Blood cell DNA methylation biomarkers in preclinical malignant pleural mesothelioma: The EPIC prospective cohort.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer mainly caused by asbestos exposure. Specific and sensitive noninvasive biomarkers may facilitate and enhance screening programs for the early detection of cancer. We investigated DNA methylation (DNAm) profiles in MPM prediagnostic blood samples in a case-control study nested in the European Prospective Investigation into Cancer and nutrition (EPIC) cohort, aiming to characterise DNAm biomarkers associated with MPM. From the EPIC cohort, we included samples from 135 participants who developed MPM during 20 years of follow-up and from 135 matched, cancer-free, controls. For the discovery phase we selected EPIC participants who developed MPM within 5 years from enrolment (n = 36) with matched controls. We identified nine differentially methylated CpGs, selected by 10-fold cross-validation and correlation analyses: cg25755428 (MRI1), cg20389709 (KLF11), cg23870316, cg13862711 (LHX6), cg06417478 (HOOK2), cg00667948, cg01879420 (AMD1), cg25317025 (RPL17) and cg06205333 (RAP1A). Receiver operating characteristic (ROC) analysis showed that the model including baseline characteristics (age, sex and PC1wbc) along with the nine MPM-related CpGs has a better predictive value for MPM occurrence than the baseline model alone, maintaining some performance also at more than 5 years before diagnosis (area under the curve [AUC] < 5 years = 0.89; AUC 5-10 years = 0.80; AUC >10 years = 0.75; baseline AUC range = 0.63-0.67). DNAm changes as noninvasive biomarkers in prediagnostic blood samples of MPM cases were investigated for the first time. Their application can improve the identification of asbestos-exposed individuals at higher MPM risk to possibly adopt more intensive monitoring for early disease identification.

Occupational exposure to nickel and hexavalent chromium and the risk of lung cancer in a pooled analysis of case-control studies (SYNERGY).

There is limited evidence regarding the exposure-effect relationship between lung-cancer risk and hexavalent chromium (Cr(VI)) or nickel. We estimated lung-cancer risks in relation to quantitative indices of occupational exposure to Cr(VI) and nickel and their interaction with smoking habits. We pooled 14 case-control studies from Europe and Canada, including 16 901 lung-cancer cases and 20 965 control subjects. A measurement-based job-exposure-matrix estimated job-year-region specific exposure levels to Cr(VI) and nickel, which were linked to the subjects' occupational histories. Odds ratios (OR) and associated 95% confidence intervals (CI) were calculated by unconditional logistic regression, adjusting for study, age group, smoking habits and exposure to other occupational lung carcinogens. Due to their high correlation, we refrained from mutually adjusting for Cr(VI) and nickel independently. In men, ORs for the highest quartile of cumulative exposure to CR(VI) were 1.32 (95% CI 1.19-1.47) and 1.29 (95% CI 1.15-1.45) in relation to nickel. Analogous results among women were: 1.04 (95% CI 0.48-2.24) and 1.29 (95% CI 0.60-2.86), respectively. In men, excess lung-cancer risks due to occupational Cr(VI) and nickel exposure were also observed in each stratum of never, former and current smokers. Joint effects of Cr(VI) and nickel with smoking were in general greater than additive, but not different from multiplicative. In summary, relatively low cumulative levels of occupational exposure to Cr(VI) and nickel were associated with increased ORs for lung cancer, particularly in men. However, we cannot rule out a combined classical measurement and Berkson-type of error structure, which may cause differential bias of risk estimates.

Rate advancement measurement for lung cancer and pleural mesothelioma in asbestos-exposed workers.

