Risk Factors for Lung Cancer in the Province of Lecce: Results from the PROTOS Case-Control Study in Salento (Southern Italy).

In the province of Lecce (southern Italy), a higher incidence of lung cancer (LC) among men compared to regional and national data was reported. In a sub-area in the center of the province (cluster area), the incidence and mortality for LC was even higher. PROTOS is a case-control study aimed at investigating possible risk factors for LC in the province area. A total of 442 patients with LC and 1326 controls matched by sex and age living in the province of Lecce for at least 10 years were enrolled and georeferenced; they filled in a questionnaire with their personal information and exposures. For each risk factor, an Odds Ratio adjusted for all the other variables was calculated. The risk of LC increased with excessive use of alcohol in women, for those subjects with a family cancer history, for each increase in pack/year of cigarettes, for men more exposed considering the industrial district in the cluster area, and for those using pesticides in agriculture without wearing personal protective equipment. The higher incidence of adenocarcinoma in both sexes suggests that, in addition to cigarette smoking, concurrent exposures to other environmental, occupational, and life-style factors may play a role in increased cancer risk and should be more deeply explored.

Factors Affecting Arsenic Methylation in Contaminated Italian Areas.

Chronic arsenic (As) exposure is a critical public health issue. The As metabolism can be influenced by many factors. The objective of this study is to verify if these factors influence As metabolism in four Italian areas affected by As pollution. Descriptive analyses were conducted on 271 subjects aged 20-49 in order to assess the effect of each factor considered on As methylation. Percentages of metabolites of As in urine, primary and secondary methylation indexes were calculated as indicators for metabolic capacity. The results indicate that women have a better methylation capacity (MC) than men, and drinking As-contaminated water from public aqueducts is associated with poorer MC, especially in areas with natural As pollution. In areas with anthropogenic As pollution occupational exposure is associated with a higher MC while smoking with a poorer MC. Dietary habits and genetic characteristics are probably implicated in As metabolism. BMI, alcohol consumption and polymorphism of the AS3MT gene seem not to influence As MC. Arsenic metabolism may be affected by various factors and in order to achieve a comprehensive risk assessment of As-associated disease, it is crucial to understand how these factors contribute to differences in As metabolism.

Biomarkers of exposure and early effect in three contaminated sites of southern Italy: protocols for etiological epidemiological studies.

INTRODUCTION: Environmental pollution has been progressively becoming one of the main risk factors to human diseases. In particular, populations living in high-contaminated sites are particularly exposed to environmental toxicants, with consequent increased risks to human health. In Italy, there are currently ongoing three epidemiological etiological studies aimed at evaluating the association between exposure to inorganic and organic chemicals and presence of biological markers of early effects in population living in three National Priority Contaminated Sites (NPCSs). Specifically, the correlations concern preclinical indicators of liver disease in Priolo NPCS, thyroid diseases in Milazzo-Valle del Mela NPCS and cardiovascular risk and kidney damage in Crotone NPCS. METHODS AND ANALYSIS: Overall, approximately 1300 subjects of both sexes will be enrolled in the three NPCSs according to specific inclusion criteria. For each subject, serum and urine specimens are collected, on which the determination of biological markers of exposure and early effects for the selected outcomes are performed. Individual information on environmental and occupational exposure, medical history, diet and life habits is obtained through questionnaires provided by web platform. In Milazzo-Valle del Mela and Crotone NPCSs, not invasive instrumental and imaging examinations are performed in order to evaluate further risk factors of thyroid carcinoma and cardiovascular disease, respectively. ETHICS AND DISSEMINATION: The protocol studies have been approved by the Ethics Committees responsible for the three involved NPCSs: the Ethics Committee 'Catania 2' for the NPCS of Priolo (21 July 2017, n. 500/2017/CECT2), the Ethics Committee of the University Hospitals of Messina for the NPCS of Milazzo-Valle del Mela (19 February 2018, n.2/2018); the Ethics Committee of the Region of Calabria for the NPCS of Crotone (20 July 2017, n. 174). Results will be disseminated among policy-makers, citizens, stakeholders and scientific community through the organisation of conferences and events, and the publication on international peer/reviewed journals.

