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Somatic mutations inPTPN11, the gene encoding the transducer SHP-2, have emerged as a novel class of lesions that upregulate RAS signalling and contribute to leukaemogenesis. In a recent study of 69 children and adolescents withde novoacute myeloid leukaemia (AML), we documented a non-random distribution ofPTPN11mutations among French–American–British (FAB) subtypes. Lesions were restricted to FAB-M5 cases, where they were relatively common (four of 12 cases). Here, we report on the results of a molecular screening performed on 181 additional unselected patients, enrolled in participating institutions of the Associazione Italiana Ematologia Oncologia Pediatrica–AML Study Group, to provide a more accurate picture of the prevalence, spectrum and distribution ofPTPN11mutations in childhood AML and to investigate their clinical relevance. We concluded thatPTPN11defects do not represent a frequent event in this heterogeneous group of malignancies (4·4%), although they recur in a considerable percentage of patients with FAB-M5 (18%).PTPN11lesions rarely occur in other subtypes. Within the FAB-M5 group no clear association ofPTPN11mutations with any clinical variable was evident. Nearly two third of the patients with this subtype were found to harbour an activating mutation inPTPN11,NRAS,KRAS2orFLT3. [ABSTRACT FROM AUTHOR]

A historical cohort of service station attendants is underway. It is aimed at evaluating possible excess cancer risk in relation to exposure intensity. In this paper we discuss the feasibility of a retrospective exposure assessment by evaluating the association between indicators of workload and the exposure intensity to some aromatic hydrocarbons measured in a sample of current employees. Available for the analysis were 703 personal samples from 111 filling station workers. Measured concentrations of benzene, toluene and xylenes (8-hour time weighted averages) averaged 0.55 mg/m3, 0.71 mg/m3 and 0.32 mg/m3, respectively. The number of vehicles filled, the daily sales of super premium gasoline and motorbike fuel, and the winter season were all significant predictors of the log concentration of benzene in simple regression analyses. The size of the station acted as an effect modifier. While no single variable was able to predict the benzene level in large stations, for small stations an increase of 0.0579 and of 0.0418 in the log benzene concentration per unit increase in super premium gasoline (100 l) and in motorbike fuel (10 l) dispensed, was estimated. The overall variance explained by the multivariate model, however, was only 12.3%. Therefore, a clear categorization of groups with homogeneous and significantly different exposure levels is not achievable. From the point of view of exposure assessment, workers in small stations with higher sales of super premium gasoline tend to have higher exposure levels. This group should be examined in detail when the final results of the cohort study are available. [ABSTRACT FROM PUBLISHER]

Background: after the outbreak of the SARS-CoV-2 pandemic in 2020, several waves of pandemic cases have occurred in Italy. The role of air pollution has been hypothesized and investigated in several studies. However, to date, the role of chronic exposure to air pollutants in increasing incidence of SARS-CoV-2 infections is still debated., Objectives: to investigate the association between long-term exposure to air pollutants and the incidence of SARS-CoV-2 infections in Italy., Design: a satellite-based air pollution exposure model with 1-km2 spatial resolution for entire Italy was applied and 2016-2019 mean population-weighted concentrations of particulate matter < 10 micron (PM10), PM <2.5 micron (PM2.5), and nitrogen dioxide (NO2) was calculated to each municipality as estimates of chronic exposures. A principal component analysis (PCA) approach was applied to 50+ area-level covariates (geography and topography, population density, mobility, population health, socioeconomic status) to account for the major determinants of the spatial distribution of incidence rates of SARS-CoV-2 infection. Detailed information was further used on intra- and inter-municipal mobility during the pandemic period. Finally, a mixed longitudinal ecological design with the study units consisting of individual municipalities in Italy was applied. Generalized negative binomial models controlling for age, gender, province, month, PCA variables, and population density were estimated., Setting and Participants: individual records of diagnosed SARS-2-CoV-2 infections in Italy from February 2020 to June 2021 reported to the Italian Integrated Surveillance of COVID-19 were used., Main Outcome Measures: percentage increases in incidence rate (%IR) and corresponding 95% confidence intervals (95% CI) per unit increase in exposure., Results: 3,995,202 COVID-19 cases in 7,800 municipalities were analysed (total population: 59,589,357 inhabitants). It was found that long-term exposure to PM2.5, PM10, and NO2 was significantly associated with the incidence rates of SARS-CoV-2 infection. In particular, incidence of COVID-19 increased by 0.3% (95%CI 0.1%-0.4%), 0.3% (0.2%-0.4%), and 0.9% (0.8%-1.0%) per 1 μg/m3 increment in PM2.5, PM10 and NO2, respectively. Associations were higher among elderly subjects and during the second pandemic wave (September 2020-December 2020). Several sensitivity analyses confirmed the main results. The results for NO2 were especially robust to multiple sensitivity analyses., Conclusions: evidence of an association between long-term exposure to ambient air pollutants and the incidence of SARS-CoV-2 infections in Italy was found.

