1. Asbestos: Consumption, Exposure, and Ban
Asbestos is a natural mineral, which in all its mineralogical varieties has fibrous morphology (actinolite, amosite, anthophillite, chrysotile, crocidolite, and tremolite). It has been used all over the world and also in Italy, and its use dates back to the time of the ancient Persians, Greeks, and Romans. It is characterized by high resistance to heat, as well as chemical and biological agents, abrasion, and wear. Asbestos is an environmental carcinogen, asbestos fibers, when mechanically disturbed, divide longitudinally, generating even thinner fibers (fibrils), which, when inhaled, may be responsible for fibrotic (asbestosis) or neoplastic processes (mesothelioma, lung cancer).
The two historical epidemiological studies that established with certainty the causal role of asbestos in the onset of pulmonary carcinoma and pleural mesothelioma were, respectively, Doll’s 1955 [1
] and Wagner’s and collaborators in 1960 [2
In 1964, the world conference on the biological effects of asbestos was held, organized by the New York Academy of Sciences, whose proceedings were published in 1965, the year in which the scientific community reached unanimous agreement on the carcinogenic action of this material [3
In 1973, the International Agency for Research on Cancer (IARC) classified asbestos (all types: actinolite, amosite, anthophyllite, crocidolite, tremolite, and chrysotile) as certain carcinogens for humans [4
]. In a 2012 IARC monograph, [5
] asbestos was confirmed as the only certain risk factor for mesothelioma in a series of target organs including the pleura, the peritoneum, the pericardium, and the vaginal tunic of the testicle. The monograph confirms asbestos as a certain carcinogen for lung cancer, and for the first time it defines asbestos as a certain carcinogen for laryngeal and ovarian cancer. It also assesses that the scientific evidence is limited for association between asbestos and tumors of the pharynx, stomach, and colon. Because of the close correlation between asbestos consumption and mortality from related asbestos pathologies, an analysis of the distribution in time and space of asbestos consumption is of great importance for epidemiological analysis [6
]. Marinaccio et al. 2005, analyzed the per capita consumption of asbestos in different countries of the world demonstrating how the mortality curve for mesothelioma significantly reflects the consumption trend after a long latency period [7
The increase in world production levels is constant from the second postwar period to the mid-seventies, a period in which it reached its peak with more than 4.5 million tons/year produced. The total world production of asbestos in the last century reached 173 million tons, of which more than 80% was after 1960, with an annual production (in 2000) of 2,130,000 tons [8
]. The asbestos industry continued to extract (2013) about 2 million tons per year, producing "clean" and controlled productions in Europe, "dirty" in other countries. The problem has been moved from Europe to Ukraine, Russia, India, Egypt, Thailand, China, and Brazil, where workers continue to empty their bags by hand without ventilation systems and without protection. The largest producers, up until 2013, were Russia (700,000 tons), China (450,000 tons), Canada (335,000 tons, of which 98% are exported), Kazakhstan (180,000 tons), Brazil (170,000 tons), Zimbabwe (130,000 tons), Greece (35,000 tons), United States (7,000 tons), and Bulgaria (7,000 tons) [9
]. More recent data are reported from the Asbestos Ban Secretariat (2019) related to 2015 (Table 1
In the United States, approximately 340 tons of asbestos was imported in 2016 [10
]. Italy has the distinction of having had the first mine opened on its territory "for commercial purposes" in 1870; therefore, it was the only country in the European Union, together with Greece, where asbestos mines were active. So, it is a country that is both an importer and a producer. Until the end of the 1980s, Italy was the second largest European fiber asbestos producer after the Soviet Union and the largest in the European community. The Italian production comes almost exclusively (if modest quantities are excluded from the Val Malenco fields) from the Balangero chrysotile mine (20 km north of Turin), the most important field in terms of size and plant in Western Europe. In Italy, from the postwar period (1946) to the 1992 announcement, 3,748,550 tons of raw asbestos (over 160,000 tons/year in the period 1976–1980) was produced, and 1,900,885 tons of raw asbestos was imported from Australia, Canada, and South Africa [11
]. Raw asbestos imports remained above 50,000 tons/year until 1991. The use of asbestos in Italy in the last century has grown to around 220,000–240,000 tons/year, reached in the second half of the 1970s. In the 1980s, use gradually decreased, although later and more slowly than in other European countries, until the ban in 1992.