Bisphenols as Environmental Triggers of Thyroid Dysfunction: Clues and Evidence.

Bisphenols (BPs), and especially bisphenol A (BPA), are known endocrine disruptors (EDCs), capable of interfering with estrogen and androgen activities, as well as being suspected of other health outcomes. Given the crucial role of thyroid hormones and the increasing incidence of thyroid carcinoma in the last few decades, this review analyzes the effects of BPS on the thyroid, considering original research in vitro, in vivo, and in humans published from January 2000 to October 2019. Both in vitro and in vivo studies reported the ability of BPs to disrupt thyroid function through multiple mechanisms. The antagonism with thyroid receptors (TRs), which affects TR-mediated transcriptional activity, the direct action of BPs on gene expression at the thyroid and the pituitary level, the competitive binding with thyroid transport proteins, and the induction of toxicity in several cell lines are likely the main mechanisms leading to thyroid dysfunction. In humans, results are more contradictory, though some evidence suggests the potential of BPs in increasing the risk of thyroid nodules. A standardized methodology in toxicological studies and prospective epidemiological studies with individual exposure assessments are warranted to evaluate the pathophysiology resulting in the damage and to establish the temporal relationship between markers of exposure and long-term effects.

The health of communities living in proximity of geothermal plants generating heat and electricity: A review.

Since the 1990s, in areas with natural geothermal manifestations studies on the association between exposure to pollutants and health effect have become increasingly relevant. These emissions consist of water vapor mixed with carbon dioxide, hydrogen sulfide (H2S), methane and, to a lesser extent, rare gases and trace elements in volatile forms. Considering the indications of the World Health Organization and the growth in the use of geothermal energy for energy production, this review aims to report studies exploring the health status of the populations living in areas where geothermal energy is used to produce heat and electricity. Studies on the health effects of the general population exposed to emissions from both natural geothermal events and plants using geothermal energy at domestic or commercial level have been considered between 1999 and 2019. Studies were classified into those based on health indicators and those based on proxy-individual level exposure metrics. Both statistically significant results (p<0.05) and interesting signals were commented. The 19 studies selected (New Zealand, Iceland and Italy) provide heterogeneous results, with an increased risk for several tumor sites. Exposure to H2S low concentrations is positively associated with an increment of respiratory symptoms, anti-asthma drugs use, mortality for respiratory diseases and lung cancer. Exposure to H2S high levels is inversely related to cancer mortality but associated with an increase in hospitalization for respiratory diseases, central nervous system disorders and cardiovascular diseases. The results indicate that the health of populations residing in areas rich in geothermal emissions presents some critical elements to be explored. The two major limitations of the studies are the ecological design and the inadequate exposure assessment. The authors suggested the prosecution and the systematization of health surveillance and human biomonitoring activities associated with permanent control of atmospheric emissions from both industrial and natural plants.

Mortality and hospitalization associated to emissions of a coal power plant: A population-based cohort study.