INTRODUCTION: Exposure to asbestos increases the risk of lung cancer and mesothelioma. Few studies quantified the premature occurrence of these diseases in asbestos-exposed workers. Focus on premature disease onset (rate advancement or acceleration) can be useful in risk communication and for the evaluation of exposure impact. We estimated rate advancement for total mortality, lung cancer and pleural mesothelioma deaths, by classes of cumulative asbestos exposure in a pooled cohort of asbestos cement (AC) workers in Italy. METHOD: The cohort study included 12 578 workers from 21 cohorts, with 6626 deaths in total, 858 deaths from lung cancer and 394 from pleural malignant neoplasm (MN). Rate advancement was estimated by fitting a competitive mortality Weibull model to the hazard of death over time since first exposure (TSFE). RESULT: Acceleration time (AT) was estimated at different TSFE values. The highest level of cumulative exposure compared with the lowest, for pleural MN AT was 16.9 (95% CI 14.9 to 19.2) and 33.8 (95% CI 29.8 to 38.4) years at TSFE of 20 and 40 years, respectively. For lung cancer, it was 13.3 (95% CI 12.0 to 14.7) and 26.6 (95% CI 23.9 to 29.4) years, respectively. As for total mortality, AT was 3.35 (95% CI 2.98 to 3.71) years at 20 years TSFE, and 6.70 (95% CI 5.95 to 7.41) at 40 years TSFE. CONCLUSION: The current study observed marked rate advancement after asbestos exposure for lung cancer and pleural mesothelioma, as well as for total mortality.

Lung asbestos fiber burden analysis: effects of the counting rules for legal medicine evaluations.

OBJECTIVES: The work shows the effect of counting rules, such as analysis magnification and asbestos fiber dimension to be count (with length ≥5 µm or also asbestos fibers with length <5 µm) in the lung asbestos fiber burden analysis for legal medicine evaluations. METHODS: On the same lung tissue samples, two different analyses were carried out to count any asbestos fibers with length ≥1 µm and with length ≥5 µm. Results of the amphibole burden of the two analyses were compared by linear regression analysis on log10-transformed values. RESULTS: The analysis should be carried out at an appropriate magnification and on samples prepared in such a way as they allow the counting of very fine fibers. If the analysis is limited to the asbestos fibers with length ≥5 µm, there is a high risk of not detecting possible residual chrysotile fiber burden and thinner crocidolite asbestos fibers. CONCLUSIONS: On average we estimated that 1 amphibole fiber with length ≥5 µm corresponds to ∼8 amphibole fibers with length ≥1 µm in the lung. The values of the Helsinki criteria should be updated taking this into account.

Mesothelioma Risk among Construction Workers According to Job Title: Data from the Italian Mesothelioma Register.

BACKGROUND: An increased risk of mesothelioma has been reported in various countries for construction workers. The Italian National Mesothelioma Registry, from 1993 to 2018, reported exposure exclusively in the construction sector in 2310 cases. We describe the characteristics of these cases according to job title. METHODS: We converted into 18 groups the original jobs (N=338) as reported by ISTAT codes ('ATECO 91'). The exposure level was attributed at certain, probable and possible in accordance with the qualitative classification of exposure as reported in the Registry guidelines. Descriptive analysis by jobs highlights the total number of subjects for each single job and certain exposure, in descending order, insulator, plumbing, carpenter, mechanic, bricklayer, electrician, machine operator, plasterer, building contractor, painter and labourer. RESULTS: The cases grow for plumbing in the incidence periods 1993-2018, while, as expected, it decreases for insulator. Within each period considered the most numerous cases are always among bricklayers and labourers, these data confirm the prevalence of non-specialised "interchangeable" jobs in Italian construction sector in the past. CONCLUSIONS: Despite the 1992 ban, the construction sector still presents an occupational health prevention challenge, circumstances of exposure to asbestos may still occur due to incomplete compliance with prevention and protection measures.

Pleural mesothelioma risk by industry and occupation: results from the Multicentre Italian Study on the Etiology of Mesothelioma (MISEM).