Asbestos is still used in developing countries and in some countries of the European Union, despite the directive 2003/18/CE of the European Parliament and of the Council of 27 March 2003 provides for the obligation to completely stop the use by 15 April 2006. The Italian law n. 257 of 27 March 1992 declared the "cessation of the use of asbestos", and in particular the ban on the extraction, import, export, marketing, and production of asbestos products and products containing asbestos.
However, the law did not prohibit indirect use, and, therefore, several million tons of compact materials containing asbestos and many tons of friable asbestos are still present in many contaminated sites, both industrial and nonindustrial, public, and private, throughout the Italian territory. In Italy the raw asbestos produced or imported, taking advantage of its remarkable material insulating properties and low cost, has been used in a wide range of industrial activities: in the sectors of industrial production of asbestos-cement manufactured articles, textile manufactures containing asbestos, shipbuilding, repair and demolition of railway rolling stock, construction, and in many other sectors of economic activity. For these reasons, the number of exposed workers in Italy is very significant [13
Several respiratory and neoplastic diseases can be caused by environmental pollutants, such as asbestos, polycyclic aromatic hydrocarbons, carbon monoxide, heavy metals, gases, and formaldehyde [14
In fact, in addition to occupational exposure, the risk of mesothelioma is now certainly linked to exposure to the environmental type of asbestos, be it of anthropic origin (for example, a residence near industries or polluted sites) or of natural origin (in areas where there are natural outcrops of asbestiform minerals of asbestos and not). In Italy there are also asbestosimic fibers, such as fluoro-edenite [21
], an asbestiferous fibers of natural origin present in the area of Etna capable of inducing mesothelioma, and balangeroite, an asbestiform fiber that has been identified in some rocks present in the Balangero mine (Turin).
Recently, as part of the SENTIERI-ReNaM project, cases of mesothelioma have been found not only in sites where asbestos is explicitly recognized as a source of contamination, but also in numerous territories defined as being of national interest for other reasons of pollution. These data confirm that the spectrum of economic activities, work, and living environments involved in exposure to asbestos is very wide, and it is not possible to limit it to industrial sectors with direct use of the material as raw material [22
Data provided by the Italian National Research Council (32 million tons of asbestos cement still to be reclaimed) and ISPRA (Higher Institute for Environmental Protection and Research), in the chapter on special waste of the 2011 Yearbook, reports that waste containing asbestos produced in Italy in 2009 amounted to about 380,000 tons. If the estimates prove to be exact based on the asbestos still present in the national territory (32 million tons) and the annual amount removed (380,000 tons), at this rate of annual removal, the disposal process could last another 85 years [8
In Italy, from the 1992 announcement, the time distance from the end of the occupational exposure for the subjects exposed in the past is now on the order of 25 years. From the day of the call for tenders, the workers’ protection legislation has guaranteed adequate information and training to work in protected conditions for those who work today for the demanufacturing and removal of materials containing asbestos. Mesothelioma (any site) and lung cancer arising from occupational exposure to asbestos have been included in the Italian list of occupational diseases since 1994 [23
2. Malignant Mesothelioma (MM)
Malignant mesothelioma (MM) is a rare tumor, rare tumors are those with incidence <6/100,000 per year (RARECARE) [25
], that originates from the inner lining of the body’s serous cavities (pleura, peritoneum, pericardium, and vaginal tunic of the testicle). It has a bad prognosis and is characterized by a short survival (about 12 months) [26
]. It is considered a "sentinel event" of past exposure to asbestos in all areas where exposure to other risk factors for MM can be ruled out [28
Because of their physical characteristics, asbestos fibers remain in the lung, regional lymph nodes, and pleural cavity and induce chronic inflammation through the production of reactive oxygen/nitrogen species. As a consequence, immunocompetent cells can have their cellular and molecular features altered by chronic and recurrent encounters with asbestos fibers, all of which eventually lead to decreased tumor immunity [29
Potential cofactors for the development of MM are also exposure to other elongated mineral particles (EMPs) such as synthetic materials (ceramics, nanoparticles), ionizing radiation, and SV-40 virus infections [34
]. Genetic factors can also play a role in the onset of MM. Indeed, family clusters in blood relatives have been described [36
Many studies have shown that polymorphism in the genes involved in xenobiotic and oxidative metabolism or in DNA repair processes may play an important role in the etiology and pathogenesis of these diseases. [40
] Early symptoms of MM are usually nonspecific, and diagnosis may be delayed. There are a number of comprehensive studies in the literature investigating potential biomarkers for the early diagnosis of MM in symptomatic patients exhibiting past exposure to asbestos. Among these, Mesothelin is one of the several well-known biomarkers used in the diagnosis of pleural MM [42
]. Other studies showed that miRNA expression in tissue and body fluids is aberrant in various tumors, revealing miRNAs as promising diagnostic biomarkers [46
It is a disease characterized by a long latency interval between the onset of exposure and the appearance of the disease (from 20 to 40 years and over) [47
]. The average overall survival rates (OS) range from 4 to 13 months for untreated patients and from 6 to 18 months for treated patients, only 7% of patients are still alive at five years from the diagnosis [8
A better survival was reported with multimodal surgical-based therapy. The Surveillance, Epidemiology, and End Results (SEER) database was explored from 1973 to 2009 to identify all 14,228 cases with diagnostic certainty. In multivariate analyses, female sex, younger age, early stage, and treatment with surgery were independent predictors of longer survival. Despite the development of surgical techniques, prognosis has not improved in the last four decades [49
After the cessation of use at work, the public health danger is the presence of both large quantities of materials containing asbestos in a friable matrix, in civil and industrial buildings as well as in transport sector facilities (e.g., naval), and significant quantities of material containing asbestos in a compact matrix whose progressive deterioration can cause the release of fibers with consequent risk to human health.
