Disease control of acromegaly does not prevent excess mortality in the long term: results of a nationwide survey in Italy.

OBJECTIVE: This study aimed to assess the long-term outcome of patients with acromegaly. DESIGN: This is a multicenter, retrospective, observational study which extends the mean observation period of a previously reported cohort of Italian patients with acromegaly to 15 years of follow-up. METHODS: Only patients from the centers that provided information on the life status of at least 95% of their original cohorts were included. Life status information was collected either from clinical records or from the municipal registry offices. Standardized mortality ratios (SMRs) were computed comparing data with those of the general Italian population. RESULTS: A total of 811 patients were included. There were 153 deaths, with 90 expected and an SMR of 1.7 (95% CI 1.4-2.0, p < 0.001). Death occurred after a median of 15 (women) or 16 (men) years from the diagnosis, without gender differences. Mortality remained elevated in the patients with control of disease (SMR 1.3, 95% CI 1.1-1.6). In the multivariable analysis, only older age and high IGF1 concentrations at last available follow-up visit were predictors of mortality. The oncological causes of death outweighed the cardiovascular ones, bordering on statistical significance with respect to the general population. CONCLUSIONS: Mortality remains significantly high in patients with acromegaly, irrespectively of disease status, as long as the follow-up is sufficiently long with a low rate of patients lost to follow-up. Therapy strategy including radiotherapy does not have an impact on mortality. Oncological causes of death currently outweigh the cardiovascular causes.

Depression and cardiovascular risk-association among Beck Depression Inventory, PCSK9 levels and insulin resistance.

BACKGROUND: Depression and cardiovascular disease (CVD) are among the most common causes of disability in high-income countries, depression being associated with a 30% increased risk of future CV events. Depression is twice as common in people with diabetes and is associated with a 60% rise in the incidence of type 2 diabetes, an independent CVD risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein cholesterol, has been related to a large number of CV risk factors, including insulin resistance. Aim of this study was to investigate whether the presence of depression could affect PCSK9 levels in a population of obese subjects susceptible to depressive symptoms and how these changes may mediate a pre-diabetic risk. RESULTS: In 389 obese individuals, the Beck Depression Inventory (BDI-II) was significantly associated with PCSK9 levels. For every one-unit increment in BDI-II score, PCSK9 rose by 1.85 ng/mL. Depression was associated also with the HOMA-IR (homeostatic model assessment index of insulin resistance), 11% of this effect operating indirectly via PCSK9. CONCLUSIONS: This study indicates a possible mechanism linking depression and insulin resistance, a well-known CV risk factor, providing evidence for a significant role of PCSK9.

Repetitive element hypermethylation in multiple sclerosis patients.

BACKGROUND: Multiple sclerosis (MS) is a complex disorder of the central nervous system whose cause is currently unknown. Evidence is increasing that DNA methylation alterations could be involved in inflammatory and neurodegenerative diseases and could contribute to MS pathogenesis. Repetitive elements Alu, LINE-1 and SAT-α, are widely known as estimators of global DNA methylation. We investigated Alu, LINE-1 and SAT-α methylation levels to evaluate their difference in a case-control setup and their role as a marker of disability. RESULTS: We obtained blood samples from 51 MS patients and 137 healthy volunteers matched by gender, age and smoking. Methylation was assessed using bisulfite-PCR-pyrosequencing. For all participants, medical history, physical and neurological examinations and screening laboratory tests were collected. All repetitive elements were hypermethylated in MS patients compared to healthy controls. A lower Expanded Disability Status Scale (EDSS) score was associated with a lower levels of LINE-1 methylation for 'EDSS = 1.0' and '1.5 ≤ EDSS ≤ 2.5' compared to an EDSS higher than 3, while Alu was associated with a higher level of methylation in these groups: 'EDSS = 1.0' and '1.5 ≤ EDSS ≤ 2.5'. CONCLUSIONS: MS patients exhibit an hypermethylation in repetitive elements compared to healthy controls. Alu and LINE-1 were associated with degree of EDSS score. Forthcoming studies focusing on epigenetics and the multifactorial pathogenetic mechanism of MS could elucidate these links further.

