissues have reacted to the fibers. The same is true of "asbestos warts," which occur on the skin (hands, usually) of asbestos workers, and represent a granulomatous, fibrotic reaction to slivers of asbestos that have penetrated.
The very dimensions of the retained fibrils may have considerable pathologic significance, in that a very small mass is associated with a vast surface area. The lungs of an individual sufficiently scarred to cause death of asbestosis may contain only 0.5 g or so of asbestos. Yet the opportunity for mineral-cellular interactions is great, truly an example of what Poli card called the interface between mineral matter and the living world. Exactly what happens at this interface is unclear. Electron microscopic studies demonstrate the presence of fine fibrils within the cells, enabling cellular-mineral contact, and also interaction be tween the fibril surfaces and the intracellular and perhaps intranuclear components. These interactions result in a fibrotic reaction (asbestosis) and/or cancer, but the pathogenetic mechanisms involved are not clear.