Search

The authors investigated the relation between alcohol consumption and lung cancer risk in the Environment and Genetics in Lung Cancer Etiology (EAGLE) Study, a population-based case-control study. Between 2002 and 2005, 2,100 patients with primary lung cancer were recruited from 13 hospitals within the Lombardy region of Italy and were frequency-matched on sex, area of residence, and age to 2,120 randomly selected controls. Alcohol consumption during adulthood was assessed in 1,855 cases and 2,065 controls. Data on lifetime tobacco smoking, diet, education, and anthropometric measures were collected. Adjusted odds ratios and 95% confidence intervals for categories of mean daily ethanol intake were calculated using unconditional logistic regression. Overall, both nondrinkers (odds ratio = 1.42, 95% confidence interval: 1.03, 2.01) and very heavy drinkers (>/=60 g/day; odds ratio = 1.44, 95% confidence interval: 1.01, 2.07) were at significantly greater risk than very light drinkers (0.1-4.9 g/day). The alcohol effect was modified by smoking behavior, with no excess risk being observed in never smokers. In summary, heavy alcohol consumption was a risk factor for lung cancer among smokers in this study. Although residual confounding by tobacco smoking cannot be ruled out, this finding may reflect interplay between alcohol and smoking, emphasizing the need for preventive measures.

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.

Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR] = 1.23, 95% confidence interval [CI] = 1.13–1.33, p = 3.02 × 10−7), but not with other histologic types (OR = 1.01, p = 0.84 and OR = 1.00, p = 0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR = 1.24, 95% CI = 1.17–1.31, p = 3.74 × 10−14 for AD; OR = 0.99, p = 0.69 and OR = 0.97, p = 0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.

We investigated the effect of chronic exposure to polycyclic aromatic hydrocarbons (PAHs) on DNA methylation states (percentage of methylated cytosines (%mC)) in Polish male nonsmoking coke-oven workers and matched controls. Methylation states of gene-specific promoters (p53, p16, HIC1 and IL-6) and of Alu and LINE-1 repetitive elements, as surrogate measures of global methylation, were quantified by pyrosequencing in peripheral blood lymphocytes (PBLs). DNA methylation was evaluated in relation to PAH exposure, assessed by urinary 1-pyrenol and anti-benzo[a]pyrene diolepoxide (anti-B[a]PDE)-DNA adduct levels, a critical genetic damage from B[a]P. We also evaluated whether PAH-induced DNA methylation states were in turn associated with micronuclei in PBLs, an indicator of chromosomal instability.

Multiple myeloma (MM) is characterized by a wide spectrum of genetic changes. Global hypomethylation of repetitive genomic sequences such as long interspersed nuclear element 1 (LINE-1), Alu and satellite alpha (SAT-alpha) sequences has been associated with chromosomal instability in cancer. Methylation status of repetitive elements in MM has never been investigated. In the present study, we used a quantitative bisulfite-polymerase chain reaction pyrosequencing method to evaluate the methylation patterns of LINE-1, Alu and SAT-alpha in 23 human myeloma cell lines (HMCLs) and purified bone marrow plasma cells from 53 newly diagnosed MM patients representative of different molecular subtypes, 7 plasma cell leukemias (PCLs) and 11 healthy controls. MMs showed a decrease of Alu [median: 21.1 %5-methylated cytosine (%5mC)], LINE-1 (70.0%5mC) and SAT-alpha (77.9%5mC) methylation levels compared with controls (25.2, 79.5and 89.5%5mC, respectively). Methylation levels were lower in PCLs and HMCLs compared with MMs (16.7 and 14.8%5mC for Alu, 45.5 and 42.4%5mC for LINE-1 and 33.3 and 43.3%5mC for SAT-alpha, respectively). Notably, LINE-1 and SAT-alpha methylation was significantly lower in the non-hyperdiploid versus hyperdiploid MMs (P = 0.01 and 0.02, respectively), whereas Alu and SAT-alpha methylation was significantly lower in MMs with t(4;14) (P = 0.02 and 0.004, respectively). Finally, we correlated methylation patterns with DNA methyltransferases (DNMTs) messenger RNA levels showing in particular a progressive and significant increase of DNMT1 expression from controls to MMs, PCLs and HMCLs (P < 0.001). Our results indicate that global hypomethylation of repetitive elements is significantly associated with tumor progression in MM and may contribute toward a more extensive stratification of the disease.

Background Altered patterns of gene expression mediate the effects of particulate matter (PM) on human health, but mechanisms through which PM modifies gene expression are largely undetermined. Objectives We aimed at identifying short- and long-term effects of PM exposure on DNA methylation, a major genomic mechanism of gene expression control, in workers in an electric furnace steel plant with well-characterized exposure to PM with aerodynamic diameters < 10 μm (PM10). Methods We measured global genomic DNA methylation content estimated in Alu and long interspersed nuclear element-1 (LINE-1) repeated elements, and promoter DNA methylation of iNOS (inducible nitric oxide synthase), a gene suppressed by DNA methylation and induced by PM exposure in blood leukocytes. Quantitative DNA methylation analysis was performed through bisulfite PCR pyrosequencing on blood DNA obtained from 63 workers on the first day of a work week (baseline, after 2 days off work) and after 3 days of work (postexposure). Individual PM10 exposure was between 73.4 and 1,220 μg/m3. Results Global methylation content estimated in Alu and LINE-1 repeated elements did not show changes in postexposure measures compared with baseline. PM10 exposure levels were negatively associated with methylation in both Alu [β = −0.19 %5-methylcytosine (%5mC); p = 0.04] and LINE-1 [β = −0.34 %5mC; p = 0.04], likely reflecting long-term PM10 effects. iNOS promoter DNA methylation was significantly lower in postexposure blood samples compared with baseline (difference = −0.61 %5mC; p = 0.02). Conclusions We observed changes in global and gene specific methylation that should be further characterized in future investigations on the effects of PM.

ObjectiveThe pathogenesis of sporadic pituitary tumors is unknown. Loss-of-function mutations of aryl hydrocarbon receptor-interacting protein (AIP) have been identified in patients with familial pituitary tumors. AIP is a chaperone protein with multifunction properties, including modulation of the transcriptional activity of the aryl hydrocarbon receptor, which mediates toxicological and carcinogenic dioxin effects.DesignWe investigated the incidence of pituitary tumors in the Seveso population exposed to 2,3,7,8-tetrachlorodibenzo-para-dioxin following an industrial accident in 1976.MethodsThrough the hospital discharge registration system of Lombardy Region, we identified incident cases of pituitary adenomas between 1976 and 1996 in the Seveso population, subdivided in zone A (n=804), B (n=5.941), and R (n=38.624) according to high, intermediate, and low exposure to dioxin respectively, and in the surrounding non-contaminated area, as reference (n=232 745).ResultsWe identified 42 pituitary adenomas in the reference area, 1 prolactinoma in zone A (rate ratio (RR) 6.2; 95% CI 0.9–45.5, P=0.07), 2 nonfuctioning pituitary tumors (NFPAs) in zone B (RR 1.9; 95% CI 0.5–7.7, P=0.39), and 3 prolactinomas and 2 NFPAs in zone R (RR 0.7; 95% CI 0.3–1.8, P=0.48).ConclusionsThe study is unique with regard to the availability of epidemiological and clinical data in an area of relatively pure dioxin exposure. The study indicates no statistically significant increase of incident pituitary tumors in this area, although the tendency toward a higher risk (three cases in zones A and B) of pituitary tumors in subjects exposed to high–intermediate dioxin concentrations in comparison with nonexposed population suggests the need for extended follow-up.

