ALL ABOUT ASBESTOS (MEDICAL ASPECTS)
By Arthur L. Frank
Department of Environmental and Occupation Health. School of Public Health Drexel University, Nesbit Hall, 3215 Market Street, Philadelphia, PA 19104, USA
Introduction: What Is Asbestos?
The term ‘asbestos” applies to six naturally occurring minerals that are commercially and collectively referred to as asbestos There are many other asbestiform minerals that are similar in structural characteristics, but are not technically classified as asbestos. Asbestos is a fiber characterized as a structure with at least a 3:1 length-to-width aspect ratio, but this ratio can be higher. There are two families of asbestos fibers [I]. The first family are the amphiboles, characterized by five distinct asbestos minerals, which are crocidolite, amosite, anthophyllite, tremolite, and actinolite. The second family is the serpentine form, called chrysotile asbestos. The amphiboles are characterized by being considered straight and needle-like, whereas the serpentine form grossly looks wavy, like a worm or snake—thus its name. Each of the six asbestos minerals is distinctive in its chemical characteristics, and several are known by their coloring. Chrysotile is called white asbestos; croccidolite, blue; and amosite, brown. These three, collectively, make up the vast bulk of the commercial uses of asbestos, with between 90% and 95% of all the asbestos used in the world coming from chrysotile. Much less amosite and croccidolite were used, with few uses of anthophyllite and even less of the other types, sometimes only occurring as a contaminant.
Every type of asbestos has been identified as causing all of the diseases that can be caused by asbestos fibers, although there is controversy regarding a number of issues, as discussed later.
Historical Uses
Although the extensive use of asbestos is a major contemporary story of the last century or so, the ancients knew about asbestos. The wicks of the lamps of the Vestal Virgins in Rome were made from asbestos because asbestos is not destroyed by fire [2]. As long as the lamps were filled with oil, the asbestos wicks would support the flame indefinitely. It was said that Charlemagne, emperor of the Holy Roman Empire, had a tablecloth woven of asbestos and that he would astound his dinner guest by having the tablecloth passed through a roaring fire to clean it after a banquet had been served. Benjamin Franklin owned an asbestos purse, now found in the mineralogic collection of the British Museum.
Current Uses
More modern uses of asbestos go back to the end of the 19th century, after the discovery of major deposits of asbestos in Canada. Johns Manville, who later was associated with a major asbestos company named after him in the United States, discovered deposits of this mineral and expanded their use. An early use of asbestos was to replace dried dung as wrapping around boilers for insulation. Ironically in the 20th century Manville would die of a mesothelioma.
The increasing use of asbestos began in the 1920s and 1930s with peak use around the world in the mid-1970s [1]. Eventually some 3-4000 products would be made using asbestos. In the United States about 775,000 tons of asbestos were used at its peak, whereas the most recent figures suggest that slightly more than 1,000 tons of raw asbestos are now imported. Asbestos in finished products is not counted as part of the amount of asbestos being brought into any country and is, therefore, unaccounted for. The use of asbestos has markedly decreased around the world; currently over 50 countries have totally banned the use of asbestos [3].
Presently the major producers of asbestos include Russia, Kazakhstan, China, and Brazil [1]. While traditionally Canada has been in the top-five worldwide producers of asbestos, there was a major political change in 2012, which led to the announcement that all the Canadian asbestos mines that were still left, in the province of Quebec, would be shut down and that Canada would cease to be an exporter of asbestos fiber. There are steps being taken to end any use of asbestos in Quebec as well. As this is being written the Brazilian Supreme Court is considering the national issue of a ban on asbestos in that country. In addition to the mining of asbestos, the countries with the greatest current use of this material include China, Russia, India, and Brazil [1]. Because of perceived differences. which may in fact not be true, for the different fiber types, virtually all countries have stopped using any of the amphiboles, so the current worldwide controversy over the use of asbestos relates to the continuing use of chrysotile asbestos alone. Unfortunately, a small number of countries with commercial interests in the use of asbestos have for decades blocked its listing under the Rotterdam Conventions as a hazardous material. Because of its potentially useful characteristics, such as being a good insulator for both hot and cold, not conducting electricity, being resistant to acids, and being relatively easy to manipulate and add to other materials, asbestos was widely used in a large range of products in the past [4]. It has been estimated that between 3000 and 4000 different products containing asbestos were found at one time in the United States, but the diminished use has now limited the materials that are likely to contain asbestos through such things as roofing felts and automotive friction products. The wide range of products in which asbestos could be found, or was considered for use, includes traditional construction materials, automotive products, filtering agents, cutting boards for specialty jewelry use, phonographic records, filters on cigarettes, and paper wrappers around other tobacco products. Over time, in some countries that have not totally eliminated the use of asbestos, limitation after limitation has been put in place that minimizes the use of asbestos. Because of its former widespread use, many Individuals with a long list of job titles have been exposed to asbestos. Of special note would be those in the construction trades, shipyard workers, auto mechanics, and many others.
Major exposures to asbestos occur through occupational and environmental exposures. It is important to note that asbestos fibers were not always contained in the workplace. In addition to the direct handling of asbestos, exposures occurred to workers who worked in the vicinity of those using it, resulting in bystander exposure. Fibers would also work their way home, giving rise to familial exposure. Neighborhoods surrounding asbestos utilizing facilities could lead to neighborhood exposure, such as that occurring near mines, factories, and shipyards.
How Does Asbestos Enter the Body?
The major routes of entry for asbestos into the body are inhalation and ingestion, with minor exposure via the skin. While the ingestion of asbestos may relate to fibers of virtually any size, the issues relating to inhalation are more complex.