BACKGROUND: The Italian mesothelioma registry (ReNaM) estimates mesothelioma incidence and addresses its etiology by assessing cases' exposures but cannot provide relative risk estimates. OBJECTIVES: i) To estimate pleural mesothelioma relative risk by industry and occupation and by ReNaM categories of asbestos exposure; and ii) to provide quantitative estimates of the exposure-response relationship. METHODS: A population-based mesothelioma case-control study was conducted in 2012-2014 in five Italian regions. Cases and age and gender frequency-matched controls were interviewed using a standard ReNaM questionnaire. Experts coded work histories according to international standard classifications of industries/occupations and assigned asbestos exposure according to ReNaM categories. Job codes were further linked to SYN-JEM, a quantitative job-exposure matrix. Cumulative exposure (CE, f/mL-years) was computed by summing individual exposures over lifetime work history. Unconditional logistic regression analyses adjusted by gender, centre and age were fitted to calculate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Among men we observed increased risks of mesothelioma in many industries and associated occupations, including: asbestos-cement (OR = 3.43), manufacture of railroad equipment (OR = 8.07), shipbuilding and repairing (OR = 2.34), iron and steel mills (OR = 2.15), and construction (OR = 1.94). ORs by ReNaM exposure categories were as follows: definite/probable occupational exposure (OR = 15.8, men; OR = 8.80, women), possible occupational (OR = 2.82, men; OR = 3.70, women), sharing home with an exposed worker (OR = 2.55, men; OR = 10.3, women), residential (OR = 2.14, men; OR = 3.24, women). Based on SYN-JEM, mesothelioma risk increased by almost 30% per f/mL-year (OR = 1.28, CI 1.16-1.42). CONCLUSIONS: Out study involved five regions with historically different types and levels of industrial development, encompassing one third of the Italian population and half of Italian mesothelioma cases. As expected, we found increased pleural mesothelioma risk in the asbestos industry and in trades with large consumption of asbestos materials. Clear associations were found using both qualitative (ReNaM classifications) and quantitative estimates (using SYN-JEM) of past asbestos exposure, with clear evidence of an exposure-response relationship.

Lung cancer risk in painters: results from the SYNERGY pooled case-control study consortium.

OBJECTIVES: We evaluated the risk of lung cancer associated with ever working as a painter, duration of employment and type of painter by histological subtype as well as joint effects with smoking, within the SYNERGY project. METHODS: Data were pooled from 16 participating case-control studies conducted internationally. Detailed individual occupational and smoking histories were available for 19 369 lung cancer cases (684 ever employed as painters) and 23 674 age-matched and sex-matched controls (532 painters). Multivariable unconditional logistic regression models were adjusted for age, sex, centre, cigarette pack-years, time-since-smoking cessation and lifetime work in other jobs that entailed exposure to lung carcinogens. RESULTS: Ever having worked as a painter was associated with an increased risk of lung cancer in men (OR 1.30; 95% CI 1.13 to 1.50). The association was strongest for construction and repair painters and the risk was elevated for all histological subtypes, although more evident for small cell and squamous cell lung cancer than for adenocarcinoma and large cell carcinoma. There was evidence of interaction on the additive scale between smoking and employment as a painter (relative excess risk due to interaction >0). CONCLUSIONS: Our results by type/industry of painter may aid future identification of causative agents or exposure scenarios to develop evidence-based practices for reducing harmful exposures in painters.

Respirable Crystalline Silica Exposure, Smoking, and Lung Cancer Subtype Risks. A Pooled Analysis of Case-Control Studies.