Since 2006, epidemiological surveillance of populations living in Italian contaminated sites has been ongoing (SENTIERI Project). Updated global estimates of mortality (2013-2017) and hospitalization (2014-2018) are reported. The excess deaths (observed-expected) for the main groups of diseases were calculated for all the 46 sites together. Through a random-effect meta-analysis of the standardized mortality and hospitalization rates (SMR/SHR), the pooled SMR/SHR for all the sites and their groupings were estimated. In the 46 sites, 8,342 exceeding deaths (1,668/year) were estimated, 4,353 in males and 3,989 in females, resulting in an excess risk of 2% in both genders. The risk of hospitalization for all causes was in excess of 3%. These excesses are mainly attributable to malignant tumours. In subgroups of sites, exceeding SMRs were observed for all mesotheliomas and pleural mesotheliomas, lung and colorectal cancers in both genders. SHR for all causes were observed in excess in the first year of life (+8%), in the group 0-19 and 20-29 years (+3-5%); no excesses of mortality were observed in the group 0-29 years.

The SENTIERI Project analyses the health profile of the populations residing in Italian national priority contaminated sites in specific calendar periods using a cross-sectional approach. An aspect that has not been evaluated so far is the analysis over a long period, for understanding the changes in health profiles over time and studying them also in function of the changes occurred in the territories. This article studies temporal trends by birth cohort and calendar period for overall mortality and lung cancer mortality from 1980 to 2018, separately for men and women, for three sites: Priolo (Sicily Region, Southern Italy), Pitelli (Liguria Region, Northern Italy), and Terni-Papigno (Umbria Region, Central Italy). A method for selecting the temporal model that best fits the data is then proposed. General mortality presents complex temporal profiles when considering cumulative risks, and usually the most important temporal axis is the birth cohort for cumulative SMRs (i.e., after adjusting for trends in the reference population). For lung cancer, the most important time axis is the birth cohort and the age-cohort model is the most appropriate, in particular for men of Priolo and Terni.