Inhalation
Only fibers of a respirable size will enter the respiratory system [5]. There are both mechanical and biological efforts by which the body attempts to keep asbestos from entering the body or eliminating it after its entry. This begins in the nose with large particles, including fibers, being trapped in nasal hairs and then in the upper airway, which is lined with ciliated epithelium and mucous-producing cells. In the mucociliary escalator, mucous traps the materials, with the cilia then beating upward and forcing the materials out to prevent entry into the lung, ultimately being swallowed and eliminated.
Nevertheless, fibers of a respirable size, unless they are extremely small and then are often inhaled and then exhaled with the next breath, will find their way into the lungs, passing the larynx where some may be deposited and entering into the lung parenchyma where they can produce fibrotic changes, with fibroblasts laying down collagen fibers. Depending on the size, the fibers can make their way down to the smallest airway level in the lung. Inside the lung there are mechanisms by which the body attempts to remove asbestos fibers. Macrophages may engulf the smallest fibers, and large fibers will be encircled by macrophages with little biological effect on the macrophages thereafter. Fluid pressure will move asbestos from the lung parenchyma out to the pleura [6] and the lining of the lung, and other fibers have been noted to migrate downward through the diaphragms into the abdominal cavity [7]. Asbestos fibers will also be transported into the lymphatic system and can then be detected in lymph nodes thereafter [8]. There is a major difference in the removal of different types of asbestos fibers from the lung, with the chrysotile variety having a perceived half-life of about 90 days, whereas the half-life for the amphiboles may be on the order of 2 to 3 years. This has led to the issue of biopersistence, but it should be noted that with regard to mesotheliomas, a disease further discussed in the following text, the comparative lung clearance rates are consistent with the finding of those who have studied pleural tissue that the majority of fibers found in the pleura of asbestos-exposed individuals would be chrysotile fibers, found there more often and in greater numbers than the amphiboles [8-10]. The amphiboles, far more readily than chrysotile, form “asbestos bodies” in the lung, which can also be found in sputum. Also called “ferruginous bodies,” large fibers of asbestos can be coated with an iron-protein matrix, thought to render them less biologically active.
Ingestion
Asbestos fibers, after being ingested, can be found in different parts of the gastrointestinal (GI) tract and have been identified in colonic tissue specifically [11]. The finding of the passage of asbestos as it moves through the GI tract is consistent with the diseases seen in those tissues, as discussed in the following text.
Other Tissues
One remarkable finding about asbestos is that it can be found in virtually all tissues of the body, except for the brain. It has been shown to cross the placenta and was subsequently found in the body of an unborn fetus observed when it was stillborn [12]. It should be recognized that asbestos can travel throughout the body, and unlike some of the toxicological agents that are metabolized and excreted, some of the fibers that enter into the human body will literally stay there over the remainder of one’s lifetime.
Diseases Caused by Asbestos
That exposure to asbestos can lead to the development of disease has been known for centuries. The Romans knew of the hazards of asbestos several thousand years ago and had slaves working in mines where asbestos was present. Some early respirator uses came in such settings where pig bladders tilled with air were used by Roman slaves to keep them from breathing the dust contaminated air while working [2].
The modern history of asbestos disease goes back to the end of the 19th century [13]. It was first appreciated that nonmalignant diseases could arise from exposure to asbestos, and later an appreciation with the malignant potential of exposure to asbestos came (rein observations of exposed workers as well.
The nature of the diseases caused by asbestos can be divided into two groups, nonmalignant diseases and malignant diseases Significant litigation has taken place over the use of asbestos and its ability to cause disease in those exposed, and extensive and inconsistent information has been disseminated about exposure to asbestos, both in the scientific literature and lay press, as well reviewed [14, 15]. The controversy over some of these diseases continues, as discussed in the following text.
Nonmalignant Diseases
There are a number of nonmalignant diseases that can be ascribed to asbestos. Of almost no clinical importance is the development of asbestos warts, the structures arising in the skin on the hands of asbestos exposed individuals due to fibers embedding themselves into the body and causing wart-like structures following such exposures. They are of no clinical consequence, lead to no known impairments, and are exceedingly rare.
The earliest clinical manifestation after exposure to asbestos is the development of a condition called benign asbestos pleural effusion (BAPE). This condition will often occur within the first 10 years of exposure to asbestos and is characterized by a bloody pleural effusion caused by irritation of the pleura with the secretion of such fluid into the pleural space in the chest. Clinically, it greatly concerns the physician who finds it. This is because of its bloody nature, and consideration must always be given to the potential for an underlying malignancy, but when none is found, and there has been this early development following exposure to asbestos, one is left with the diagnosis of a benign effusion caused by irritation from asbestos fibers. Such benign effusions can occur more than once in the same individual. Later in life those individuals may, or may not, develop other asbestos related conditions.
The other condition of note, and found most frequently among the nonmalignant diseases, is that of “asbestosis” a term first coined in 1924 by Cooke [16]. There is no disagreement that the term “asbestosis’ applies to changes in the lung parenchyma characterized by the fibrotic changes resulting from exposure to asbestos. Where there is controversy, apparently of relatively recent origin, is the use of the term “pleural asbestosis” regarding the same fibrotic changes occurring not in the lung parenchyma but in the pleura. There are good reasons to consider that the term “pleural asbestosis” is, in fact, a proper and legitimate scientific term, but since it appears to cause confusion to some, other terms can be used that are interchangeable. Many now prefer the term “asbestos-related pleural disease”, although pleural asbestosis is scientifically correct and accurate as well.
