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UNDERSTANDING MESOTHELIOMA
Special Report
Mesothelioma, a rare form of cancer of the membranes lining the chest or abdominal cavities, has recently been front and center in the European media. Numerous news reports have alerted the public to forecasts of increases in the number of mesothelioma cases in the coming years. Most of the reports have linked these increased rates to 'asbestos exposure', without differentiating between fibre of product types. In general, only cursory attention has been paid to the large body of scientific evidence that has been accumulating since the 1960s regarding the nature of mesothelioma and its risk factors.
CONTENTS
Mesothelioma and asbestos exposure
Differences in pathogenic potential of fibre types
Inconsistency in findings of animal and human research
Chrysotile, tremolite and mesothelioma
Mesothelioma: Who is at risk?
Mesothelioma without asbestos exposure
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Mesothelioma and asbestos exposure
The discovery that exposure to certain types of asbestos is linked to pleural mesothelioma is a result of the pioneering work of Dr. Christopher Wagner, who documented the high incidence of the disease amongst people working at or living near crocidolite (blue) asbestos mines as well as in household members of workers at these mines. Later research by Newhouse and Thompson (1965) also found elevated mesothelioma risks amongst workers (and their household members) at a manufacturing plant using crocidolite.
Generally, once diagnosed, cases of mesothelioma are rapidly fatal, but the very long latency of the disease means that symptoms may only begin to appear 20, 30 or even more than 50 years after initial exposures.
From the 1940s through to the 1970s, crocidolite and another amphibole, amosite, were used extensively, either alone or in conjunction with chrysotile, in friable insulation applications in the ship-building and construction industries, primarily in North America and Europe. These sprayed-on applications have been discontinued since the 1970s. To a lesser extent, amphiboles were also used in the manufacture of asbestos-cement pipe. In the past, in most of these industries, workers were exposed to extremely high fibre levels. However, what is particularly disturbing is that a number of cases of mesothelioma have been reported in individuals who have had relatively short but intense exposure to amphiboles.
The discovery of mesothelioma and its association with certain types of asbestos exposure prompted new research programmes, regulatory attention and increased public awareness of the health risks of asbestos.
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Differences in pathogenic potential of fibre types
The results of human epidemiological studies and lung mineral content analyses demonstrate that amphiboles (crocidolite and amosite) are more strongly associated with mesothelioma than is chrysotile. Comparative analysis of fibre durability and chemical composition are helping to explain the greater toxicity of amphiboles.
Of the thousands of asbestos-related mesotheliomas reported, virtually all can be directly attributed to exposure to amphiboles. In his widely cited 1988 review of evidence related to mesothelioma causation, Dr. Andrew Churg found that only 53 cases of chrysotile-related mesothelioma had ever been reported from the tens of thousands of workers studied. Of these, ten cases were observed in secondary industry workers for which there was a strong suspicion of amphibole contamination, and 41 cases have occurred in individuals exposed to chrysotile mine dust, which contained traces of the naturally occurring amphibole; tremolite (Churg, 1988).
Other evidence of the extremely weak association between chrysotile exposure and mesothelioma has been revealed through the cohort study of some 11,000 Québec chrysotile miners born between 1891 and 1920. The last follow-up of this cohort found that only 37 mesothelioma deaths had been identified among 8,000 deaths from all causes (McDonald et al., 1993). No cases were detected in workers with less than two years of exposure.
In addition, unlike crocidolite mining towns, there has been no indication of environmentally-related mesothelioma in chrysotile mining communities. Also in contrast to amphiboles, the risks to household members of chrysotile workers through non-occupational contact appear to be extremely low, as only 2 or 3 isolated cases allegedly related to this "second hand" exposure have been reported.
According to Churg, the research data indicates that although chrysotile asbestos can produce mesothelioma in man, the total number of such cases is small and the required doses extremely large. Another important factor is that while in general, amphiboles have been shown to cause lung disease and cancer after short but intense exposures, chrysotile-related illness is associated with very high, long-term exposures only.
