Fine airborne particles: when alarming levels are the standard.

OBJECTIVES: To quantify the contribution of each individual month to the annual mortality burden attributable to particulate matter (PM) in 2015 in Milan, Italy, after authorities and media considered December 2015 as an outlying month carrying an exceptional population exposure to PM. STUDY DESIGN: We used routinely available daily time series of air pollution and mortality to perform an assessment of the impact of PM exposure on population health. METHODS: By combining daily death counts with daily PM levels, as well as the yearly average of the number of deaths with the yearly average of PM concentrations, impact estimates were calculated in terms of deaths attributable (AD) to levels of PM10 and PM2.5 exceeding the daily or the annual European Union (EU) exposure limits. RESULTS: On a monthly basis, the estimated AD for exceeding the daily EU limits for more than 35 days were 18.4 (PM10) and 33.2 (PM2.5) between January and March, and 20.0 and 31.9 between October and December, respectively. On an annual basis, the EU limit for PM10 was almost met and, therefore, the estimated impact in terms of AD was practically null. CONCLUSIONS: Impact results should be interpreted in the light of the skewness of the daily PM concentration distribution. The number of days above the limits is more important than the average annual concentration in determining the number of attributable deaths. The impact of PM on mortality is substantial during the whole winter season irrespective of its annual average concentration. Our estimates further stress the need for a revision of the current European air quality standards.

Particulate matter phagocytosis induces tissue factor in differentiating macrophages.

Airborne exposure to particulate matter with diameter < 10 mcM (PM10) has been linked to an increased risk of thromboembolic events, but the mechanisms are not completely understood. The aim of this study was to evaluate the effect of PM10 phagocytosis on the release of procoagulant molecules in human differentiating macrophages, and that of PM10 inhalation in an experimental model in rats. Human monocytes were separated from the peripheral blood by the lymphoprep method, differentiated in vitro and treated with standard PM10 or vehicle. Sprague-Dawley rats were instilled intratracheally with PM10 or vehicle alone. The outcome was expression of proinflammatory genes and of tissue factor (TF). In human differentiating macrophages, PM10 exposure upregulated inflammatory genes, but most consistently induced TF mRNA and protein levels, but not TF protein inhibitor, resulting in increased TF membrane expression and a procoagulant phenotype. Differentiation towards the anti-inflammatory M2 phenotype inhibited PM10 -mediated TF expression. TF induction required phagocytosis of PM10 , whereas phagocytosis of inert particles was less effective. PM10 phagocytosis was associated with a gene expression profile consistent with intracellular retention of iron, inducing oxidative stress. Both PM10 and iron activated the stress kinases ERK1/2 pathway, involved in the induction of TF expression. In rats, alveolar exposure to PM10 was associated with pulmonary recruitment of inflammatory cells and resulted in local, but not systemic, induction of TF expression, which was sufficient to increase circulating TF levels. In conclusion, TF induction by differentiating lung macrophages, activated following phagocytosis, contributes to the increased risk of thromboembolic complications associated with PM10 exposure.

Extracellular histones mediate the effects of metal-rich air particles on blood coagulation.

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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 diameters <1 µm (PM1) or <10 µm (PM10) and PM10 metal components were estimated for each participant. RESULTS: The coagulation marker ETP, measured in the presence of soluble thrombomodulin (ETP TM+), showed significant positive associations with PM1 (ß=107.84, p=0.03), PM10 (ß=83.06, p=0.02), and zinc (ß=75.14, p=0.03); and a marginal association with iron (ß=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 (ß=0.20, p=0.02; ß=0.16, p=0.05, respectively). H3K4me3, but not H3K9ac, was associated with zinc (ß=0.13, p=0.03) and iron (ß=0.32, p=0.01) contained in PM. ETP TM+ was increased in association with higher plasma H3K4me3 (ß=0.50, p=0.05) and H3K9ac (ß=0.54, p=0.05). CONCLUSIONS: This observational study suggests potential roles of extracellular histones in PM-induced hypercoagulability. Experimental studies are warranted to further characterize these findings.