D uring the past 10 years, human biological material—body fluids, cells, tissues, intracellular substances or DNA—and the related data have become an important resource for academic medical research, and for the industrial development of diagnostics and therapeutics (Godard et al, 2003). The increasing creation and use of biobanks that store both the material and the related data bears witness to their scientific value, but there is still no consensus— either internationally, or at the European or national levels—about the regulations that should govern biobanks in ethical or legal terms (Cambon-Thomsen et al, 2007; Kaye, 2005). In particular, consent models designed to appropriately regulate biobankbased research are characterized by a maze of laws, policies and ethical recommendations that range from strict (specific informed consent) to basically unrestricted use (broad consent; Boggio et al, 2007).

Malignant Mesothelioma (MM) is a rare neoplasm associated with asbestos exposure. In 24,5% of MM cases reported to the Lombardy Mesothelioma Registry (LMR), asbestos exposure has been defined as "unknown".To evaluate the cases with "unknown exposure to asbestos" diagnosed in 2000-2004 in agreement with new knowledge about source of asbestos exposure.Information regarding exposure has been reviewed in order to select the cases susceptible of further investigations, including: interview of relatives and/or colleagues; further evaluations by local PSAL (Prevention and Security in workplace) services; contact of industrial hygienists; analysis of production processes. The same procedure has been followed for extra-occupational exposure. These cases have been subjected to the LMR evaluation group.Fourthy four out of 364 (12,1%) MM have been reclassified. In 47,7% of the cases, a "possible occupational exposure" has been recognized, 15,9% have been attributed a "certain occupational exposure", while 36,4% an extra-occupational (domestic, environmental and leisure-time) exposure. No significant differences between age, sex, cancer site, diagnostic certainty, residence, year of diagnosis, interviewed subjects were detected. The occupational sector with the highest amount of reclassifications was the clothing production.The detailed reconstruction of clinical and occupational history and of lifestyle habits of patients affected by MM, close cooperation with Local Services of Occupational Medicine and literature review make it possible for previously overlooked asbestos exposure to be acknowledged.

Background: Particulate air pollution is a risk factor for cardiovascular diseases and thrombosis. Long-term exposure to particulate matter with a diameter

The role of haplotypes and the interaction of haplotypes and smoking in lung cancer risk have not been well characterized. We analyzed data from an Italian population-based, case-control study with 1815 lung cancer patients and 1959 healthy controls in discovery, and performed a validation using a case-control study with 2983 lung cancer patients and 3553 healthy controls of European ancestry for replication. Sliding window haplotype analysis within chromosome 15, evaluating 4722250 haplotypes and pair-wise haplotype analysis identified that CHRNA5 rs588765-rs16969968 was the most significant haplotype associated with lung cancer risk (omnibus P = 8.35×10(-15) in discovery and 7.26×10(-14) in replication), and improved the prediction of case status over that provided by the individual SNPs rs16969968 or rs588765 (likelihood ratio test P = 0.006 for rs16969968 and 3.83×10(-14) for rs588765 in discovery, 0.009 for rs16969968 and 4.62×10(-13) for rs588765 in replication, compared with rs588765-rs16969968). Compared with the wild-type homozygous diplotype, CA/CA homozygote exhibited an approximately 2-fold increase risk for lung cancer (OR = 2.12; 95% CI 1.46-3.07 in discovery, and OR = 2.01; 95% CI 1.51-2.67 in replication). Even among never-smokers, CA/CA homozygote showed an increased risk of lung cancer with borderline significance in discovery (adjusted OR = 1.75, 95% CI 0.96-3.19) and statistical significance in replication (adjusted OR = 2.10, 95% CI 1.12-3.96), compared with combined genotypes (CG/CG + CG/TG). Accordingly, rs588765-rs16969968 may be a genetic marker to lung cancer risk, even among never-smokers.

Increased nut consumption has been associated with a reduced risk of colon cancer. No study has examined the association between nut consumption and lung cancer risk. We investigated the associatio...

Background: Population-based estimates of absolute risk of lung cancer recurrence, and of mortality rates after recurrence, can inform clinical management. Methods: We evaluated prognostic factors for recurrences and survival in 2098 lung cancer case patients from the general population of Lombardy, Italy, from 2002 to 2005. We conducted survival analyses and estimated absolute risks separately for stage IA to IIIA surgically treated and stage IIIB to IV non–surgically treated patients. Results: Absolute risk of metastases exceeded that of local recurrence in every stage and cell type, highlighting the systemic threat of lung cancer. In stage I, the probability of dying within the first year after diagnosis was 2.7%, but it was 48.3% within first year after recurrence; in stage IV, the probabilities were 57.3% and 80.6%, respectively. Over half the patients died within one year of first metastasis. Although in stages IA to IB about one-third of patients had a recurrence, stage IIA patients had a recurrence risk (61.2%) similar to stage IIB (57.9%) and IIIA (62.8%) patients. Risk of brain metastases in stage IA to IIIA surgically treated non–small cell lung cancer patients increased with increasing tumor grade. Absolute risk of recurrence was virtually identical in adenocarcinoma and squamous cell carcinoma patients. Conclusions: This population-based study provides clinically useful estimates of risks of lung cancer recurrence and mortality that are applicable to the general population. These data highlight the need for more effective adjuvant treatments overall and within specific subgroups. The estimated risks of various endpoints are useful for designing clinical trials, whose power depends on absolute numbers of events. Lung cancer is the leading cause of cancer deaths worldwide (

According to Italian Legislative Decree 81/2008 and subsequent modifications the Regions and Autonomous Provinces have a innovative and complex role: 1) to regulate and coordinate the total prevention system and 2) to develop interventions/initiatives through regional/local occupational safety and health (OSH) department using not only inspections and controls but education, training and support. Recommendations also include consolidating the role of actors involved in preventing risks to occupational health throughout occupational safety and health education and training, keys for a successful process to improve prevention system. As result of changing world of work and OSH legislation the INSuLa project has creating a national survey involving of all Italian prevention system actors, in order to evaluate implementation and impact of the actual regulations. According to overall objective of the INSuLA project, for the first time in Italy, we studied about operators in regional/local OSH department. The purpose of this paper is to show and recognize the individual learning paths, the perception of adequacy education degree, the exploring criticalities andthe training needs.

Background: Exposure to air pollution is associated with a short-term increase in mortality, and this field has begun to focus on health impact assessment. Objectives: Our aim was to estimate the impact of PM10 on mortality within 2 days from the exposure in the Italian region of Lombardy for the year 2007, at the municipality level, examining exposure entailed by daily intermunicipality commuting and accounting for uncertainty propagation. Methods: We combined data from different sources to derive probabilistic distributions for all input quantities used to calculate attributable deaths (mortality rates, PM10 concentrations, estimated PM10 effects, and commuting flows) and applied a Monte Carlo procedure to propagate uncertainty and sample the distribution of attributable deaths for each municipality. Results: We estimated that annual average PM10 concentrations above the World Health Organization-recommended threshold of 20 μg/m3 were responsible for 865 short-term deaths (80% credibility interval: 475, 1,401), 26% of which were attributable to PM10 above the European Union limit of 40 μg/m3. Reducing annual average PM10 concentrations > 20 μg/m3 by 20% would have reduced the number of attributable deaths by 36%. The largest estimated impacts were along the basin of the Po River and in the largest cities. Commuting contributed to the spatial distribution of the estimated impact. Conclusions: Our estimates, which incorporated uncertainty quantification, indicate that the short-term impact of PM10 on mortality in Lombardy in 2007 was notable, and that reduction in air pollution would have had a substantial beneficial effect on population health. Using commuting data helped to identify critical areas for prioritizing intervention. Citation: Baccini M, Grisotto L, Catelan D, Consonni D, Bertazzi PA, Biggeri A. 2015. Commuting-adjusted short-term health impact assessment of airborne fine particles with uncertainty quantification via Monte Carlo simulation. Environ Health Perspect 123:27–33; http://dx.doi.org/10.1289/ehp.1408218