With regard to the term “pleural asbestosis,” there are historical and biological roots to the proper use to this term, as noted by Selikoff [2]. In 1867 Zenker [17] coined the term “pneumoconiosis,” coming from Greek and meaning “dust disease of the lung.” The first case of pneumoconiosis was in a young man in his twenties who was diagnosed at autopsy by Zenker as having stanosis, that is, tin dust lung disease, and he particularly made note of the fibrotic changes that he found in both the parenchyma and the pleura and applied the term “pneumoconiosis’ to both. The generally accepted use of the term “pneumoconiosis” applied to fibrotic changes in the pleura carded on for well over half a century, with the textbooks in the 1930s referring to the pleural aspects of asbestosis [18]. Asbestos appears to be the major cause of pleural change in those exposed to pneumoconiosis producing dust, with a very much smaller number of such changes being seen with tin dust, as noted in the preceding text, occasionally in a few percent from talc, and it has very occasionally been reported in cases of silicosis. Pleural fibrotic changes caused by asbestos are often found bilaterally, though it has been reported that in approximately 7% of the cases the fibrotic changes in the pleura will be unilateral. In such cases it becomes imperative to rule out other causes such as prior trauma or Infection. Bilateral changes are virtually always from asbestos.
Another basis that allows for the use of the term “pleural asbestosis” is that the changes in the parenchyma, the laying down of collagen by fibroblasts that had been activated by macrophages, appears to be exactly the same mechanism that leads to the laying down of collagen in the pleura as well, or elsewhere in the body. The biological basis for these changes is therefore thought to be same and justifies the use of this term. The last basis that makes the use of the term “pleural asbestosis” quite legitimate would be the fact that the International Labor Office (ILO) classification for pneumoconiosis looks to identify changes both in the parenchyma and pleura [19]. The ILO classification does not allow for the specific designation of a specific pneumoconiosis, and the X-ray changes are nothing more than generic descriptive changes. However, if one looks at what is found in question two of the standard ILO form, as it makes inquiry of both parenchymal and pleural changes, it is hard to escape the fact that while there may be no evidence of parenchymal disease, the question regarding pleural disease asks if there is evidence of a pneumoconiosis in the pleura. This can be answered in the affirmative when a proper history is done and the cause of this pneumoconiosis is supported by a documented prior exposure to asbestos. It is clear that this should be called pleural asbestosis. This was the generally accepted view until the 1960s.
The genesis of the change away from the term “pleural asbestosis’ originated in a community of pathologists, some involved in asbestos litigation in the 1960s and later [20] when lawsuits began to become common. A pathologic redefinition resulted in having certain cases not called asbestosis, with the concept that pleural changes were nothing more than a “beauty mark,” rather than representing, as it does, a disease in and of itself and also being a predictor of other diseases [21. 22]. It matters little what one ultimately calls this condition. As discussed in the preceding text, the terms “pleural thickening,” “pleural plaques,” “asbestos-induced pleural disease,” or other terms have been used interchangeably with the term “pleural asbestosis.”
Physiological changes and pleural disease
It should be noted that in most circumstances where only pleural disease is present there are most often no symptoms associated with such findings. Many individuals with only pleural disease report no symptomatology, and there are usually no physiological changes that one can identify from pleural disease alone. A notable exception to this is the findings among the population of Libby, Montana (MT), that was exposed to vermiculite contaminated with tremolite asbestos, winchite, and richterite in combination. Among Libby-exposed individuals, even when what is noted is minimal pleural disease only, such a finding can sometimes be associated with rather significant physiological abnormalities and a markedly reduced diffusion capacity. Why this occurs is at present unknown, but it may be that the combination of these three fibers, or the addition of two asbestiform minerals, but not asbestos, may be at play because there are such marked differences among this population compared to other asbestos-exposed populations throughout the world [23].
Parenchymal asbestosis
The classical use for many of the term “asbestosis” is that change of a fibrotic nature that occurs in the parenchyma of the lung caused by exposure to asbestos. Beginning generally after 10 years from first onset of exposure, without the exposure necessarily lasting over those 10 years, changes characterized by irregular opacities in the lungs are seen, and they generally occur first at the lung bases, then in the middle area of the lungs, and sometimes, but not often, also affecting the upper areas of the lungs as well. Pathologically, subpleural fibrosis is often a finding described with other evidence of fibrotic changes in the lung tissue. Pathologists have developed and used grading systems of various forms that vary from no to mild, moderate, and severe asbestostic changes that are graded, sometimes subjectively [20]. For many individuals the diagnosis of asbestosis that affects the parenchyma is made on the basis of the history of exposure to asbestos, an appropriate latency period of about 10 years or longer and characteristic changes on the X-rays, with a differential diagnosis revealing no other causative factor for these changes. The finding of irregular opacities in lungs is not specific to asbestos; other dust such as talc, other conditions such as autoimmune diseases, including rheumatoid arthritis, or exposure to paraquat through the inhalation of contaminated marijuana or direct exposure from the use of this pesticide, can also give rise to irregular opacities in the lung.
In addition to the grading system used by pathologists, radiologic changes are graded using the ILO system with a 12-point scale [19]. The first 3 grades of the 12 characterize a “normal” film, with increasing abnormal levels for the next 9 points on the scale. The ILO system is descriptive only, not diagnostic. The precise diagnosis can only be made after a clear history of exposure to appropriate dusts that can cause fibrosis. One should also consider the changes from other potential causes using the standard approach of “differential diagnosis.”