BACKGROUND: Coal-fired thermal power plants represent a significant source of air pollutants, especially sulfur dioxide (SO2) that has been associated with an increased risk of mortality and morbidity for respiratory and cardiovascular disease. A coal power plant in Vado Ligure (Italy) (CPPVL) started in 1970 was stopped in 2014 by the Prosecutor's Office on the grounds of environmental and health culpable disaster. OBJECTIVE: To investigate the association between the exposure of residents to atmospheric pollutants emitted by CPPVL and the risk of mortality and hospitalization, considering both cancer and non-cancer causes in a population-based cohort study. METHODS: SO2 and nitrogen oxides (NOx), estimated using the ABLE-MOLOCH-ADMS-Urban dispersion model, were selected as representative surrogates of exposure to CPPVL emissions (SO2-CPPVL) and cumulative emissions from other sources of pollution (NOx-MS), respectively. The relationship between each health outcome and categories of exposure to SO2-CPPVL was estimated by the Hazard Ratio (HR) using multiple sex-specific Cox regression models, adjusted for age, exposure to NOx-MS, and socio-economic deprivation index using SO2-CPPVL first quartile as a reference. RESULTS: 144,019 individuals were recruited (follow-up 2001-2013). An excess of mortality was found for all natural causes (men: 1.49; 95% CI 1.38-1.60; women: 1.49; 95% CI 1.39-1.59), diseases of the circulatory system (men: 1.41; 95% CI 1.24-1.56; women: 1.59; 95% CI 1.44-1.77), of the respiratory system (men: 1.90; 95% CI 1.47-2.45; women: 1.62; 95% CI 1.25-2.09), and of the nervous system and sense organs (men: 1.34; 95% CI 0.97-1.86; women: 1.38; 95% CI 1.03-1.83), and in men for trachea, bronchus, and lung cancers (1.59; 95% CI 1.26-2.00). Results of hospitalization analysis were consistent with those of mortality. CONCLUSION: Results obtained, also when considering multiple sources of exposure, indicate that exposure to CPP emissions represents a risk factor for selected health outcomes as well as the urgently adoption of primary prevention measures and of a specific surveillance programme.

Respiratory Symptoms in Relation to Living near a Crude Oil First Treatment Plant in Italy: A Cross-Sectional Study.

Exposure to air pollution has been shown to increase the risk of developing chronic respiratory diseases. The largest crude oil first treatment plant in Italy emits harmful polluting substances. This cross-sectional study assesses the occurrence of respiratory symptoms in a sample of the adult population living near the plant. A proximal and a reference area were defined in order to recruit 200 subjects. Each subject performed a spirometry test and completed a questionnaire. Associations between the distance from the plant and selected respiratory outcomes were assessed (distance-based approach). The prevalence of outcomes between a proximal and a reference area (area-based approach) were also compared. Odds ratios were adjusted for potential confounders. Living near the plant was associated with a higher prevalence of respiratory symptoms, with significant associations for severe dyspnoea equivalent to the halving of risk as the distance of residence from the plant increased by 1 km (adjusted odds ratio (OR) 0.48, confidence interval at the 95% probability level (95% CI): 0.25⁻0.92). Several signals emerged for respiratory allergic symptoms. The area-based approach generally confirmed the results obtained with the distance-based approach. This is the first study to be carried out on a crude oil first treatment plant aimed at assessing the association with the occurrence of respiratory symptoms. These findings contribute to the evidence supporting the need for a space⁻time surveillance system in the investigated area.

[Recommendations from a health impact assessment in Viggiano and Grumento Nova (Basilicata Region, Southern Italy)]. / EPICHANGE/2. Indicazioni emerse dalla VIS a Viggiano e Grumento Nova (PZ).

In Europe, Health Impact Assessment (HIA) is a consolidated practice aimed at predicting health impacts supporting the predisposition of plans and projects subjected to authorization procedures. In Italy, further developments are needed to harmonize the practice and consolidate methodologies in order to extend the HIA application in different fields. The recent HIA conducted in Val d'Agri (Basilicata) on the impacts of a first crude oil treatment plant represents an opportunity to illustrate its tools, methods and fields of application. In this experience, participation methods in impact assessment have been adapted to the context, emphasizing aspects of ethics, equity and democracy. Environmental and epidemiological studies were included in the HIA Val d'Agri in order to characterize the environment and assess the health status of the resident population. On the basis of the results public health recommendations have been elaborated, shared with the stakeholders and shared with local and regional administrators. The experience in Val d'Agri introduces elements of reflection on the potential of HIA at local level in order to support the public health and the environmental control systems in the area, as well as planning based on preventive environment and HIA.