Several epidemiologic investigations have demonstrated that ambient air pollution is associated with increased risk of cardiovascular disease (Brook et al. 2004). In particular, acute increases in ambient particulate matter (PM) levels have been associated with myocardial infarction, stroke, and other adverse effects on cardiovascular function (Biggeri et al. 2004; Forastiere et al. 2005; Katsouyanni et al. 2001; O’Neill et al. 2005; Samet et al. 2000b; Schwartz et al. 2005; Wellenius et al. 2005; Zanobetti and Schwartz 2005; Zanobetti et al. 2004). The mechanisms linking inhalation of air pollutants to an increased cardiovascular risk are not fully understood (Bhatnagar 2006; Brook et al. 2002; Donaldson et al. 2001; Nel 2005; Peters et al. 1997, 2001). Epidemiologic investigations have demonstrated that high plasma levels of total homocysteine (tHcy) are an independent risk factor for vascular disease, including coronary artery, cerebrovascular, and peripheral occlusive disease (Davey Smith and Ebrahim 2005; Welch and Loscalzo 1998). In addition to fasting tHcy measurements, tHcy determination after oral methionine load is used to identify individuals with mild impairment of Hcy metabolism, in whom fasting tHcy may be normal but postmethionine-load (PML) tHcy concentration is increased (Refsum et al. 2004). Alveolar and systemic inflammation has been proposed as a central component in the series of events linking the exposure to inhaled pollutants to the observed increases in cardiovascular morbidity and mortality (Brook et al. 2004; Seaton et al. 1995). Inflammation is a known determinant of hyperhomocysteinemia (Gori et al. 2005; von Eckardstein et al. 1994), and both air pollution and plasma tHcy have been associated with increased levels of C-reactive protein, fibrinogen, and interleukin-6 (Evans et al. 1997; Ghio et al. 2003; Gori et al. 2005; Pekkanen et al. 2000; Peters et al. 2001; Schwartz 2001; Seaton et al. 1999; von Eckardstein et al. 1994). However, whether air pollution exposure is correlated with increased tHcy levels has never been determined. Gori et al. (2005) suggested previously that short-term changes in inflammatory markers are associated with hyperhomocysteinemia when coupled with a mild persistent inflammatory state. In healthy subjects, tobacco smoking is a common cause of persistent low-level inflammation, and smoking has been also shown to induce elevated tHcy levels (Bazzano et al. 2003; De Bree et al. 2002; Guttormsen et al. 1996). In the present study, we investigate the effects of air pollution levels on fasting and PML tHcy in 1,213 normal subjects from Lombardia, Italy. In addition, we examined potential effect modification by cigarette smoking of the relation between air pollution and tHcy.

Benzene is a human carcinogen and an ubiquitous environmental pollutant. Identification of specific and sensitive biological markers is critical for the definition of exposure to low benzene level and the evaluation of the health risk posed by this exposure. This investigation compared urinary trans,trans-muconic acid (t,t-MA), S-phenylmercapturic acid, and benzene (U-benzene) as biomarkers to assess benzene exposure and evaluated the influence of smoking and the genetic polymorphisms CYP2E1 (RsaI and DraI) and NADPH quinone oxidoreductase-1 on these indices. Gas station attendants, urban policemen, bus drivers, and two groups of controls were studied (415 subjects). Median benzene exposure was 61, 22, 21, 9 and 6 μg/m3, respectively, with higher levels in workers than in controls. U-benzene, but not t,t-MA and S-phenylmercapturic acid, showed an exposure-related increase. All the biomarkers were strongly influenced by cigarette smoking, with values up to 8-fold higher in smokers compared with nonsmokers. Significant correlations of the biomarkers with each other and with urinary cotinine were found. A possible influence of genetic polymorphism of CYP2E1 (RsaI and/or DraI) on t,t-MA and U-benzene in subjects with a variant allele was found. Multiple linear regression analysis correlated the urinary markers with exposure, smoking status, and CYP2E1 (RsaI; R2 up to 0.55 for U-benzene). In conclusion, in the range of investigated benzene levels (

Exposure measurements of concentrations that are non-detectable or near the detection limit (DL) are common in environmental research. Proper statistical treatment of non-detects is critical to avoid bias and unnecessary loss of information. In the present work, we present an overview of possible statistical strategies for handling non-detectable values, including deletion, simple substitution, distributional methods, and distribution-based imputation. Simple substitution methods (e.g., substituting 0, DL/2, DL/ radical2, or DL for the non-detects) are the most commonly applied, even though the EPA Guidance for Data Quality Assessment discouraged their use when the percentage of non-detects is >15%. Distribution-based multiple imputation methods, also known as robust or "fill-in" procedures, may produce dependable results even when 50-70% of the observations are non-detects and can be performed using commonly available statistical software. Any statistical analysis can be conducted on the imputed datasets. Results properly reflect the presence of non-detectable values and produce valid statistical inference. We describe the use of distribution-based multiple imputation in a recent investigation conducted on subjects from the Seveso population exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in which 55.6% of plasma TCDD measurements were non-detects. We suggest that distribution-based multiple imputation be the preferred method to analyze environmental data when substantial proportions of observations are non-detects.

Biomarkers of benzene exposure and effect were evaluated in 158 Bulgarian petrochemical workers and 50 matched controls. Air exposures to benzene averaged about 1.8 ppm, for workers and 0.02 ppm for controls. Urinary trans,trans-muconic acid, and S-phenylmuconic acid, showed dose response relationships with benzene air exposure. The dose response curve for DNA single strand breaks (SSB), but not for the metabolites, showed a saturation effect. NQO1 genotype had a significant effect on SSB. We conclude that the pathways for these metabolites may be distinct from those involved in some forms of genotoxic damage induced by benzene.

Summary Background The Seveso, Italy accident of 1976 exposed a large population to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or simply dioxin). The accident resulted, mostly among children, in one of the largest ever-reported outbreaks of chloracne, the typical skin disorder due to halogenated-hydrocarbon compounds. Objectives Approximately 20 years after the accident, we conducted an epidemiological study in Seveso to investigate (a) the health status of chloracne cases; (b) TCDD-chloracne exposure–response relationship; and (c) factors modifying TCDD toxicity. Methods From 1993 to 1998, we recruited 101 chloracne cases and 211 controls. Trained interviewers administered a structured questionnaire assessing, among other epidemiological variables, information on an extensive list of diseases. During the interview, individual pigmentary characteristics were determined. We measured plasma TCDD levels using high-resolution gas chromatography/mass spectrometry. Results Plasma TCDD was still elevated (> 10 ppt) in 78 (26·6%) of the 293 subjects with adequate plasma samples, particularly in females, in subjects who had eaten home-grown animals, and in individuals with older age, higher body mass index and residence near the accident site. After 20 years, health conditions of chloracne cases were similar to those of controls from the Seveso area. Elevated plasma TCDD was associated with chloracne [odds ratio (OR) = 3·7, 95% confidence interval (CI) 1·6–8·8, adjusted for age, sex and residence]. Chloracne risk was higher in subjects younger than 8 years at the accident (OR = 7·4, 95% CI 1·8–30·3) and, contrary to previous hypotheses, did not increase at puberty onset or in teenage years. Subjects with elevated TCDD levels and light hair colour had higher relative odds of chloracne (OR = 9·2, 95% CI 2·6–32·5). Conclusions Dioxin toxicity in chloracne cases was confined to the acute dermatotoxic effects. Chloracne occurrence appeared related to younger age and light hair colour. Age-related dioxin elimination or dilution must be taken into account in interpreting these results.