With regard to the physiologic changes, it should be noted that there is a poor correlation between pulmonary function findings and symptomatology of individuals as related to the findings on X-ray [24]. Individuals with minimal changes can have significant symptomatology, while some individuals with significant radiographic changes may report little or no symptomatology characteristics. Many individuals with radiographic evidence of asbestosis will, in fact, have normal pulmonary function values and an abnormal set of pulmonary function tests (PFTs) should not be required to make the diagnosis of asbestosis. Each case must be individually evaluated. However, as a general rule, with many exceptions, there is some correlation between X-ray changes and pulmonary function abnormalities, especially at higher abnormal grade levels. Generally, these findings also reflect greater amounts of exposure over time. A major exception, as noted in the preceding text, are the changes observed from vermiculite exposure in Libby, MT. Smoking, as an additional factor, increases the severity of changes on x-rays caused by exposure to asbestos.
Threshold
For the development of asbestos-related pleural changes or parenchymal changes, they can arise following all types of exposures, as noted in the preceding text, and from all fiber types. The development of asbestotic changes in the lung clearly follows a dose-response relationship, that is, the greater the exposure the greater the likelihood of developing such changes. All asbestos diseases follow this principle. Such nonmalignant changes characterized as pneumoconiosis, however, do not begin to occur with low levels of exposures. It is well agreed to that there is a threshold below which one would not expect to see changes of asbestosis following exposure to asbestos. The difficulty lies in characterizing how much asbestos is required for the development of asbestosis, that is, at what level does this threshold begin. It appears that there are orders of magnitude differences among scientist as to where this threshold exists. Nevertheless, it is recognized that there is such a threshold level below which asbestosis is not anticipated. As all forms of asbestos can lead to these nonmalignant diseases; this threshold concept would apply to all fiber types. At present there does not appear to be any well documented individualized risk factors such as genetic or immunologic factors that account for such variability in estimating the threshold. Individual risk factors may exist based on the observation of differences in responses in exposed groups. For example, among asbestos insulators, after 30 years from onset of exposure, about 94% have evidence of asbestosis, but even with similar work histories about 6% did not. The basis for the difference observed is not known.
Pulmonary function testing for nonmalignant disease
The standard methods of pulmonary function testing, spirometry, or more advanced testing can he used to assess the physiologic changes caused by asbestos for a given individual. As noted in the preceding text, there is poor correlation between the level of radiographic change according to the ILO classification and any pulmonary function abnormality. While the pneumoconiosis, including asbestosis, are generally thought of as diseases of a restrictive nature, there is also significant scientific literature showing that, especially early on after exposure, there are obstructive changes caused by exposures to asbestos [25], with the long-term effects characterized by restrictive changes. Restrictive diseases are characterized by lungs that hold less air than expected and do not expand fully. Obstructive changes make note of decreases in moving air in and out of the lungs. Also, as noted in the preceding text, while it is essential for the ongoing care of individuals that a pulmonary function test be carded out to see how changes may be occurring in the future, it is not a test that is necessary to make the diagnosis of asbestosis. Nor is it necessary to have specific pathologic changes, or tissue evaluation, beyond an appropriate chest X-ray, a history of exposure, a proper latency period, and no plausible alternative explanation to make a diagnosis. Various groups have written on what diagnostic tools can be used to make such a diagnosis [26].
Treatment
One of the characteristics of treating the nonmalignant diseases caused by asbestos is that there is no specific treatment once these changes have occurred, other than the removal of the excess fluid in the case of benign asbestotic pleural effusion. There is no treatment that will specifically stop or reverse fibrotic changes in the parenchyma or pleura of the lung, and even the cessation of exposure may not halt the continuing changes that are seen following exposure to asbestos. Not all cases of radiographic change progress over time. In fact, a minority will progress, but it should be noted that the more advanced the changes at initial determination, the more likely the changes will progress in the future, even with the cessation of additional exposure [27]. It Is not, at this time, possible for clinicians to determine which individuals will or will not progress radiographically, just as it is not possible to predict which individuals will progress with physiological changes either. Smoking increases the severity of the ILO classification on x-rays [28]. Asbestos exposed individuals should have special counseling about the additional hazards of’ smoking, and smoking cessation should be stressed.
While disease cannot be prevented, secondary prevention steps should be taken such as yearly flu shots and periodic pneumococcal vaccine injections to prevent secondary complications.
Predictive value of plaques
Although there is some controversy with some individuals, as noted in the preceding text, calling pleural changes “beauty marks,” this is clearly a non-normal condition, and even the finding of nonsymptomatic plaques should be considered a disease, such as would be the characteristics of the finding of a calcified Ghon complex following exposure to tuberculosis, even though the individual is asymptomatic and may never experience any physiological changes from his or her prior exposure to the tuberculosis organism. With regard to pleural changes, there are scientific studies that show that they are predictive of the development of future malignant changes, going back to the work of Edge and Hillerda [21, 22]. Any individual with plaques or parenchymal changes should be cautioned about his or her increased likelihood of developing a malignancy In the future, and while there are no methodologies currently available to prevent such cancers from occurring, there is information that should be shared with an individual regarding the future. Giving up cigarette smoking reduces the risk of lung cancer [28]. There should be more frequent medical evaluation of individuals, with the hope of detecting any of the many cancers that can be caused by asbestos at an earlier, potentially more curable stage. While it is true that for most individuals the finding of pleural plaques carries with it no physiologic or symptomatology changes, they are at an increased risk for malignancy and should be so cautioned.