Hormone use and risk for lung cancer: a pooled analysis from the International Lung Cancer Consortium (ILCCO).

BACKGROUND: The association between oral contraceptive (OC) use, hormone replacement therapy (HRT) and lung cancer risk in women is still debated. METHODS: We performed a pooled analysis of six case-control studies (1961 cases and 2609 controls) contributing to the International Lung Cancer Consortium. Potential associations were investigated with multivariable unconditional logistic regression and meta-analytic models. Multinomial logistic regressions were performed to investigate lung cancer risk across histologic types. RESULTS: A reduced lung cancer risk was found for OC (odds ratio (OR)=0.81; 95% confidence interval (CI): 0.68-0.97) and HRT ever users (OR=0.77; 95% CI: 0.66-0.90). Both oestrogen only and oestrogen+progestin HRT were associated with decreased risk (OR=0.76; 95% CI: 0.61-0.94, and OR=0.66; 95% CI: 0.49-0.88, respectively). No dose-response relationship was observed with years of OC/HRT use. The greatest risk reduction was seen for squamous cell carcinoma (OR=0.53; 95% CI: 0.37-0.76) in OC users and in both adenocarcinoma (OR=0.79; 95% CI: 0.66-0.95) and small cell carcinoma (OR=0.37; 95% CI: 0.19-0.71) in HRT users. No interaction with smoking status or BMI was observed. CONCLUSION: Our findings suggest that exogenous hormones can play a protective role in lung cancer aetiology. However, given inconsistencies with epidemiological evidence from cohort studies, further and larger investigations are needed for a more comprehensive view of lung cancer development in women.

Circulating levels of immune and inflammatory markers and long versus short survival in early-stage lung cancer.

BACKGROUND: Some patients diagnosed with early-stage lung cancer and treated according to standard care survive for only a short period of time, while others survive for years for reasons that are not well understood. Associations between markers of inflammation and survival from lung cancer have been observed. MATERIALS AND METHODS: Here, we investigate whether circulating levels of 77 inflammatory markers are associated with long versus short survival in stage I and II lung cancer. Patients who had survived either <79 weeks (~1.5 years) (short survivors, SS) or >156 weeks (3 years) (long survivors, LS) were selected from a retrospective population-based study. Logistic regression was used to calculate adjusted odds ratios (ORs) and corresponding 95% confidence intervals (CIs). The false discovery rate was calculated to adjust for multiple testing. RESULTS: A total of 157 LS and 84 SS were included in this analysis. Thirteen markers had adjusted OR on the order of 2- to 5-fold when comparing the upper and lower quartiles with regard to the odds of short survival versus long. Chemokine CCL15 [chemokine (C-C motif) ligand 15] was the most significant marker associated with increased odds of short survival (ORs = 4.93; 95% CI 1.90-12.8; q-value: 0.042). Smoking and chronic obstructive pulmonary disease were not associated with marker levels. CONCLUSIONS: Our results provide some evidence that deregulation of inflammatory responses may play a role in the survival of early-stage lung cancer. These findings will require confirmation in future studies.

[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.

Epstein-Barr virus microRNAs and lung cancer.

BACKGROUND: We conducted the first analysis of viral microRNAs (miRNAs) in lung cancer, with a focus on Epstein-Barr virus (EBV). METHODS: We evaluated viral miRs with a two-channel oligo-array targeting mature, anti-sense miRNAs in 290 cases. In 48 cases, we compared microarray and real-time quantitative PCR (qPCR) expression for three EBV miRNAs. We tested for EBV DNA, RNA, and protein in tumour tissue from six cases with and six cases without strong qPCR-based evidence of EBV miRNAs. RESULTS: The EBV miRNAs strongly differentiated between adenocarcinoma and squamous cell carcinoma using the microarray (P<0.01 for 9 out of 16 EBV miRNAs). However, microarray and qPCR measurements of BART1, BART2, and BHRF1-3 expression were not significantly correlated (P=0.53, 0.94, and 0.47, respectively). Although qPCR provided substantial evidence of EBV miRNAs in 7 out of 48 cases, only 1 of these 7 cases had detectable EBV DNA in tumour tissue. None had detectable EBV RNA or protein by histochemical stains. CONCLUSION: In a comprehensive evaluation of EBV miRNA, DNA, RNA, and protein in lung cancer, we found little evidence of EBV in lung tumour tissue. Discrepancies between microarray- and qPCR-based strategies highlight the difficulty of validating molecular markers of disease. Our results do not support a role of EBV in lung cancer.