[Residential cohort study on mortality and hospitalization in Viggiano and Grumento Nova Municipalities in the framework of HIA in Val d'Agri (Basilicata Region, Southern Italy)]. / Studio di coorte residenziale su mortalità e ricoveri nei Comuni di Viggiano e Grumento Nova nell'ambito della VIS in Val d'Agri (Basilicata).

OBJECTIVES: to evaluate the associations among the emissions produced by "Centro olio Val d'Agri" (COVA), with mortality and hospitalization of residents in the Viggiano and Grumento Nova Municipalities, located in Val d'Agri (Basilicata Region, Southern Italy). DESIGN: residential cohort study. SETTINGS AND PARTICIPANTS: Lagrangians dispersion models to estimate the level of exposure at the address of residence to NOX concentrations as tracers of COVA emissions. Based on the tertile of NOX distribution, individual exposure was classified and a Cox model analysis was performed (hazard ratio, HR, trend with relative 95%CI). The association among exposure to NOX and the cohort mortality/hospitalization was evaluated considering age, socioeconomic status, and distance from the high traffic density road. The cohort included 6,795 residents (73,270 person-years) in the period 2000-2014. MAIN OUTCOME MEASURES: causes of mortality and hospitalization due to cardio-respiratory diseases, recognised as associated to air pollution, with medium-short latency induction period, consistent with the period of operation at the COVA. RESULTS: increasing trends were observed on three exposure classes for mortality due to circulatory system diseases (HR trend: 1.19; 95%CI 1.02-1.39), stronger considering women (HR trend: 1.19; 95%CI 1.02-1.39). From hospitalizations results, an increased risk emerges for respiratory diseases (HR trend: 1.12; 95%CI 1.01-1.25) and, for women, for diseases of the circulatory system (HR trend: 1.19; 95%CI 1.03-1.38), for ischemic diseases (HR trend: 1.33; 95%CI 1.02-1.74) and respiratory diseases (HR trend: 1.22; 95%CI 1.03-1.46). CONCLUSIONS: the excesses of mortality and hospitalization emerged in areas most exposed to pollutants of industrial origin are relevant for preventive actions. It is recommended to define and implement a surveillance system for the entire resident population based on indicators of environmental pollution and related health outcomes on the basis of the scientific literature and the results achieved by the present study.

Mortality of populations residing in geothermal areas of Tuscany during the period 2003-2012.

INTRODUCTION: The limited scientific knowledge on the relationship between exposure and health effects in relation to geothermal activity motivated an epidemiologic investigation of Tuscan geothermal area. AIM: This study aims at describing mortality of populations living in Tuscan municipalities in the period 2003-2012. METHOD: Sixteen municipalities were included in the study area: eight in the northern and eight in the southern area. Mortality data come from the Regional Mortality Registry of Tuscany. Fifty-four causes of death, considered of interest for population health status or consistent with "Project SENTIERI" criteria, are analyzed. RESULTS: Results show a worse mortality profile in the southern area, especially in males, for whom excesses of all cancers and some causes of cancer emerge, while in the northern area an excess of cerebrovascular diseases among females merits attention. Further and more appropriate studies are needed to clarify the etiology of some diseases and to better assess a potential cause-effect relationship.

[Atmospheric non-methane hydrocarbons near plants of crude oil first treatment]. / Idrocarburi non metanici nell'atmosfera in prossimità di impianti di primo trattamento del greggio.