Malignant Conditions Following Exposure to Asbestos
There is a wide variety of cancers that are related to exposure to asbestos, and the historical roots of this understanding are to be found as early as the mid-1930s when it was suggested by two South Carolina physicians that the number of lung cancers they were seeing among workers from a local asbestos textile factory exceeded what they expected in the general population [29]. By 1942 Hueper [30] wrote in his classic textbook Occupational Tumors and Allied Diseases that he believed asbestos was a cause of lung cancer. His statement should have carried some weight, given that he was serving as the director of occupational cancer studies at the National Cancer Institute in Bethesda, Maryland. By 1955, Doll, of Great Britain, had published the first epidemiologic study on the relationship of exposure to asbestos and the subsequent development of lung cancer [31). The carcinogenic potential of asbestos has long been known dating back to the 1920s. The first mesothelioma was noted in Great Britain in 1928 by a company operating textile facilities, and over the successive years additional cases were found but were never shown in open scientific inquiry [14]. That health issue was more recently generally recognized. In 1960 Dr. Wagner in South Africa noted in the scientific literature that in a four-year period he saw some 40 cases of mesothelioma, all from the North Western Cape Province of South Africa, where there were asbestos mines [32]. What was interesting about his description was that it was not only among the miners of asbestos but among their family members as well as others who lived in the same villages. The definitive role of asbestos in causing mesothelioma (there had case reports in the literature previously) and the various settings from which disease could occur were not immediately known to other parts of the world.
Beginning around this same time, the work of Selikoff began to be published, and he not only pointed out that lung cancers and mesotheliomas were found in excess among users of asbestos products, beyond the role of those involved in manufacturing, but he also shed light on the potential for additional types of cancer that have now been shown to occur following exposure to asbestos [33]. As noted earlier, asbestos has the propensity of being found in tissues throughout the body, and therefore it is not surprising that many malignancies can be documented following exposure to asbestos. One should also note that, as studied, all forms of asbestos are capable of producing these types of malignancy, as further discussed in the following text, although there continues to be some controversy over the relative potency of different fiber types. There should also be note taken of the other controversies in the literature, some tied back to what has been called “doubt science” [15].
Lung cancer
As noted in the preceding text, the first suggestion of lung cancer arising following exposure to asbestos was made in 1935, and it was so identified as a carcinogen in 1942. Studies from around the world have fully documented that all forms of asbestos can cause lung cancer, and there is some continuing controversy over the relative ability of the different types to do so, but no serious disagreement that they all can produce lung cancer. When speaking of lung cancer, one is referring to the “usual” 95% of lung cancers that are most often found (i.e. squamous cell, adenocarcinomas, small-cell carcinomas) and not the unusual types making up the other 5%. These three cell types have been shown to be caused by both smoking and by asbestos. Clearly, smoking, worldwide, causes most lung cancers since by way of carcinogenic exposure more people are exposed to this agent than is noted with exposure to other lung carcinogens like asbestos, arsenic, isopropyl oil, and many others [34].
When discussing nonmalignant disease a point was made of the fact that there is a threshold of exposure before which it is not thought possible to develop some of the nonmalignant diseases. Even though there is clearly a dose-response relationship, some threshold must be reached to develop some of the nonmalignant changes. This does not routinely apply to carcinogens.
From a toxicological standpoint, it is generally believed that carcinogens have no threshold, unless there is convincing evidence to indicate otherwise, clearly recognizing that low levels of exposure carry a low risk and the risk increases with increasing exposures. This concept is not unique to asbestos—for example, the lack of a threshold for cancer induction in a statement in the late 1940s that there was no safe level of exposure to benzene above zero [35].
With regard to asbestos, there are both human and animal data documenting what should be considered low levels of exposure that can lead to the development of malignancy [36, 37]. With regard to lung cancer, Wagner showed in his animal studies in the early 1970s that when he gave animals increasing amounts of asbestos over time, even a single one-day exposure was sufficient to produce lung cancers (and mesotheliomas); this led scientists to believe that there could be reasonable levels of exposure shorter than this without a documentable threshold. With regard to human findings, while there are no case reports that document one day of exposure for lung cancer, there are data from workers at a manufacturing facility in New Jersey that was studied by Selikoff that showed that one month or less (one to four weeks) of exposure to asbestos, occurring as it did during World War II with enormous worker turnover, would double the risk of developing lung cancers among that population [30]. There was a general dose-response relationship seen, and with two or more years of exposure at this facility there was a sevenfold increase risk in the development of lung cancer on the population of that factory. Over the years, from many settings, with many types of exposures, it has become clear that exposures to asbestos gave rise to cases of lung cancer.
There is an important principle, that of synergism, or a multiple-factor effect, that was first noted and described regarding the interaction of asbestos with smoking [39]. It was shown that even nonsmokers, not using asbestos, could develop lung cancer at a background rate set at one. Asbestos work without smoking gave a fivefold increase, and an average smoker with no asbestos exposure was shown to have an approximately tenfold increase. However, the risk for a smoker who worked with asbestos was not additive but multiplicative, at about a 50-fold increased risk.
Mesothelioma
Mesotheliomas are a rare cancer of the lining tissue found in various structures such as the outer surface of the lung and the inner surface of the chest wall, around the heart, and in the abdominal cavity, as well as other sites in the body. The relationship between exposure to asbestos and the development of mesotheliomas is so clearly related that mesotheliomas are known as a “signal tumor,” that is, a tumor associated with a specific exposure. Another example would be angiosarcomas caused by vinyl chloride. This does not mean that there are no other potential causes for mesotheliomas [40, 41], for example, there are multiple but unusual causes for angiosarcomas, but there is a clear relationship that earns asbestos this designation.
