Non-Asbestos-Related Causes of Mesothelioma

A new academic review, published in the Archives of Pathology and Laboratory Medicine (APLM), has identified evidence in support of non-asbestos-related causes of mesothelioma.[i] Though it is well-known that many mesothelioma cases are due to the latent effects of asbestos exposure, it is also clear that not all mesothelioma is related to asbestos. In this feature article, we consider whether exposure to alternative substances, listed in the review, are also valid causes of mesothelioma.

ASBESTOS-INDUCED MESOTHELIOMA

Currently, most cases of pleural mesothelioma (70% to 90%) in European and North American men are attributable to asbestos exposure. The proportion is lower for peritoneal mesothelioma. In women, the proportion of asbestos-related mesothelioma varies geographically; in North America, few cases are attributable to asbestos. In Europe, the proportion is higher, and varies considerably by location.

Knowledge of asbestos-related diseases, such as mesothelioma, grew throughout the 20th century. Asbestos prohibition laws were first introduced in the UK in the 1980’s. Indeed, in 1985, the Government banned the importation and use of blue (crocidolite) and brown (amosite) asbestos. In 1992, this ban was extended to include specific use of white (chrysotile) asbestos, which were subsequently extended in the Asbestos (Prohibitions) (Amendment) Regulations 1999, one month after the EU banned chrysotile.[ii]

The UK’s Control of Asbestos Regulations Act 2006 (as amended in 2012) combined all previously existing legislation (the Control of Asbestos at Work Regulations 2002, the Asbestos (Licensing) Regulations 1983 and the Asbestos (Prohibitions) Regulations 1992) into one single Act, prohibiting the use, supply and importation of all asbestos. However, the Law still allows for existing asbestos to remain intact if it is in good condition and is undisturbed.

As knowledge of alternative mesothelioma causes develops, such as those highlighted in the review, law making bodies may have to strengthen regulations to align with emerging exposure risks.

MESOTHELIOMA-CAUSING MINERAL FIBRES?

In certain locations, mineral fibres, such as erionite, fluoroedenite, and possibly balangeroite, may cause mesothelioma.

Erionite

Erionite is a mineral with physical properties similar to amosite and crocidolite. It is found in volcanic regions associated with rhyolitic tuffs, such as parts of Turkey, Italy and the United States.  In North Dakota, hundreds of miles of roads were surfaced with gravel that contained erionite, leading to high airborne concentrations of the mineral.  An outbreak of mesothelioma in two villages in Turkey was studied, and was found to be the result of exposure to erionite fibres used in the whitewash on the walls of houses.  Some asbestos has also been found in the region.  It was determined that more than 50% of mesothelioma cases in the villages were caused by erionite, and some researchers have suggested that the families involved could have a genetic predisposition to fibre-induced cancers.  However, other authors have challenged this view.  In the United States, a high incidence of mesothelioma has been identified in rural areas with erionite contamination, and there have been several cases of Mexican-born residents of the United States diagnosed with mesothelioma. Considerable quantities of erionite fibres were found in lung tissue.  Studies in experimental animals have also demonstrated increased risk of mesothelioma with erionite exposure.

Source: Erionite (Wikipedia)

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Fluoro-Edenite

Fluoro-edenite has similar properties to lesser-used asbestos amphiboles, actinolite and tremolite. The mineral has been found in Sicily, and has been used in road paving and plaster and mortar construction of residential and commercial buildings.  A study has found a 10-fold increase in pleural neoplasms in those who are exposed, while pleural plaques have also been reported.

Source: Fluoro-edenite (E-Rocks)

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Balangeroite

Balangeroite is a mineral that has some similar physical properties to amphibole asbestos fibres.[iii]  It is found as a contaminant in chrysotile, mined in Balangero, Italy.  Some authors have attributed mesothelioma cases in this area to balangeroite. Others have questioned its toxicity.  Crocidolite and amosite have also been found in lung tissues in Balangero mining workers, the source of which is likely to be South African amphiboles that were occasionally milled at Balangero.  Since these workers were exposed to chrysotile, amphibole asbestos and balangeroite, it is difficult to determine the contributions of each separate mineral to mesothelioma cases.

Source: Balangeroite (Mineral-Forum)

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MESOTHELIOMA-CAUSING MAN-MADE FIBRES?

A variety of man-made fibres, such as rock wool, slag wool, glass fibre and glass filament have been studied to evaluate whether they have the potential to induce mesothelioma in humans. Systematic reviews have found little evidence of any toxic effects.  There have been anecdotal case reports of metals, beryllium and nickel, and crystalline silica, found in sugar cane, causing mesothelioma. However, this is insufficient to claim that there is an association.

MESOTHELIOMA-CAUSING RADIATION?

Radiation is a known cause of cancer. There are three different types of radiation exposure that have been linked with mesothelioma: radiation received as treatment for a previous cancer; use of the medical imaging medium, ‘Thorotrast’ (thorium dioxide); and work in the nuclear energy industry.

