**2. Epidemiology and aetiological factors**

#### **2.1. The history of asbestos and mesothelioma**

Following the earliest descriptions of mesothelioma, it remained an exceptionally rare malignancy until after industrialisation. For a long time, primary pleural malignancies were so rare that their very existence was disputed [1]. In the early 1950s, a number of reports noted small clusters of MPM but it was not until the late 1950s in South Africa when Kit Sleggs noted that patients with tuberculous pleurisy from the east of Kimberly were recovering with streptomycin and isoniazid, but a number of patients apparently with the same disease from

the west of Kimberly continued to die. The pathologist Christopher Wagner observed that these patients had in fact a rare cancer of the pleura but yet without any other primary tumours, leading to the conclusion they had primary mesothelioma. In the same period, there were no mesotheliomas observed amongst 10,000 lungs examined from other areas of South Africa. This begged the question of why they were diagnosing so many of these rare tumours in west Kimberly. Wagner observed asbestos bodies in the lung beneath the tumour and surmised their association with mesothelioma, from that moment on the link was made [2]. His publi‐ cation "Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province" became the most cited paper in industrial medicine. This started a lifelong investi‐ gation into the association of MPM with asbestos [3].

has not been possible to determine a threshold level below which exposure could be deemed

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As of August 2012, 54 countries have banned the use of all types of asbestos [13]. For the rest of the countries, nearly all of the asbestos mined and consumed today is chrysotile asbestos. Developing countries are the highest consumers of asbestos, with China topping the list. With its rapid growth, China's production could not keep pace with its insatiable domestic appetite and needs to import a quarter of its asbestos. Russia, the world's largest producer with re‐ serves that will last over a century, exports most of its asbestos [14]. Whilst the European Union andUnitedStateshavecompletebansonasbestos,Canadacontinues tominechrysotileasbestos and is the fifth largest exporter of chrysotile to developing countries. This is in spite of severe restrictions on its domestic use. Although international agencies have long condemned the use of asbestos, it has been difficult to come to an agreement for an international ban. In June 2011, Canada for a third time objected to the inclusion of chrysotile asbestos under Annex III of the

Thecarcinogenicityoftheamphibolesisnowindisputable,butforchrysotilethishasbeenfiercely debated. Most of the asbestos mined and utilised today is chrysotile, on the belief that this fibre is safe. This assumption is based on studies showing lesser biopersistence of the fibres, which is likely the result of the fibre's fragility, leading to fragmentation and quicker clearance from the lungs. Epidemiological studies which suggest chrysotile causes mesothelioma were dis‐ missed by blaming contamination by amphiboles – the so-called 'Amphibole hypothesis' [15]. The experimental methodologies behind these studies have been questioned [16] [17] and it has become clear that even though chrysotile may be less potent at inducing mesothelioma, the

An epidemic of malignant mesothelioma unfolded in 3 villages in Cappadocia, Turkey in the 1980's accounting for an unprecedented 50% of deaths in the region. In comparison to unaffected neighbouring villages, villages with mesothelioma also had high levels of airborne erionite, a fibrous zeolite with some similarities to asbestos [20]. Certainly, in animal models erionite is a very potent inducer of mesothelioma [21]. However, the incidence of mesothelioma in a nearby village with similar erionite levels was significantly lower, implicating other factors at play. Lineage studies have since incriminated an autosomal dominant transmission of susceptibility to fibre carcinogenesis to explain the disparity [22], but exposure to erionite itself

Whilst erionite is also present in other parts of the world, mesothelioma directly attributable to erionite is still very rare [24]. Nevertheless, with a long latency period over three decades, the possibility of a future epidemic in erionite-rich areas, such as parts of America, is a concern [25].

heightened risks of asbestosis, lung cancer and death is still a glaring reality [18, 19].

safe [12] and this has important implications for legislation.

Rotterdam Convention.

**2.2. The chrysotile controversy**

**2.3. Other implicated aetiological factors**

remains the dominant driver of carcinogenesis [23].

