Environmental asbestos exposure and clustering of malignant mesothelioma in community: a spatial analysis in a population-based case-control study.

BACKGROUND: Neighborhood exposure to asbestos increases the risk of developing malignant mesothelioma (MM) in residents who live near asbestos mines and asbestos product plants. The area of Casale Monferrato (Northwest Italy) was impacted by several sources of asbestos environmental pollution, due to the presence of the largest Italian asbestos cement (AC) plant. In the present study, we examined the spatial variation of MM risk in an area with high levels of asbestos pollution and secondly, and we explored the pattern of clustering. METHODS: A population-based case-control study conducted between 2001 and 2006 included 200 cases and 348 controls. Demographic and occupational data along with residential information were recorded. Bivariate Kernel density estimation was used to map spatial variation in disease risk while an adjusted logistic model was applied to estimate the impact of residential distance from the AC plant. Kulldorf test and Cuzick Edward test were then performed. RESULTS: One hundred ninety-six cases and 322 controls were included in the analyses. The contour plot of the cases to controls ratio showed a well-defined peak of MM incidence near the AC factory, and the risk decreased monotonically in all directions when large bandwidths were used. However, considering narrower smoothing parameters, several peaks of increased risk were reported. A constant trend of decreasing OR with increasing distance was observed, with estimates of 10.9 (95% CI 5.32-22.38) and 10.48 (95%CI 4.54-24.2) for 0-5 km and 5-10 km, respectively (reference > 15 km). Finally, a significant (p < 0.0001) excess of cases near the pollution source was identified and cases are spatially clustered relative to the controls until 13 nearest neighbors. CONCLUSIONS: In this study, we found an increasing pattern of mesothelioma risk in the area around a big AC factory and we detected secondary clusters of cases due to local exposure points, possibly associated to the use of asbestos materials.

Wild rats as urban detectives for latent sources of asbestos contamination.

Based on a large body of evidence asbestos minerals have been classified as carcinogens. Despite the Italian ban on asbestos in 1992 and the subsequent remediation activities, latent sources of contamination may still represent a hazard where asbestos were particularly used. Using wild rats as sentinel animals, this study aimed at uncovering sites with the greatest potential for non-occupational exposure to asbestos in the city of Casale Monferrato (Piedmont Region, Italy), where the largest Italian manufacturing plant of asbestos-cement had been active. During the study period (2013-2015) a total of 40 wild rats were captured from 16 sampling capture points. The lungs of wild rats have been investigated by using scanning electron microscopy (SEM) with energy dispersive spectroscopy (EDS). The SEM-EDS detected the presence of asbestos fibers (tremolite/actinolite, amosite, and chrysotile) in rats' lungs from 11 sampling points. The hypothetical rats' home-range and the observed site-specific concentration of asbestos fibers per gram of dry lung tissue were used to identify areas to be targeted by additional search of latent sources of asbestos. In conclusion, our results showed that the use of wild rats as sentinel animals may effectively integrate the strategies currently in use to reduce the exposure to asbestos.

CDKN2A and BAP1 germline mutations predispose to melanoma and mesothelioma.

BAP1 germline mutations predispose to a cancer predisposition syndrome that includes mesothelioma, cutaneous melanoma, uveal melanoma and other cancers. This co-occurrence suggests that these tumors share a common carcinogenic pathway. To evaluate this hypothesis, we studied 40 Italian families with mesothelioma and/or melanoma. The probands were sequenced for BAP1 and for the most common melanoma predisposition genes (i.e. CDKN2A, CDK4, TERT, MITF and POT1) to investigate if these genes may also confer susceptibility to mesothelioma. In two out of six families with both mesothelioma and melanoma we identified either a germline nonsense mutation (c.1153C > T, p.Arg385*) in BAP1 or a recurrent pathogenic germline mutation (c.301G > T, p.Gly101Trp) in CDKN2A. Our study suggests that CDKN2A, in addition to BAP1, could be involved in the melanoma and mesothelioma susceptibility, leading to the rare familial cancer syndromes. It also suggests that these tumors share key steps that drive carcinogenesis and that other genes may be involved in inherited predisposition to malignant mesothelioma and melanoma.

