Due to the continuous update of scientific information and to the existence of some controversial aspects regarding asbestos-related diseases, we conducted a systematic search for articles regarding epidemiologic advances in asbestos-related diseases in the last 18 months from 1 January 2021 until present using the string Search: ((asbestos) AND (epidemiology)) AND ((‘2021/01/01’[Date - Create]: ‘3000’ [Date - Create])); (‘asbestos’ [MeSH Terms] OR ‘asbestos’ [All Fields]) AND (‘epidemiologies’[All Fields] OR ‘epidemiology’[MeSH Subheading] OR ‘epidemiology’[All Fields] OR ‘epidemiology’[MeSH Terms] OR ‘epidemiologies’ [All Fields]) AND 2021/01/01:3000/12/31 [Date - Create]. Because of the diversity of the results, it was not possible to perform any meta-analysis. In this article, we report results considered relevant.
Asbestos is the generic name for a group of naturally occurring minerals that are carcinogenic to humans when inhaled. Nowadays, the use of asbestos is banned in more than 60 countries worldwide, including Western Europe and Australia. Conversely, the use of asbestos in developing countries like Russia, Kazakhstan, China, and so forth, is still increasing .
Despite the ban, exposure to asbestos persists due to installed asbestos-containing materials (ACMs) or naturally occurring asbestos (NOA). ACMs can determine intense exposure during natural or caused disasters (e.g. September 11 attack) or low-level exposure by continual emission of airborne asbestos arising from the detonation of ACM. Epidemiological studies have demonstrated a risk of disease associated with proximity to asbestos cement roofing (ACR) .
In Libby, Montana where the Vermiculite ore contains on average 24% of amphibole asbestiform fibres, asbestos is the leading cause of mortality following both occupational and nonoccupational exposure in individuals with asbestos-related disease .
Documenting and quantifying asbestos exposure, especially in nonoccupational settings is difficult. However, some authors [4▪] have assessed the overall asbestos exposure intensity because of NOA of residents near abandoned asbestos mines based on measured concentrations of NOA available for 19 out of 38 mines in South Korea. They evaluated the average of airborne NOA concentrations according to the environmental exposure category. Results showed airborne NOA concentrations in agricultural activity of 5.49 × 10−2 f/cc and in daily activity of 6.95 × 10−2 f/cc.
Regarding occupational exposure, cohort studies have shown that the occupations with the higher risk and the highest excess mortality for asbestos-related diseases are asbestos miners, cement-asbestos manufacturers, construction trade occupations, shipbuilding and repairing insulators, pipefitters, plumbers, and carpenters, workers in welding and flame cutting, boiler making, as well as those in industrial chemical and primary metal manufacturing industries [5–7].
The most common asbestos-related cancers include mesothelioma and lung cancer.
Malignant mesothelioma is an aggressive tumour with a poor survival (4–12 months; median survival of 8 months for the sarcomatoid histology, 13 months for the biphasic histology and 19 months for the epithelioid histology  that originates from the mesothelial cells that form the serosal lining of the pleural cavity. The median age at diagnosis is 75 years, and overall survival is 38% at 1 year and 7% at 3 years, reflecting the poor prognosis. Due to the long latency period between first exposure and the development of malignant mesothelioma, new mesothelioma cases are still diagnosed yearly. The Western Australia Mesothelioma Registry reported that the estimate of latency in cases diagnosed between 2010 and 2019 was 52 years . Other authors reported latencies of 15–60 years [9▪], and of 14–72 years [10▪].
Overall, 30 870 new cases of mesothelioma and 26 278 deaths associated with mesothelioma were identified in 2020, and more than 70% of these cases and deaths were among male individuals. Standardized (world) incidence and mortality rates for mesothelioma are reported in Table 1. The proportion of incident cases among those 70 years or older continued to increase (from 36.49% in 1990 to 44.67% in 2017), but the proportion of patients younger than 50 years decreased (from 16.74% in 1990 to 13.75% in 2017) over time. In addition, mesothelioma incident cases and age-standardized incidence rates began to decrease after 20 years of a complete ban on asbestos use , although other authors claim the continuous rising number of cases . In a recent study , it has been reported a strong association between childhood environmental asbestos exposure and malignant mesothelioma. The results of the cohort study suggest that environmental asbestos exposure in childhood may increase the overall cancer risk later in life.