Update of the mortality study of workers exposed to polychlorinated biphenyls (Pcbs) in two Italian capacitor manufacturing plants.

BACKGROUND: PCB carcinogenicity to humans is still controversial. Cohort mortality studies in PCB-exposed workers reported elevated risks for the following causes of death: liver, stomach, digestive, brain, prostate cancers and non-Hodgkin lymphoma. OBJECTIVES: The purpose of this study was to update as of December 2006 the mortality experience of two Italian cohorts of workers employed in the manufacture of capacitors impregnated with PCBs. METHODS: Age-gender-and calendar period adjusted Standardized Mortality Ratios (SMRs) and 95% Confidence Intervals (CI) were calculated using regional rates. Analyses by duration of employment and time since first employment were performed Results: Vital status was ascertained for 98.9% of the study subjects. Mortality from biliary tract cancer among males (SMR 3.91; 95%CI 1.47-10.41), digestive cancer "not otherwise specified" in the whole cohort (SMR 2.54; 95%CI 1.21-5.34), and brain cancer in Plant I (SMR 2.13; 95%CI 1.02-4.48), were significantly increased. Increased risks were also observed for Hodgkin's and non-Hodgkin lymphoma. No linear associations between mortality and duration of employment or latency were observed for these cancers. Mortality from stomach cancer did not differ from expectation in the whole cohort, however an increasing risk with increasing duration of employment was detected (p for trend=0.02). CONCLUSIONS: The current update suggests possibly increased cancer risks in PCB-exposed workers, affecting in particular the digestive system, brain, and lymphohemopoietic tissue. However the limited sample size, the lack of clear trends with duration of employment or with latency period, preclude to derive definite conclusions about PCB exposure and the increased cancer risks.

Epigenetics and pesticides.

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.

[Hazard identification and risk evaluation in the metal industry: the epigenetic challenge]. / Le prospettive nello studio dei rischi in metallurgia: la sfida epigenetica.

The contribution of scientific knowledge to workplace health and safety measures is becoming more and more relevant. To identify hazards, an increasing number of mechanistic markers (of exposure, of effect, of individual susceptibility) are now available. To be effective, prevention measures should take into consideration not just the hazards, but also the risk which may vary among different populations and across individuals exposed to the same hazard. A new, extremely promising class of molecular markers of gene-environment interaction comes from epigenetics research (e.g., DNA methylation, histone modification, mi-RNA). A recent epigenetic epidemiology study in workers exposed to metals and PM in the metal industry disclosed their potential role as predictor of extremely early effects on gene expression regulating inflammation and blood coagulation function. A possible, worrisome development in applying mechanistic knowledge in exposure monitoring and exposed individuals' surveillance is to divert the attention from the control of exposure and put the focus on the screening of susceptible individuals only. This raises ethical, social and legal issues which may ultimately impact throughout the practice of occupational and environmental health.