Introduction Adn Objectives: The Sixth Report presents the results of the "SENTIERI Project: implementation of the permanent epidemiological surveillance system of populations residing in Italian Sites of Remediation Interest", promoted and financed by the Italian Ministry of Health (Centre for Disease Control and Prevention - CCM Project 2018). The aim of this study is to update the mortality and hospitalization analyses concerning the 6,227,531 inhabitants (10.4% of the Italian population) residing in 46 contaminated sites (39 of national interest and 7 of regional interest). The sites include 316 municipalities distributed as follows: 15 in the North-East (20.3% of the investigated population); 104 in the North-West (12% of the investigated population), 32 in the Centre (12.6% of the investigated population), 165 in the South and Islands (55.5% of the investigated population). Analyses were carried out on the paediatric-adolescent (1,128,396 residents) and youth (665,284 residents) population, and a study on congenital anomalies (CA) was carried out at sites covered by congenital malformation registers. Accompanying the epidemiological assessments, site-specific socioeconomic conditions were examined and an overall estimate of excess risk for populations residing at contaminated sites was drawn up. By means of a systematic review of the scientific literature, the epidemiological evidence on causal links between sources of environmental exposure and health effects was updated to identify pathologies of a priori interest., Methodology: In the 46 sites included in the SENTIERI Project, mortality (time window: 2013-2017) and hospital admissions (time window: 2014-2018) of the general population of all ages, divided by gender, and of the paediatric-adolescent (0-1 year, 0-14 years, 0-19 years), youth (20-29 years), and overall (0-29 years) age groups, divided by gender, were analysed. In 21 sites, CA diagnosed within the first year of life were studied. Standardised mortality ratios (SMR) and hospitalization ratios (SHR) were calculated with reference to the rates in the regions to which the sites belong. The reference population was calculated net of residents in the sites. CA were studied by calculating the prevalence per 10,000 births and the ratio, multiplied by 100, between the cases observed at the site and those expected on the basis of the prevalences observed in the reference area (region or sub-regional area of belonging, according to the geographical coverage of the registry). The socioeconomic condition studied in the 46 sites is based on the convergence of three deprivation indicators with respect to the reference region: deprivation index at municipal level, deprivation index at census section level, premature mortality indicator (age range 30-69 years) for chronic non-communicable diseases. For the estimation of excess risk for the entire study population, meta-analysis of the mortality and hospitalization risk estimates for each site was carried out and the number of excess deaths estimated for the sites as a whole. The epidemiological evidence was updated through a systematic literature review (January 2009-May 2020), following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The search was carried out on the search engines MEDLINE, EMBASE and Web of Science; the quality of the studies included in the review was assessed using the AMSTAR 2 checklist for systematic reviews and the NewCastle-Ottawa Scale for observational studies in the case of cohort and case-control studies and a modified version thereof for ecological and cross-sectional studies. The update was based on the selection of 14 systematic reviews, 15 primary studies, 6 monographs/reports from international scientific organisations on health effects due to the presence of environmental exposure sources., Results: Mortality. The a priori causes of interest that occur most frequently in excess are, in descending order: malignant lung cancer, malignant mesothelioma of the pleura, malignant bladder cancer, respiratory diseases, non-Hodgkin lymphomas, malignant liver cancer, all malignant tumours, malignant colorectal cancer, malignant stomach cancer, total mesotheliomas, malignant breast cancer, and asbestosis. Hospitalization. The a priori causes of interest that occur most frequently in excess are represented in descending order by: respiratory diseases, malignant lung cancer, malignant tumours of the pleura, malignant bladder cancer, malignant breast cancer, malignant liver cancer, asthma, malignant colorectal cancer, all malignant tumours, malignant stomach cancer, non-Hodgkin's lymphomas, acute respiratory diseases, leukaemias. The differences observed between mortality and hospitalization can be attributed to the intrinsic characteristics of the diseases (higher or lower lethality, gender differences in incidence), lifestyles, and occupational phenomena. Age classes. Excesses of general mortality were observed in the first year of life at the Manfredonia, Basso Bacino Fiume Chienti, Litorale Domizio Flegreo and Agro Aversano sites; in the 0-1 