III Italian Consensus Conference on Malignant Mesothelioma of the Pleura. Epidemiology, Public Health and Occupational Medicine related issues.

The III Italian Consensus Conference on Pleural Mesothelioma (MM) convened on January 29th 2015. This report presents the conclusions of the 'Epidemiology, Public Health and Occupational Medicine' section. MM incidence in 2011 in Italy was 3.64 per 100,000 person/years in men and 1.32 in women. Incidence trends are starting to level off. Ten percent of cases are due to non-occupational exposure. Incidence among women is very high in Italy, because of both non-occupational and occupational exposure. The removal of asbestos in place is proceeding slowly, with remaining exposure. Recent literature confirms the causal role of chrysotile. Fibrous fluoro-edenite was classified as carcinogenic by IARC (Group 1) on the basis of MM data. A specific type (MWCNT-7) of Carbon Nanotubes was classified 2B. For pleural MM, after about 45 years since first exposure, the incidence trend slowed down; with more studies needed. Cumulative exposure is a proxy of the relevant exposure, but does not allow to distinguish if duration or intensity may possibly play a prominent role, neither to evaluate the temporal sequence of exposures. Studies showed that duration and intensity are independent determinants of MM. Blood related MM are less than 2.5%. The role of BAP1 germline mutations is limited to the BAP1 cancer syndrome, but negligible for sporadic cases. Correct MM diagnosis is baseline; guidelines agree on the importance of the tumor gross appearance and of the hematoxylin-eosin-based histology. Immunohistochemical markers contribute to diagnostic confirmation: the selection depends on morphology, location, and differential diagnosis. The WG suggested that 1) General Cancer Registries and ReNaM Regional Operational Centres (COR) interact and systematically compare MM cases; 2) ReNaM should report results presenting the diagnostic certainty codes and the diagnostic basis, separately; 3) General Cancer Registries and COR should interact with pathologists to assure the up-to-date methodology; 4) Necroscopy should be practiced for validation. Expert referral centres could contribute to the definition of uncertain cases. Health surveillance should aim to all asbestos effects. No diagnostic test is recommended for MM screening. Health surveillance should provide information on risks, medical perspective, and smoking cessation. The economic burden associated to MM was estimated in 250,000 Euro per case.

XRCC1 and ERCC1 variants modify malignant mesothelioma risk: a case-control study.

Malignant pleural mesothelioma (MPM) is a rare aggressive tumor associated with asbestos exposure. The possible role of genetic factors has also been suggested and MPM has been associated with single nucleotide polymorphisms (SNPs) of xenobiotic and oxidative metabolism enzymes. We have identified an association of the DNA repair gene XRCC1 with MPM in the population of Casale Monferrato, a town exposed to high asbestos pollution. To extend this observation we examined 35 SNPs in 15 genes that could be involved in MPM carcinogenicity in 220 MPM patients and 296 controls from two case-control studies conducted in Casale (151 patients, 252 controls) and Turin (69 patients, 44 controls), respectively. Unconditional multivariate logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). Two DNA repair genes were associated with MPM, i.e. XRCC1 and ERCC1. Considering asbestos-exposed only, the risk increased with the increasing number of XRCC1-399Q alleles (Casale: OR=1.44, 95%CI 1.02-2.03; Casale+Turin: OR=1.34, 95%CI 0.98-1.84) or XRCC1 -77T alleles (Casale+Turin: OR=1.33, 95%CI 0.97-1.81). The XRCC1-TGGGGGAACAGA haplotype was significantly associated with MPM (Casale: OR=1.76, 95%CI 1.04-2.96). Patients heterozygotes for ERCC1 N118N showed an increased OR in all subjects (OR=1.66, 95%CI 1.06-2.60) and in asbestos-exposed only (OR=1.59, 95%CI 1.01-2.50). When the dominant model was considered (i.e. ERCC1 heterozygotes CT plus homozygotes CC versus homozygotes TT) the risk was statistically significant both in all subjects (OR=1.61, 95%CI 1.06-2.47) and in asbestos-exposed only (OR=1.56, 95%CI 1.02-2.40). The combination of ERCC1 N118N and XRCC1 R399Q was statistically significant (Casale: OR=2.02, 95%CI 1.01-4.05; Casale+Turin: OR=2.39, 95%CI 1.29-4.43). The association of MPM with DNA repair genes support the hypothesis that an increased susceptibility to DNA damage may favour asbestos carcinogenicity.