Inherited polymorphisms in the RNA-mediated interference machinery affect microRNA expression and lung cancer survival.

BACKGROUND: MicroRNAs (miRs) have an important role in lung carcinogenesis and progression. Single-nucleotide polymorphisms (SNPs) in genes involved in miR biogenesis may affect miR expression in lung tissue and be associated with lung carcinogenesis and progression. METHODS: we analysed 12 SNPs in POLR2A, RNASEN and DICER1 genes in 1984 cases and 2073 controls from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We investigated miR expression profiles in 165 lung adenocarcinoma (AD) and 125 squamous cell carcinoma tissue samples from the same population. We used logistic and Cox regression models to examine the association of individual genotypes and haplotypes with lung cancer risk and with lung cancer-specific survival, respectively. SNPs-miR expression associations in cases were assessed using two-sample t-tests and global permutation tests. RESULTS: a haplotype in RNASEN (Drosha) was significantly associated with shorter lung cancer survival (hazard ratio=1.86, 95% CI=1.19-2.92, P=0.007). In AD cases, a SNP within the same haplotype was associated with reduced RNASEN mRNA expression (P=0.013) and with miR expression changes (global P=0.007) of miRs known to be associated with cancer (e.g., let-7 family, miR-21, miR-25, miR-126 and miR15a). CONCLUSION: inherited variation in the miR-processing machinery can affect miR expression levels and lung cancer-specific survival.

Characteristics of 1573 healthcare workers who underwent nasopharyngeal swab testing for SARS-CoV-2 in Milan, Lombardy, Italy.

OBJECTIVES: The management of healthcare workers (HCWs) exposed to confirmed cases of coronavirus disease 2019 (COVID-19) is still a matter of debate. We aimed to assess in this group the attack rate of asymptomatic carriers and the symptoms most frequently associated with infection. METHODS: Occupational and clinical characteristics of HCWs who underwent nasopharyngeal swab testing for the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a university hospital from 24 February 2020 to 31 March 2020 were collected. For those who tested positive and for those who tested positive but who were asymptomatic, we checked the laboratory and clinical data as of 22 May to calculate the time necessary for HCWs to then test negative and to verify whether symptoms developed thereafter. Frequencies of positive tests were compared according to selected variables using multivariable logistic regression models. RESULTS: There were 139 positive tests (8.8%) among 1573 HCWs (95% confidence interval, 7.5-10.3), with a marked difference between symptomatic (122/503, 24.2%) and asymptomatic (17/1070, 1.6%) workers (p < 0.001). Physicians were the group with the highest frequency of positive tests (61/582, 10.5%), whereas clerical workers and technicians had the lowest frequency (5/137, 3.6%). The likelihood of testing positive for COVID-19 increased with the number of reported symptoms; the strongest predictors of test positivity were taste and smell alterations (odds ratio = 76.9) and fever (odds ratio = 9.12). The median time from first positive test to a negative test was 27 days (95% confidence interval, 24-30). CONCLUSIONS: HCWs can be infected with SARS-CoV-2 without displaying any symptoms. Among symptomatic HCWs, the key symptoms to guide diagnosis are taste and smell alterations and fever. A median of almost 4 weeks is necessary before nasopharyngeal swab test results are negative.

Particulate Air Pollution, Blood Mitochondrial DNA Copy Number, and Telomere Length in Mothers in the First Trimester of Pregnancy: Effects on Fetal Growth.