The Clinica del Lavoro was created in Milan at the beginning of the 20th century by Luigi Devotto, who deemed it essential for physicians and health researchers to get involved in the life and health problems of working populations. The main roles of the Clinica del Lavoro were to educate medical students and train physicians; study actual workplaces, examine health and safety hazards and their noxious effects; and create initiatives and services to protect and promote workers' health. Important scientific contributions were made in several fields, including chemical carcinogenesis, effects of mineral and biologicalfibers, mechanism of action of silica dust, methods for the detection and measurements of toxic substances in both the work environment and workers' biological media.

In 1997 the International Agency for Research on Cancer (IARC) classified 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD; the most potent dioxin congener) as a group 1 carcinogen based on limited evidence in humans, sufficient evidence in experimental animals, and extensive mechanistic information indicating that TCDD acts through a mechanism involving the aryl hydrocarbon receptor (AhR), which is present in both humans and animals. The judgment of limited evidence in humans was based primarily on an elevation of all cancers combined in four industrial cohorts. The group 1 classification has been somewhat controversial and has been challenged in the literature in recent years. In this article we review the epidemiologic and mechanistic evidence that has emerged since 1997. New epidemiologic evidence consists primarily of positive exposure–response analyses in several of the industrial cohorts, as well as evidence of excesses of several specific cancers in the Seveso accident cohort. There are also new data regarding how the AhR functions in mediating the carcinogenic response to TCDD. The new evidence generally supports the 1997 IARC classification.

Approximately 20 years after the Seveso, Italy accident, we conducted a population-based study to evaluate the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure upon immune and mechanistically based biomarkers of dioxin response in humans. TCDD toxic effects are known to be mediated by the aryl-hydrocarbon receptor (AhR). We randomly selected 62 study subjects from the highest exposed zones and 59 from the surrounding non-contaminated area. Current lipid-adjusted plasma TCDD concentrations in these subjects ranged from 3.5 to 90 ng/kg (or ppt) and were negatively associated with plasma IgG concentrations (r=-0.35; P = 0.0002). The expression of genes in the AhR-dependent pathway, including AhR, aryl-hydrocarbon receptor nuclear translocator (ARNT), CYP1A1, and CYP1B1 transcripts, and the CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity was measured in lymphocytes. AhR mRNA levels in uncultured lymphocytes were negatively associated with plasma TCDD (P=0.03). When mitogen-induced lymphocytes were cultured with 10nM TCDD, all AhR-dependent genes were induced 1.2- to 13-fold. In these cells, plasma TCDD was associated with decreased EROD activity. Markers within the AhR pathway were correlated with one another. Our findings suggest the presence of long-term effects in the subjects exposed to TCDD after the Seveso accident.

Approximately 20 years after the Seveso, Italy, accident we conducted a population-based study to evaluate the impact of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure on cancer using mechanistically based biomarkers of dioxin response in humans. TCDD toxic effects are mediated by the aryl hydrocarbon receptor (AhR). We studied the AhR-dependent pathway in lymphocytes from 62 subjects randomly sampled from the highest exposed zones and 59 subjects from the surrounding non-contaminated area, frequency matched for age, gender and smoking. To our knowledge, this is the most comprehensive investigation to date designed to evaluate the key genes in the pathway, including AhR, aryl hydrocarbon receptor nuclear translocator, CYP1A1 and CYP1B1 transcripts and CYP1A1-associated 7-ethoxyresorufin O-deethylase (EROD) activity in a population heavily exposed to dioxin. Current lipid-adjusted plasma TCDD concentrations in these subjects ranged from 3.5 to 90 ng/kg (or p.p.t.) and were negatively associated with AhR mRNA in unstimulated peripheral blood mononuclear cells (P = 0.03). When mitogen-induced lymphocytes were cultured with 10 nM TCDD, all AhR-dependent genes were induced 1.2- to 13-fold. In these cells, plasma TCDD was associated with decreased EROD activity. In addition, there was a strong positive correlation between AhR and CYP1A1 expression (P = 0.001) and between AhR and CYP1B1 expression (P = 0.006). CYP1A1 expression was also strongly correlated with EROD activity (P = 0.001). The analysis of the expression of dioxin-inducible genes involved in carcinogenesis may help in determining dose-response relationships for human exposure to dioxin in vivo and in assessing the variability of human response, which may indicate the presence of subjects more susceptible to disease as a result of such exposures.

Background Blood pressure (BP) is a complex, multifactorial clinical outcome driven by genetic susceptibility, behavioral choices, and environmental factors. Many molecular mechanisms have been proposed for the pathophysiology of high BP even as its prevalence continues to grow worldwide, increasing morbidity and marking it as a major public health concern. To address this, we evaluated miRNA profiling in blood leukocytes as potential biomarkers of BP and BP-related risk factors. Methods The Beijing Truck Driver Air Pollution Study included 60 truck drivers and 60 office workers examined in 2008. On two days separated by 1–2 weeks, we examined three BP measures: systolic, diastolic, and mean arterial pressure measured at both pre- and post-work exams for blood NanoString nCounter miRNA profiles. We used covariate-adjusted linear mixed-effect models to examine associations between BP and increased miRNA expression in both pooled and risk factor-stratified analyses. Results Overall 43 miRNAs were associated with pre-work BP (FDR

Few studies have examined the incidence of malignant mesothelioma (MM) associated with distinct sources of asbestos exposure (occupational, familial, or environmental). We assessed the impact of asbestos exposure—global and by source—on the incidence of MM in Broni, an Italian town in which an asbestos cement factory once operated (1932–1993). Based on data collected by the Lombardy Mesothelioma Registry, we calculated the number of observed and expected MM cases among workers, their cohabitants, and people living in the area in 2000–2011. We identified 147 MM cases (17.45 expected), 138 pleural and nine peritoneal, attributable to exposure to asbestos from the factory. Thirty-eight cases had past occupational exposure at the factory (2.33 expected), numbering 32 men (26 pleural, six peritoneal) and six women (four pleural, two peritoneal). In the families of the workers, there were 37 MM cases (4.23 expected), numbering five men (all pleural) and 32 women (31 pleural, one peritoneal). Among residents in Broni or in the adjacent/surrounding towns, there were 72 cases of pleural MM (10.89 expected), numbering 23 men and 49 women. The largest MM excess was found in the towns of Broni (48 observed, 3.68 expected) and Stradella (16 observed, 1.85 expected). This study documents the large impact of the asbestos cement factory, with about 130 excess MM cases in a 12-year period. The largest MM burden was among women, from non-occupational exposure. Almost half of the MM cases were attributable to environmental exposure. Keywords: Asbestos, Mesothelioma, Cancer incidence, Occupational exposure, Familial exposure, Environmental exposure