year and 0-19 year age groups at Casale Monferrato; in the paediatric age group at Serravalle Scrivia and at the Trento Nord site; in the 0-19 year age group at Sassuolo Scandiano; in the young age group (0-29 years) at the two municipalities of Cerchiara and Cassano (Crotone-Cassano-Cerchiara site). With regard to hospitalization due to natural causes, risk excesses in both genders are found in the first year of life in 35% of the sites (Porto Torres industrial areas, Bari-Fibronit, Basso bacino fiume Chienti, Bolzano, Crotone-Cassano-Cerchiara, Cerro al Lambro, Bologna ETR large repair workshop, Gela, Manfredonia, Massa Carrara, Pioltello Rodano, Pitelli, Priolo, Sesto San Giovanni, Trento Nord, and Trieste). These same sites, with the addition of Casale Monferrato, Cengio e Saliceto, Serravalle Scrivia, and Sulcis-Iglesiente-Guspinese (total: 43% of sites), show excesses for all natural causes, in both genders, even in the paediatric-adolescent age group (0-19 years). Among young adults (20-29 years), the analyses show excesses of hospitalization for all natural causes in both genders in the Bolzano, Crotone-Cassano-Cerchiara, Gela, Manfredonia, Pitelli, Priolo, and Sulcis-Iglesiente-Guspinese sites. Among young women only, excesses for all natural causes are also found in Brescia Caffaro, Brindisi, Broni, Casale Monferrato, Crotone-Cassano-Cerchiara, Falconara Marittima, Fidenza, and Massa Carrara. Congenital anomalies. In the 21 sites investigated for CA, 10,126 cases of CA, validated by participating registers, were analysed out of 304,620 resident births. Genital CA is the subgroup for which the greatest number of excesses was observed (in 6 out of 21 sites). The available evidence does not allow a causal link to be established between the excesses observed for specific subgroups of ACs and exposure to industrial sources, but the results suggest further action. The interpretation of the results appears, in fact, particularly complex as the scientific literature on the association between exposure to industrial sources and AC is very limited. Socioeconomic status. The sites in which the indicators converge to show the presence of fragility are: Litorale Vesuviano area, Val Basento industrial areas, Basso Bacino fiume Chienti, Biancavilla, Crotone-Cassano-Cerchiara, Litorale Domizio Flegreo and Agro Aversano, Livorno, Massa Carrara, Trieste. Global impact. Over the period 2013-2017, an estimated 8,342 excess deaths (CI90% 1,875-14,809) or approximately 1,668 excess cases/year, 4,353 excess deaths among males (CI90% 334-8,372) and 3,989 among females (CI90% -1,122;9,101). The pooled excess risk of general mortality is 2% in both genders (pooled SMR 1.02; CI90% 1.00-1.04). The proportion of excess deaths to total observed deaths is almost constant over time, rising from 2.5% in 1995-2002 to 2.6% in 2013-2017. The number of deaths in absolute value is also very similar between the periods analysed. Deaths from all malignant tumours contribute the most by accounting for 56% of the observed excesses, the excess risk of mortality from malignant tumours across all sites, compared to the reference populations, is 4% in the male population (pooled SMR 1.04; CI90% 1.01-1.06) and 3% among the female population (pooled SMR 1.03; CI90% 1.01-1.05). Hospitalization (2014-2018) in the 46 sites as a whole was in excess of 3% for all causes, in both genders, for all major disease groups (males: SHR pooled 1.03; CI90% 1.01-1.04 - females: SHR pooled 1.03; CI90% 1.01-1.05). The results for the pooled estimates at the 46 sites on the general population, both with regard to mortality and hospitalization, are consistent in indicating excess risk in both genders for all the diseases considered and, in particular, for all malignancies. A total of 1,409 paediatric-adolescent deaths and 999 young adult deaths were observed, and the pooled analysis of mortality across the 46 sites showed no critical issues, with pooled estimates for all causes, perinatal morbid conditions and all malignancies falling short of expectations. The analysis of hospitalizations, on the other hand, showed an excess risk of 8% (males: SHR pooled 1.08; CI90% 1.03-1.13 - females: SHR pooled 1.08; CI90% 1.03-1.14) for all causes in the first year of life, and in paediatric-adolescent and juvenile age of 3-4% among males (age 0-19 years: SHR pooled 1.04; CI90% 1.02-1.06 - age 20-29 years: SHR pooled 1.03; CI90% 1.00-1.05) and 5% among females (in both age groups; SHR pooled 1.05; CI90% 1.02-1.08). The pooled analysis of mortality for the a priori identified diseases reported excesses for specific diseases in the group of sites with sources of exposure associated with them. Mortality from total mesotheliomas is three times higher at sites with asbestos present (males: pooled SMR 3.02; CI90% 2.18-3.87 - females: pooled SMR 3.61; CI90% 2.33-4.88) and that from pleural mesotheliomas more than two times higher at the group of sites with asbestos and port areas (males: pooled SMR 2.47; CI90% 1.94-3.00 - females: pooled SMR 2.43; CI90% 1.67-3.19). Lung cancer was in excess by 6% among