Mesotheliomas can affect a variety of connective tissues. The most common site for the development of mesotheliomas is in the pleural linings of the chest cavity. Approximately 90% of all mesotheliomas occur as pleural mesotheliomas. Of the remaining amount, the majority, approximating 10%, are peritoneal mesotheliomas, tumors arising in the connective tissue of the abdominal cavity. A small number of such cancers is found in the pericardium surrounding the heart, as well as testicular mesotheliomas, with the connective tissue from the abdomen reaching down into the scrotal sac. There have even been reports of the rare occurrence of mesotheliomas arising in the connective tissues surrounding the liver in the abdominal cavity. Deaths generally occurred within 6-12 months. With the advent of some new chemotherapeutic drugs and, in some cases, extensive surgery, the life span of a mesothelioma patient has been extended by a number of months. There are three types of mesothelioma at the cellular level: the epithelioid variety, the sarcomatoid variety, and in some cases a mixed pattern. The new chemotherapeutic drugs work best on the epithelioid type of mesothelioma.
Mesotheliomas are indeed a rare tumor, with only some 3000-4000 or so cases per year being found in the United States. According to published literature the rate of this malignancy in other countries is equally uncommon [42], but in most cases asbestos exposure appears to be at the root cause of the development of this disease. There are two notable exceptions. One is the finding of endemic mesotheliomas in the central Anatolian plain of Turkey, where inhabitants of that region developed mesotheliomas as a result of exposure to a different type of fibrous material, fibrous zeolites [40]. Similarly, on the northwest slopes of Mt. Etna, on the island of Sicily, there is an area with mesotheliomas occurring from another fibrous material, fluoroedinite [41]. These have all been recognized, in humans, as causes of mesotheliomas, and in various animal studies other fibrous materials with similar dimensions have been noted to cause mesotheliomas in animals. These materials would include fibrous glass materials, aluminum whiskers, and nanotubules [43. 44).
Some believe that there are other causes of mesothelioma, but this is not entirely accepted in the scientific community, as they are not supported by epidemiologic association nor animal studies. Some believe that exposures to ionizing radiation generally thought of in the form of therapeutic radiation used to treat malignancies, can lead to the later development of mesotheliomas. Many of the reports of such cases fail to acknowledge the potential presence or absence of prior exposure to asbestos. A simian virus, SV 40, has also been suggested as a potential cause of mesothelioma but has not found significant scientific backing for it to be recognized as such to date.
Extremely low levels of exposure to asbestos had been reported or recognized as giving rise to this malignancy. The animal studies of Wagner reported a number of cases of mesothelioma after one day of exposure [36] and there are a number of case reports from around the world of a single day of exposure to asbestos giving rise to that disease. There are many reports of weeks to months of exposure giving rise to mesotheliomas, such as a single summer’s employment in the construction trades or working for short periods in an asbestos-manufacturing facility [38].
One of the continuing controversies about asbestos potency has to do with the propensity of each of the fiber types to cause mesothelioma. A few still believe that chrysotile is unable to so, or that it takes enormous amounts of exposure to do so. There are a number of viewpoints on the subject ranging from the role of the amphiboles as being paramount to others thinking that chrysotile is responsible for most mesotheliomas (remembering that 90%-95% of all asbestos used was chrysotile), and there also exist some data which reveal that exposures to mixtures of amphibole and chrysotile appear to have a synergistic effect in the production of mesotheliomas. Another viewpoint, and having some support, is that the most appropriate scientific studies looking at equal numbers of fibers of equal sizes in the connection of mesothelioma have not been done and that this should be considered an open question. There is a recent publication showing fewer chrysotile fibers are needed compared to the amphiboles [45], but this needs more confirmation. In spite of the view of some that chrysotile is thought incapable of producing mesotheliomas, the United States Environmental Protection Agency (USEPA) and the International Agency for Research on Cancer (IARC) clearly document that chrysotile should he considered as a cause of mesothelioma [46. 47].
The USEPA in 2013 has classified asbestos as a group A, known human carcinogen and calculated an inhalation unit risk estimate of 2.3 x 10-1 (fibers/mL) -1. In the agency’s evaluation, “asbestos” applies to a group of six different minerals that occur naturally in the environment. The fiber types used for risk assessment were predominantly chrysotile, plus amosite, and mixed chrysotile, crocidolite, and amosite. No quantitative estimate of carcinogenic risk from oral exposure was made (http://wwwepa.gov/IRIS/ subst/0371.htm; last updated October 2014).
Whereas the latency period for lung cancers begins at 10 years and appears to peak out at some 30-35 years, mesotheliomas also begin to appear at about 10 years but peak a bit later. Some data show that for pleural mesotheliomas the peak seems to be at 35 years from first exposure and for peritoneal mesotheliomas the peak is about 40 years [48]; other data lengthen these times. There an some reports, however, of this disease occurring in very much shorter intervals front first exposure, but these reports are much rarer that the longer time frames noted here [2].
With regard to the issue raised by some of chrysotile being incapable or hardly capable of producing mesotheliomas, this is inconsistent with tissue analysis that in many laboratories around the world has documented that the most likely fiber type found in the pleura of patients with mesothelioma is chrysotile, particularly short chrysotile fibers [8-10]. There is a study looking at the fluid pressures in the lung that documents that chrysotile is much more likely to be moved through fluid pressure out to the pleura compared to the amphiboles [6], and this fits with the findings noted by many that chrysotile is cleared from the lung much more quickly and that amosite and crocidolite will take up a longer-term biologic residence, but the concept of biopersistence, stating that the amphiboles persist, while chrysotile disappears, and therefore cause mesotheliomas, falls apart when one recognizing that while lung tissue has been studied, those who have looked at the pleura find that the chrysotile fibers migrate preferentially to the pleura.