Background Exposure to ambient particulate matter (PM) has been associated with reduced lung function. Elemental components of PM have been suggested to have critical roles in PM toxicity, but their contribution to respiratory effects remains under-investigated. We evaluated the effects of traffic-related PM2.5 and its elemental components on lung function in two highly exposed groups of healthy adults in Beijing, China. Methods The Beijing Truck Driver Air Pollution Study (BTDAS) included 60 truck drivers and 60 office workers evaluated in 2008. On two days separated by 1-2 weeks, we measured lung function at the end of the work day, personal PM2.5, and nine elemental components of PM2.5 during eight hours of work, i.e., elemental carbon (EC), potassium (K), sulfur (S), iron (Fe), silicon (Si), aluminum (Al), zinc (Zn), calcium (Ca), and titanium (Ti). We used covariate-adjusted mixed-effects models including PM2.5 as a covariate to estimate the percentage change in lung function associated with an inter-quartile range (IQR) exposure increase. Results The two groups had high and overlapping exposure distributions with mean personal PM2.5 of 94.6 μg/m3 (IQR: 48.5-126.6) in office workers and 126.8 μg/m3 (IQR: 73.9-160.5) in truck drivers. The distributions of the nine elements showed group-specific profiles and generally higher levels in truck drivers. In all subjects combined, forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) did not significantly correlate with PM2.5. However, FEV1 showed negative associations with concentrations of four elements: Si (-3.07%, 95% CI: -5.00; -1.11, IQR: 1.54), Al (-2.88%, 95% CI: -4.91; -0.81, IQR: 0.86), Ca (-1.86%, 95% CI: -2.95; -0.76, IQR: 1.33), and Ti (-2.58%, 95% CI: -4.44; -0.68, IQR: 0.03), and FVC showed negative associations with concentrations of three elements: Si (-3.23%, 95% CI: -5.61; -0.79), Al (-3.26%, 95% CI: -5.73; -0.72), and Ca (-1.86%, 95% CI: -3.23; -0.47). In stratified analysis, Si, Al, Ca, and Ti showed associations with lung function only among truck drivers, and no significant association among office workers. Conclusion Selected elemental components of PM2.5 showed effects on lung function that were not found in analyses of particle levels alone. Electronic supplementary material The online version of this article (doi:10.1186/s12989-014-0051-7) contains supplementary material, which is available to authorized users.

Methods In 3249 ever-smokers (n = 1812 case subjects; n = 1437 control subjects) from a population-based case–control study in Italy, we examined the association between TTFC and lung cancer using logistic regression and estimated lung cancer incidence by levels of TTFC, and intensity, duration, and pack-years using absolute risk regression. Significance tests were two-sided. Results Compared with smokers with TTFC greater than 60 minutes, the lung cancer odds ratios for TTFC of 31 to 60 minutes, 6 to 30 minutes, and 5 or fewer minutes (by increasing dependency) were 2.57 (95% confidence interval [CI] = 2.03 to 3.26), 2.27 (95% CI = 1.79 to 2.88), and 3.50 (95% CI = 2.64 to 4.64), respectively (Ptrend < .0001). The average lung cancer incidence rates for smokers of 1 to 10, 11 to 20, 21 to 30 and more than 30 cigarettes per day were consistently higher among smokers with TTFC of 60 or fewer minutes vs more than 60 minutes (64.1 vs 11.7; 125.6 vs 28.6; 130.1 vs 40.7; and 260.8 vs 108.9 per 100 000 person-years, respectively). The slopes of increase in lung cancer rates with smoking duration and pack-years were statistically significantly greater among smokers with higher dependency (Pinteraction < .001). Conclusions Lung cancer risk increases with shorter TTFC; this simple nicotine dependency measure increases lung cancer risk stratification beyond standard smoking measures. Assessing TTFC may improve lung cancer risk prediction and could be useful in lung cancer screening and smoking cessation programs.

Several studies have proposed telomere length and telomerase activity as prognostic factors in chronic lymphocytic leukemia (CLL), whereas information addressing the role of telomere-associated genes is limited. We measured relative telomere length (RTL) and TERT expression levels in purified peripheral CD19(+) B-cells from seven healthy donors and 77 untreated CLLs in early stage disease (Binet A). Data were correlated with the major biological and cytogenetic markers, global DNA methylation (Alu and LINE-1), and clinical outcome. The expression profiles of telomere-associated genes were also investigated. RTL was decreased in CLLs as compared with controls (P 0.001); within CLL, a progressive and significant RTL shortening was observed in patients from 13q- through +12, 11q-, and 17p- alterations; short telomeres were significantly associated with unmutated IGHV configuration and global DNA hypomethylation. Decreased RTL was associated with a shorter time to first treatment. A significant upregulation of POT1, TRF1, RAP1, MRE11A, RAD50, and RPA1 transcript levels was observed in CLLs compared with controls. Our study suggests that impairment of telomere/telomerase system represents an early event in CLL pathogenesis. Moreover, the correlation between telomere shortening and global DNA hypomethylation supports the involvement of DNA hypomethylation to increase chromosome instability. © 2014 Wiley Periodicals, Inc.

We thank Pira and Coggiola for their comments1 on our paper.2 We agree that to estimate lifetime exposure to occupational carcinogens in a general population setting is a difficult task and requires valid assessment tools. It is for this reason that we chose as our job exposure matrix (JEM) the DOM-JEM that was developed specifically to be applied in studies of this kind.3 Pira and Coggiola express concern that the DOM-JEM is unable to distinguish between ‘no’, ‘low’ and ‘high’ exposed jobs/subjects. Their reasoning comes from the fact that among the 2529 men in our study classified as non-exposed to crystalline silica, two subjects reported at interview having been diagnosed with silicosis. We believe that our method is sound. First, with a JEM approach in a population-based study (as this lung cancer case-control is) the JEM constructors would have to aim for a more specific than sensitive JEM3 in order to prevent serious misclassification of non-exposed individuals and consequent attenuation of risk estimates.4 By creating a very specific JEM, like DOM-JEM, only jobs with relatively high intensity and high prevalence of exposed individuals performing these jobs will be assigned (high) exposure. So for instance, within DOM-JEM the job titles shown in Table 1, coded using the five-digit International Standard Classification for Occupations (ISCO) 1968 codes,5 are assigned a ‘high’ exposure to crystalline silica. Table 1 International Standard Classification for Occupations (ISCO) 1968 codes Also, to take into account the small actual difference in silica exposures between the ‘no’ and ‘low’ categories we decided to use the intensity weights of 0, 1 and 4 when estimating cumulative years of silica exposure. Second, as stated in our paper, the DOM-JEM has been compared with other JEMs and individual expert assessments in previous international studies.6,7 Notably, in the study of Peters et al.,6 the odds ratio for the association between lung cancer and silica obtained by applying the DOM-JEM was 1.26, almost identical to those obtained using case-by-case expert assessment (1.26) and a population-specific JEM (1.24). Similar results were obtained for exposure to diesel motor exhaust, whereas for asbestos DOM-JEM showed more consistent results as compared with the other two methods. Third, it is of course possible on rare occasions for a worker performing a theoretically non-exposed job to be exposed (e.g. a schoolteacher exposed to asbestos from a ceiling), but any resultant occurrence of cases of silicosis in the ‘no’ exposure group does not intrinsically invalidate the JEM. This misclassification can only be addressed (if at all) when the exposure can be assigned at the individual level, but it requires a much more detailed job history. Assigning all schoolteachers an exposure to asbestos based on an anecdotal example would be wrong and would create an enormous amount of falsepositively assigned exposures resulting in risk estimates attenuated towards the null. Fourth, the two cases of silicosis that we classified as non-exposed maybe incorrect due to reporting or diagnosis error. In fact, silicosis was only reported at interview in our study. Also, silicosis diagnosis is far from straightforward; radiographic evaluation even by qualified and experienced chest radiographers8 has a poor sensitivity and, whereas specificity is very good, false-positives may occur.9 In summary, we believe that the critique made by Pira and Coggiola of the DOM-JEM, based on a couple of (supposedly) misclassified subjects, without consideration of the whole study, is unfounded. DOM-JEM is a job-exposure matrix specifically developed for population-based studies, with only job-title information in the job histories and with the explicit philosophy of being rather more specific than sensitive in the assignment of exposures so as to avoid misclassification of non-exposed subjects as much as possible. The assigned levels are an informative relative ranking of ‘no’, ‘low’ and ‘high’ exposure and without calibration will have no absolute meaning on a ratio scale (e.g. mg/m3-years of silica exposure). Therefore, we stand by our conclusion that past occupational exposure to asbestos, silica and nickel-chromium, even at low levels, contributes substantially to the current lung cancer burden. Our estimates of population-attributable fractions of 18.1%, 5.7% and 7.0%, respectively, are necessarily imperfect but state-of-the-art and reasonable measures of the impact of these occupational carcinogens on lung cancer risk in this study population.2