males (pooled SMR 1.06; CI90% 1.03-1.10) and 7% among females (pooled SMR 1.07; CI90% 1.00-1.13). In addition, there are excess mortalities for colorectal cancer at sites with chemical plants, by 4 % among males (SMR pooled 1.04; CI90% 1.01-1.08) and 3 % among females (SMR pooled 1.03; CI90% 1.00-1.07) and for bladder cancer among the male population of sites with landfills (+6 %: SMR pooled 1.06; CI90% 1.02-1.11). Among the diseases of a priori interest, stomach and soft tissue cancers are at fault as a cause of death among all the sites considered., Literature Review: The update of the epidemiological evidence underlying the Sixth SENTIERI Report has highlighted in the general population a possible association, previously undiscovered, between certain diseases and residence near petrochemical and steel plants, landfills, coal mines and asbestos sources., Conclusions and Perspectives: Despite the fact that this is an ecological study, and the excesses of pathologies with multifactorial aetiology can never be mechanically attributed solely to the environmental pressure factors that exist or existed in the areas studied, the ability to identify the excesses found in the contaminated sites investigated by the SENTIERI Project confirms the validity of this method of assessing the site-specific health profile, based on the use of epidemiological evidence to identify pathologies of interest a priori. In interpreting the data and lending robustness to what has been observed, comparison with the results obtained in previous Reports is essential. The global estimates give an overall picture that shows excess mortality and hospitalization in these populations compared to the rest of the population, and show how, for specific pathologies, comparable effects are produced at sites with similar contamination characteristics. The themes developed in the in-depth chapters broaden the vision and understanding of the complex interactions between environment and health, describe the possibilities offered by new ways of communicating the results, and confirm the modernity of a Project that began way back in 2006, and that could be grafted onto the objectives of the National Recovery and Resilience Plan within the framework of the Operational Programme Health, Environment, Biodiversity and Climate.

This paper describes the development and the envisioned use of concept maps in the framework of the SENTIERI communication strategies as an information and scientific communication tool applied to epidemiological surveillance in contaminated sites. The concept map of SENTIERI 2019-2022 was designed and implemented to foster access to complex scientific information ensuring usability of the contents and communication with the various stakeholders. The concept map aims to promote environmental health literacy in contaminated sites. The methodology adopted to create the map includes the following phases: 1. choice of a dynamic focus question; 2. selection of the representative terms of the addressed topics; 3. elaboration of the glossary of the selected terms; 4. representation of the links among the selected terms; 5. identification of the significant propositions that make explicit the meaning of each link. Online access to the map is guaranteed by the Mindomo software. The use of the concept map promotes active learning of the topics that characterize SENTIERI 2019-2022 through knowledge paths chosen because of the specific interests and learning purposes. The concept map derives from the integration of specific approaches of the epidemiological discipline with those of the social sciences and offers the possibility of developing site-specific maps through the interactions with local actors and the integration of elements related to emerging problems as well as institutional and local interests.

Some human literature suggests a possible role of endocrine disruptors (EDs) exposure in thyroid cancer (TC) development. We investigated TC incidence in selected Italian National Priority Contaminated Sites (NPCS) with documented presence of EDs considered thyroid carcinogens. Adjusted Standardized Incidence Ratios (SIRs), with their 90% confidence intervals, were computed by gender, and age-specific groups (aged 15-39 years, and 40 years or over) for each NPCS in the period 2006 to 2013. In the age group of 15-39 years, a significant excess of TC risk was found in two NPCSs in males; non-significant excess risks were observed in four NPCSs in males, and in five in females. In the age group of 40 years and over, significant excess risks were found in six NPCSs in males and in seven NPCSs in females; non-significant excess risks were identified in two NPCSs in males and females. The findings of several excesses in incidence, mainly observed in adults aged 40 years or over, are suggestive of a possible adverse effect associated with residence in NPCSs, even if a role of other factors cannot be excluded, due to the adoption of an ecological study design. Future analytical studies are needed to clarify if EDs are a TC risk factor for individuals living in NPCSs.