With regard to peritoneal mesotheliomas, one of the concepts explaining why these are far fewer could be simply the small number of fibers that reach the connective tissue surfaces in the abdomen, given that the routes of entry are not as direct as will occur in the lung with movement out to the pleura. Studies have shown that some fibers will migrate down through the diaphragm [7], and others have shown that fibers will literally pass from inside the bowel lumen through the bowel wall into the peritoneal cavity, where they can then be found [7]. The anatomical opening between the abdominal cavity and the testicular sac helps explain how fibers can reach down into that area, and in each of the tissues discussed fibers have been found and documented.
When studying mesotheliomas an issue that was extensively raised by Stanton was that of fiber size [43]. Any product containing asbestos will have fibers of varying sizes, and it is only through difficult laboratory preparation that carefully sized fibers can be created in quantities sufficient to study in animals. Stanton found that there was variability, depending on fiber size, with regard to the subsequent development of mesotheliomas. He did not, in his work, subscribe to the concept that only fibers of five microns or longer were those that should be considered biologically active, as is held by some individuals, and the finding of predominately short chrysotile fibers, less than five microns, in the pleura, as found in laboratories in the United States, Japan, and France, when pleural tissue had been studied, in cases of mesothelioma, or other cases, also speaks against this.
One should also note that at present there is no standardized laboratory measurement that has been agreed upon to characterize the finding of asbestos in tissues. Virtually every laboratory uses different techniques, and this may range from how tissue is prepared and digested, to the use of which microscopic apparatus, to the range of sizes of fibers that are to be identified. Some laboratories immediately dismiss any fibers below five microns, recognizing that such fibers may make up a considerable burden of what’s in tissue but are, for reasons that are not entirely clear, ignored. Others use a higher power resolution and look for virtually all fibers and will be able to describe a range of sizes of fibers that will be found in tissue. The lack of documentation in a paper of a tissue burden of asbestos does not mean that any one laboratory’s findings can be compared to any other laboratory, and the best methodology is to use the internal controls of each specific laboratory, with the obvious caveat that strict scientific protocols and procedures are followed and that there is no preferential selection of data.
Laryngeal cancer
Although suspected for some time, there is now a generally widely accepted agreement that laryngeal cancers can be caused by exposure to asbestos [49]. Fibers, on their way into the lung, will be deposited on laryngeal tissue and have been shown to be present there, and it is now generally agreed upon that asbestos has a role to play in the production of this malignancy, above and beyond the malignant potential caused by cigarette smoking in Individuals who were also exposed to asbestos. Beyond the work on fiber type and lung cancer and mesothelioma, there has been no definitive work on fiber type and the development of laryngeal cancers or others that will he discussed in the following text.
Gastrointestinal tract malignancies
A recognized area of continuing controversy is that of the ability of asbestos to cause various GI tract cancers [50, 51]. The data with regard to these malignancies are, in some ways, much less definitive then for other forms of malignancy. There are relatively few animal studies to corroborate human data, and as with almost all epidemiologic studies, there can be great variability and many reasons why studies come out positive or negative. It was the work of Selikoff in the 1960s that first suggested a variety of more unusual cancers being caused by asbestos [52], and it does appear, when all evidence from around the world for the individual types of cancer is considered, that there are more data favoring the relationship than not [53].
Esophageal cancer
Esophageal cancer has been noted in a number of studies to be elevated following exposure to asbestos [54]. This type of cancer, as well as others noted in the following text, is not especially common, and so there is some potential difficulty in finding suitable populations to study. That said, it is not only from the work of Selikoff but also from other studies that there does appear to be relationship between prior exposure to asbestos and the subsequent development of esophageal cancer.
Stomach cancer
Similarly, one is struck with the same difficulties in studying the problem of stomach cancer. There are both positive and negative studies, but on balance it seems both biologically plausible, and there are epidemiologic data supporting the relationship between exposure to asbestos and the subsequent development of stomach cancer [53]. This would include a study in China [55], where normally high rates of stomach cancer were well controlled for in the general population as compared to the rates among asbestos-exposed individuals.
Small bowel cancer
An exceedingly rare form of cancer, and one that is rarely studied in almost any setting, is that of cancers of the small intestine. Newhouse was one of the few investigators who looked into this issue and found that there was a relationship between small bowel cancer and prior exposures to asbestos [56].
Colorectal cancer
A more common, and therefore more studied, type of cancer is that found in the colorectal area. Selikoff first suggested an excess occurrence in the 1960s [52], and studies from around the world have found mixed answers when addressing this question [56, 57]. Again, we find evidence of asbestos in colonic tissue, and we also find relatively little animal data to support the human findings that will come down on both sides of the issue. Nevertheless, the widespread finding of excess colorectal cancers in a multitude of populations exposed to asbestos makes one think that this is indeed a proper relationship. There are even some studies that break down right-sided versus left-sided cancers and feel that asbestos may be more related to one than the other [58]. Clearly, while at this time one should consider GI tract cancers as resulting from exposure to asbestos, more research in this area would be warranted, and a better study of interactive effects with other potential factors would also seem warranted.
Kidney cancer
Asbestos fibers make their way into the kidney and can be extracted from urine specimens as well. Again, it was the work of Selikoff that first suggested that kidney cancer could arise following exposure to asbestos [52], and subsequent studies around the world that have looked for this relationship in some cases have found it. While other agents have been noted to cause bladder cancer, asbestos does not appear to do this, but the finding of excess kidney cancer cases, a relatively rare cancer, appears to be a justified scientific conclusion [59].