Rationale: Millions of workers around the world are exposed to respirable crystalline silica. Although silica is a confirmed human lung carcinogen, little is known regarding the cancer risks associated with low levels of exposure and risks by cancer subtype. However, little is known regarding the disease risks associated with low levels of exposure and risks by cancer subtype.Objectives: We aimed to address current knowledge gaps in lung cancer risks associated with low levels of occupational silica exposure and the joint effects of smoking and silica exposure on lung cancer risks.Methods: Subjects from 14 case-control studies from Europe and Canada with detailed smoking and occupational histories were pooled. A quantitative job-exposure matrix was used to estimate silica exposure by occupation, time period, and geographical region. Logistic regression models were used to estimate exposure-disease associations and the joint effects of silica exposure and smoking on risk of lung cancer. Stratified analyses by smoking history and cancer subtypes were also performed.Measurements and Main Results: Our study included 16,901 cases and 20,965 control subjects. Lung cancer odds ratios ranged from 1.15 (95% confidence interval, 1.04-1.27) to 1.45 (95% confidence interval, 1.31-1.60) for groups with the lowest and highest cumulative exposure, respectively. Increasing cumulative silica exposure was associated (P trend < 0.01) with increasing lung cancer risks in nonsilicotics and in current, former, and never-smokers. Increasing exposure was also associated (P trend ≤ 0.01) with increasing risks of lung adenocarcinoma, squamous cell carcinoma, and small cell carcinoma. Supermultiplicative interaction of silica exposure and smoking was observed on overall lung cancer risks; superadditive effects were observed in risks of lung cancer and all three included subtypes.Conclusions: Silica exposure is associated with lung cancer at low exposure levels. An exposure-response relationship was robust and present regardless of smoking, silicosis status, and cancer subtype.

Diesel Engine Exhaust Exposure, Smoking, and Lung Cancer Subtype Risks. A Pooled Exposure-Response Analysis of 14 Case-Control Studies.

Rationale: Although the carcinogenicity of diesel engine exhaust has been demonstrated in multiple studies, little is known regarding exposure-response relationships associated with different exposure subgroups and different lung cancer subtypes.Objectives: We expanded on a previous pooled case-control analysis on diesel engine exhaust and lung cancer by including three additional studies and quantitative exposure assessment to evaluate lung cancer and subtype risks associated with occupational exposure to diesel exhaust characterized by elemental carbon (EC) concentrations.Methods: We used a quantitative EC job-exposure matrix for exposure assessment. Unconditional logistic regression models were used to calculate lung cancer odds ratios and 95% confidence intervals (CIs) associated with various metrics of EC exposure. Lung cancer excess lifetime risks (ELR) were calculated using life tables accounting for all-cause mortality. Additional stratified analyses by smoking history and lung cancer subtypes were performed in men.Measurements and Main Results: Our study included 16,901 lung cancer cases and 20,965 control subjects. In men, exposure response between EC and lung cancer was observed: odds ratios ranged from 1.09 (95% CI, 1.00-1.18) to 1.41 (95% CI, 1.30-1.52) for the lowest and highest cumulative exposure groups, respectively. EC-exposed men had elevated risks in all lung cancer subtypes investigated; associations were strongest for squamous and small cell carcinomas and weaker for adenocarcinoma. EC lung cancer exposure response was observed in men regardless of smoking history, including in never-smokers. ELR associated with 45 years of EC exposure at 50, 20, and 1 µg/m3 were 3.0%, 0.99%, and 0.04%, respectively, for both sexes combined.Conclusions: We observed a consistent exposure-response relationship between EC exposure and lung cancer in men. Reduction of workplace EC levels to background environmental levels will further reduce lung cancer ELR in exposed workers.

Mortality and mesothelioma incidence among chrysotile asbestos miners in Balangero, Italy: A cohort study.