Excess of mesotheliomas after exposure to chrysotile in Balangero, Italy.

BACKGROUND: Chrysotile from the mine in Balangero, Italy is considered to be free of tremolite. In a cohort study of miners and millers only two pleural cancers were reported, a finding considered to indicate that chrysotile has a low potency for inducing mesothelioma. However, follow-up ended in 1987 and white-collar workers and the employees of subcontractors were not studied. METHODS: To complete the case ascertainment, the study searched the Registry of Malignant Mesotheliomas of Piedmont for records of cases of pleural mesothelioma among the following: mine employees; employees of subcontractors or of other firms transporting or refining Balangero asbestos, asbestos ore or mine tailings; individuals exposed to air pollution from the mine or living with mine employees; and individuals exposed to mine tailings from Balangero. RESULTS: The study identified four new cases of pleural mesothelioma among blue-collar workers in the mine, in addition to the two reported in the cohort study. Thus, six mesotheliomas occurred, compared to the 1.5 expected (p<0.01). The study also identified three mesothelioma cases among white-collar employees at the mine, five in workers in the mine hired by subcontracting firms, and three among workers processing Balangero chrysotile outside the mine. Finally, 10 additional cases due to non-occupational exposure or exposure to re-used mine tailings were identified. CONCLUSIONS: The cluster of 14 mesothelioma cases among workers who were active in the mine and 13 among other people exposed to Balangero chrysotile provides further evidence that tremolite-free chrysotile is carcinogenic.

Cancer risk after cessation of asbestos exposure: a cohort study of Italian asbestos cement workers.

OBJECTIVES: We aimed to study mortality for asbestos related diseases and the incidence of mesothelioma in a cohort of Italian asbestos cement workers after cessation of asbestos exposure. METHODS: The Eternit factory operated from 1907 to 1986. The cohort included 3434 subjects active in 1950 or hired in 1950-86, ascertained from company records, without selections. Local reference rates were used for both mortality and mesothelioma incidence. RESULTS: Mortality was increased in both sexes for all causes (overall 1809 observed (obs) vs 1312.3 expected (exp); p<0.01), pleural (135 obs vs 3.6 exp; p<0.01) and peritoneal (52 vs 1.9; p<0.01) malignancies and lung cancer (249 vs 103.1; p<0.01). In women, ovarian (9 vs 4.0; p<0.05) and uterine (15 vs 5.8; p<0.01) malignancies were also in excess. No statistically significant increase was found for laryngeal cancer (16 obs vs 12.2 exp). In Poisson regression analyses, the RR of death from pleural neoplasm linearly increased with duration of exposure, while it showed a curvilinear increase with latency and time since cessation of exposure. RR for peritoneal neoplasm continued to increase by latency, duration and time since cessation of exposure. RR for lung cancer showed a reduction after 15 years since cessation of exposure and levelled off after 40 years of latency. CONCLUSION: This study of a cohort of asbestos exposed workers with very long follow-up confirmed the reduction in risk of death from lung cancer after the end of exposure. It also suggested a reduction in risk for pleural mesothelioma with over 40 years of latency, while risk for peritoneal mesothelioma showed a continuing increase.

[Mortality from pleural and peritoneal cancer in a cohort of asbestos workers, many years after start of the exposure: possible role of fibers clearance]. / Mortalità per tumore pleurico e peritoneale in una coorte di lavoratori del cemento amianto, dopo lunghi periodi di latenza: valutazione di un possibile ruolo della clearance delle fibre.

