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Objectives To assess dermal exposure to 16 polycyclic aromatic hydrocarbons (PAHs) in asphalt workers by applying polypropylene pads to six body sites (neck, shoulder, upper arm, wrist, groin, ankle), to identify the compounds and exposure sites most representative, and to integrate dermal exposure results with environmental and biological data. Methods Twenty-four asphalt workers were recruited. Dermal exposure was assessed during a single work shift. Sixteen PAHs (from naphthalene to indeno[1,2,3-cd]pyrene) were quantified via gas chromatography-mass spectrometry. Airborne exposure, urinary PAHs and monohydroxy metabolites were also investigated. Results Phenanthrene (PHE), present in all samples, was the most abundant compound (median 0.805–1.825 ng/cm 2 ). Benzo[a]pyrene (BaP) was present in 75% of the samples (0.046–0.101 ng/cm 2 ). Wrist had the highest contamination, with median PHE, pyrene (PYR), and BaP concentrations of 1.825, 0.527, and 0.063 ng/cm 2 . PHE and PYR on wrist correlated with almost all 3- to 4-ring PAHs (0.405≤r≤0.856), but not with BaP; BaP correlated with almost all 4- to 6- ring PAHs (0.584≤r≤0.633). Significant correlations were observed between PHE level, airborne exposure, and the corresponding urinary PHE and monohydroxy metabolites. For PYR, significant correlations existed only between urinary PYR and monohydroxy metabolites. Multiple linear regression analysis revealed that 42% of the end-of-shift monohydroxy metabolites were the result of airborne exposure, dermal exposure, and baseline levels of biomarkers. Conclusions Dermal exposure to PAHs was in the low ng/cm 2 range. PHE or PYR and BaP were the most representative compounds and the wrist was the best location to perform dermal exposure assessments. Both dermal and airborne exposure contributed to the total body burden of PAHs, though the relative contribution was analyte-dependent.

Objectives A large number of epidemiological studies addressed the issue of carcinogenicity of occupational exposures in petroleum refining. We present the results of the extension of the follow-up as of December 2006 of two Italian Refineries (refinery A and B). The mortality of the two cohorts was previously examined up to 1991 and 1999 respectively. Methods Standardised mortality ratios (SMR) and 95% CIs were calculated using as reference the regional mortalitys (Lombardy and Latium) specific by age and calendar period. Analyses by duration of employment, latency, year of first employment were performed. Results The main findings in refinery A were a twofold increased mortality from brain cancer and leukaemia; the leukaemia excess was particularly elevated among subjects employed before 1969. No consistent trends by duration of employment or latency was observed for brain cancer. In refinery B, increased risks for lung cancer, non-Hodgkin9s lymphoma (NHL) and brain cancer were detected. All deaths from brain cancer (3, SMR 5.0, 95% CI 1.6 to 15.6) and NHL occurred after 20 years of latency (4, SMR 5.2 95%CI 1.9 to 13.8). The lung cancer mortality was elevated among workers with duration of employment 10–19 years (SMR 2.8, 95%CI 1.7 to 4.6). Conclusions The main finding of an elevated mortality from lymphoemopoietic cancers (leukaemia and lymphoma) is in agreement with other studies in refinery workers. The observed excess is limited to workers employed before 1969. Exposure to benzene might be a plausible explanation. The increased lung cancer mortality cannot be entirely explained by confounding by smoking.

Objectives To investigate the effects of PM and metal components on blood DNA methylation of inflammation/coagulation related genes, among a group of foundry workers with well-characterised exposure to fine particles. Methods We recruited 63 male foundry workers (mean age=44y) in which we previously demonstrated a PM exposure-related pro-coagulant effect. Individual exposure to PM10, PM1, and metals was estimated based on area PM measurements and time spent by the study subjects in each area. Quantitative DNA methylation analysis of NOS3 and Et-1 genes was performed trough bisulfite PCR-pyrosequencing on blood leucocyte DNA obtained on the first day of a work week and after 3 days of work. Linear mixed models were fitted to evaluate the association between particles-metals exposure and methylation and between methylation and coagulation function (PT, aPTT, Endogenous Thrombin Potential (ETP)). Results Workers resulted exposed to a wide range of particle levels (PM10 from 73 to 1220 microg/m3) and of metal components (particularly Mn, Fe, Zn). We observed negative PM exposure-related correlations with NOS3 DNA methylation (β=-0.86, p=0.01 for PM10 and β=-1.12, p=0.02 for PM1). Zinc and Iron levels were negatively associated with NOS3 and Et-1 methylation. Finally, NOS3 and Et-1 methylation were negatively associated with ETP (β=-45.02, p=0.001 for NOS3 and β=-16.40, p=0.03 for Et-1). Conclusions Our results linked for the first time a test for global coagulation function (ETP) and DNA hypo-methylation of two candidate inflammation-related genes, and in turn DNA methylation and metal-rich PM exposure, suggesting a possible common path for PM exposure, methylation and blood coagulation.