Environmental and biological monitoring of PAHs exposure in coke-oven workers at the Taranto plant compared to two groups from the general population of Apulia, Italy.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) exposure in the coke industry poses a risk for workers' health as well as for subjects living in the plant vicinity. OBJECTIVES: To assess PAHs exposure in coke-oven workers (CW) at the Taranto plant, Apulia, and in subjects from the general population living near (NC) and far away (FC) from the plant. METHODS: Exposure was assessed by personal air sampling and urinary 1-hydroxypyrene (1-OHP) measured in 100 CW 18 NC and 15 FC. RESULTS: Median airborne benzo[a]pyrene (BaP) levels were 152, 1.5, and 3.6 ng/m3 in CW NC, and FC, respectively. In CW, median 1-OHP increased from 1.45 to 1.96 microg/g creatinine (crt) during the work shift (p > 0.05); in NC and FC, 1-OHP levels were 0.56 and 0.53 microg/g crt. No significant differences between NC and FC for both air and urinary indices were found. BaP exposure in CW exceeded the recently proposed German acceptable (70 ng/m3) and tolerable (700 ng/m3) risk-based limit values in 82 and 11% of subjects, respectively. In NC and FC, BaP exposure exceeded the European target value for ambient air (1 ng/m3) in 67 and 60% of subjects, respectively. Biomonitoring showed that 21% of CW had 1-OHP levels higher than the proposed biological limit value for the coke-oven industry (4.4 microg/g crt), while 93% of FC, and 88% of NC, had 1-OHP levels exceeding the Italian reference value (0.3 microg/g crt). Among non-smokers, a linear regression between 1-OHP and BaP (Pearson value r = 0.65, p < 0.05) allowed us to estimate levels of 1.2 and 1.9 microg/g crt for 1-OHP end-of-shift corresponding to acceptable and tolerable limit values. CONCLUSIONS: Although lower than in the past, PAHs exposure in the coke plant still poses a health risk for workers and the general population and requires further efforts to improve workplace conditions.

Plasma levels of dioxins, furans, non-ortho-PCBs, and TEQs in the Seveso population 17 years after the accident.

BACKGROUND: The Seveso accident (Italy) in 1976 caused the contamination of a large population by 2,3,7,8-tetrachlorodibenzo-para-dioxin (2,3, 7,8-TCDD). The contaminated territory was divided into three zones: A (very high contamination), B (high contamination), and R (low contamination). We report here the plasma concentrations of seven polychlorinated dibenzo-para-dioxins (PCDDs), 10 polychlorinated dibenzofurans (PCDFs), four non-ortho-polychlorinated biphenyls PCBs (nPCBs), and Toxic Equivalencies (TEQs) in a sample of residents in the most polluted zones A and B and in a reference non-contaminated zone. METHODS: From December 1992 to March 1994, 62 individuals were randomly selected from the population living in zone A (No. =7) and B (No. =55). A sample of 59 subjects living in a surrounding non-contaminated area (non-ABR), frequency-matched by gender, age, and smoking history, was used as reference. All subjects were administered a questionnaire surveying demographic, lifestyle, medical history, and accident-related factors. We assayed plasma PCDD, PCDF, and nPCB concentrations by high-resolution gas chromatography/high resolution mass spectrometric (HRGC/HRMS) analysis, with results reported as pg/g of lipid, or parts per trillion (ppt). We calculated TEQs using the WHO 2005 Toxic Equivalency Factors (TEFs). RESULTS: We found elevated median levels of 2,3, 7,8-TCDD in plasma samples of subjects living in zone A (73.3 ppt) and zone B (12.4 ppt), compared with residents in the reference zone (5.5 ppt). In analyses adjusted for gender, age, smoking, and body mass index (BMI), none of the other congeners showed levels higher than reference in the contaminated zones. Compared with men, women showed higher levels (113%) of 2,3, 7,8-TCDD and a slight elevation (17%) of TEQ for the other congeners. Age was strongly positively associated with most congener levels; TEQs for PCDDs, PCDFs, and nPCBs showed respectively 12%, 24%, and 41% increases for every 10 years of age. Current smokers had lower (from -37% to -67%) TEQ levels than subjects who had never smoked. BMI was negatively associated with levels of a few congeners, but with no impact on TEQ values. CONCLUSIONS: The Seveso accident caused a severe exposure of the population to 2,3,7,8-TCDD only. None of the other congeners analyzed showed variation across zones. Age showed a strong positive association with TEQs for all classes of compounds (PCDDs, PCDFs, and nPCBs).

Global DNA methylation and low-level exposure to benzene.