*2.3.1. Erionite and genetic susceptibility*

Asbestos is a family of long, thin, fibrinous, hydrated magnesium-silicate crystals. The first record of its human use is from over 5,000 years ago, and Persians were known to make cloth with it that could be cleansed by throwing it into the fire [4]. They are classified according to their morphology into the straight and rod-like amphiboles, and the curly serpentines fibres. The amphiboles, which include crocidolite, amosite and tremolite, are strongly associated with the development of mesothelioma. The serpentine fibre chrysotile, believed to be less carci‐ nogenic by some and non-carcinogenic by others, continues to be mined and sold in Canada to this day. The carcinogenicity of different asbestos preparations is also related to the fibre dimensions, with long, thin fibres being most strongly carcinogenic [5].

Asbestos is a versatile material valued for being weavable, resistant to heat, electricity and chemicals, being readily available and cheap. It is used in the building and construction, machinery, shipbuilding and transport industries, hence asbestos-related diseases including mesothelioma are mainly industrial work-related and therefore more common in males. The main cohorts with exposure are *occupational* - those working directly with the mining and preparation of asbestos (eg. mixing asbestos cement, cutting sheets, lagging) and end-users of asbestos such as builders, plumbers and shipyard workers, *paraoccupational* - in people living with people working with asbestos and *environmental* - from exposure to naturally occurring asbestos.

The background incidence of mesothelioma is approximately 1 per million, rising to 7 per million in Japan, 12 per million in the United States, 33 per million in the United Kingdom and 40 per million in Australia in a pattern consistent with the distribution of asbestos exposure. In Wittenoon, Western Australia where crocidolite was mined in the 1930s, follow-up records of 6,493 employees found MPM caused 3.4% deaths in exposed male workers [6]. The predicted peak incidence is expected to occur between 2005 and 2025 in countries which banned its use [7]. It is more common in males, and with a latency period between three and four decades [8], the median age at diagnosis is in the sixth and seventh decades, although there are instances when it can present in the second decade, often with a history of perinatal exposure.

There is an exposure dose-response relationship between asbestos and mesothelioma, both in terms of historic exposure (duration and episodes) and lung asbestos fibre content [9], [10] [11]. The risk is highest with crocidolite and amosite, and less with chrysotile. However, there is a background rate of mesothelioma, and virtually all mankind has been exposed to asbestos at some point – fibres have been found in the lungs of the general population. Because of this, it has not been possible to determine a threshold level below which exposure could be deemed safe [12] and this has important implications for legislation.

As of August 2012, 54 countries have banned the use of all types of asbestos [13]. For the rest of the countries, nearly all of the asbestos mined and consumed today is chrysotile asbestos. Developing countries are the highest consumers of asbestos, with China topping the list. With its rapid growth, China's production could not keep pace with its insatiable domestic appetite and needs to import a quarter of its asbestos. Russia, the world's largest producer with re‐ serves that will last over a century, exports most of its asbestos [14]. Whilst the European Union andUnitedStateshavecompletebansonasbestos,Canadacontinues tominechrysotileasbestos and is the fifth largest exporter of chrysotile to developing countries. This is in spite of severe restrictions on its domestic use. Although international agencies have long condemned the use of asbestos, it has been difficult to come to an agreement for an international ban. In June 2011, Canada for a third time objected to the inclusion of chrysotile asbestos under Annex III of the Rotterdam Convention.

#### **2.2. The chrysotile controversy**

the west of Kimberly continued to die. The pathologist Christopher Wagner observed that these patients had in fact a rare cancer of the pleura but yet without any other primary tumours, leading to the conclusion they had primary mesothelioma. In the same period, there were no mesotheliomas observed amongst 10,000 lungs examined from other areas of South Africa. This begged the question of why they were diagnosing so many of these rare tumours in west Kimberly. Wagner observed asbestos bodies in the lung beneath the tumour and surmised their association with mesothelioma, from that moment on the link was made [2]. His publi‐ cation "Diffuse pleural mesothelioma and asbestos exposure in the North Western Cape Province" became the most cited paper in industrial medicine. This started a lifelong investi‐

Asbestos is a family of long, thin, fibrinous, hydrated magnesium-silicate crystals. The first record of its human use is from over 5,000 years ago, and Persians were known to make cloth with it that could be cleansed by throwing it into the fire [4]. They are classified according to their morphology into the straight and rod-like amphiboles, and the curly serpentines fibres. The amphiboles, which include crocidolite, amosite and tremolite, are strongly associated with the development of mesothelioma. The serpentine fibre chrysotile, believed to be less carci‐ nogenic by some and non-carcinogenic by others, continues to be mined and sold in Canada to this day. The carcinogenicity of different asbestos preparations is also related to the fibre