Epidemiological studies have shown associations of particulate matter (PM) exposure with hypercoagulability and thrombosis. Extracellular circulating histones have recently been identified as novel mediators of inflammatory and procoagulant responses. The potential roles of extracellular histones in PM-related hypercoagulability have yet not been investigated.In 63 steel workers, we evaluated the effects of exposure to PM and PM metal components on two extracellular histone modifications (H3K4me3 and H3K9ac); and the association of H3K4me3 and H3K9ac with coagulation markers.Extracellular H3K4me3 and H3K9ac were determined in plasma through enzyme-linked immunosorbent assays. Coagulation markers included endogenous thrombin potentials (ETPs), tissue-type plasminogen activator antigen (t-PA) and D-dimer. Exposure to PM with aerodynamic diameters1 μm (PM1) or10 μm (PM10) and PM10 metal components were estimated for each participant.The coagulation marker ETP, measured in the presence of soluble thrombomodulin (ETP TM+), showed significant positive associations with PM1 (β=107.84, p=0.03), PM10 (β=83.06, p=0.02), and zinc (β=75.14, p=0.03); and a marginal association with iron (β=122.58, p=0.07). Additional PM effects were observed on t-PA, D-dimer, and ETP TM+. PM1 exposure was associated with increased plasma H3K4me3 and H3K9ac (β=0.20, p=0.02; β=0.16, p=0.05, respectively). H3K4me3, but not H3K9ac, was associated with zinc (β=0.13, p=0.03) and iron (β=0.32, p=0.01) contained in PM. ETP TM+ was increased in association with higher plasma H3K4me3 (β=0.50, p=0.05) and H3K9ac (β=0.54, p=0.05).This observational study suggests potential roles of extracellular histones in PM-induced hypercoagulability. Experimental studies are warranted to further characterize these findings.

Evidence indicates that oxidative stress generation may contribute to health effects associated with particulate matter (PM) exposure. We investigated oxidative stress markers in 113 workers exposed to metal-rich PM and 61 nonexposed comparable volunteers. The plasma levels of soluble NOX2-derived peptide (sNOX2-dp) and two oxidative stress markers, urinary 8-hydroxydeoxyguanosine (8-OHdG) and 8-iso-prostaglandinF2alpha (8-iso-PGF2α), were analyzed. The plasma levels of the antioxidant alpha-tocopherol were also evaluated. The workers' average exposure to PM with an aerodynamic diameter

Objectives To assess the short-term impact of expected exposure to PM10 due to a major construction site (Jan 2013–Jan 2015) on the health of the population residing in the seven towns nearby (N = 235 000). Method Estimates of PM10 short-term effects on all-cause and cause-specific mortality and on selected causes of hospital admissions were estimated for a pre-construction period (2007–2011) using Poisson regression models. Expected PM10 concentrations at ground level were estimated applying the ISCST3 Gaussian dispersion model to forecast PM10 emission rates due to the site. Mean counts of the 2007–2011 deaths and hospitalizations were taken to estimate the expected numbers of health events. The 2013–2015 impact was evaluated in terms of numbers of attributable deaths and hospitalizations during the construction site progress, under several counterfactual scenarios. Results Between 2013 and 2015, PM10 levels exceeding the mean PM10 pre-construction concentrations would be responsible for 0.54 attributable deaths (0.13 cardiovascular and 0.04 respiratory) and for 0.14 cardiac, 0.05 cerebrovascular and 0.51 hospital admissions. If considering the EU limit of 40 µg/m3, PM10 levels would be responsible for 11.06 attributable deaths (2.69 cardiovascular and 0.90 respiratory) and for 2.81 cardiac, 1.17 cerebrovascular and 10.89 respiratory hospital admissions. Corresponding values above the WHO threshold of 20 µg/m3 would be 51.73 attributable deaths (12.58 cardiovascular and 4.17 respiratory) 13.60 cardiac, 5.37 cerebrovascular and 49.13 respiratory hospital admissions. Conclusions The expected exposure appears to have a limited impact on health. Future monitoring of the actual exposure levels during the progress of the works will allow evaluating the accuracy of those estimates.

Cardiovascular disease risk has been consistently linked with particulate matter (PM) exposure. Cell-derived microvesicles (MVs) are released into plasma and transfer microRNAs (miRNAs) between tissues. MVs can be produced by the respiratory system in response to proinflammatory triggers, enter the circulatory system and remotely modify gene expression in cardiovascular tissues. However, whether PM affects MV signaling has never been investigated. In this study, we evaluated expression of microRNAs contained within plasma MVs upon PM exposure both in vivo and in vitro. In the in vivo study, we isolated plasma MVs from healthy steel plant workers before and after workplace PM exposure. We measured the expression of 88 MV-associated miRNAs by real-time polymerase chain reaction. To assess a possible source of the MV miRNAs identified in vivo, we measured their miRNA expression in PM-treated A549 pulmonary cell lines in vitro. MiRNA profiling of plasma MVs showed 5.62- and 13.95-fold increased expression of miR-128 and miR-302c, respectively, after 3 days of workplace PM exposure (P

Follow-up of the population exposed to dioxin after the 1976 accident in Seveso, Italy, was extended to 1996. During the entire observation period, all-cause and all-cancer mortality did not increase. Fifteen years after the accident, mortality among men in high-exposure zones A (804 inhabitants) and B (5,941 inhabitants) increased from all cancers (rate ratio (RR) = 1.3, 95% confidence interval (CI): 1.0, 1.7), rectal cancer (RR = 2.4, 95% CI: 1.2, 4.6), and lung cancer (RR = 1.3, 95% CI: 1.0, 1.7), with no latency-related pattern for rectal or lung cancer. An excess of lymphohemopoietic neoplasms was found in both genders (RR = 1.7, 95% CI: 1.2, 2.5). Hodgkin's disease risk was elevated in the first 10-year observation period (RR = 4.9, 95% CI: 1.5, 16.4), whereas the highest increase for non-Hodgkin's lymphoma (RR = 2.8, 95% CI: 1.1, 7.0) and myeloid leukemia (RR = 3.8, 95% CI: 1.2, 12.5) occurred after 15 years. No soft tissue sarcoma cases were found in these zones (0.8 expected). An overall increase in diabetes was reported, notably among women (RR = 2.4, 95% CI: 1.2, 4.6). Chronic circulatory and respiratory diseases were moderately increased, suggesting a link with accident-related stressors and chemical exposure. Results support evaluation of dioxin as carcinogenic to humans and corroborate the hypotheses of its association with other health outcomes, including cardiovascular- and endocrine-related effects.

DNA methylation, mitochondrial DNA copy number and telomeres shortening are cellular modifications associated with an increasing number of tumors, cardiovascular and aging diseases. In our studies these modifications were evaluated in subjects occupationally exposed to low levels of benzene and in the general population. In peripheral blood lymphocytes a decrease of DNA methylation with the increase of personal benzene exposure was found, both in Alu and LINE-1 repetitive elements, and in the global DNA. Telomere length shortening in subjects exposed to traffic exhausts and an increase in mitochondrial DNA copy number correlated to benzene exposure was also found. DNA methylation measured in specimen repeats collected at intervals of 8 years decreased more markedly in exposed subjects than in controls. Our studies highlighted the association of epigenetic modifications of DNA with low benzene exposure.

According to the 1995 World Disaster Report, accidents are second only to floods in frequency. Chemical accidents leading to a serious danger to the general public and to the environment rank 10th, just after epidemics and followed by landslides. Can the occurrence of these environmental accidents be reduced in the future and their consequences minimized? The answer is yes, provided that decisions are made and actions implemented now. Future management of environmental accidents requires that the same effort so far devoted to relief measures in the postimpact phase be devoted to advance planning in the preaccident period. International cooperation should be activated to predispose risk reduction measures, including a hazard-oriented approach to prevention, preparedness plans for possible incidents in major hazardous installations, and collaborative programs and resource sharing for response to accidents and the follow-up of their consequences. Clear and unequivocal communication with the public, with other professionals, decision makers, and the media play a key role in each step.