Table 1 -
Standardized (world) incidence and mortality rates, mesothelioma
|Australia and New Zealand
|Central and Eastern Europe
Asbestos is a well established risk factor for mesothelioma although other risk factors like other natural fibres and ionizing radiations have been associated with this tumour [1,8,9▪,10▪,12,15]. Ionizing radiation, particularly for the treatment of a primary cancer, is known to increase the risk of malignant mesothelioma development even if the pleural layer has not been directly involved, and long latency periods are associated with higher relative risks, with a nonlinear dose–response relationship [10▪].
The fraction attributable to exposure to asbestos is about 80% [8,10▪,16] of all cases. When analysed for site and sex, the cases attributable to asbestos are 88% of pleural mesothelioma and 58% of peritoneal mesotheliomas in men and only 23% of all mesotheliomas in women [10▪].
Exposure to amphiboles carries a higher risk of mesothelioma than chrysotile . Moreover, old epidemiologic studies have shown a time trend in the risk of mesothelioma as the risk is linked with the third or fourth power of time since first exposure. It also depends on the fibre type .
Recently Taeger et al.[18▪] observed 40 mesothelioma cases and 64 incident lung cancer in a cohort of 2439 male participants of a German surveillance program for asbestos workers. Results confirmed a trend for mesothelioma for time since last exposure. Lung cancer risks by duration of asbestos exposure did not show a consistent time trend. Findings also suggests that the presence of pleural plaques were associated with a strongly increased risk [standardized incidence ratio (SIR): 13.14; 95% confidence interval (CI): 8.51–19.40] for mesothelioma but not for lung cancer (SIR: 1.05; 95% CI: 0.76–1.41).
Regarding the fibre burden, most studies on the inorganic lung content reveals very inconsistent conclusions about the link between the concentration of asbestos in the lungs and the risk of developing malignant mesothelioma.
Visonà et al.[19▪] have conducted a study in a population sample from Broni, Italy, both occupationally and environmentally exposed and who died for asbestos-related diseases (confirmed by histological evaluation) and underwent a forensic autopsy. The aim of the study was to measure, classify and quantify the inorganic fibres in human lungs, using a SEM-EDS, with special regard for the asbestos derived from anthropogenic environmental and/or occupational exposure. The amount of asbestos fibres was not significantly different across the groups of exposure, thus individuals who worked in contact with asbestos had similar concentrations of asbestos in their lungs to subjects who lived nearby the plant.
Subjects who died of malignant mesothelioma showed a significantly lower median amount of asbestos fibres by grams of dry weight (ff/gdw) as compared with subjects who died of other causes (P < 0.001) (e.g. asbestosis). Thus malignant mesothelioma risk is not directly related to the dose of asbestos in the lungs. We also found noteworthy the discussion generated by this article [20,21].
Another factor to consider is individuals who were heavily exposed to asbestos but did not develop mesothelioma. In fact, only up to 10% of people with occupational exposure to asbestos develop mesothelioma . Therefore, the possibility that there is a genetic predisposition to mesothelioma has been suggested. It has been established that genetic factors play a fundamental role in determining individual susceptibility and modulating response to environmental factors . Individual cancer susceptibility can be the result of several host factors. No specific genetic mutation common to all mesothelioma has been identified so far although some mutations are present in a large number of mesothelioma cases: with the commonest in BAP1, CDKN2A and NF2 but also in TP53, SMARCB1, PDGFRA, KIT, KDR, HRAS, PIK3CA, STK11, BRCA2, CRTAM, SDK1, RASGFR, MLH1, MLH3) [1,8,10▪,14,22]. Other genetic characteristic like the GSTT1 null genotype as well as the GSTP1 rs1695 polymorphism may show a protective effect regarding the malignant mesothelioma risk [10▪].
Clinical and therapeutical decisions in modern medicine are very much influenced by the patient's genetic profile. For instance, mesotheliomas in carriers of BAP1 germline mutations are known to be significantly less aggressive. Some BAP1 carriers may have asymptomatic mesothelioma, and they can be followed by close clinical observation without apparent adverse outcomes with long survival without therapy. Others may grow aggressively but very often respond to therapy. Thus, the detection of BAP1 germline mutations has substantial medical, social and economic impact .
Patients with mesothelioma require a multidisciplinary approach that involves anatomopathologists, genetic counselling, medical genetics, surgical, medical, and radiation oncology expertise.
For an accurate diagnosis of mesothelioma and the histological subtype, special training for the pathologist is needed. Between the types and subtypes of mesothelioma, the prognosis varies significantly, and this underlines the importance of making an accurate histological diagnosis. It is recommended that all the mesothelioma histologic diagnoses should be confirmed in a centre with expertise in the pathological diagnosis of this tumour [9▪].