Growing evidences have shown that particulate matter (PM) exposures during pregnancy are associated with impaired fetal development and adverse birth outcomes, possibly as a result of an exaggerated systemic oxidative stress and inflammation. Telomere length (TL) is strongly linked to biological age and is impacted by oxidative stress. We hypothesized that PM exposure during different time windows in the first trimester of pregnancy influences both mitochondrial DNA copy number (mtDNAcn), an established biomarker for oxidative stress, and TL. Maternal blood TL and mtDNAcn were analysed in 199 healthy pregnant women recruited at the 11th week of pregnancy by quantitative polymerase chain reaction. We also examined whether maternal mtDNAcn and TL were associated with fetal growth outcomes measured at the end of the first trimester of pregnancy (fetal heart rate, FHR; crown-rump length, CRL; and nuchal translucency, NT) and at delivery (birth weight, length, head circumference). The possible modifying effect of prepregnancy maternal body mass index was evaluated. PM10 exposure during the first pregnancy trimester was associated with an increased maternal mtDNAcn and a reduced TL. As regards ultrasound fetal outcomes, both FHR and CRL were positively associated with PM2.5, whereas the association with FHR was confirmed only when examining PM10 exposure. PM10 was also associated with a reduced birth weight. While no association was found between mtDNAcn and CRL, we found a negative relationship between mtDNAcn and fetal CRL only in overweight women, whereas normal-weight women exhibited a positive, albeit nonsignificant, association. As abnormalities of growth in utero have been associated with postnatal childhood and adulthood onset diseases and as PM is a widespread pollutant relevant to the large majority of the human population and obesity a rising risk factor, our results, if confirmed in a larger population, might represent an important contribution towards the development of more targeted public health strategies.

[DNA methylation analysis in environmental and occupational cancer research]. / Studio della metilazione del DNA nella valutazione della cancerogenicità di agenti ambientali e occupazionali.

The present paper reviews recent laboratory methods and experimental evidence concerning epigenetic biomarkers involved in carcinogenesis mechanisms. We introduce DNA methylation and its role in gene expression control. DNA methylation analysis may allow to identify early changes leading to cancer and other chronic diseases. We describe here strategies for laboratory analyses and their possible applications. We examine results from recent experimental studies suggesting that the effects of certain occupational agents are mediated by alterations in DNA methylation. Planning and conducting investigations on exposed human subjects will allow to verify whether DNA methylation changes identified in animal and in-vitro studies may be used as early-effect and susceptibility biomarkers. DNA methylation analysis has the potential for future applications in risk assessment and prevention programs conducted on subjects exposed to human carcinogens.

The Seveso studies on early and long-term effects of dioxin exposure: a review.

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).

2,3,7,8-Tetrachlorodibenzo-p-dioxin plasma levels in Seveso 20 years after the accident.

In 1976, near Seveso, Italy, an industrial accident caused the release of large quantities of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) into the atmosphere, resulting in the highest levels of the toxicant ever recorded in humans. The contaminated area was divided into three zones (A, B, R) corresponding to decreasing TCDD levels in soil, and cohort including all residents was enumerated. The population of the surrounding noncontaminated area (non-ABR) was chosen as referent population. Two decades after the accident. plasma TCDD levels were measured in 62 subjects randomly sampled from the highest exposed zones (A and B) and 59 subjects from non-ABR, frequency matched for age, gender, and cigarette smoking status. Subjects living in the exposed areas have persistently elevated plasma TCDD levels (range = 1.2-89.9 ppt; geometric mean = 53.2 and 11.0 ppt for Zone A and Zone B, respectively). Levels significantly decrease by distance from the accident site (p = 0.0001), down to general population values (4.9 ppt) in non-ABR, thus validating the original zone classification based on environmental measurements. Women have higher TCDD levels than men in the entire study area (p = 0.0003 in Zone B; p = 0.007 in non-ABR). This gender difference persists after adjustment for location within the zone, consumption of meat derived from locally raised animals, age, body mass index, and smoking. There is no evidence for a gender difference in exposure, so variation in metabolism or elimination due to body fat or hormone-related factors may explain this finding. Elevated TCDD levels in women may contribute to adverse reproductive, developmental, and cancer outcomes.