In addition, asbestos is extremely widespread and can be hidden in living areas and in everyday objects (ironing board covers, curtains, cardboard, toys, etc.) [50
The analysis of data provided by epidemiological studies has shown that the risk of MM increases with the increase in exposure to asbestos fibers, so there are no doubts regarding the proportional relationship between cumulative dose and MM frequency [51
]. It is also agreed that the most recent exposure has a lower role, but not a null one [54
]. As with all carcinogens, however, there is no safety "threshold" below which there is no risk [53
The incidence is increasing worldwide, and it is expected to reach its peak in the coming years, especially in developing countries where asbestos is still used and often without adequate control measures [55
]. Because of the long latency period of the disease, deaths are expected to peak between 2015—2025 and, according to some experts, even in 2040 [8
5. ReNaM Data: The Size of the Problem in Italy
The inverse relationship between diagnostic certainty and age at diagnosis is confirmed. The share of certain cases varies between 90% and 73%, up to the age groups "under 84", and is reduced to 42.5% in cases "over 85". The proportion of certain cases does not differ significantly by anatomical site.
The gender ratio M/F = 2.5. Seventy-two percent of the 27,356 archived cases were male.
The percentages of women were 27.4% for pleural mesotheliomas to 32.8% and 41.1%, respectively, for pericardium and peritoneum cases.
Average age at diagnosis was 70 years, with no appreciable gender differences (70.8 years in women and 69.5 in men). Cases with age under 45 years accounted for 2%.
Exposure classification included professional (certain, probable, or possible), family, environmental, out-of-work, unlikely, unknown, to be defined, and not classifiable.
The ReNaM complete archivefrom 1993 to 2015 reported 27,356 cases of MM, of which 21,387 (78.2% of the total recorded cases) cases of MM met the definition of exposure (Table 6
Among these, 4261 (19.9%) did not present exposure to asbestos, and the exposure was unlikely or unknown. In all cases with defined exposure, 69.2% had a professional exposure (certain, probable, or possible). The Exposure median period was 1959 [1951–1966].
Occupational exposure 14.818 (69.2%)
Family Exposition 1047 (4.9%)
Environmental exposure 939 (4.4%)
Exposure for hobby activities 322 (1.5%)
Unknown / unlikely exposure 4261 (19.9%)
Interview with the subject 11.832 (55.3%)
Interview with family members 9.044 (42.2%)
Documentation (extra-interview) 511 (2.3%).
Most involved sectors of activity (1993–2015 period, subjects affected by the illness for professional reasons):
Heavy industry (engineering) (8.6%)
Textile industry (6.4%)
Metal product manufacturing activities (5.7%)
Military defense (4.3%)
Railway rolling stock (3.2%)
Cement-asbestos industry (3.1%)
The set of these sectors is responsible for about 60% of the cases registered in the archives of the ReNaM.
Other sectors involved (exposure due to the presence of the material in the workplace and not for direct use):
production, repair, and maintenance of motor vehicles and motorcycles (4.4%)
land transport (3.8%),
Chemical and plastics industry (3.5%)
food industries (2%)
maritime sector (2%)
electricity and gas production (1.6%)
cargo handling in ports (1.5%)
glass production (1.3%)
rubber production (1.3%)
oil extraction and refineries (1%)
paper production (0.9%)
sugar factories (0.8%).