La continua espansione delle attività di perforazione ai fini dell'estrazione petrolifera in prossimità di aree abitate ha fatto sì che negli ultimi anni l'attenzione si focalizzasse sull'impatto di questo processo fortemente industrializzato sulla salute pubblica. Le comunità che vivono nei dintorni di impianti di questo tipo devono, infatti, fronteggiare diversi problemi, quali l'inquinamento atmosferico e acustico, la contaminazione del suolo e delle acque sotterranee, il traffico dei camion da e verso il sito, incidenti e malfunzionamenti all'interno dell'impianto. In questo contesto, la valutazione del rischio per la salute è ostacolata dal fatto che l'esposizione alle sostanze chimiche presenti non può essere valutata in via definitiva, poiché non sempre si è a conoscenza di tutti i composti immessi nell'ambiente né delle loro concentrazioni, per non parlare del problema delle coesposizioni ad altri inquinanti. Nonostante l'oramai conclamato e vasto interesse generato da questo argomento, ad oggi esistono pochi studi basati su popolazioni riguardanti gli effetti sulla salute delle comunità che vivono in prossimità dei siti di perforazione ed estrazione; ciò genera la necessità di condurre campagne di monitoraggio mirate e studi epidemiologici che verifichino l'eventuale esistenza e natura di pattern di malattie associati a tali attività. La presente rassegna bibliografica individua, quindi, i principali inquinanti atmosferici presenti in prossimità di un impianto di primo trattamento del greggio e cerca di fornire un quadro generale delle loro potenziali sorgenti e caratteristiche.

[Studies on markers of exposure and early effect in areas with arsenic pollution: methods and results of the project SEpiAs. Epidemiological studies on population exposed to low-to-moderate arsenic concentration in drinking water]. / Studi su marcatori di esposizione ed effetto precoce in aree con inquinamento da arsenico: metodi e risultati del progetto SEpiAs. Studi epidemiologici su popolazioni umane esposte a basse e moderate concentrazioni di arsenico nelle acque potabili.

Arsenic and its inorganic compounds are classified as human carcinogens. Several epidemiological studies conducted in areas of the world characterized by high arsenic concentration in drinking water, even up to 3,000 µg/l, report associations between arsenic exposure and skin, bladder, lung, liver and kidney cancer as well as cardiovascular diseases, diabetes and reproductive and developmental effects. Since general population is not exposed to these high arsenic concentrations in the last years attention focused on adverse health effects that low-to-moderate arsenic concentrations (0-150 µg/l) in drinking water could induce. The World Health Organization recommends a maximum limit of 10 µg/l for arsenic in drinking water. Almost all epidemiological studies conducted on populations exposed to low-to-moderate arsenic concentrations in drinking water are limited due to problems arising from both individual exposure assessment and low subjects number. The aim of the present review is to collect literature-based evidences regarding adverse health effects associated with exposure to low-to-moderate arsenic concentrations in drinking water (10-150 µg/l) in order to obtain a comprehensive picture of the health outcomes that such exposure can have on general population.

[Studies on markers of exposure and early effect in areas with arsenic pollution: methods and results of the project SEpiAs. Epidemiological surveillance in areas with environmental pollution by natural or anthropogenic arsenic]. / Studi su marcatori di esposizione ed effetto precoce in aree con inquinamento da arsenico: metodi e risultati del progetto SEpiAs. Sorveglianza epidemiologica in aree interessate da inquinamento ambientale da arsenico di origine naturale o antropica (SEpiAS CCM 2010).