Radiation treatment for previous abdominal cancers, such as Hodgkin and non-Hodgkin lymphoma, Wilms tumour of the kidney and breast cancer, are associated with mesothelioma. The latent period has been shown to be between 5 and more than 50 years.

The radioactive material, Thorotrast, was used in X-ray imaging until the 1950s. It has been implicated in causing a range of tumours, including pleural and peritoneal mesothelioma.  Thorotrast decays slowly in the body after it is administered, and emits radiation for the duration of its presence in the body.

A link between mesothelioma and work in the nuclear energy industry has also been suggested. British Atomic Energy workers, employed between 1946 and 1990, and workers at the Idaho National Engineering and Environmental Laboratory, have been found to be at increased risk of mesothelioma.

MESOTHELIOMA-CAUSING INFLAMMATION?

It has also been suggested that chronic pleural and peritoneal inflammation may be a cause of mesothelioma. There have been anecdotal reports of pleural mesothelioma following conditions, such as tuberculosis and emphysema, and of peritoneal mesothelioma in patients with disorders such as Chron’s Disease.

MESOTHELIOMA-CAUSING VIRUSES?

The SV40 virus has been suspected as a cause of mesothelioma, as there have been positive findings in animal experiments. However, the epidemiological evidence suggests that there is no causative role in humans.

Source: SV40 Virus (Wikipedia)

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Simian virus 40 (SV40) is a virus that commonly infects Asian macaque monkeys. In normal monkeys, the infection is usually symptomless, but it can have different effects on other species.  Tumour-causing effects have been reported in cell and animal studies.

Human exposure to SV40 is believed to occur as a result of polio vaccinations, prepared from infected monkey cells. The authors estimate that between 1954 and 1963, hundreds of millions of people may have been infected in the Soviet bloc, China, Japan and several countries in Africa. That means hundreds of millions could have been exposed to SV40 after 1963.

In 2004, the US Food and Drug Administration (FDA) was a defendant in lawsuits alleging that the SV40-contaminated polio vaccine used in the US has caused cancer.[iv]

In spite of cell and animal study evidence, researchers of the review are uncertain as to whether SV40 causes mesothelioma in humans, because SV40 it is difficult to detect. As such, the proportion of mesothelioma patients infected with SV40 is largely unknown and even if evidence of SV40 infection is detected in a mesothelioma patient, this does not mean that the virus is causative of mesothelioma.

MESOTHELIOMA CAUSED BY GENETICS?

There is also some evidence that genetics may play a role in mesothelioma development. There has been much recent interest in the role of the gene known as BAP-1 (BRCA1-associated protein-1).  This gene produces a protein that is believed to function as a tumour suppressor, and it has been suggested that a mutation in this gene may be associated with mesothelioma onset. Mutations that may lead to increased susceptibility to cancer are hereditary.

Some sources claim that the mutation is found in an estimated 70% of mesothelioma cases.[v] However, the review submits that studies of mesothelioma patients have shown only a small proportion to have such a mutation. In spite of this, experiments in mice have found that these genetic mutations may make individuals with low level exposure to asbestos more susceptible to mesothelioma, inferring an interaction between genetics and asbestos exposure.  Other studies have found that the mutation itself is enough to increase the risk of mesothelioma alone, i.e. without exposure to asbestos. 

The reviewers are aware of only one study in humans in which the link between genetics and asbestos exposure has been investigated. In this instance, BAP-1 mutations were found in 9 of 150 patients with mesothelioma and a family history of cancer. Meanwhile, BAP-1 mutations were found in no patients, in a group with history of asbestos exposure but no family history of cancer.  However, this study classified asbestos exposure as either exposed or not exposed. Unfortunately, when it is clear that factors, such as fibre type and exposure duration can have significant effects on the risk of mesothelioma, this study was insufficient to determine differences between the two groups of participants.

Although there are complex proprietary issues on the ‘right to control the use and disclosure of … genetic information’, it is possible that the BAP-1 gene could be adduced as a defense to liability in EL claims. Ortwein v Certainteed Corporation was the 1st case to rule on this. The claimant was a 50 year old woman suffering with pleural mesothelioma. At the California Superior Court, Judge Jo-Lynne Lee granted the defendant’s motion to compel production of the claimant’s lung tissue samples for genetic testing.[vi]

MESOTHELIOMA-CAUSING NANOTUBES?

More recently, carbon nanotubes have emerged as a potentially new and emerging cause of mesothelioma.

Carbon nanotubes are long, thin tubes that have a wide range of applications. Concerns have been expressed about its physical similarities with asbestos fibres.  Though the findings from such studies do not necessarily indicate risks in humans, cell studies have shown toxic effects and rodent studies have shown development of mesotheliomas resulting from carbon nanotube exposure.  In issue 208 of BCDN (here), we reported on a study in mice, in which 10% to 25% of test subjects exposed to carbon nanotubes developed mesothelioma. Then, in issue 221 (here), we reported that a small study had found cardiovascular effects in exposed humans. Some studies have found that carbon nanotube fibres may lead to inflammation, and that the length of the fibres correlates with inflammation.