Ovarian cancer
The suggestion that exposure to asbestos could give rise to ovarian cancer was made as far back as the 1960s by Graham [60]. One difficulty with studying this problem is that with very few exceptions, most of the exposures to asbestos over the decades have been in populations of male workers. Among the female populations other asbestos cancers have been studied, such as mesotheliomas, but it has been difficult to study this specific issue. Additional support for this relationship comes from the observations in certain parts of the world, such as from countries like Pakistan where body talcs are generally used in large quantities, and ovarian cancers seem to be elevated. Talc deposits in many locations are well known to be contaminated with asbestos fibers, and, in fact, until better regulated in the United States, baby talcs some decades ago were known to have asbestos particles to them.
More recently, worldwide data have finally reached a level of sufficiency where it has been generally acknowledged that exposure asbestos can and does give rise to excess cases of ovarian cancer [61].
Oropharyngeal cancers
It was also through the work of Dr. Selikoff that attention was brought to the subject of an excess of oropharyngeal cancers following exposure to asbestos [52]. This is another area that has had limited study, but when it has been looked at there had been excess oropharyngeal cancer cases reported following exposure to asbestos [61, 62]. The structures involved have included the tonsillar area, the tongue, and other structures that make up the oropharynx. Again, smoking would be very much related to cancers of these organs, but data show that asbestos too can cause malignancies in these tissues.
Areas of Scientific Controversy
Without doubt there are some legitimate issues with regard to the science of asbestos and asbestos-related disease, but many among these include inappropriate questions of scientific doubt [15] or hypotheses with no basis. Among the legitimate area of controversy would be such questions as the relative ability of the different fiber types to cause disease. Included in this discussion would be the unusual patterns of disease seen following exposure to vermiculite that is contaminated not only with asbestos but with winchite and richterite as well. These other contaminants may play a yet unrecognized role in altering the usual biologic occurrence of disease among those exposed to vermiculite. Continuing legitimate discourse also exists with regard to the matter of fiber size, little work having been done in this area since the initial papers by Stanton and Wrench [43].
One should also recognize and be cautious about peer review patterns of papers published in journals. As the vast majority of asbestos related diseases were never published in the scientific literature and are unreported, relying on a study or studies that only make use of mesothelioma cases from published data in the literature would be deficient in the context of the overall database [63]. Government agencies that evaluate the evidence and make determinations regarding asbestos-related diseases in their countries should have a sufficiently robust data collection system and should use unbiased studies that involve no financial interest in the conduct of the studies.
In the case of automotive friction products, the USEPA has conducted its evaluation and twice issued documents on the hazards of automotive brake products, including stating that auto mechanics put at risk family members, carrying home asbestos on their persons [64].
There is a mischaracterization made by some that should be clarified of the issue of biopersistence that routinely neglects the movement of asbestos around the body. As was written in an editorial in the American Journal of Respiratory and Critical Care Medicine some years ago [65], the most important aspect of denoting exposure in tissues is a history of such exposure, not the finding, or lack thereof, of fibers in tissue. As noted earlier there is even controversy over what laboratory techniques to be used to look for tissue levels of asbestos, and skewing tissue review by laboratories resulted in missing certain sizes of fibers.
Medical—Legal Aspects of Asbestos-Related Disease
There have been various medical-legal aspects of asbestos issues related to prior and ongoing litigation involving extensive arguments put forth by plaintiff and defense counsels and political struggles over asbestos. In many judicial jurisdictions throughout the United States courts have weighed in on the subject of asbestos and disease. Scientists are generally not trained in the law, and jurists often have little scientific training; this makes it difficult to arrive at a common understanding and interpretation of science and law. As a societal issue this should be recognized, and perhaps over time a closer coming together, in a rational manner, of science and law can lead to better interpretations that more honestly reflect the reality of science.
The difficulty arises when there are requirements for testimony that is impossible for science to undertake. For example, sometimes substitute measures are put in place but it is not recognized that these substitute measures did not accurately reflect exposures. In cases when scientific data, as noted in the preceding text, reported that one-day exposure for mesothelioma or one-month exposure for lung cancer appears to be sufficient to cause disease, discounting decades of regular occupational exposure that are not quantitatively measured would lack scientific justification. Similarly, in other cases, to decide that some exposures play a role in disease and others do not fails to recognize that it is truly the cumulative exposure to asbestos over time that led to the disease, made up of all the exposures that have taken place over one’s lifetime, and that no portion of the exposure can be eliminated from consideration. It is clear that not all exposures are equal in intensity, and it is important to address culpability in a manner that reflects science.
An excellent review of the basic epidemiology of asbestos-related disease that included discussions on risk assessment, health effects, and how some information has or has not been used in medical-legal cases can be found in the writings of Lemen [67].
Conclusion
This chapter has touched upon the basic and some of the larger aspects of diseases caused by asbestos, and related discussions continue. A dose-response relationship exists for disease in humans following exposure to many kinds of agents, including asbestos. Not everyone exposed to asbestos, which is generally all of us, will develop an asbestos-related disease. For some individuals, minimal exposures have shown a deleterious effect, while for others, often for unknown reasons, a massive exposure over a lifetime did not show an apparent ill effect.
As a substance of scientific interest, asbestos has a role in further studying significant scientific questions. From a viewpoint of protecting the health of individuals, exposure should be avoided. Over 50 countries in the world have banned asbestos. Such action and further activities to find and use existing healthier alternatives would provide health protection.
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