Background: the mixed and complex nature of industrially contaminated sites (ICSs) leads to heterogeneity in exposure and health risk of residents living nearby. Health, environment, and social aspects are strongly interconnected in ICSs, and local communities are often concerned about potential health impact and needs for remediation. The use of human biomonitoring (HBM) for impact assessment of environmental exposure is increasing in Europe. The COST Action IS1408 on Industrially Contaminated Sites and Health Network (ICSHNet) decided to reflect on the potential and limitations of HBM to assess exposure and early health effects associated with living near ICSs., Objectives: to discuss challenges and lessons learned for addressing environmental health impact near ICSs with HBM in order to identify needs and priorities for HBM guidelines in European ICSs., Methods: based on the experience of the ICSHNet research team, six case studies from different European regions that applied HBM at ICSs were selected. The case studies were systematically compared distinguishing four phases: the preparatory phase; study design; study results; the impact of the results at scientific, societal, and political levels., Results: all six case studies identified opportunities and challenges for applying HBM in ICS studies. A smart choice of (a combination of) sample matrices for biomarker analysis produced information about relevant time-windows of exposure which matched with the activities of the ICSs. Combining biomarkers of exposure with biomarkers of (early) biological effects, data from questionnaires or environmental data enabled fine-tuning of the results and allowed for more targeted remediating actions aimed to reduce exposure. Open and transparent communication of study results with contextual information and involvement of local stakeholders throughout the study helped to build confidence in the study results, gained support for remediating actions, and facilitated sharing of responsibilities. Using HBM in these ICS studies helped in setting priorities in policy actions and in further research. Limitations were the size of the study population, difficulties in recruiting vulnerable target populations, availability of validated biomarkers, and coping with exposure to mixtures of chemicals., Conclusions: based on the identified positive experiences and challenges, the paper concludes with formulating recommendations for a European protocol and guidance document for HBM in ICS. This could advance the use of HBM in local environmental health policy development and evaluation of exposure levels, and promote coordination and collaboration between researchers and risk managers.

Background: human exposure to mixtures of chemicals of toxicological interest, typically found in industrial contaminated sites (ICSs), has been associated with a broad range of different health outcomes. Deprived population groups endure most of the burden of disease and premature death associated to the exposure to those pollutants. Characterising the impacts on health of an ICS is a challenging process. Currently the two main methodological approaches used are Human Health Risk Assessment (HHRA) and Environmental Epidemiological (EE) studies., Objectives: review existing guidance and scientific evidence for HHRA and EE studies applied to contaminated sites that orientate in selecting the most suitable methodological approach for characterising health impacts in ICSs according to the site characteristics, and the availability of environmental, health and sociodemographic data., Results: HHRA has evolved into a more holistic approach, placing more emphasis in planning, community involvement and adapting the dimension of the assessment to the problem formulation and to the availability of resources. Many different HHRA guidelines for contaminated sites has been published worldwide, and although they share a similar framework, the scientific evidence used for deriving reference values and the variet of policy options can result in a wide variability of health risk estimates. This paper condenses different options with the recommendations to use those tools, default values for environmental and exposure levels and toxicological reference values that most suit to the population and characteristics of the ICSs under evaluation., Conclusions: the suitability to use one or another approach to assess the impact of ICSs on health depends on the availability of data, cost-benefit aspects and the kind of problem that needs to be answered. Risk assessment based on toxicological data can be very rapid and cheap, providing direct information when the intervention to protect the health of population is urgent and no suitable dose-response functions are available from epidemiological studies. Conducting EE studies provide a deeper insight into the problem of the exposure to industrial pollutants that do not require extrapolation from data obtained from toxicological studies or other population, addressing the community concern's more directly. Complementing the results obtained from different approaches, including those from public health surveillance systems, might provide an efficient and complete response to the impact of ICSs.