INTRODUCTION: Arsenic and its inorganic compounds are classified as carcinogenic to humans. Exposures to inorganic arsenic (iAs) in drinking water are associated with both carcinogenic and non-carcinogenic effects. The risk assessment of exposures to low-moderate levels of environmental arsenic (As) is a challenging objective for research and public health. The SEpiAs study, funded by the Italian Ministry of Health (CCM), was carried out in four areas with arsenic pollution prevalently of natural origin, Amiata and Viterbo areas, or of industrial origin, Taranto and Gela. MATERIALS AND METHODS: 271 subjects (132 men) aged 20-44, were randomly sampled stratifying by area, gender and age classes. Individual data on residential history, socio-economic status, environmental and occupational exposures, lifestyle and dietary habits, were collected through interviews using questionnaire. In urine samples of recruited subjects, the concentration of inorganic arsenic (iAs) and methylated species (MMA, DMA) was measured using inductively coupled mass spectrometer (DRCICP- MS), after chromatographic separation (HPLC). Molecular biomarkers and biomarkers of DNA damage, as well as markers of cardiovascular risk were measured The distributions of iAs and iAs+MMA+DMA were described by area and gender, geometric mean (GM), percentiles and standard deviation (SD). The associations between As species and variables collected by questionnaire were evaluated by multiple regression analysis. RESULTS: Results showed a high variability of As species within and among areas. Gela and Taranto samples showed higher iAs concentration compared to Viterbo and Amiata. Subjects with iAs>1,5 µg/L or iAs+MMA+DMA>15 µg/L (thresholds suggested by the Italian Society of Reference Values), are 137 (50,6%) and 68 (25,1%), respectively. A positive association between iAs and use of drinking water emerged in the Viterbo sample, between iAs and occupational exposure in the Gela and Taranto samples. Fish consumption was associated with higher iAs concentration in the whole sample, and particularly in men of the Gela sample. Similar results were observed for iAs+MMA+DMA. Subjects with iAs or iAs+MMA+DMA values higher than the 95th percentile were 15 (6Taranto, 5 Gela, 3Viterbo, 1 Amiata). The relationships between iAs and organic species (methylation efficiency ratios) were different between sex in the four areas. The relevance of polymorphisms AS3MT Met287Thr, GST-T1, GST-M1, OGG1 was confirmed. The analysis of carotid intima-media-thickness showed normal values, but higher among man of Viterbo, Taranto and Gela areas. CONCLUSIONS: Results are informative of exposure to inorganic and organic As in large or at least non-negligible quotas of the samples. The SEpiAs results suggest a further deepening on routes of exposure to arsenic species, and support the recommendation to implement primary prevention measures to reduce population exposure.

Genotoxic and epigenetic mechanisms in arsenic carcinogenicity.

Arsenic is a human carcinogen with weak mutagenic properties that induces tumors through mechanisms not yet completely understood. People worldwide are exposed to arsenic-contaminated drinking water, and epidemiological studies showed a high percentage of lung, bladder, liver, and kidney cancer in these populations. Several mechanisms by which arsenical compounds induce tumorigenesis were proposed including genotoxic damage and chromosomal abnormalities. Over the past decade, a growing body of evidence indicated that epigenetic modifications have a role in arsenic-inducing adverse effects on human health. The main epigenetic mechanisms are DNA methylation in gene promoter regions that regulate gene expression, histone tail modifications that regulate the accessibility of transcriptional machinery to genes, and microRNA activity (noncoding RNA able to modulate mRNA translation). The "double capacity" of arsenic to induce mutations and epimutations could be the main cause of arsenic-induced carcinogenesis. The aim of this review is to better clarify the mechanisms of the initiation and/or the promotion of arsenic-induced carcinogenesis in order to understand the best way to perform an early diagnosis and a prompt prevention that is the key point for protecting arsenic-exposed population. Studies on arsenic-exposed population should be designed in order to examine more comprehensively the presence and consequences of these genetic/epigenetic alterations.

[State of health of populations residing in geothermal areas of Tuscany]. / Stato di salute delle popolazioni residenti nelle aree geotermiche della Toscana.