The industrial accident that occurred in the town of Seveso, Italy, in 1976 exposed a large population to substantial amounts of relatively pure 2,3,7,8-tetrachlorodibenzo-p-dioxin. Extensive monitoring of soil levels and measurements of a limited number of human blood samples allowed classification of the exposed population into three categories, A (highest exposure), B (median exposure), and R (lowest exposure). Early health investigations including liver function, immune function, neurologic impairment, and reproductive effects yielded inconclusive results. Chloracne (nearly 200 cases with a definite exposure dependence) was the only effect established with certainty. Long-term studies were conducted using the large population living in the surrounding noncontaminated territory as reference. An excess mortality from cardiovascular and respiratory diseases was uncovered, possibly related to the psychosocial consequences of the accident in addition to the chemical contamination. An excess of diabetes cases was also found. Results of cancer incidence and mortality follow-up showed an increased occurrence of cancer of the gastrointestinal sites and of the lymphatic and hematopoietic tissue. Experimental and epidemiologic data as well as mechanistic knowledge support the hypothesis that the observed cancer excesses are associated with dioxin exposure. Results cannot be viewed as conclusive. The study is continuing in an attempt to overcome the existing limitations (few individual exposure data, short latency period, and small population size for certain cancer types) and to explore new research paths (e.g., differences in individual susceptibility). Images Figure 1

Dioxin (2,3,7,8-tetrachlorodibenzo-para-dioxin, or TCDD) is a powerful carcinogen in experimental animals, whereas the evidence in humans is limited. We examined cancer mortality from 1976 to 1991 among residents of Seveso, Italy, which was highly contaminated after an industrial accident. The area was divided into zones with decreasing exposure to dioxin (A = highest, B = lower, R = lowest). The population of a surrounding noncontaminated area was used as a reference group. Zone A was small (11,516 person-years); in that zone, we saw a moderate increase in mortality from digestive cancer among women [relative risk (RR) = 1.5; 95% confidence interval (CI) = 0.5-3.5]. In zone B, we also saw excesses at digestive sites (83,610 person-years), 10 years after the accident. Women had an increased mortality from stomach cancer (RR = 2.4; 95% CI = 0.8-5.7), and men had increased mortality from rectal cancer (RR = 6.2; 95% CI = 1.7-15.9). Hematologic neoplasms were increased. The highest risks were seen in zone B for leukemia in men (RR = 3.1; 95% CI = 1.3-6.4), multiple myeloma in women (RR = 6.6; 95% CI = 1.8-16.8), and Hodgkin's disease in both genders (RR = 3.3; 95% CI = 0.4-11.9 in men; and RR = 6.5; 95% CI = 0.7-23.5 in women). Soft tissue sarcoma was elevated only among zone R males (256,408 person-years; RR = 2.1; 95% CI = 0.6-5.4). We found no increase for all-cancer mortality or major specific sites (for example, respiratory among males, breast among females). The specific excesses that we observed were not explained by bias or confounding, and their association with dioxin exposure is plausible. The follow-up is continuing.

Background Cross-sectional data are frequently encountered in epidemiology and published results are predominantly presented in terms of prevalence odds ratios (POR). A recent debate suggested a switch from POR, which is easily obtained via logistic regression analysis available in many statistical packages, to prevalence rate ratios (PRR). We thought it useful to explore the mathematical relationship between PRR and POR and to evaluate the degree of divergence of the two measures as a function of the prevalence of disease and exposure. Methods With the use of some algebra and the common definitions of prevalence of the disease (Pr(D)), prevalence of the exposure (Pr(E)), PRR, and POR in a 2 x 2 table, we have identified a useful formula that represents the mathematical relationship between these four quantities. Plots of POR versus PRR for selected values of Pr(D) and Pr(E) are reported. Results Mathematically speaking the general relationship takes the form of a second order curve which can change curvature and/or rotate around the point POR = PRR = 1 according to the values of Pr(D) and Pr(E), with POR being always further from the null value than is PRR. The discrepancies are much more influenced by variations in Pr(D) than in Pr(E). Conclusions We think that the choice between POR or PRR in a cross-sectional study ought to be based on epidemiological grounds and not on the availability of software tools. The paper offers a formula and some-examples for a better understanding of the relationship between PRR and POR as a function of the prevalence of the disease and the prevalence of the exposure.

The genetic regulation of the human epigenome is not fully appreciated. Here we describe the effects of genetic variants on the DNA methylome in human lung based on methylation-quantitative trait loci (meQTL) analyses. We report 34,304 cis- and 585 trans-meQTLs, a genetic-epigenetic interaction of surprising magnitude, including a regulatory hotspot. These findings are replicated in both breast and kidney tissues and show distinct patterns: cis-meQTLs mostly localize to CpG sites outside of genes, promoters and CpG islands (CGIs), while trans-meQTLs are over-represented in promoter CGIs. meQTL SNPs are enriched in CTCF-binding sites, DNaseI hypersensitivity regions and histone marks. Importantly, four of the five established lung cancer risk loci in European ancestry are cis-meQTLs and, in aggregate, cis-meQTLs are enriched for lung cancer risk in a genome-wide analysis of 11,587 subjects. Thus, inherited genetic variation may affect lung carcinogenesis by regulating the human methylome.

We read the interesting Review Article by Slootweg et al. [1] recently published in this Journal. We concur on the importance of an accurate morphology definition of sinonasal cancers (SNC), which is crucial not only for therapeutic decisions but also from the etiologic point of view. In fact, sinonasal carcinomas are strongly associated with occupational exposures, in particular wood and leather dusts and nickel compounds [2]. In Italy since 2008 incidence and etiology of primary epithelial tumors of nasal cavity and paranasal sinuses are surveyed through a nationwide cancer registry. The Lombardy Registry of Sinonasal Cancers was established at the end of 2007 in the most populated (almost 10 million residents at the 2011 census) and industrialized Italian region [3]. It collects all epithelial SNC cases occurring among residents in the region at the time of first diagnosis. The primary sources of information on SNC cases are the departments of pathology, otolaryngology, maxillofacial surgery, and radiotherapy in over 100 hospitals. Histological types are defined according to the World Health Organization (WHO) Classification [4]. Occupational exposure to selected agents is collected through a standardized questionnaire administered to patients or their next of kins by trained interviewers. In the period 2008–2012 we recorded 255 SNC cases with median age at diagnosis of 68 years, 167 (65.5 %) among males, and 88 (34.5 %) among females. Using the European population as standard, the SNC incidence rates (9million) are 6.8 (95 % CI 5.7–8.2) in men and 2.6 (95 % CI 1.9–3.4) in women. The anatomical site mostly affected was the nasal cavity, with 54 cases in males (32.3 %) and 32 (36.4 %) in females, followed by the maxillary sinus, 35 cases (21.0 %) in males and 25 (28.4 %) in females. The ethmoidal sinus was rarely involved in females (7 cases, 8.0 %) while there were 37 cases (22.2 %) in males. The most frequent morphology was squamous cell carcinoma, with a similar distribution across gender, 73 cases (43.7 %) in males and 41 (46.6 %) in females. Conversely, adenocarcinomas were twice as frequent in men (53 cases, 31.7 %) than in women (13 cases, 14.8 %). The majority of adenocarcinomas were intestinal-type adenocarcinomas (ITAC), 37 (22.2 %) in men and 8 (9.1 %) in women. There was a strong association between anatomical site and morphology. Out of 114 squamous cell carcinomas, 52 (45.6 %) originated from the nasal cavity, while among 66 adenocarcinoma cases 27 (40.9 %) were located in the ethmoidal sinus. The higher rates in men and the different distribution of SNC site and morphology between men and women most probably reflect differences in previous exposure to carcinogens. In fact, among the 66 subjects with adenocarcinoma, occupational exposure was recorded for the majority (50, or 75.8 %). Of these, 33 (50 %) had been ever exposed to wood dust and 19 (28.8 %) to leather dust. Conversely, the proportion of subjects ever exposed was about 10 % for squamous cell carcinoma and about 20 % for other morphologies. Although lower, the proportion of subjects with squamous cell carcinoma or other C. Mensi (&) L. Riboldi C. Sieno P. A. Bertazzi D. Consonni Department of Preventive Medicine, Fondazione IRCCS Ca’ Granda-Ospedale Maggiore Policlinico, Via San Barnaba 8, 20122 Milan, Italy e-mail: carolina.mensi@unimi.it