The multistage theory of carcinogenesis assumes rates of mesothelioma increasing monotonically as a function of time since first exposure (TSFE) to asbestos. However, some authors have suggested that the increase in mesothelioma rate with TSFE might be attenuated by clearance of asbestos from the lungs. We estimated mortality time trends from pleural and peritoneal cancer in a cohort of 3443 asbestos-cement workers. The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalized to include a term representing elimination over time. We observed 139 deaths from pleural and 56 from peritoneal cancer during the period 1950-2003. The rate of pleural cancer increased during the first 40 years of TSFE and reached a plateau thereafter. In contrast, the rate of peritoneal cancer increased monotonically with TSFE. The model allowing for asbestos elimination fitted the data better than the traditional model for pleural (p = 0.02) but not for peritoneal cancer (p = 0.22). The risk for pleural cancer, rather than showing an indefinite increase, might reach a plateau when a sufficiently long time has elapsed since exposure. The different trends for pleural and peritoneal cancer might be related to clearance of the asbestos from the workers' lungs.

[Mesothelioma incidence and time trend in the worlds]. / Incidenza e variazioni temporali dei mesoteliomi nel mondo.

BACKGROUND: Due to its adaptability to different uses, asbestos was increasingly employed in many working and domestic areas up to the 1970s-1980s, when its aetiological role in the onset of pleural mesothelioma (Mm) was recognized. Since then Mm cases have been continuously increasing and no decline is expected until 2020, despite the fact that most industrialized countries banned asbestos use a few decades ago. OBJECTIVES: The aim of this study was to analyse Mm incidence in the World during the last ten years, also considering asbestos consumption in diferent areas. METHODS: Incidence age-standardized rates (ASR) from Cancer Registries included in Cancer Incidence in Five Continents, Vol. VII and VIII, and, when appropriate, standardized rate ratio (SRR) with confidence interval were estimated. RESULTS: The highest incidence rates among males were observed in Liguria and Australia. After Liguria, Maastricht and Scotland in Europe, North East Regions and Piedmont in Italy showed high rates. Among females, the highest incidence rates were observed in Liguria, among black women in New Orleans and in the province of Varese. SRRs revealed increased rates, not always significant, in almost all areas among males and in about 50% of the areas among females, although the variation was significant only in Varese. CONCLUSIONS: These results confirmed a relationship between Mm risk and asbestos use, revealing high incidence rates in Australia (mining), Italy (shipyards, building, goods handling, heavy industries and sea trade) and Great Britain (shipyards). Mm cases increased in areas with elevated incidence rates, suggesting that larger amounts of asbestos were probably used for a longer period. Finally, no Mm cases were registered in some areas, which probably signifies a lack (or a delay) of risk referred to the investigated period.

Occupational exposure to diesel exhausts and risk for lung cancer in a population-based case-control study in Italy.

BACKGROUND: We studied the effect of exposure to diesel exhausts on lung cancer risk in a population-based case-control study in the city of Turin, Italy. PATIENTS AND METHODS: Information on occupational histories of 595 incident lung cancer cases diagnosed in 1991-1992 and 845 population controls was obtained. During the interviews, diesel job-specific modules (D-JSMs) were administered whenever subjects had worked in occupations included in the following nine categories: railroad workers, miners, professional drivers and transport conductors, heavy-machine operators, mechanics and testers, filling station attendants, motor-vehicle park attendants, transport equipment operators, and occupations carried out in/near urban roads. All D-JSMs were evaluated for probability, intensity and frequency of exposure. RESULTS: The odds ratio for ever exposure to diesel exhausts was 1.04 (95% confidence interval 0.79-1.37), after adjusting for age, sex, smoking and having worked in occupations entailing exposure to known lung carcinogens. No association was found with intensity, probability and duration of exposure. CONCLUSIONS: Although misclassification of the exposure may have contributed to the negative results, we did not find an association between occupational exposure to diesel exhausts and lung cancer risk.

Polymorphisms in DNA repair genes as risk factors for asbestos-related malignant mesothelioma in a general population study.