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Greater toxicity of amphiboles linked to durability in the lung
The greater durability of amphiboles compared to chrysotile appears to be one of the principle reasons for their greater carcinogenic potential. Many researchers now believe that the longer a foreign substance persists in the body, the more likely it is to cause cellular damage and lead to accelerated cell reproduction and chromosomal damage, which are associated with tumour growth. Contrary to chrysotile fibres, which dissolve relatively quickly, amphiboles persist at sites of tumour development and serve as the stimulus for neoplastic (new tissue) growth (Jaurand, 1979; 1984). Because of chrysotile's rapid dissolution, particularly under conditions of low to moderate exposure, it may not persist in the human body over the extended period necessary for the development of tumours.
Several studies published in the early 1980s were conducted on lung tissue samples from workers whose deaths were considered to be asbestos related and compared to those of control groups. The results showed that the concentrations of amphiboles in their lungs were up to 100 times greater than those found in the control groups - while the amounts of chrysotile observed were similar for the subjects and the controls. Further-more, in asbestotic cases, the amounts of amphiboles, but not of chrysotile, related well quantitatively to the severity of the disease. These differences in biopersistence, according to fibre type, were particularly striking in cases of mesothelioma. For instance, several studies have shown that the mesothelioma cases are correlated with vastly increased lung burdens of amphiboles, but not chrysotile.
The most recent data available on the retention of asbestos fibres in lung tissue of asbestos workers is a Swedish study which shows different kinetics for amphibole and chrysotile fibres in human lung tissue (Albin et al., 1994). Amphibole fibre concentrations increase with duration of exposure, whereas chrysotile concentrations do not. Furthermore, the authors indicate that their study supports a former finding of a possible adaptive clearance of chrysotile, and conclude that it "support the hypothesis that adverse effects are associated rather with the fibres that are retained (amphiboles), than with the ones being cleared (largely chrysotile)."
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Amphiboles, iron and oxygen radicals
In addition to the longer biopersistence of amphiboles, their iron-content particles appears to trigger an oxidative stress process - the generation of "Active Oxygen Species" (AOS), which some researchers believe can cause membrane damage, induce the release of inflammatory compounds, which can lead to fibrosis, and even cause DNA strand breaks, which can lead to lung cancer. AOS production is normally held in check by protective agents and scavenger enzyme mechanisms. However, it is believed that high and sustained generation of AOS can eventually overwhelm scavenger mechanisms and lead to 'oxydative lung injury.'
Thus, studies of the impact of chemical composition on the carcinogenicity of fibrous materials have been undertaken. Iron-containing particles can produce AOS by oxidizing their iron (Guilianelli et al., 1993). Brooke Mossman, of the University of Vermont College of Medicine, suggests that the lower amounts and bio-availability of iron in chrysotile fibres may render them less biologically active over time. Other studies have confirmed the importance of fibre length and geometry in the generation of AOS by alveolar macrophages. Longer fibres such as crocidolite and erionite have been found to generate larger amounts of AOS, whereas short fibres and particles are generally relatively inactive (Hansen & Mossman, 1987).
Albin A, Pooley FD, Strömberg U, Attewell R, Mitha R and Welinder H, (1994) Retention patterns of asbestos fibres in lung tissue among asbestos cement workers. Occup. Environ. Med., 51: 205- 211.
Churg, A. (1988) Chrysotile, Tremolite, and Malignant Mesothelioma in Man. Chest, 93: 621-628.
Guilianelli, C et al. Effect of Mineral Particles Containing Iron on Primary Cultures of Rabbit Trachael Epithelial Cells: Possible Implication of Oxidative Stress. Env. Health Persp., 1993; 101.
Hansen, K, Mossman, BT. Generation of superoxide from alveolar macrophages exposed to asbestiform and non-fibrous particles. Cancer Res. 1987;47:1681-6.
Jaurand, MC, Bignon, J, Sebastien, P, & Goni, J. Leaching of chrysotile asbestos in human lungs. Correlation within vitro studies using rabbit alveolar macrophages. Envir. Res. 1979; 14:245-54.