Exposure to dioxin and nonneoplastic mortality in the expanded IARC international cohort study of phenoxy herbicide and chlorophenol production workers and sprayers.

The authors studied noncancer mortality among phenoxyacid herbicide and chlorophenol production workers and sprayers included in an international study comprising 36 cohorts from 12 countries followed from 1939 to 1992. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin or higher chlorinated dioxins (TCDD/HCD) was discerned from job records and company questionnaires with validation by biologic and environmental measures. Standard mortality ratio analyses suggested a moderate healthy worker effect for all circulatory diseases, especially ischemic heart disease, among both those exposed and those not exposed to TCDD/HCD. In Poisson regression analyses, exposure to TCDD/HCD was not associated with increased mortality from cerebrovascular disease. However, an increased risk for circulatory disease, especially ischemic heart disease (rate ratio [RR] 1.67, 95% confidence interval [Cl] 1.23-2.26) and possibly diabetes (RR 2.25, 95% Cl 0.53-9.50), was present among TCDD/HCD-exposed workers. Risks tended to be higher 10 to 19 years after first exposure and for those exposed for a duration of 10 to 19 years. Mortality from suicide was comparable to that for the general population for all workers exposed to herbicides or chlorophenols and was associated with short latency and duration of exposure. More refined investigations of the ischemic heart disease and TCDD/HCD exposure association are warranted.

Cancer in a young population in a dioxin-contaminated area.

An industrial accident in Seveso, Italy, in 1976, caused contamination of the residential community with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We investigated cancer occurrence in the first post-accident decade (1977-1986) among nearly 20,000 subjects aged 0-19 years. People who left the area were actively followed with a 99% follow-up rate. For reported cancer cases confirmation was obtained through consultation with original medical records. Two ovarian cancers were observed versus none expected. A suggestive increase was seen for Hodgkin's lymphoma (relative risk [RR] = 2.0; 95% confidence interval [CI] = 0.5-7.6). Myeloid leukaemia showed a clear, but not statistically significant increase (RR = 2.7; 95% CI = 0.7-11.4). The most prominent result concerned thyroid cancer, not just for the magnitude of the increase (two cases, RR = 4.6; 95% CI = 0.6-32.7), but also for its consistency with experimental findings and previous observations in humans. Any conclusive interpretation would be premature because of the short time since initial exposure, ecological definition of exposure status, and limited number of events.

Mortality of a young population after accidental exposure to 2,3,7,8-tetrachlorodibenzodioxin.

The mortality experience of 19,637 people aged 1-19 years living in an area around Seveso, Italy, contaminated by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) after an accidental explosion in a chemical plant was examined for the period 1976-1986. For comparison, the mortality of the population of nearly 100,000 people living in the surrounding districts was examined. People who left the study area were followed up. Vital status ascertainment was successful in over 99% of the cases. A group of 186 children who contracted chloracne, a reversible marker of TCDD intoxication, shortly after the accident were in the study: none of them died during the observation period. Among the exposed, mortality owing to all causes, to all accidents and to all cancers failed to show major departure from expectations. Five leukaemia deaths were observed, four among males and one among females; the corresponding relative risks were 2.1 (95% confidence interval (CI): 0.7-6.9), and 2.5 (95% CI: 0.2-27.0), respectively. Two lymphatic leukaemias among males yielded a RR = 9.6 (95% CI: 0.9-106.0). Mortality owing to congenital anomalies showed a nearly twofold increase in the contaminated area; however, five out of seven observed cases were born before the accident. Interpretation is limited by the small number of deaths, short latency period and low validity of death certificate information for certain causes, and by the definition of exposure which was based merely on residence. The follow-up is continuing. A cancer morbidity study is in progress.

Mortality of short-term workers in two international cohorts.