Differences in response to carcinogenic agents are due to the allelic variants of the genes that control it. Key genes are those involved in the repair of the DNA damage caused by such agents. This paper describes the results of a case-control epidemiological study designed to determine the genotypes of four of these genes in persons exposed to a single genotoxic factor, i.e. asbestos, who had or had not developed malignant mesothelioma (MM). Our working hypothesis was that an imperfect DNA repair, as revealed by subtle polymorphic variants, could reduce protection against the chronic DNA insult provoked by asbestos and eventually result in mutagenesis and cancer. Seven variants (i.e. XRCC1-R399Q-NCBI SNP, XRCC1-R194W, XRCC3-T241M, XRCC3-IVS6-14, XPD-K751Q, XPD-D312N, OGG1-S326C) were investigated in 81 patients and 110 age and sex-matched controls, all residents at Casale Monferrato, a Piedmontese town highly exposed to asbestos pollution. Unconditional multivariable logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). When considered as a categorical variable, XRCC1-399Q showed an increased OR both in heterozygotes (OR=2.08; 95% CI=1.00-4.33) and homozygotes (2.38; 95% CI=0.82-6.94), although individual ORs were not significant. When it was considered as a continuous variable OR was significant (OR=1.68; 95% CI: 1.02-2.75). When genotypes were divided into "non-risk" and "risk" genotypes, i.e. those thought to be associated with increased risk in the light of the functional significance of the variants, XRCC1-399Q (Q homozygotes+Q/R heterozygotes versus R homozygotes) had an OR=2.147 (95% CI: 1.08-4.28), whereas that of XRCC3-241T (T homozygotes+M/T heterozygotes versus M homozygotes) was 4.09 (95% CI: 1.26-13.21) and that of OGG1-326C was increased, though not significantly. None of the haplotypes showed a significantly different frequency between patients and controls. This is the first report of an association between polymorphisms in DNA repair genes and asbestos-associated MM. Our data indicate that genetic factors are involved in MM development.

Epidemiologic surveillance for primary prevention of malignant mesothelioma: the Italian experience.

BACKGROUND: The Italian National Mesothelioma Registry (ReNaM) was set up at the National Institute for Occupational Safety and Health (ISPESL) to estimate Italian incidence of malignant mesothelioma (MM), define modalities of asbestos exposures, assess impact and diffusion of MM, identify underestimated sources of environmental contamination. OBJECTIVES: To describe ReNaM activity, database dimension and epidemiological characteristics of the caselist. METHODS: Regional Operating Centers (COR) in 16 Italian regions were set up to identify and investigate all cases of MM diagnosed in each region, applying national guidelines. COR collect cases in health care institutions. Occupational history, lifestyle and residence are obtained by direct interview using a standard questionnaire. Exposure modalities are classified by industrial hygienists, evaluating whether work, private life or any particular environmental condition could have involved asbestos exposure. RESULTS: Data refer to 3,446 cases collected in 9 Italian regions during 1993-2001. Pleural mesothelioma affected 94% cases, pleural/peritoneal ratio was 16:1. Gender ratio (M/F) was 2.7:1 (1.3:1 for peritoneum). There was a variety of occupational exposures, some already known as high risk sectors and others unexpected. The most common exposures occurred in building and construction, metallurgy and steel, shipbuilding, and railway stock. High risk categories were encountered such as bricklayers, plumbers, carpenters, electricians, welders, installers and maintenance workers in metallurgy and the steel industry, general labourers, tool makers and painters in shipbuilding/repair/demolition. CONCLUSIONS: Despite some ReNam's limitations, identification of MM cases and analysis of modality of exposure, with standardized criteria, are a fundamental tool for primary prevention of asbestos related diseases.

[Interaction between occupational and environmental exposure to asbestos. Epidemiologic survey]. / Interazione tra esposizione lavorativa ed ambientale ad amianto. Indagini epidemiologiche.

In this short review we present the evidence of association of Malignant Mesothelioma and asbestos exposure in Italy, with focus on environmental exposure. After almost 10 years from the cessation of industrial use of asbestos, areas of high incidence attributable to environmental exposure are still observed.

Increased risk of malignant mesothelioma of the pleura after residential or domestic exposure to asbestos: a case-control study in Casale Monferrato, Italy.