OBJECTIVE: The limited scientific knowledge on relationship between exposure and health effects in relation to geothermal activity motivated an epidemiologic investigation in Tuscan geothermal area. The study aims to describe the health status of populations living in Tuscany municipalities where concessions for exploitation of geothermal resources were granted. DESIGN: This is an ecological study, so it is not useful to produce evidence to sustain a judgment on the cause-effect link. The major limits of this type of study are the use of the residence at municipal level as a proxy of exposure to both environmental and socioeconomic factors and the use of aggregated data of health outcomes that can lead to the well-known ecological fallacy. SETTING AND PARTICIPANTS: Sixteen municipalities were included in the study area: eight are part of the so-called "traditional" geothermal area, defined as Northern Geothermal Area (NGA) and eight located in the Amiata Mountain defined as Southern Geothermal Area (SGA). In 2000-2006, the average resident population in the overall area was approximately 43,000 inhabitants. Thirty-one geothermal power plants were active, with a production capacity of 811 MW, 5 of them with 88 MW located in the SGA. Statistical analyses on the entire geothermal area, NGA and SGA subareas, and the sixteen municipalities were performed. MAIN OUTCOME MEASURES: Mortality data were obtained from Tuscany Regional Mortality Registry for the 1971-2006 period, analysing 60 causes of death, of interest for population health status or consistent with "Project SENTIERI" criteria. Hospital discharge records of residents in Tuscany Region in 2004-2006, anywhere admitted to hospital, were analyzed considering only the main diagnosis, excluding repeated admissions for the same cause. The causes taken into account are the same analysed for mortality were considered. Age-standardized mortality rates (TSDM) and the temporal trends of TSDM for four periods (1971-1979, 1980-1989, 1990-1999, 2000-2006) were computed. Age-standardized mortality/hospitalization ratios (SMR/SHR), with and without adjustment for the deprivation index based on 2001 census data, were calculated: mortality in the years 2000-2006 and hospitalization in 2004-2006. The expected number of events were computed using rates of residents in neighbouring municipalities (municipalities included in 50 km radius circle centred on the study area). Bayesian estimates of mortality/hospitalization ratios (BMR/BHR) at municipal level only and relating maps of the Bayesian risk estimators were elaborated. Congenital malformations (MC) were analysed using data from Tuscan Registry of Birth Defect in 1992-2006 period, relative to outcomes of pregnancies in women resident in the municipalities of study area, wherever the birth or termination of pregnancy occurred. The ratio between observed and expected cases (O/A), with expected defined according to regional rate, were calculated and O/A Bayesian estimates (BMR) are showed only at municipal level. The low weight and the males/females ratio at birth were analysed using data from Tuscany Birth Certificates, covering period 2001-2007, excluding births occurred in facilities outside Tuscany Region. For Low birth weight (< 2,500 grams), very low birth weight (< 1,500 grams), low birth weight in women with normal gestational age or greater than 36 weeks, gestational age less than 36 weeks, and the frequency of males, the observed/expected ratio was calculated, with the expected number defined according to regional rate. RESULTS: ENVIRONMENTAL BACKGROUND: High levels of arsenic in drinking water distribution emerges as a critical element, so that several municipalities resorted to granting exemptions for the parameters laid down by the Legislative Decree in force (D.Lgs 31/01). However, during the final phase of the study, new blast systems activated in the SGA decreased the arsenic levels in the water supply, reaching values not requiring derogations, which, instead, are still effective in some NGA municipalities. Air quality data, from Tuscany Regional Agency for Environmental Protection-ARPAT, show that geothermal activities are able to affect air quality, especially with hydrogen sulphide in NGA, and hydrogen sulphide and mercury in SGA. A significant contribution to the presence of mercury in air is due to previous metallurgical sites. Although mercury levels are below WHO guideline values, in SGA nearby Siena, values were significantly higher than in other geothermal areas, because of power plant PC2 (turned off in July 2011) in Piancastagnaio municipality. The hydrogen sulphide concentration levels were generally lower than WHO reference values, with occasional excesses over guideline value for health protection (150 µg/m3 as average of the 24 hours). Olfactory pollution was more critic