BACKGROUND: We studied cancer mortality and mesothelioma incidence in 974 male workers employed at least 6 months at the Balangero mine (Italy), the largest chrysotile mine in Western Europe, active from 1917 to 1985. METHODS: Vital status as of 31 May 2013, causes of deaths and mesothelioma incidence from 1990 were ascertained. Past exposure to asbestos by working area and calendar period was estimated, based on historical data of fibers concentrations. Individual cumulative exposure was assessed by applying estimates to the job history of cohort members. Standardized mortality ratios (SMRs) for selected causes and standardized incidence ratios for malignant mesothelioma (MM) were calculated based on regional reference rates. Poisson regression analysis was used to study MM and lung cancer risk by latency, duration, and cumulative exposure. RESULTS: Mortality was increased for all causes (SMR = 1.28; 95% confidence interval [CI] = 1.17-1.40), pleural cancer (SMR = 4.30; 95% CI = 1.58-9.37), asbestosis (SMR = 375.06; 95% CI = 262.68-519.23). An increase was also found for lung cancer (SMR = 1.14; 95% CI = 0.81-1.55) and peritoneal cancer (SMR = 3.25; 95% CI = 0.39-11.75). The risk of both pleural and peritoneal cancer mortality and of mesothelioma incidence increased with increasing cumulative exposure, duration, and latency. Poisson regression analyses showed an increase in mesothelioma risk with cumulative asbestos exposure and suggest a similar trend for lung cancer. Asbestosis mortality also increased with cumulative exposure. CONCLUSIONS: Among Balangero chrysotile miners and millers, the occurrence of malignant and nonmalignant asbestos-related diseases was increased by exposure, with dose-response relation. The study confirms the carcinogenicity of chrysotile asbestos, in particular for pleural mesothelioma.

[Effects of Asbestos on Human Health. Document of the Italian Epidemiological Association (AIE)]. / Effetti dell'amianto sulla salute. Documento dell'Associazione Italiana di Epiemiologia (AIE).

OBJECTIVES: the Italian Epidemiological Association (AIE) intends to formulate assessments and recommendations on the most relevant and critical aspects in the preparation, conduct, and interpretation of epidemiological investigations on the health effects of exposure to asbestos and asbestos-like fibres. DESIGN, SETTING, AND PARTICIPANTS: the document was prepared by a working group of AIE associates, with a broad curriculum of epidemiological investigations, starting from the evaluation of scientific evidence, and was subsequently evaluated by the AIE governing body. RESULTS: the topics covered included: • consumption and presence of asbestos; • association between asbestos exposure and disease; • epidemiological surveillance of asbestos related diseases in Italy; • risk function for asbestos related diseases; • increased risk and anticipation of the disease; • interaction between asbestos and other carcinogens; • diagnosis in epidemiological studies; • assessment of exposure to asbestos; • epidemiological evidence on asbestos related diseases. CONCLUSIONS: the document ends with a summary of the conclusions of scientific research shared by AIE, with reflection on the methodology to be followed for the application at individual level of the results of epidemiological studies, and the proposal of themes on which to direct research.

[Asbestos exposure and related diseases among friction products workers (1971-2016)]. / Esposizione ad amianto e patologie correlate in addetti alla produzione di materiali di attrito (1971-2016).

SUMMARY: Worldwide studies have been published on the mortality of workers employed in asbestos-based materials for the production of clutches and brakes. However no one of these studies is related to Italian cases. Furthermore, not even surveys have been conducted in Italy to characterize the correlation between asbestos exposures and the possible occurring of asbestos-related disease. Our objectives are the following: i) to assess and quantify the asbestos exposure cases, ii) to describe the nature and the frequency of asbestos-related diseases among blue collar employees of an important factory producing brakes and clutches with chrysotile asbestos content from 1971 to 1993 and iii) to provide preliminary data on cumulative asbestos exposure estimated using lung fibre burden analysis. Critical appraisal of airborne asbestos fibre measurements and identification of cases of asbestos-related diseases between the blue collar employees, either notified to the local health authority or recovered from the Italian national Mesothelioma registry was investigated. Lung fibre burden analysis using the lung tissue samples from two deceased blue collar employees was also performed. Airborne asbestos fibre measurements (carried out in 1982) suggested asbestos fibres average concentrations of about 0.3 f/ml, while all 1992 measurements showed results below 0.1 f/ml. Furthermore, since 1988, we identified four cases of pleural plaques, three cases of asbestosis and seven cases of lung cancer. No case of malignant mesothelioma was found. In both lung cancer cases, analysed to measure the lung fibre burden, commercial amphiboles were absent or in limited concentration but chrysotile and, especially, tremolite asbestos were present in noticeable amount. In conclusion, since 1971 and up to early 1980s, exposure to chrysotile asbestos and talc, likely contaminated by tremolite, had been significant and comparable to levels causing asbestosis long-term risk. No case of malignant mesothelioma was found, that is consistent with the absence of amphiboles and with the lower risk of mesothelioma associated with the chrysotile asbestos. However a subset of the blue collar employees, the ones employed later on, could still have not reached the full risk condition, and so being still at risk of developing malignant mesothelioma. In the two lung cancer cases studied, the lung fibre burden was essentially made of chrysotile and tremolite. Lastly, lung cancer occurrence in the population of blue collar employees has been likely underestimated and the correct determination of lung cancer risk should be done through the mortality analysis of this population.