INTRODUCTION: Global genomic hypomethylation is a common event in cancer tissues that is frequently observed in hematopoietic malignancies, including leukemia. Benzene, an established leukemogen at high doses, has been suggested to induce hypomethylation based on investigations of DNA methylation in LINE-1 and Alu repetitive elements. Whether global genomic DNA methylation content is reduced in response to benzene exposure is still undetermined. METHODS: We measured global DNA methylation in 78 gasoline station attendants and 58 controls in peripheral blood cells using high-resolution gas chromatography-mass spectrometry. PCR-Pyrosequencing measures of DNA methylation at Alu and LINE-1 repetitive elements, representing a large proportion of methylation in non-coding regions, were also available. Exposure markers included personal airborne benzene, and urinary benzene, t,t-muconic acid (t,t-MA) and S-phelylmercapturic acid. RESULTS: Mean global DNA methylation was 5.474 (+/- 0.083) %5mC in controls and 5.409 (+/- 0.142) %5mC in exposed participants (p = 0.01). All methylation markers were negatively correlated with airborne benzene. Alu and LINE-1 methylation, but not global DNA methylation, were negatively associated with t,t-MA; no association with the other urinary biomarkers was found. Multiple linear regression analysis adjusted for gender and age confirmed the results of correlation analysis and showed a 1.6% decrease in global DNA methylation associated with being gasoline station attendants. Alu and LINE-1 methylation levels were not associated with global DNA methylation. CONCLUSION: Our results show that benzene exposure is associated with alterations in both global DNA and repetitive element methylation. Global and repetitive element methylation levels are not correlated in blood DNA, likely representing independent responses to benzene exposure.

[Prevalence of obstructive sleep apnea syndrome in a group of obese workers]. / La prevalenza della sindrome delle apnee ostruttive del sonno un gruppo di lavoratori affetti da obesità.

The Obstructive Sleep Apnea Syndrome (OSAS) is a quite diffused in workers disease, mainly in obese or overweight subjects. This syndrome can cause cardiovascular and cerebral complications and have negative effects on job performances. We evaluated 214 obese/overweight workers referred from different job areas. A diagnosis of OSAS was pre-existent in about 5% of the examined subjects, and clinical elements suggesting suspect of OSAS were present in about 15% of the sample. The risk of development Obstructive Sleep Apnea Syndrome seems to be linear correlated with BMI, neck and waist circumference. We did not find any correlation between OSAS risk and job area. We strongly suggest that health surveillance should include the evaluation of the possible presence of sleep disorders to reduce the risks associated and the negative consequences on job performances.

[Identification of biomarkers of short- and medium-term exposure in urine and hair of subjects exposed to terbuthylazine]. / Identificazione di indici biologici di esposizione a breve e medio termine nelle urine e nei capelli di soggetti esposti a terbutilazina.

Terbuthylazine (TBA) is a herbicide widely used for weed control in corn crop. In mammals it is completely metabolized and excreted in urine, mostly as desetilterbutilazina (DET). This work aims to evaluate the use of urine and hair as matrices for monitoring short- and medium-term exposure to TBA. Levels of TBA and DET have been evaluated in hair and urine samples of 12 exposed farmers, 14 rural residents, 17 urban residents. In hair TBA was quantified in all samples of farmers and rural residents, but not of urban residents. In urine DET was detected in post-application samples of farmers but not in rural and urban residents. These results suggest that TBA in hair can be used as an index of cumulative exposure to TBA, while DET in the urine can be used as an index of short-term exposure in farmers.

[Applicability of the test SIO on obesity-related disability (TSD-OC) in occupational medicine for the evaluation of work problems linked to overweight-obesity condition]. / Applicabilità del Test SIO sulla disabilità correlata all'obesità (TSD-OC) in Medicina del Lavoro per la valutazione di problematiche lavorative legate al sovrappeso-obesità.

Obesity is frequently associated with functional changes that may affect work capacity, so we administered to a group of 198 overweight-obese subjects with median BMI of 32.7 and median waist circumference of 101 cm, the test-TSD OC which consists of 7 sections (pain, stiffness, activities of daily life, activities of the house, instrumental activities of daily living, work, social relations) for a total of 36 visual analogical scales. After the identification of 4 workers categories (health, services, administration, commerce/industry), resulted homogeneous for age, BMI, CV, we saw that the work section was more compromised for health and services. The overall disability increases especially in relation to BMI and seems influenced by age and sex.