The association of malignant mesothelioma (MM) and nonoccupational asbestos exposure is currently debated. Our study investigates environmental and domestic asbestos exposure in the city where the largest Italian asbestos cement (AC) factory was located. This population-based case-control study included pleural MM (histologically diagnosed) incidents in the area in 1987-1993, matched by age and sex to two controls (four if younger than 60). Diagnoses were confirmed by a panel of five pathologists. We interviewed 102 cases and 273 controls in 1993-1995, out of 116 and 330 eligible subjects. Information was checked and completed on the basis of factory and Town Office files. We adjusted analyses for occupational exposure in the AC industry. In the town there were no other relevant industrial sources of asbestos exposure. Twenty-three cases and 20 controls lived with an AC worker [odds ratio (OR) = 4.5; 95% confidence interval (CI), 1.8-11.1)]. The risk was higher for the offspring of AC workers (OR = 7.4; 95% CI, 1.9-28.1). Subjects attending grammar school in Casale also showed an increased risk (OR = 3.3; 95% CI, 1.4-7.7). Living in Casale was associated with a very high risk (after selecting out AC workers: OR = 20.6; 95% CI, 6.2-68.6), with spatial trend with increasing distance from the AC factory. The present work confirms the association of environmental asbestos exposure and pleural MM, controlling for other sources of asbestos exposure, and suggests that environmental exposure caused a greater risk than domestic exposure.

[Database of occupations and industrial activities that involve the risk of pulmonary tumors]. / Database di occupazioni e attività industriali che comportano rischio di tumore del polmone.

Lists of occupations and industries associated with lung cancer are a useful tool to estimate attributable risks for occupational exposures. They were first published in 1982, based on IARC Monographs. List A included industries, processes and occupations definitely entailing carcinogenic risk, list B those probably/possibly carcinogenic. In 1995 the lists had been updated. We carried out a further update, reviewing IARC Monographs Volumes 62-75, focusing on Group 1, 2 A, and 2 B agents, and coded the lists according to widely used classifications: ISIC Rev. 2, ISIC Rev. 3, NACE Rev. 1, and ISTAT ATECO 1991 (for economic activities); ILO-ISCO 1968 and ISTAT-Classificazione delle professioni 1991 (for occupations). In order to evaluate temporal and geographical variations in attributable risk, exposure assessment must be performed consistently across different studies and standard tools to identify exposures, such as the one we propose here, are needed. The lists can also help to develop maps of industrial activities entailing carcinogenic risk at local, regional, and national level, and to identify economic activities that deserve priority action to control occupational exposures to carcinogens. The classifications were originally developed for economic and demographic purposes, and some exposure circumstances cannot be coded with sufficient specificity. This applies to productions or processes (i.e.: PVC production) that could be classified only by codes corresponding to wide groups of economic activities and/or occupations: in these instances we associated no code, so as not to inflate the estimates of exposed workers. As a consequence, however, certain exposures are not represented in the coded version of the lists. Even keeping in mind such limitations, coding makes the lists easier to apply, and increases the comparability of studies on lung cancer and occupation, as well as of surveys on exposure prevalence.

Multicentric study on malignant pleural mesothelioma and non-occupational exposure to asbestos.

Insufficient evidence exists on the risk of pleural mesothelioma from non-occupational exposure to asbestos. A population-based case-control study was carried out in six areas from Italy, Spain and Switzerland. Information was collected for 215 new histologically confirmed cases and 448 controls. A panel of industrial hygienists assessed asbestos exposure separately for occupational, domestic and environmental sources. Classification of domestic and environmental exposure was based on a complete residential history, presence and use of asbestos at home, asbestos industrial activities in the surrounding area, and their distance from the dwelling. In 53 cases and 232 controls without evidence of occupational exposure to asbestos, moderate or high probability of domestic exposure was associated with an increased risk adjusted by age and sex: odds ratio (OR) 4.81, 95% confidence interval (CI) 1.8-13.1. This corresponds to three situations: cleaning asbestos-contaminated clothes, handling asbestos material and presence of asbestos material susceptible to damage. The estimated OR for high probability of environmental exposure (living within 2000 m of asbestos mines, asbestos cement plants, asbestos textiles, shipyards, or brakes factories) was 11.5 (95% CI 3.5-38.2). Living between 2000 and 5000 m from asbestos industries or within 500 m of industries using asbestos could also be associated with an increased risk. A dose-response pattern appeared with intensity of both sources of exposure. It is suggested that low-dose exposure to asbestos at home or in the general environment carries a measurable risk of malignant pleural mesothelioma.