Exposure to particulate matter (PM) has been associated with lung cancer risk in epidemiology investigations. Elemental components of PM have been suggested to have critical roles in PM toxicity, but the molecular mechanisms underlying their association with cancer risks remain poorly understood. DNA methylation has emerged as a promising biomarker for environmental-related diseases, including lung cancer. In this study, we evaluated the effects of PM elemental components on methylation of three tandem repeats in a highly exposed population in Beijing, China. The Beijing Truck Driver Air Pollution Study was conducted shortly before the 2008 Beijing Olympic Games (June 15-July 27, 2008) and included 60 truck drivers and 60 office workers. On two days separated by 1-2 weeks, we measured blood DNA methylation of SATα, NBL2, D4Z4, and personal exposure to eight elemental components in PM2.5 , including aluminum (Al), silicon (Si), sulfur (S), potassium (K), calcium (Ca) titanium (Ti), iron (Fe), and zinc (Zn). We estimated the associations of individual elemental component with each tandem-repeat methylation in generalized estimating equations (GEE) models adjusted for PM2.5 mass and other covariates. Out of the eight examined elements, NBL2 methylation was positively associated with concentrations of Si [0.121, 95% confidence interval (CI): 0.030; 0.212, False Discovery Rate (FDR) = 0.047] and Ca (0.065, 95%CI: 0.014; 0.115, FDR = 0.047) in truck drivers. In office workers, SATα methylation was positively associated with concentrations of S (0.115, 95% CI: 0.034; 0.196, FDR = 0.042). PM-associated differences in blood tandem-repeat methylation may help detect biological effects of the exposure and identify individuals who may eventually experience higher lung cancer risk.

In Europe 23.5% of the working-age population suffers from chronic or rare diseases, including Ehlers-Danlos syndrome (EDS), an inherited disorder of the connective tissue that frequently leads to impairment also at work.We sought to evaluate the impairment of different functional areas in EDS subjects, using EDS-Disability Test (EDS-DT) (7 visual analogical scales: pain, stiffness, daily activities of life, in the home, outside the home, at work, in social relationships).We administered the EDS-DT to 50 workers with EDS (classic type n=35, hypermobile n=14, vascular n=3) and 150 healthy workers (non-EDS).EDS subjects showed higher perceived disability (median 29.31 vs 7.22, plt; 0.0001) than non-EDS. We observed a trend suggesting that the hypermobile type has a higher level of pain (54 vs 42) and work impairment (62.5 vs 42.5) (pgt;0.20), whereas the classic type has greater impairment of daily living activities (18.57 vs 11.43) and in the home (34.29 vs 25.71) (pgt;0.20). Subjects reporting moderate-to-vigorous occupational physical activities (OPA) showed a higher disability level in the work area (p=0.04).People with EDS suffer from chronic pain, impaired quality of life and employment difficulties. The hypermobile type seems more compromised in functional areas such as pain and work, while the classic type is more compromised in daily routine and home activities. The employment section was more impaired for EDS subjects who perform tasks with greater physical effort.

Background Short‐term exposures to fine (PM ) have been related with increased blood pressure ( BP ) in controlled‐human exposure and community‐based studies. However, whether coarse (2.5 to 10 μm) PM exposure increases BP is uncertain. Recent observational studies have linked PM exposures with blood DNA hypomethylation, an epigenetic alteration that activates inflammatory and vascular responses. No experimental evidence is available to confirm those observational data and demonstrate the relations between PM , hypomethylation, and BP . Methods and Results We conducted a cross‐over trial of controlled‐human exposure to concentrated ambient particles ( CAP s). Fifteen healthy adult participants were exposed for 130 minutes to fine CAP s, coarse CAP s, or HEPA ‐filtered medical air (control) in randomized order with ≥2‐week washout. Repetitive‐element ( Alu , long interspersed nuclear element‐1 [ LINE ‐1]) and candidate‐gene ( TLR4 , IL‐12 , IL‐6 , iNOS ) blood methylation, systolic and diastolic BP were measured pre‐ and postexposure. After adjustment for multiple comparisons, fine CAP s exposure lowered Alu methylation (β‐standardized=−0.74, adjusted‐ P =0.03); coarse CAP s exposure lowered TLR4 methylation (β‐standardized=−0.27, adjusted‐ P =0.04). Both fine and coarse CAP s determined significantly increased systolic BP (β=2.53 mm Hg, P =0.001; β=1.56 mm Hg, P =0.03, respectively) and nonsignificantly increased diastolic BP (β=0.98 mm Hg, P =0.12; β=0.82 mm Hg, P =0.11, respectively). Decreased Alu and TLR4 methylation was associated with higher postexposure DBP (β‐standardized=0.41, P =0.04; and β‐standardized=0.84, P =0.02; respectively). Decreased TLR4 methylation was associated with higher postexposure SBP (β‐standardized=1.45, P =0.01). Conclusions Our findings provide novel evidence of effects of coarse PM on BP and confirm effects of fine PM . Our results provide the first experimental evidence of PM ‐induced DNA hypomethylation and its correlation to BP .

Pesticides, a wide class of environmental contaminants, may cause both acute and delayed health effects in exposed subjects. These effects can range from simple irritation of the skin and eyes to more severe effects such as affecting the nervous system, the reproductive system and cancer. The molecular mechanisms underlying such effects are still under investigation. Epigenetics is the study of heritable changes in gene expression that occur without a change in the DNA sequence. Several epigenetic mechanisms, including DNA methylation, histone modifications and microRNA expression, can be triggered by environmental factors. We review current evidences indicating that epigenetic modifications may mediate pesticide effects on human health. In vitro, animal, and human investigations have identified several classes of pesticides that modify epigenetic marks, including endocrine disruptors, persistent organic pollutants, arsenic, several herbicides and insecticides. Several investigations have examined the effects of environmental exposures and epigenetic markers, and identified toxicants that modify epigenetic states. These modifications are similar to the ones found in pathological tissue samples. In spite of the current limitations, available evidence supports the concept that epigenetics holds substantial potential for furthering our understanding of the molecular mechanisms of pesticides health effects, as well as for predicting health-related risks due to conditions of environmental exposure and individual susceptibility.

The Ehlers-Danlos syndrome (EDS), inherited disorder of connective tissue, frequently leads to impairment of various functional areas, including employment. In 35 subjects with classic type EDS, 14 hypermobile, 3 vascular was administered 7 visual analogical scales (pain, stiffness, activities of daily living, instrumental activities of daily living, work, social relations). An impairment of particular significance in total score and in individual areas emerges is in the hypermobile group, followed by classic, less for the vasculature. Overall there is a significant alteration of the quality of life that deserves proper evaluation to facilitate the definition of fitness and the improvement of job insertion in patients with EDS.