Objectives Genetic susceptibility in work-related lung cancer aetiology could have an important public health impact. Few studies have previously evaluated this issue, with inconsistent results. We aimed to investigate interactions between exposure to occupational carcinogens and genetic polymorphisms in lung cancer aetiology, adopting a systematic integrated approach. Method EAGLE, a population-based case-control study, enrolled 2100 lung cancer cases and 2120 controls (Italy, 2002–2005). Lifetime work histories were collected for 4059 subjects and translated into exposure to six occupational carcinogens (asbestos, silica, polycyclic aromatic hydrocarbons, diesel exhausts, chromium, and nickel) using a job-exposure matrix. We selected 23 candidate genes among phase II metabolic genes reported in association with lung cancer susceptibility and/or metabolism of selected carcinogens. 298 tagging single nucleotide polymorphisms (SNPs) were genotyped on 4050 subjects. We tested for interaction within smoking-adjusted logistic regressions where SNPs were modelled individually, by gene group (using gene scores and haplotypes), and by pathways. False discovery rate (FDR) was used to account for multiple testing. Gene expression changes in lung tissues were studied for SNPs-carcinogens significant interactions. Results As asbestos had the highest impact on lung cancer burden, we restricted interaction tests to this carcinogen. GSTM4 polymorphisms consistently showed positive interactions across different analysis levels, especially by SNP group score (FDR-adjusted p-value for interaction Conclusions GSTM4 polymorphisms may play a role in asbestos-related lung cancer aetiology. These findings are biologically plausible and have never previously been reported; they should therefore be validated in further studies.

Objectives To examine the mortality experience of workers employed in four Italian oil refineries. Method The cohort included 5112 male workers ever employed between 1949 and 2011. The average follow-up period was 49 years. SMR and 95% CI were calculated using as reference age-gender-calendar specific regional rates. Analyses by duration of employment and latency were performed. Results In the whole cohort, pleural (6 deaths, SMR 1.59; 95% CI 0.7–3.5), brain cancers (14 deaths, SMR 1.47; 95% CI 0.9–2.5) and lymphatic leukaemia (LL) (8 deaths, SMR 1.81; 95% CI 0.9–3.6) showed increased risks. All pleural cancers occurred after 10 years of latency and the highest risk was observed among workers with duration ≥ 20 years; the brain cancer excess was confined in the shortest duration and latency. The LL excess regarded workers with latency and duration longer than 10 years. Mortality from Non-Hodking lymphoma (NHL) (13 deaths) and acute myeloid leukaemia (AML) did not differ from the expectation. All AML cases (4 deaths) occurred after 20 years of latency (SMR 1.55, 95% CI 0.6–4.1) and a two fold-increased risk was observed in the longest duration. Mortality for NHL + LL (recently classified as subtypes of NHL) showed increased risks among workers with duration and latency longer than 20 years. Conclusions Our findings confirmed recent epidemiological evidences of an increased risk for pleural cancer and are coherent with most recent meta-analyses suggesting a limited evidence of an increased risk for lymphatic neoplasms in refinery workers possibly due to past exposure to benzene.