Peritoneal mesothelioma and asbestos exposure: a population-based case-control study in Lombardy, Italy.

OBJECTIVES: Asbestos is the main risk factor for peritoneal mesothelioma (PeM). However, due to its rarity, PeM has rarely been investigated in community-based studies. We examined the association between asbestos exposure and PeM risk in a general population in Lombardy, Italy. METHODS: From the regional mesothelioma registry, we selected PeM cases diagnosed in 2000-2015. Population controls (matched by area, gender and age) came from two case-control studies in Lombardy on lung cancer (2002-2004) and pleural mesothelioma (2014). Assessment of exposure to asbestos was performed through a quantitative job-exposure matrix (SYN-JEM) and expert evaluation based on a standardised questionnaire. We calculated period-specific and gender-specific OR and 90% CI using conditional logistic regression adjusted for age, province of residence and education. RESULTS: We selected 68 cases and 2116 controls (2000-2007) and 159 cases and 205 controls (2008-2015). The ORs for ever asbestos exposure (expert-based, 2008-2015 only) were 5.78 (90% CI 3.03 to 11.0) in men and 8.00 (2.56 to 25.0) in women; the ORs for definite occupational exposure were 12.3 (5.62 to 26.7) in men and 14.3 (3.16 to 65.0) in women. The ORs for ever versus never occupational asbestos exposure based on SYN-JEM (both periods) were 2.05 (90% CI 1.39 to 3.01) in men and 1.62 (0.79 to 3.27) in women. In men, clear positive associations were found for duration, cumulative exposure (OR 1.33 (1.19 to 1.48) per fibres/mL-years) and latency. CONCLUSIONS: Using two different methods of exposure assessment we provided evidence of a clear association between asbestos exposure and PeM risk in the general population.

Role of asbestos clearance in explaining long-term risk of pleural and peritoneal cancer: a pooled analysis of cohort studies.

OBJECTIVES: Models based on the multistage theory of cancer predict that rates of malignant mesothelioma continuously increase with time since first exposure (TSFE) to asbestos, even after the end of external exposure. However, recent epidemiological studies suggest that mesothelioma rates level off many years after first exposure to asbestos. A gradual clearance of asbestos from the lungs has been suggested as a possible explanation for this phenomenon. We analysed long-term trends of pleural and peritoneal cancer mortality in subjects exposed to asbestos to evaluate whether such trends were consistent with the clearance hypothesis. METHODS: We used data from a pool of 43 Italian asbestos cohorts (51 801 subjects). The role of asbestos clearance was explored using the traditional mesothelioma multistage model, generalised to include a term representing elimination of fibres over time. RESULTS: Rates of pleural cancer increased until 40 years of TSFE, but remained stable thereafter. On the other hand, we observed a monotonic increase of peritoneal cancer with TSFE. The model taking into account asbestos clearance fitted the data better than the traditional one for pleural (p=0.004) but not for peritoneal (p=0.09) cancer. CONCLUSIONS: Rates of pleural cancer do not increase indefinitely after the exposure to asbestos, but eventually reach a plateau. This trend is well described by a model accounting for a gradual elimination of the asbestos fibres. These results are relevant for the prediction of future rates of mesothelioma and in asbestos litigations.

Gender differences in pleural mesothelioma occurrence in Lombardy and Piedmont, Italy.