[Epigenetic effects as mediators of procoagulant action of thin dust with high metal content. Study on occupational epidemiology]. / Effetti epigenetici come mediatori dell'azione pro-coagulante delle polveri sottili ad alto contenuto metallico. Uno studio di epidemiologia occupazionale.

Blood hypo-methylation mediates the effects of metal-rich airborne particles on blood coagulation: An occupational epidemiological study. Particulate matter (PM) exposure is associated with increased coagulation and thrombosis, but the biological mechanism has not yet been clarified. DNA methylation represents a potential mechanism because it can be modified by environmental factors. Foundry workers are exposed to PM components and showed increased cardiovascular risk. In a group of 63 steel workers we found that PM and zinc airborne levels were negatively associated with leukocyte DNA methylation in genes NOS3 and ET-1 (b = -1.1; p = 0.002 and b = -1.5; p = 0.003, for zinc exposure respectively in multivariate regression models; b = -0.9 with p = 0.01 for PM10 exposure and NOS3) and in turn, DNA hypo-methylation resulted associated with increased Endogenous Thrombin Potential (for NOS3 b = -45.0, p = 0.001; and for ET-1 b = -16.4, p = 0.03). Our study based on healthy subject exposed in occupational setting, suggests that gene specific hypomethylation contributes to environmentally-induced hypercoagulability.

[Environmental and biological monitoring of exposure to PAHs in Taranto coke-oven workers and in two groups of the general population from Apulia]. / Monitoraggio ambientale e biologico dell'esposizione a IPA nei lavoratori della cokeria di Taranto e confronto con due gruppi della popolazione generale pugliese.

The exposure to PAHs was assessed by personal air sampling and urinary 1-hydroxypyrene (1-OHP) in 100 coke-oven workers (CW) of the Taranto plant and in subjects from the general population living close (NC, 18) and far away (FC, 15) from the plant. Median airborne benzo[a]pyrene (BaP) and 1-OHP levels were 152, 1.5, and 3.6 ng/m3 and 2.0, 0.5 and 0.6 microg/g creatinine in CW, NC, and FC, respectively. BaP exposure exceeded the German acceptable (70 ng/m3) and tolerable (700 ng/m3) limit risk based values in 82 and 11% of CW and the European target value for ambient air (1 ng/m3) in about 65% of NC and FC. 1-OHP levels exceed the proposed biological limit value for the coke-oven industry (4.4 microg/g crt) in 21% of CW and the Italian reference value (0.3 microg/g crt) in about 90% of NC and FC. The exposure resulted lower than in the past, but this study highlights that PAHs exposure from the coke plant still poses a health risk for workers and the general population.

[Comparison of indexes for assessing insulin resistance for the health surveillance among workers]. / Confronto tra indici per la valutazione dell'insulinoresistenza nella sorveglianza sanitaria dei lavoratori.

Night shift workers present a high risk to develop metabolic and cardiovascular disorders for alterations that involve effects on circadian rhythms at the level of insulin resistance (IR). Monitor such parameter in this category of workers, therefore, is a crucial step in health surveillance. To this aim, the currently in use test consists in the calculation of the HOMA index [basal insulin (MU/ml) x basal glycemy(mmol/l)/22.5], a measurement with a considerable cost (about 13 Euros). Recent studies demonstrated that the measurement of TyG index calculated as Ln[Triglycerids (mg/dl) x Glucose(mg/dl)/2] and of the triglycerids/HDL-cholesterol ratio correlates with HOMA index. These analyses cost altogether about 5 Euros, allowing a clear decrease of expenses. Our study, carried out on 217 workers at Centre for Obesity and Occupational Medicine of the Occupational Medicine Clinic of Milan, confirmed such correlation and identified the TyG as the index with the best cost/performance ratio. Our future goal is to establish cut-off values, necessary to adopt the TyG as first choice index.