Unconscious exposure (unknown presence of asbestos in workplaces often open to the public):
Public administration (1.1%)
Hotels, bars, and restaurants (0.6%)
Banks, post offices, and insurance companies (0.5%)
A new scenario of exposures is represented by the increase in cases with exposure in buildings, which today produces the greatest number of cases and which raises concerns also for the possibility of current exposures. The distribution in the territory of cases originating from this sector is widespread. It is a significant sector for primary prevention. Of particular interest for the possibility of exposures still current is the number of mesothelioma cases registered in so-called ’minor’ categories (production and maintenance of transport vehicles, food industry, wood, tobacco, manufacturing industries, agriculture and livestock, catering education, and services in the administrative sector). Activities of the regional registers have brought to light areas of professional activity and economic sectors with exposure to unexpected asbestos that are unrecognized [13
Examination of the geographic distribution of mesothelioma cases has enabled the identification of clusters in the municipalities with the highest incidence rates, in particular Casale Monferrato, Broni, Genoa, La Spezia, Grugliasco-Collegno, Monfalcone, Trieste, Castellamare di Stabia, Bari, Taranto, Biancavilla, and Augusta. In these municipalities, there were companies that used asbestos in well-defined time periods and up to the ban (shipbuilding, production of insulated rolling stock) and which polluted the surrounding areas (production of asbestos cement). Some of these municipalities (Casale Monferrato, Broni, Trieste, Bari, Taranto, Biancavilla, and Augusta) have been recognized as Sites of National Interest (SIN) for land reclamation [80
In Casale Monferrato (Eternit factory), Broni, and Bari (Fibronit factory), a mesothelioma epidemic was recorded among the inhabitants. For 25% of cases in Casale Monferrato and 33% of cases in Broni and Bari a single risk factor was recognized: residing near an asbestos cement factory, which configured an involuntary and unknown environmental/residential exposure. The calculated relative risk was very high (10.5 and 5.25 respectively) for those who lived less than 500 m from the factory, and the fiber load in the lungs of the deceased cases was 10 times higher than in those of other areas [115
From the data reported by ReNaM it appears that in Italy the incidence of MM in women is high, both for nonoccupational (environmental and domestic) and occupational exposure. A total of 10.2% of MM cases derive from unprofessional exposure to asbestos. Cases of familial MM (in blood relatives) are less than 2.5% [53
]. The economic burden associated with a MM case was estimated at 250,000 euros per case [118
The data of the ReNaM show that an emerging public health problem is the environmental exposure of the population. [8
About 10% of the cases of MM, for which the previous methods of exposure were reconstructed, were found to be exposed for environmental reasons (residence) or for family reasons (cohabitation with professionally exposed family members) [106
]. The activity of the registry has shown the territorial distribution of cases and the methods of exposure (residence near asbestos cement companies, cohabitation with exposed subjects) [119
The risk of mesothelioma has been studied as a consequence of environmental exposure both anthropic, from residing near sites with important exposure sources, and of natural origin, from its presence on the territory of rock outcrops of asbestos or asbestiform minerals. In women, the percentage of cases with nonoccupational exposure exceeds 20%.
At the Governmental Conference (November 2012) in Venice [23
] and in the National Asbestos Plan (2013) [120
] the topic of MM cases of environmental origin was indicated as a research priority, with a specific mandate for the ReNaM and the CORs. "The regions will have to investigate the magnitude of the mesothelioma risk associated with non-occupational exposure (environmental or para-occupational) by mandating regional CORs or other relevant structures". As there are environmental exposures, and taking into account the interest of citizens for the protection of public health, elaboration on specific communication interventions is essential in the risk management process. Particularly important are the psychological support interventions in communities affected by mesothelioma [121
]. A summary of actions to be undertaken for nonoccupational asbestos exposures, on which the international scientific community agrees, is shown in Table 8
In conclusion, as the resolution of the European Conference on asbestos held in Brussels in 2005 already recalled, it would be necessary to establish a ban on the use of asbestos in the countries that produce it and export it, in particular for developing countries (East, Africa, South America). Therefore, it is reiterated that, worldwide, it is necessary to introduce and sanction the ban on the extraction, processing, and marketing of asbestos and products containing asbestos. The global ban on asbestos in recent decades is strongly supported by many scientists [61