BACKGROUND: Higher mesothelioma rates in men (vs women) reflect more frequent and more intense asbestos exposure. We assessed the impact of exposure difference between genders on age-specific rates of pleural mesothelioma (PM) occurrence using data from two Italian regions. METHODS: We used data from the Lombardy and Piedmont mesothelioma registries (period 2000-2016, age 45-74 years) to compare rates of PM in men and women and to estimate the rate advancement period (RAP). RESULTS: Based on 3384 cases (2405 men, 979 women) in Lombardy and 2042 (1389 men, 653 women) in Piedmont, the rate ratio was 2.81 (90% confidence interval: 2.61-3.03) in Lombardy and 2.39 (2.17-2.62) in Piedmont. In both regions RAP ranged from 7 to 10 years (at age 45 and 63 in men, respectively). CONCLUSION: Men showed more than twofold increased PM rates and reached the same incidence as women 7-10 years earlier. RAP can be a useful measure of exposure impact on premature disease occurrence.

Cumulative asbestos exposure and mortality from asbestos related diseases in a pooled analysis of 21 asbestos cement cohorts in Italy.

BACKGROUND: Despite the available information on cancer risk, asbestos is used in large areas in the world, mostly in the production of asbestos cement. Moreover, questions are raised regarding the shape of the dose response relation, the relation with time since exposure and the association with neoplasms in various organs. We conducted a study on the relationship between cumulative asbestos exposure and mortality from asbestos related diseases in a large Italian pool of 21 cohorts of asbestos-cement workers with protracted exposure to both chrysotile and amphibole asbestos. METHODS: The cohort included 13,076 workers, 81.9% men and 18.1% women, working in 21 Italian asbestos-cement factories, with over 40 years of observation. Exposure was estimated by plant and period, and weighted for the type of asbestos used. Data were analysed with consideration of cause of death, cumulative exposure and time since first exposure (TSFE), and by gender. SMRs were computed using reference rates by region, gender and calendar time. Poisson regression models including cubic splines were used to analyse the effect of cumulative exposure to asbestos and TSFE on mortality for asbestos-related diseases. 95% Confidence Intervals (CI) were computed according to the Poisson distribution. RESULTS: Mortality was significantly increased for 'All Causes' and 'All Malignant Neoplasm (MN)', in both genders. Considering asbestos related diseases (ARDs), statistically significant excesses were observed for MN of peritoneum (SMR: men 14.19; women 15.14), pleura (SMR: 22.35 and 48.10), lung (SMR: 1.67 and 1.67), ovary (in the highest exposure class SMR 2.45), and asbestosis (SMR: 507 and 1023). Mortality for ARDs, in particular pleural and peritoneal malignancies, lung cancer, ovarian cancer and asbestosis increased monotonically with cumulative exposure. Pleural MN mortality increased progressively in the first 40 years of TSFE, then reached a plateau, while peritoneal MN showed a continuous increase. The trend of lung cancer SMRs also showed a flattening after 40 years of TSFE. Attributable proportions for pleural, peritoneal, and lung MN were respectively 96, 93 and 40%. CONCLUSIONS: Mortality for ARDs was associated with cumulative exposure to asbestos. Risk of death from pleural MN did not increase indefinitely with TSFE but eventually reached a plateau, consistently with reports from other recent studies.

Sensitivity to asbestos is increased in patients with mesothelioma and pathogenic germline variants in BAP1 or other DNA repair genes.