Asbestos is a versatile material valued for being weavable, resistant to heat, electricity and chemicals, being readily available and cheap. It is used in the building and construction, machinery, shipbuilding and transport industries, hence asbestos-related diseases including mesothelioma are mainly industrial work-related and therefore more common in males. The main cohorts with exposure are *occupational* - those working directly with the mining and preparation of asbestos (eg. mixing asbestos cement, cutting sheets, lagging) and end-users of asbestos such as builders, plumbers and shipyard workers, *paraoccupational* - in people living with people working with asbestos and *environmental* - from exposure to naturally occurring

The background incidence of mesothelioma is approximately 1 per million, rising to 7 per million in Japan, 12 per million in the United States, 33 per million in the United Kingdom and 40 per million in Australia in a pattern consistent with the distribution of asbestos exposure. In Wittenoon, Western Australia where crocidolite was mined in the 1930s, follow-up records of 6,493 employees found MPM caused 3.4% deaths in exposed male workers [6]. The predicted peak incidence is expected to occur between 2005 and 2025 in countries which banned its use [7]. It is more common in males, and with a latency period between three and four decades [8], the median age at diagnosis is in the sixth and seventh decades, although there are instances

when it can present in the second decade, often with a history of perinatal exposure.

There is an exposure dose-response relationship between asbestos and mesothelioma, both in terms of historic exposure (duration and episodes) and lung asbestos fibre content [9], [10] [11]. The risk is highest with crocidolite and amosite, and less with chrysotile. However, there is a background rate of mesothelioma, and virtually all mankind has been exposed to asbestos at some point – fibres have been found in the lungs of the general population. Because of this, it

gation into the association of MPM with asbestos [3].

130 Principles and Practice of Cardiothoracic Surgery

asbestos.

dimensions, with long, thin fibres being most strongly carcinogenic [5].

Thecarcinogenicityoftheamphibolesisnowindisputable,butforchrysotilethishasbeenfiercely debated. Most of the asbestos mined and utilised today is chrysotile, on the belief that this fibre is safe. This assumption is based on studies showing lesser biopersistence of the fibres, which is likely the result of the fibre's fragility, leading to fragmentation and quicker clearance from the lungs. Epidemiological studies which suggest chrysotile causes mesothelioma were dis‐ missed by blaming contamination by amphiboles – the so-called 'Amphibole hypothesis' [15]. The experimental methodologies behind these studies have been questioned [16] [17] and it has become clear that even though chrysotile may be less potent at inducing mesothelioma, the heightened risks of asbestosis, lung cancer and death is still a glaring reality [18, 19].

#### **2.3. Other implicated aetiological factors**

#### *2.3.1. Erionite and genetic susceptibility*

An epidemic of malignant mesothelioma unfolded in 3 villages in Cappadocia, Turkey in the 1980's accounting for an unprecedented 50% of deaths in the region. In comparison to unaffected neighbouring villages, villages with mesothelioma also had high levels of airborne erionite, a fibrous zeolite with some similarities to asbestos [20]. Certainly, in animal models erionite is a very potent inducer of mesothelioma [21]. However, the incidence of mesothelioma in a nearby village with similar erionite levels was significantly lower, implicating other factors at play. Lineage studies have since incriminated an autosomal dominant transmission of susceptibility to fibre carcinogenesis to explain the disparity [22], but exposure to erionite itself remains the dominant driver of carcinogenesis [23].

Whilst erionite is also present in other parts of the world, mesothelioma directly attributable to erionite is still very rare [24]. Nevertheless, with a long latency period over three decades, the possibility of a future epidemic in erionite-rich areas, such as parts of America, is a concern [25].