Jaurand, MC, Gaudichet, A, Halpern, S & Bignon, S. In Vitro biodegradation of chrysotile fibres by alveolar macrophages and mesothelial cells in culture: comparison with a pH effect. Br. J. Ind. Med. 1984;41:389-95.
McDonald, JC, Liddell, FD, Dufresne, A and McDonald, AD. The 1891-1920 birth cohort of Quebec chrysotile miners and millers: mortality 1976-88. Br. J. Ind. Med., 1993;60:1073.
Wagner, JC, Slegges, CA and Marchand, P. (1960) Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province. Brit. J. Ind. Med. 17:260-271.
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Inconsistency in findings of animal and human research
Past animal studies comparing chrysotile and amphiboles have failed to confirm epidemiological findings of the stronger association between amphiboles and mesothelioma. A review of experimental protocols used demonstrates why.
Up until recently, most studies published in the field of animal experimentation, following administration of different asbestos fibre types by inhalation or injections, have not identified significant differences in the pathogenic potential of the various asbestos fibre types. The reported effects were not consistent with epidemiological observations indicating that amphibole fibres are markedly more potent than chrysotile in inducing asbestosis, lung cancer and mesothelioma. However, in many of these studies, the comparisons of effects (fibrogenicity and tumor yield) has been based on gravimetric measures: that is, using mass as the means defining the dose of the tested minerals.
The use of fibre mass rather than fibre number in animal studies has resulted in an overstatement of the health effects of chrysotile compared to other fibres. It is widely known that similar masses of chrysotile and amphiboles or other mineral fibres can vary significantly in fibre number. For example, for fibres longer than 8 microns, the number of fibres per mg of chrysotile may be up to 100 times higher than that for crocidolite (Palekar et al., 1988).
In fact, attempts to transform gravimetric doses into fibre numbers have indicated that fibre for fibre, chrysotile is less pathogenic than the amphibole varieties. More recently, studies using both fibre mass and fibre number as units of dose have confirmed that amphiboles are more pathogenic than chrysotile. The in vitro models of Yegles et al. (1993) and of Heintz et al. (1993) and the inhalation experiments of McConnell et al. (1994) all support this finding.
Another important factor in the apparent inconsistency between human and animal data is that inadequate measures have been applied to control for the fibre dimensions of the different substances being tested. Fibre length and diameter are now recognized as extremely important determinants of the fibrogenic and carcinogenic potential of a given substance.
Heintz NH, Janssen YM and Mossman BT. (1993) Persistent induction of c-fos and c-jun expression by asbestos. Proc. Natl Acad. Sci. 90: 3299-3303.
McConnell EE, Chevalier HJ, Hesterberg TW, Hadly JG and Mast RW. (1994) in ILSI Monograph "Toxic and carcinogenic effects of solid particles in the respiratory tract", eds. DL Dungworth, JL Mauderly and G. Oberdörster, ILSI Press, pp. 461-467.
Palekar LD, Most BM & Coffin DL. (1988) Environ. Res., 46:142-152.
Yegles M, St-Etienne L, Renier L, Janson X and Jauran MC. (1993) Induction of metaphase and anaphase abnormalities by asbestos fibers in rat pleural mesothelial cells in vitro. Amer. J. Resp. Cell. Mol. Biol. 9: 186-191.
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Chrysotile, tremolite and mesothelioma
Although it has been demonstrated that there is a very weak association between chrysotile exposure and mesothelioma, the presence of occasional fibrous tremolite, an amphibole mineral, in some chrysotile ore body has been cited as a potential risk factor amongst chrysotile workers. The available evidence, however, shows that mesotheliomas in chrysotile mining populations are extremely rare relative to rates in amphibole-exposed populations. In fact, less than 40 mesothelioma cases over several decades have been reported amongst chrysotile miners and millers (McDonald et al. 1993).
In their analysis of the implications of the 37 mesothelioma cases identified up until 1992 in the 11,000 person cohort, McDonald & McDonald (1995) found that they were concentrated in workers from specific areas of the mines. Further post-mortem lung tissue analysis showed that workers in these areas had tremolite lung content four times higher than those workers in other areas of the mines studied, suggesting that the rare cases of mesothelioma among chrysotile miners are mainly, if not wholly, due to tremolite exposure.