with values exceeding 7-10 µg/m3 range even in areas without geothermal plants. RESULTS: POPULATION'S HEALTH STATUS: This study evaluated health status of resident population in geothermal areas analysing geographic and temporal distribution of mortality, hospitalization and reproductive health outcomes (congenital malformations, low birth weight, sex ratio among newborns). In both geothermal areas mortality rates steadily declined from 1971 to 2006, in males and females, in line with the regional trends. In 2000-2006 period, in the overall geothermal area a significant mortality excess was observed for all causes among males (2,312 deaths, 2,146 expected), but not among females, using as reference residents in neighbouring municipalities. The mortality excess among males was more evident for infectious diseases (25 deaths, 10 expected), especially tuberculosis (8 deaths, 2 expected), for respiratory diseases (218 deaths, 170 expected), in particular pneumoconiosis, including deaths from silicosis (51 deaths, 14 expected), and for nervous system diseases (72 deaths, 56 expected). Among females significant mortality excess for liver cirrhosis (35 deaths, 25 expected) emerged, while mortality from cardiovascular diseases and ischemic heart diseases were significantly lower than expected. In the NGA, mortality among men was lower than expected for all cancers (-15%), in particular for lung cancer (- 25%), while values significantly in excesses were observed for infectious diseases (11 observed, 4 expected) and respiratory diseases (90 observed, 73 expected), expecially pneumoconiosis (20 observed, 6 expected). Among females, significant mortality excesses for ovarian cancer (17 observed, 10 expected) and for circulatory disorders of brain (170 observed, 140 expected) resulted. In the SGA, mortality was more critical, accounting for majority of the excesses detected in overall Geothermal Area. In fact, only infectious diseases and pneumoconiosis were detected in excess in both the geothermal areas. In the SGA, excess of general mortality among males (1,431 deaths; 1,245 expected) but not among females emerged. Even for all cancers, an excess among males (505 deaths, 419 expected) was observed, in particular for cancer of stomach (53 deaths, 44 expected, not statistically significant after adjusting for DI), liver (39 deaths, 23 expected) and lung (124 deaths, 102 expected) cancer. Mortality in SGA was also in excess for respiratory diseases only among men (128 deaths, 97 expected), mostly due to silicosis (31 deaths, 8 expected), although steadily decreasing since 1971 as observed at regional level. Also tuberculosis resulted in excess in SGA (7 deaths, 1 expected). Among females acute respiratory disease mortality was significantly in excess (41 observed, 29 expected). Temporal trend showed a decline from the 70s to the 90s, with a rising trend in recent years in line with Tuscany region. It should be considered that pneumonia was the commonest cause of death of acute respiratory diseases, which allow for lower reliability of death certificate, especially among the elderly (> 64 years). Among females resident in SGA a mortality excess from digestive system diseases was observed (72 observed, 55 expected). The hospitalization in the overall Geothermal Area did not show any excess for all causes and all tumours in both genders. Statistically significant excesses for hospital admission from stomach cancer among males (49 observed, 38 expected) and females (42 observed, 28 expected), and from lymphohematopoietic tumours among females, particularly from lymphatic leukaemia (15 observed, 5 expected), were observed. As mortality analysis highlighted, also hospital admissions by geothermal areas and gender showed a worst picture in SGA than in NGA. In the latter, a significant excess of hospital admissions from all causes among females (1,357 observed, 1,284 expected) but not among males (1,193 observed, 1,141 expected) and an excess - close to statistical significance - from all tumours only among females (297 observed; 272 expected) were observed. Furthermore, statistically significant excesses of hospital admissions from digestive system diseases in both genders (M: 392 observed, 350 expected; F: 300 observed, 268 expected), from dementias (16 observed, 8 expected) and from lympho hematopoietic cancers among females, particularly from lymphatic leukaemia (9 observed, 2 expected), were observed. In the SGA, statistically significant excesses of hospital admissions for stomach cancer (M: 32 observed, 21 expected, not significant after adjusting by DI; F: 29 observed, 18 expected), for respiratory diseases (M: 408 observed, 351 expected; F: 339 observed, 277 expected) and for renal failure (M: 61 observed, 41 expected; F: 52 observed, 34 expected) were observed in both genders. (ABSTRACT TRUNCATED)