The purpose of this study was to compare the pattern of mortality of blue-collar workers employed less and more than 1 year in the man-made vitreous fiber (MMVF) and the reinforced plastic industries, the latter group being exposed to styrene. We conducted an analysis among 21,784 workers with less than 1 year of employment (short-term workers) and 19,117 workers with 1 or more years of employment (long-term workers) employed in eight European countries. We conducted analyses based on external as well as internal comparisons. In both cohorts, the standardized mortality ratio for all causes among short-term workers was approximately 40% higher, compared with that for longer-term workers. In internal comparisons, the difference was reduced to 9% in the MMVF cohort and 11% in the styrene cohort. Workers with less than 1 month of employment displayed an increased mortality in both cohorts and in most countries. The increased mortality among short-term workers was not concentrated shortly after they quit employment. In both cohorts, short-term workers had a higher mortality from external causes, while little difference was seen in mortality from ischemic heart disease and malignant neoplasms. Although extra-occupational factors may contribute to increase the mortality of short-term workers and, in particular, of those employed for less than 1 month, the difference observed in analyses adjusted for characteristics of employment suggested a relatively small difference in mortality from most causes.

Exposure to formaldehyde and cancer mortality in a cohort of workers producing resins.

The mortality of 1,332 male workers employed at least 30 days in 1959-1980 in a resins-manufacturing plant was examined. Ambient measurements taken in the plant between 1974 and 1979 documented a potential for exposure to levels of formaldehyde as high as greater than 3.0 mg/m3. Vital status was ascertained for 98.6% of the cohort members, and their mortality was compared with expected deaths drawn from the national and local population rates. A statistically significant increase in lung cancer was observed, based on 18 deaths, which was not fully accounted for by possible confounding factors linked to personal habits or sociocultural characteristics. This elevated risk, however, could not be attributed specifically to exposure to formaldehyde. Mortality from digestive cancer (14 deaths observed) and hematologic neoplasms (5 deaths observed) was not substantially higher than expected. The study was limited by information bias due to incomplete work histories, by the small number of deaths from some relevant causes, and by the possibly insufficient length of the observation period. Therefore these results do not provide sufficient grounds either to link formaldehyde exposure in the plant to the increased cancer risk noted or to exclude that formaldehyde might pose such a risk to humans under certain exposure circumstances.

[Methodology in occupational and environmental epidemiology]. / Metodologia nell'epidemiologia occupazionale ed ambientale.

The close links between environment and health have long been known. The methodological bases for this study were especially developed in the occupational settings, and notably so in the study of occupational carcinogens. Many pollutants recently spread from the confined work places to the general environment (e.g., lead, benzene, PAHs, asbestos, noise) either as effluents of industrial sites or as exhausts of diverse environmental combustion sources (e.g., traffic, heating). The methodologies developed in the occupational settings proved extremely useful in addressing these new environmental problems. Main experiences in Italy include the study of a large residential population exposed to dioxin; the study of benzene and PHA's exposure in the city environment; the effect of point industrial pollution sources on the surrounding territory; the short and long term effect on respiratory and cardiovascular health outcomes and functions after exposure to PM10 and 2.5 in large cities.

[Seveso. Dioxin: an example of environmental medicine. Epidemiologic data as guidelines for health programming]. / Seveso-diossina: esempio di environmental medicine. Il dato epidemiologico come indirizzo per la programmazione sanitaria.

The 1976 dioxin accident in Seveso, Italy, represented a major environmental health problem for the population of the surrounding territory and a challenge for the entire regional area and the health and scientific institutions. The role of occupational health and of epidemiology in the incident investigation and management is discussed. Of major relevance was the consideration of all the different component factors of the interested environment, from chemical pollution to cultural attitudes and psycho-social stressors. Scientific research was helpful in elucidating the incompletely known toxic effects of dioxin and the complex mechanism of cancer induction by this widespread pollutant of our industrialized environments. The experience gained in Seveso was also useful in prompting national and international legislation concerning major industrial accidents, and the lessons learned contributed to the content of this legislation. Preparedness to these events requires mapping of the potential sources of these accidental occurrences and the monitoring of the social and health characteristics of the possibly affected populations. In the Lombardy Region, the numerous epidemiological investigations performed and the expertise implemented for the study and the control of the accident consequences, formed the basis on which the Regional Epidemiology Surveillance System established.