The authors note that it should be kept in mind that these mesothelioma cases occurred as a result of long, heavy exposures 20 to 70 years ago. They conclude: "The geological distribution of tremolite within the Québec chrysotile ore body may well vary in time and place and, at present levels of environmental controls, any mesothelioma risk from exposure (...) would be far below the limits of epidemiological detection."
The previous review by Dr. Andrew Churg, a pathologist at the University of British Colombia in Canada, supports this conclusion. Churg (1988) writes, "whether tremolite or chrysotile be the critical agent, these observations suggest that chrysotile ore, in both crude and processed forms, does cause mesothelioma in man, but that it is an extremely weak carcinogen and that in today's terms, the doses required are extremely high. As a practical matter, the data indicate that chrysotile will not produce mesotheliomas in those exposed to any current or recently regulated number of fibers..."
Churg, A. (1988) Chrysotile, Tremolite, and Malignant Mesothelioma in Man. Chest 93: 621-628.
McDonald, JC and McDonald, AD (1995) Chrysotile, Tremolite, and Mesothelioma. Science 267: 776-777.
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Mesothelioma: Who is at risk?
Reports of persisting incidence of mesothelioma cases despite the fact that most countries have banned the use of amphiboles and sprayed-on applications has sparked concern over the safety of present-day workers. Epidemiological evidence is helping to identify exactly what populations have been at risk and under what conditions.
Past exposures and the latency effect
The long latency period of mesothelioma means that it will take several decades before the impact of lower amphibole exposures begins to be seen. Therefore, current cases are related to the legacy of past misuse. The 30, 40 and even 50 year latency period has unfortunately ensured that we will continue to witness the effects of this misuse until early into the next century. The very legitimate question which is now being raised is: How can we be sure that these rates will indeed drop in the future?
The fact that amphiboles have been banned in almost all countries and sprayed-on applications discontinued years ago, suggests that the conditions giving rise to asbestos-related mesotheliomas we are witnessing today have in large measure been eliminated. To ensure a rapid decline in mesothelioma rates beyond the year 2010, a number of challenges must be met. Firstly, measures need to be taken to prevent dangerous levels of exposure to amphibole asbestos from work with in-place friable insulation materials. Secondly, those few countries, which have not yet discontinued the use of amphibole asbestos, must be encouraged to do so - particularly given that the necessary technology is well known and readily available.
Minimizing amphibole exposure from in-place insulation materials
Numerous studies and reports have concluded that at the levels of exposure generally found in buildings with intact asbestos insulation materials, occupants are not at risk. However, workers who may come into frequent and direct contact with these materials need to be protected. The potential for mesothelioma induction after relatively short, intense exposures to amphibole varieties has raised a red flag amongst industrial hygienists who are justifiably concerned over the risks to building construction and maintenance workers, employees involved in ship renovation or demolition work, and any other categories of workers who may come into regular contact with amphiboles or amphibole-containing materials.
It will take a concerted effort, at several levels, to ensure that exposures are controlled to the extent that no new cases of amphibole-related mesothelioma develop. Most importantly, building owners should be required by law to verify whether their buildings contain friable asbestos insulation materials and if so, put in place a comprehensive management programme, which includes survey and assessment procedures, a plan for instituting corrective measures, and education and training for custodial workers.
For renovation and demolition work, the law should also require that the competent authorities be notified and that only qualified contractors and workers be hired to perform the work. Regular air monitoring should be carried out to monitor the efficiency of preventive and control measures.
The need to inform and enforce
Today, current regulations in most countries provide an adequate framework for controlling mesothelioma risks. However, regulations alone do not guarantee safe work environments. Awareness campaigns targetted at building owners, removal contractors, custodial and maintenance workers will be important. However, to ensure worker health and safety, governments must act to strictly enforce regulations, and in the event of non-compliance, impose meaningful fines and penalties on those found to be in violation. Only in this way will there be assurance that asbestos-related mesothelioma will become a disease of the past.