### *2.3.2. SV40*

SV40 is a polyoma virus which has long been studied as a carcinogen. The concerns over SV40 arose from the widespread administration of SV40-contaminated polio vaccines which were distributed worldwide in the 1960's. Certainly in the laboratory, SV40 virus has the ability to transform human cells and induce mesothelioma in experimental animals both directly, and as a co-carcinogen acting synergistically with asbestos [26] [27]. However, its relevance to clinical mesothelioma is less clear and the evidence is largely circumstantial. SV40 DNA fragments have been identified in 40 to 60% of mesothelioma samples [28] [29], but the copy numbers were exceedingly low (less than one per cell) [29]. Furthermore, there is no current treatment for SV40 infection.

fibres become deposited and transported to the parietal pleura, they are progressively taken up by macrophages. However, because of their sheer size and biopersistence, they could not be cleared effectively, markedly lengthening their dwell time at the mesothelium compared to other particulates. Furthermore, macrophages are unable to engulf the entirety of these large fibres. Such frustrated phagocytosis is a potent stimulation of the macrophage's inflammatory response which results in respiratory bursts and secretion of toxic metabolites such as reactive oxygen species, growth factors and cytokines. The asbestos fibres have also themselves been implicated in carcinogenesis through direct interference with the mitotic apparatus, and direct generation of free radicals through its interaction with mobilisable iron on the fibre surface [36]. Over a long period of time, it could be envisaged the unrelenting exposure to these

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A central player which promotes mesothelial transformation is believed to be tumour necrosis factor-alpha (TNF-α). Asbestos stimulates both macrophages and human mesothelial cells to express TNF-α. TNF-α has been shown to promote mesothelial cell survival in the face of asbestos exposure *in vitro*, and the effect appears to be mediated through Nuclear Factor Kappa-light-chain-enhancer of Activated B Cells (NF-κB) [35]. NF-κB activation results in release of a p16 subunit which translocates to the nucleus to induce expression of antiapoptotic genes. Meanwhile, activated macrophages also secrete a host of other cytokines and growth factors including interleukins, vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF), as well as reactive oxygen and nitrogen species which directly causes DNA and chromosomal damage. Together, this sustained insult of mutagens and growth

Whilst most cancers have inactivation of the p53 and pRb tumour suppressor genes, mutation of these genes in mesothelioma is surprisingly rare [37] [38]. In contrast, over 70% of meso‐ theliomas have deletions of 9p21 and about 40% mesothelioma have loss of heterozygosity at the 22q12 locus [39] [40] [41] [42] [43]. 9p21 contains the INKa/ARF locus which encodes two proteins p16INK4a and p14ARF alternatively spliced from the same mRNA. Functionally, p14ARF stabilises p53 whilst p16INK4a inhibits the inactivation of pRb, thereby restricting progression through the cell cycle G1 checkpoint. Thus, mutations in the INKa/ARF locus effectively lead to loss of both tumour suppressor pathways. Positional cloning also identified the neurofibromatosis NF2 gene within the 22q12 locus, which encodes for the protein merlin. Merlin integrates signals from various adhesion molecules and cytoskeletal components and promotes cell adhesion, establishes apical polarity and mediates contact inhibition. It also has

The precise mechanism of NF2 tumour suppression remains unclear [44] but it is likely to have a salient role. Whilst only 40% mesothelioma have truncations of NF2 or merlin, in the remaining cases, merlin is functionally inactivated through increased phosphorylation at Ser518 [45] and changes in microRNA expression [46]. Simultaneous loss of both INKa/ARF and NF2 appears to be important in the pathogenesis of mesothelioma. In experimental models of asbestos-induced mesothelioma, loss of the remaining NF2 allele is accompanied by the

stimulators causes the first genetic alterations behind malignant mesothelioma.

the capacity to migrate to the nucleus to modulate gene expression.

mutagens and growth signals could drive neoplastic transformation.

**3.2. Molecular pathogenesis**

#### *2.3.3. Irradiation*

Irradiation causes cancer and mesothelioma is no exception, Thorotrast is an alpha-emitting thorium dioxide radiocontrast used between 1930s and 1950s. It has a physical half-life of 1010 years and a biological half-life of several hundred years, and so it is retained lifelong, constantly exposing tissue including mesothelium to irradiation. Thorotrast is associated with many malignancies including mesothelioma [30]. Patients with lymphoma who underwent mantle radiotherapy represent another cohort with irradiation to the pleura. They also have a higher risk of mesothelioma compared to population with similar levels of asbestos exposure [31] [32].