Histological examination should be performed on thoracoscopic biopsies from multiple sites. Larger biopsies increase diagnostic confidence and allows for histological subtyping. Moreover, deeper biopsies allow for the assessment of tumour invasion by including fat and/or skeletal muscle .
The histologic diagnosis of malignant mesothelioma should be based on appropriate morphology and immunohistochemical (IHC) findings. Information on antibody clones and their sources is an evolving area; therefore, the IHC stains should be chosen based on the updated literature. Molecular testing is also very helpful in selected cases. Lately, in addition to the most common mesothelial positive markers [e.g. calretinine, CK 5/6, Podoplanin (D2-40) and WT1], a strong immunoreactivity against ATG7 was observed in mesothelioma cases (50% of the cases in a series of 20 patients with mesothelioma) .
Another important topic is the possibility to improve the diagnostic timing with biomarkers that can be used in screening programs in subjects at risk. New potential biomarkers like the proinflammatory molecule HMGB1 [10▪] or miRNAs (hsa-miR-323a-3p and hsa-miR-20b-5p ) are emerging as potential diagnostic tools or therapeutic target in malignant mesothelioma while biomarkers such as SMRP, osteopontin and fibrilin-3 may provide some prognostic information .
Previous literature findings showed a linear association between asbestos exposure level and lung cancer risk, which may level off at very high exposures. The relative risk for lung cancer increases between 1 and 4% per fibre-year (f-y)/ml, corresponding to a doubling of risk at 25-100 f-y/ml .
Although documenting and quantifying asbestos exposure may be very difficult, because of the recall bias (information not recalled, recalled erroneously or recall influenced by the possibility of compensation) or data complexity (workers within the same workplace may be exposed to varying quantities and types of asbestos), an exposure assessment should be performed in all cases of lung cancer attributable to asbestos exposure.
Currently, the Helsinki Criteria  is still a valuable tool for the assessment of the asbestos-related lung cancer patients that are seeking compensation.
Hyland et al.[28▪] recently applied the Criteria to a cohort of lung cancer patients in order to study the differences between asbestos-related lung cancer (ARLC) and non-ARLC patients. Results showed that patients with ARLC were significantly older than the non-ARLC patients (72.1 years versus 66.5 years respective). The average duration of asbestos exposure was significantly higher in the ARLC group. ARLC patients were more likely to have a previously certified dust disease.
The risk for asbestos-related malignancies depends, also, on the type of fibre. Ramada Rodilla et al. recently conducted a study aiming to review the available scientific evidence on exposure levels for asbestos and their relationship to health effects. They found that for lung cancer, the highest risk was observed with exposure to amphiboles especially for longer (those >10 μm in length), thinner fibres while mesothelioma was associated with amphiboles at least 5 μm. Regarding the exposure level, no studies observed an increased risk for lung cancer at asbestos exposure levels less than 0.1 f/ml.
On the contrary, Harris et al. claimed an association between low asbestos exposure and the presence of lung parenchymal abnormalities. During the screening program, subjects previously exposed to asbestos underwent annual low-dose computed tomography (LDCT), health assessments and pulmonary function testing within the Asbestos Review Program. Authors defined asbestosis using the Helsinki Criteria and the presence of Interstitial Lung Abnormalities (ILA) using a protocol for occupational CT reports. In this cohort with relatively low asbestos exposure, LDCT detected ILA that fits criteria for asbestosis was common, but physiological decline was not. Findings contrast with the traditionally accepted views that asbestosis requires high exposures.
In response to this article, Sangani et al.[31▪] felt the need to clarify that the suggestion by Harris et al. that ILAs can be utilized in diagnosing asbestosis might be premature for several reasons such as: the definition is yet to be standardized, and specific occupational and environmental exposures, including asbestos, may actually exclude the finding of ILAs; the employment of ILAs in the diagnosis of asbestosis would be significantly confounded by smoking, as over 30% of some smoking populations demonstrate ILAs; ILAs may represent a reversible phenomenon; the histologic confirmation of diagnosis was not available in the current study. A radiologic pattern of involvement consistent with interstitial lung disease (e.g. usual interstitial pneumonitis, nonspecific interstitial pneumonitis and respiratory bronchiolitis–interstitial lung disease) should be observed on the CT scan before accepting its support of a diagnosis of asbestosis.
Other possible asbestos-related cancer
Other possible asbestos-related malignancies have been reported.