Source: Carbon Nanotubes (Extreme Tech)

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At this stage, there is little epidemiological information associating carbon nanotubes with mesothelioma. When mesothelioma has been the result of asbestos exposure, exposure occurred many years earlier. Quite simply, humans are yet to be exposed to carbon nanotubes for a long enough period of time. If carbon nanotubes can cause mesothelioma in humans, it is unlikely that significant epidemiological evidence will be available for several decades. At that point, it is assumed that latency periods will have begun to elapse. In the meantime, studies of carbon nanotubes in animals and studies into other adverse health effects in humans must be monitored carefully to understand the full extent of risks posed by nanotubes.

MESOTHELIOMA WITHOUT CAUSE?

The latest review reports that all of the etiologies discussed in the above sections account for a small proportion of mesothelioma cases, and, after excluding tumours caused by asbestos exposure, spontaneous onset of mesothelioma is the most common cause. Evidence in support of a ‘background’ rate of spontaneous mesothelioma includes:

  • Lack of changes in the number of cases in women with time and commercial use of asbestos in the USA;
  • The occurrence of mesothelioma in children too young to have undergone a latency period typical of asbestos exposure;
  • Cases of mesothelioma in persons with no history of asbestos exposure, despite extensive investigation; and
  • The spontaneous occurrence of various tumours, including malignant mesothelioma, in laboratory animals.

The review includes a table, which collates the proportions of mesotheliomas attributable to asbestos, recorded in each study. Different studies report different figures, due to varying study designs, different patient selection schemes, different views of which occupations entail significant asbestos exposure, and differences in the historic use of amphiboles and chrysotile in different countries. It can, however, be seen from the table that:

  1. there is a definite fraction of mesotheliomas that have no identifiable cause;
  2. this fraction is greater in women than in men (because more men had occupational asbestos); and
  3. the fraction is greater in peritoneal than pleural mesothelioma.

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In edition 213 of BC Disease News (here), we reported on an Italian study, which found that 38% and 13% of female and male cases of pleural mesothelioma, respectively, were the result of ‘unknown’ or ‘not probable’ asbestos causes. The same was observed in 47% of females and 21% of males with peritoneal mesothelioma. The observations in the table above are consistent with the findings in the Italian study.

Consideration of age, sex and site of mesothelioma provides further evidence that mesotheliomas can arise without asbestos exposure. Recent analysis of mesotheliomas diagnosed between 2003 and 2008, in the USA, showed that male rates are declining as female rates remain unchanged.  During this 5 year period, mesothelioma was more common in women than men below 45 years of age, of which 51% of cases were peritoneal. These findings suggest that there is a background of cases that are not caused by asbestos.  In addition, recently updated trend analysis shows that the incidence of peritoneal mesotheliomas among both males and females has little or no association with commercial trends in asbestos use in the USA.

CONCLUSION

Overall, the proportion of mesothelioma cases attributable to asbestos varies according to sex, anatomic location, fibre type, occupation and industry. The APLM-published report concludes that the alternative causes of mesothelioma account for only a small proportion of cases, and that most cases not clearly attributable to asbestos are spontaneous, or the result of no particular cause. More research is needed to prove that the factors discussed are causative of mesothelioma if successful claims are to be brought, either in respect of public exposure, or workplace exposure.

 

[i] Attanoos, R. L., Churg, A., Galateau-Salle, F., Gibbs, A. R. & Roggli, V. L. Malignant Mesothelioma and Its Non-Asbestos Causes. Arch. Pathol. Lab. Med. (2018). doi:10.5858/arpa.2017-0365-RA <http://www.archivesofpathology.org/doi/pdf/10.5858/arpa.2017-0365-RA?code=coap-site> (Accessed 26 April 2018)

[ii] Matt Mauney, ‘Mesothelioma in the UK’ (28 September 2017 Asbestos.com) <https://www.asbestos.com/mesothelioma/uk/> accessed 3 May 2018.

[iii] Andy Darnton, ‘HSE ASSESSMENT OF RECENTLY UPDATED INFORMATION

RELATING TO COHORTS WITH CHRYSOTILE EXPOSURE’ (October 2010 HSE) <http://www.hse.gov.uk/aboutus/meetings/iacs/acts/watch/271010/watch-october-2010-additional-chrysotile-exposure.pdf> accessed 3 May 2018.

[iv]  Debbie Bookchin, ‘Vaccine scandal revives cancer fear’ (7 July 2004 New Scientist) <https://www.newscientist.com/article/dn6116-vaccine-scandal-revives-cancer-fear/> accessed 3 May 2018.

[v] Tim Povtak, ‘BAP1 Mesothelioma Mutation Focus of Upcoming Clinical Trial’ (5 July 2017 Asbestos.com) <https://www.asbestos.com/news/2017/07/05/bap1-mesothelioma-mutation-clinical-trial/> accessed 3 May 2018.

[vi] ‘Genetic Mutation Defense in Asbestos Cases’ (Pitzer Snodgrass) <https://www.pspclaw.com/genetic-mutation-defense-in-asbestos-cases/> accessed 3 May 2018.