[The assessment of risk for xylene exposure in a laboratory of anatomy: comparison between computational models and environmental and biological monitoring]. / La valutazione del rischio per esposizione a xilene in un laboratorio di anatomia patologica: confronto tra algoritmi matematici e monitoraggio ambientale e biologico.

Exposure to xylene in a pathology laboratory was evaluated using two algorithms: Stoffenmanager and Archi.me.de. The results were compared with those obtained by applying the environmental and biological monitoring of the exposure. The use of models required a period of self-learning and, for Stoffenmanager, knowledge of the English language. Information on the toxicity and safety of xylene, available from the medial and safety data sheets, and the conditions and amount of use, obtained through a survey and interviews with operators, have been imputed. Stoffenmanager estimated low the inhalation exposure and medium the dermal exposure, with a value of personal exposure during the work shift of 1.4 mg/m3. A.r.chi.me.d.e. estimated negligible the risk to health. These ratings are consistent with those obtained using the experimental approach. This result, combined with the simplicity and low cost, makes the algorithms very interesting tools for the assessment of chemical risk in the workplace.

The contribution of Enrico C. Vigliani (1907-1992) to the international development of occupational medicine and industrial hygiene.

BACKGROUND: One of the last century's greatest personalities in Occupational Medicine was Enrico Carlo Vigliani (1907-1992), director of the "Clinica del Lavoro" in Milan (1942-1977), editor-in-chief of "La Medicina del Lavoro" (1942-1991), Secretary-Treasurer and then President of the "Permanent Commission and International Association on Occupational Health" (1957-1981), the original nucleus of the ICOH. OBJECTIVES: The 20th anniversary of his death provides us with the opportunity to discuss the role of this brilliant scholar in the international development of Occupational Medicine and Industrial Hygiene. METHODS: A comprehensive analysis of Vigliani's scientific works was conducted. In addition, his close collaborators and pupils were interviewed. RESULTS: In the 1930s, as a young doctor, Vigliani, first in the world, demonstrated the effect of lead on porphyrin metabolism. Afterwards he conducted pioneering studies on occupational oncology (benzene-induced leukaemia, bladder cancer due to aromatic amines, asbestos-related tumours), pathogenesis of silicosis, encephalopathy in carbon disulfide poisoning, byssinosis and metal fume fever, so influencing international research and the implementation of preventive measures against these conditions. Vigliani's scientific authority was widely recognized internationally, as confirmed by his role in ICOH. During his period of active service, the Commission developed from an academic institution to a more open association, substantially increasing its membership. Furthermore, he contributed to establishing subcommittees devoted to specific topics (now called "scientific committees"), one of the strengths of the present Commission. CONCLUSIONS: Vigliani's contribution to the development of Occupational Health may be considered as an expression of his genial eclecticism which ranged from clinical medicine to the environment.

[Vitamin D as a cardiovascular risk factor in workers]. / La vitamina D come fattore di rischio cardiovascolare nei lavoratori.

Numerous evidence suggests that vitamin D deficiency is implicated in the development of cardiovascular risk. It has been investigated the relationship between cardiovascular risk factors and vitamin D concentrations in 264 consecutive workers from Centro Obesità e Lavoro della Clinica del Lavoro di Milano. For these studies, glicometaboliche analysis, anthropometric measurements and impedance evalutation were performed and questionnaires to estimate nutrient levels in the diet were administered. The levels of vitamin D are found to be deficient in 166 patients (less than 20 ng/mL), insufficient in 63 patients (less than 30 ng/mL) and optimal for the remaining 35 patients. A significant negative association was observed between the concentrations of vitamin D and cardiovascular risk factors (HOMA ratio and TG/HDL) ratios and BMI. Vitamin D is a cardiovascular risk factor "corrected" for example by changing the eating habits of workers.