Source: W. Denault & Associates, Paper presented at the International Conference on Asbestos Products, Kuala Lumpur, Malaysia, 1991.
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Mesothelioma without asbestos exposure
For a time, mesothelioma was thought to be exclusively related to asbestos, but more recent reviews indicate that a significant number of cases have occurred in the absence of any known asbestos exposure.
Although the association between amphibole asbestos and mesothelioma is indisputable, fewer than 10% of the people exposed to asbestos develop mesothelioma, and fiarly large proportions (up to 50% according to some authors) of the reported cases have no documented exposure to asbestos.
A comprehensive survey of adult mesothelioma cases in Canada and the U.S. carefully classified patients based on their likelihood of past exposure to asbestos. The researchers found that asbestos exposure had been unlikely in between 1/4 and 1/3 of cases (McDonald & McDonald, 1980).
While it is well documented that asbestos-induced mesothelioma has a latency of 20 years or more, a number of studies have highlighted pleural and pericardial mesotheliomas in children as young as 1-1/2 years old (Lemesch et al., 1976). Surveys of reported mesotheliomas in the U.S., Canada and Israel found a combined total of more than 110 cases in persons under the age of 20.
In addition to these unexplained cases of mesothelioma, a number of other fibrous and non-fibrous materials have been associated with mesothelioma induction. It is now generally accepted in the scientific community that durable, long and thin fibres have fibrogenic and carcinogenic potential. A number of natural and man-made fibres with these characteristics have been established as the cause of mesothelioma in laboratory animals. These include glass fibres, aluminum oxide, attapulgite, dawsonite, silicon carbide and potassium titanate (Stanton et al., 1977).
The reported outbreak of mesothelioma in rural Turkey has been associated with exposure to fibrous zeolite found in these regions. In his 1980 report, Baris had identified 185 cases of erionite/zeolite-related mesothelioma in two areas of Turkey with no local asbestos deposits or industry.
Several non-fibrous agents, both organic and inorganic, have also been shown to induce malignant mesothelioma. For example, a causal link between mesothelioma and radiation has been established based on numerous case reports of mesotheliomas developing at the exact sites of radiation therapy. Other suspected causes include biogenic silica fibres, chronic irritation stemming from tuberculosis and other factors, and heavy metals such as beryllium.
Polio vaccines and the SV40 virus
More recently, it has been reported that a virus (SV40) contaminating some polio vaccine preparations may well be associated with mesothelioma, as some DNA sequences of the virus are sometimes found in cancerous mesothelial cells. These vaccine preparations had been produced in 1954, some eight years before SV40 was first isolated, and had been prepared by growing polio virus in cell cultures from rhesus monkey kidney cells. As a result, millions of people have been injected with SV40-contaminated polio vaccines.
Recent findings by Dr. M. Carbone and colleagues of the Dept. of Pathology at the University of Chicago and by co-workers at the National Cancer Institute first indicated that the SV40 virus, which induces mesothelioma in hamsters, is also oncogenic for humans. Later on, they found SV40-like DNA sequences in human mesothelioma cases (Carbone et al., 1994). Similar evidence is now beginning to appear from France and the U.K.
Recent evidence of the significance of the SV40 virus and other potential sources of mesothelioma, suggests that factors other than asbestos exposure may have played a role in recently reported mesothelioma cases in Europe in which the victims are reported to have had only casual, low level contact with asbestos-containing products.
Baris YI, Artvinli M and Sahin AA. Environmental mesothelioma in Turkey. Ann. NY. Acad. Sci., 1979; 330:423-432.
Carbone et al.. Oncogene, 1994; 9:1781-1790.
Lemesch C, Steinitz R and Wassermann M. Edipemiology of mesothelioma in Israel. Environ. Res., 1976; 12:255-261.
Pelnar PV. Non-asbestos related malignant mesothelioma. Canadian Asbestos Information Centre, 1983.
Stanton MF and Wrench C. Mechanisms of mesothelioma induction with asbestos and fibrous glass. J. Natl. Cancer Inst., 1972 (March); 48(3):797-821.
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