Wentzensen and O’Brien  conducted a review in order to establish whether there is a causal relationship between talc body powder and ovarian cancer. The epidemiological data from case–control studies and cohort studies suggest that there may be a small, positive association between genital powder use and ovarian cancer, although there are no clear causal factors underlying this association. Asbestos was proposed as a causal factor as contaminant of the talc powder.
Vidican et al. investigated the frequency of asbestos exposure and cases of ovarian cancer based on the histological subtype. Results showed a prevalence of direct and indirect asbestos exposure in ovarian cancer patients of 13 and 46%, respectively. No association with histological subtype was observed. Moreover, after adjustment for familial history of ovarian cancer, no significant associations between asbestos exposure (direct and/or indirect) and high-grade serous carcinoma were found.
Zhou et al. also claimed that occupational exposure to asbestos should be considered an important risk factor for ovarian cancer along with high BMI.
Dalsgaard et al. conducted a cohort study in a group of former school children exposed to environmental asbestos in childhood with a focus on female cancers. Their results showed an association between environmental asbestos exposure in childhood and risk of cancer of the corpus uteri (SIR 1.29, 95% CI 1.01–1.66) and malignant mesothelioma in women (SIR 7.26, 95% CI 3.26–16.15). On the contrary, they observed a significantly lower risk of ovarian cancer. Saito et al. in an ecological study analysing sex-specific mortality from asbestos-related diseases in Municipalities with High Asbestos Consumption in Brazil, concluded that the mortality rates from 2000 to 2017 for lung and ovarian cancer in municipalities with a history of asbestos mining and asbestos-cement production exceed those of the whole country.
Another causal relationship with asbestos was investigated for intrahepatic cholangiocarcinoma (iCCA). Brandi et al. confirmed their findings from 2013 claiming that, overall, the body of evidences coming from epidemiological and mechanistic studies addresses to a putative causal role of asbestos in the genesis of iCCA, deserving further investigations in large observational studies with accurate asbestos exposure assessment. Results were also confirmed by Seeherunwong et al., in their review, showing that the carcinogen resulting in a higher risk for iCCA was asbestos with the highest adjusted odds ratio (OR) =4.81, 95% CI =1.73–13.33.
A causal relation between asbestos and gastric cancer was also investigated. Fang et al. concluded that in their asbestos occupational cohort, compared with the general population, the SIR for gastric cancer was increased both in male (1.05, 95% CI 1.02–1.09) and female individuals (1.10, 95% CI 1.01–1.18). The relative risk for gastric cancer was 1.76 (95% CI 1.63–1.90) in 123 worksites.
Epidemiologic findings helped to understand the distribution of asbestos-related diseases in people and to project prevention, and treatment strategies for ‘old’ and, maybe ‘new’ diseases. Therapies are improving and mortality rates are decreasing yet, as stated by the WHO  ‘the most efficient way to eliminate asbestos related diseases is to stop using all types of asbestos’.
More studies on the treatment options of the MPM are being carried out. In the future histology, genotype, and ‘taylored’ therapy should be among the main focal points.
Moreover, data collection is another important aspect as ‘big data’ could put together information that can allow analysis not otherwise possible in small data sets.
Asbestos-related malignancies, especially mesothelioma, are still diagnosed yearly even after more than 30 years since the ban in more than 60 countries worldwide. Moreover, results from some cohort studies suggest that environmental asbestos exposure in childhood may increase the overall cancer risk later in life. Latest studies confirm the time trend for mesothelioma but not for lung cancer. For asbestos-related lung cancer, findings showed a linear association between asbestos exposure level and lung cancer risk.
There is no proof of any link between the concentration of asbestos lung burden and the risk of developing malignant mesothelioma. Only 10% of the subjects heavily exposed develop mesothelioma; thus, it is considered that genetics play a major role in developing this tumour. Findings suggest that some mutations like not only BAP1, CDKN2A and NF2 but also TP53, SMARCB1, PDGFRA, KIT, KDR, HRAS, PIK3CA, STK11, BRCA2, CRTAM, SDK1, RASGFR, MLH1, MLH3 are present in a large number of patients with mesothelioma and this may represent a starting point for a more accurate diagnose, for improving the prognosis, for a ‘taylored’ therapy and, eventually, for improving the prevention strategies for asbestos-related cancers.
Financial support and sponsorship
Conflicts of interest
E.P. acted as consultant on matters related to asbestos-related diseases. C.C. and A.G. have no potential conflicts to report.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
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