Pathogenic germline variants in the BAP1 tumor suppressor gene can cause a cancer syndrome called BAP1 tumor predisposition syndrome (BAP1-TPDS), which is characterized by predisposition to mesothelioma, melanoma, renal cell carcinoma, basal cell carcinoma, and other tumors. Other genes that may predispose to mesothelioma are CDKN2A and DNA repair genes. Asbestos exposure has often been reported in patients with malignant pleural mesothelioma (MPM) and germline variants in BAP1, but this exposure has never been quantified. We aimed to search for germline variants in BAP1 among 25 new Italian probands with suspected BAP1-TPDS, summarize the prevalence of these variants in 39 Italian patients with familial MPM and other tumors recruited over a 5-year period, and compare cumulative asbestos exposure in 14 patients with MPM and pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes with that of 67 patients without germline variants in 94 cancer-predisposing genes. We report here a new pathogenic germline variant in BAP1: c.783 + 2 T > C. The prevalence of pathogenic germline variants in BAP1 was 7.7% among patients with familial MPM (3/39). Patients with pathogenic germline variants in BAP1, CDKN2A, or DNA repair genes showed lower cumulative asbestos exposure than patients without germline variants in 94 cancer-predisposing genes (P = .00002). This suggests an interaction between genetic risk factors and asbestos in the development of mesothelioma.

The epidemiology of malignant mesothelioma in women: gender differences and modalities of asbestos exposure.

INTRODUCTION: The epidemiology of gender differences for mesothelioma incidence has been rarely discussed in national case lists. In Italy an epidemiological surveillance system (ReNaM) is working by the means of a national register. METHODS: Incident malignant mesothelioma (MM) cases in the period 1993 to 2012 were retrieved from ReNaM. Gender ratio by age class, period of diagnosis, diagnostic certainty, morphology and modalities of asbestos exposure has been analysed using exact tests for proportion. Economic activity sectors, jobs and territorial distribution of mesothelioma cases in women have been described and discussed. To perform international comparative analyses, the gender ratio of mesothelioma deaths was calculated by country from the WHO database and the correlation with the mortality rates estimated. RESULTS: In the period of study a case list of 21 463 MMs has been registered and the modalities of asbestos exposure have been investigated for 16 458 (76.7%) of them. The gender ratio (F/M) was 0.38 and 0.70 (0.14 and 0.30 for occupationally exposed subjects only) for pleural and peritoneal cases respectively. Occupational exposures for female MM cases occurred in the chemical and plastic industry, and mainly in the non-asbestos textile sector. Gender ratio proved to be inversely correlated with mortality rate among countries. CONCLUSIONS: The consistent proportion of mesothelioma cases in women in Italy is mainly due to the relevant role of non-occupational asbestos exposures and the historical presence of the female workforce in several industrial settings. Enhancing the awareness of mesothelioma aetiology in women could support the effectiveness of welfare system and prevention policies.

Postnatal risk factors for testicular cancer: The EPSAM case-control study.

Testicular cancer is considered to originate from an impaired differentiation of fetal germ cells, but puberty could represent another time window of susceptibility. Our study aimed at investigating the association between environmental exposures acting during puberty/adolescence (13-19 years of age) and the risk of testicular cancer. We used data of the EPSAM study, a case-control study on germ-cell testicular cancer conducted in the province of Turin, Italy, involving cases diagnosed between 1997 and 2008. Histologically confirmed cases (n = 255) and controls (n = 459) completed a postal questionnaire focusing in particular on the pubertal period (namely age 13 years) with questions on physical activity (competitive sports, gardening), lifestyle (alcohol consumption, smoking), occupational history and medical conditions. All analyses were adjusted for the matching variables, cryptorchidism and educational level. Having done at least one competitive sport during puberty (odds ratio [OR]: 0.72, 95% confidence interval: 0.52-1.00), gardening activities during puberty (OR: 0.62, 0.42-0.94) and having a lower weight than peers during puberty (OR: 0.64, 0.42-0.97) were all inversely associated with the risk of testicular cancer. No evidence of association between smoking or alcohol consumption during puberty and the risk of testicular cancer was observed. Regarding agriculture-related occupations, we found an association with the risk of testicular cancer both for occasional jobs during puberty (OR: 2.40, 95% CI: 1.08-5.29) and ever employment in adolescence (OR: 2.59, 95% CI: 0.83-8.10). Our results suggest that postnatal exposures could play a role in testicular cancer aetiology, at least when acting in puberty or adolescence.