Objectives Epidemiological findings suggest an association between particulate matter (PM) exposure and hypercoagulability and thrombosis. The underlying mechanism for PM-related procoagulative effects is still unknown, but recently, elevated levels of extracellular histones have been indicated as possible mediators in inflammatory conditions. In 63 steel workers, we evaluated the effects of exposure to PM and PM metal components on two extracellular histone modifications (histone H3 lysine 4 trimethylation: H3K4me3; histone H3 lysine 9 acetylation: H3K9ac), and the association between both H3K4me3 and H3K9ac and coagulation markers. Methods H3K4me3 and H3K9ac were determined in plasma samples through ELISA. Prothrombin time (PT), activated partial thromboplastin time (APTT), endogenous thrombin potentials (ETPs) with/without exogenous triggers and with/without soluble thrombomodulin, tissue-type plasminogen activator (t-PA) antigen, D-dimer, C-reactive protein (CRP) were measured as coagulation markers. Exposure to inhalable metal components (aluminum, manganese, nickel, zinc, arsenic, lead, iron), and to particle mass (PM with aerodynamic diameters, Results Both H3K4me3 and H3K9ac were increased in association with PM1(β[H3K4me3)=0.34, P=0.01; β[H3K9ac)=0.27, P=0.02). H3K4me3 was increased in association with air levels of zinc (β=0.25, P=0.04) and iron (β=0.38, P=0.01). H3K9ac showed borderline positive association with air level of zinc (β=0.18, P=0.07). Histone modifications also showed significant association with ETP TM+ (β[H3K4me3)=355.27, P=0.05; β[H3K9ac)=389.03, P=0.05), and borderline association with t-PA antigen (β[H3K4me3)=-3.42, P=0.06; β[H3K9ac)=-3.23, P=0.06). Conclusions Our results indicate a potential role of extracellular histones in hypercoagulability induced by PM exposure

Objectives The Lombardy Mesothelioma Registry (RML) was established in 2000 in the most populated (9 100 000 residents) and industrialised region of Italy. We evaluated the trend of malignant mesothelioma (MM) in 2000-07 and the sources of asbestos exposure collected from the patient/next-of-kin by a standardised questionnaire. Methods We calculated age-standardised rates (standard: Europe) and analysed the number of cases/year using Poisson regression. We evaluated asbestos exposure profile (occupational, non-occupational, unlikely/unknown) using multinomial logistic regression. Results We recorded 2462 verified MM cases (1574 men, 888 women). The age-standardised rates (×100 000/year) were 3.6 (men) and 1.4 (women). In both genders, we found a 3.0% increase of MM cases/year (p=0.001). Interview was obtained in 2333 cases (94.7%) and directly from patients in 1282. Occupational exposure was found for 1124 (71.4%) men and 322 (36.3%) women. Non-occupational asbestos exposure was more frequent among women (No. 118, 13.3%) than in men (No. 51, 3.2%). We did not find evidence of exposure to asbestos in 399 men (25.3%) and 448 women (50.4%). The exposure profile did not vary over years (p=0.49). Direct interviews were more likely to identify asbestos exposure (p Conclusions The MM burden in Lombardy (among the highest in Italy), are increasing. This increase is real and not due to ascertainment bias. Asbestos exposure was mainly occupational and more frequent among men; we found no variation of the exposure profiles over time. This work was supported by Regione Lombardia Conv. 14013/RU01/06/2010

Objectives Exposure to occupational carcinogens is an important preventable cause of lung cancer. Most of the previous studies were in highly exposed industrial cohorts The authors9 aim was to quantify lung cancer burden attributable to occupational carcinogens in a general population. Methods They applied a new job-exposure matrix (JEM) to translate lifetime work-histories into never, low, and high exposure levels for 6 known/suspected lung carcinogens in the Environment And Genetics in Lung cancer Etiology (EAGLE) case-control study, that enrolled 2100 lung cancer cases and 2120 population controls in Lombardy, Italy, in 2002–2005. ORs and 95% CIs were calculated in men (1537 cases and 1617 controls), by logistic regression adjusted for potential confounders, including smoking and co-exposure to JEM carcinogens. The population attributable fraction (PAF) was estimated as impact measure. Results Men showed an excess risk even at low exposure to asbestos (OR=1.76, 95% CI: 1.42 to 2.18), crystalline silica (OR=1.31, 95% CI: 1.00 to 1.71), and nickel-chromium (OR=1.18, 95% CI: 0.90 to 1.53), with positive trends for intensity. An increased risk only for high exposure to polycyclic aromatic hydrocarbons was found (OR=1.64, 95% CI: 0.99 to 2.70). The PAFs for any exposure to asbestos, silica and nickel-chromium were 18.1%, 5.7%, and 7.0%, respectively, corresponding to about 300–800 cases/year in Lombardy. Conclusions These findings support the substantial role of occupational carcinogens on lung cancer burden, even in a low exposed general population.