Objective Studies of loud noise exposure and vestibular schwannomas (VS) have shown conflicting results. The population-based INTERPHONE case‒control study was conducted in 13 countries during 2000-2004. In this paper, we report the results of analyses on the association between VS and self-reported loud noise exposure. Methods Self-reported noise exposure was analyzed in 1024 VS cases and 1984 matched controls. Life-long noise exposure was estimated through detailed questions. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using adjusted conditional logistic regression for matched sets. Results The OR for total work and leisure noise exposure was 1.6 (95% CI 1.4-1.9). OR were 1.5 (95% CI 1.3-1.9) for only occupational noise, 1.9 (95% CI 1.4-2.6) for only leisure noise and 1.7 (95% CI 1.2-2.2) for exposure in both contexts. OR increased slightly with increasing lag-time. For occupational exposures, duration, time since exposure start and a metric combining lifetime duration and weekly exposure showed significant trends of increasing risk with increasing exposure. OR did not differ markedly by source or other characteristics of noise. Conclusion The consistent associations seen are likely to reflect either recall bias or a causal association, or potentially indicate a mixture of both.

Introduction and Objectives: This volume provides an update of the health status of the populations living in the National Priority Contaminated Sites (NPCSs) included in the SENTIERI Project. This update is part of an epidemiological surveillance programme carried out in NPCSs, promoted by the Italian Ministry of Health as a further step of a project started in 2006, when the health status of residents in contaminated sites was first addressed within the National Strategic Program "Environment and Health". The Report focuses on five health outcomes: mortality, cancer incidence, hospital discharges, congenital anomalies, and children, adolescents and young adults' health. A key element of SENTIERI project is the a priori evaluation of the epidemiological evidence of a causal association between the considered cause of disease and the exposure. When an a priori evidence is identified, it is given a greater importance in the comment of the study findings., Methods: The present update of the SENTIERI Project concerns 45 NPCSs including in all 319 Italian Municipalities (out of over 8,000 Municipalities), with an overall population of 5,900,000 inhabitants at the 2011 Italian Census. Standardized Mortality Ratios (SMRs) and Standardized Hospitalization Ratios (SHRs), referring to a time window of 2006-2013, were computed for all the 45 NPCSs, using as a reference the corresponding mortality and hospitalization rates of the Regions where each NCPS is located. Standardized Incidence Ratios (SIRs) were computed by the Italian Association of Cancer Registries (AIRTUM) for the 22 NPCSs served by a Cancer Registry. AIRTUM covers about 56% of Italy, with partly different time-windows. SIRs have been estimated using as reference population the 4 macroareas in which Italy is divided (North-West, North-East, Centre, South). Prevalence of congenital anomalies was computed for 15 NPCSs., Results: An all-cause excess of 5,267 and 6,725 deaths was observed, respectively, in men and women; the cancer death excess was of 3,375 in men and 1,910 in women. It was estimated an excess of cancer incidence of 1,220 case in men and 1,425 in women over a five-year time window. With regard to the diseases with an a priori environmental aetiological validity, an excess for malignant mesothelioma, lung, colon, and gastric cancer, and for non-malignant respiratory diseases was observed. Cancer excess mainly affected NPCSs with presence of chemical and petrochemical plants, oil refineries, and dumping hazardous wastes. An excess of non-malignant respiratory disease was also detected in NPCSs in which steel industries and thermoelectric plants were present. An excess of mesothelioma was observed in NPCSs characterized by presence of asbestos and fluoro-edenite; it was also observed where the presence of asbestos was not reported in the legislative national decrees which define the NPCS areas. It is worth noting that, even if the presence of asbestos is not reported in many NPCSs legislative decrees, petrochemical plants and steel industries, for instance, are often characterized by the presence of a large amount of this mineral that, in the past, was extensively used as an insulating material. For the first time, the present Report includes a focus on the health status of children and adolescents (1,160,000 subjects, aged 0-19 years), and young adults (660,000 subjects, aged 20-29 years). Among infants (0-1 year), an excess of 7,000 hospitalizations was observed, 2,000 of which due to conditions of perinatal origin. In the age class 0-14, an excess of 22,000 hospitalizations for all causes was observed; 4,000 of them were due to acute respiratory diseases, and 2,000 to asthma. Data on cancer incidence for subjects aged 0-24 years were derived from general population cancer registries for twenty NPCSs, and from children cancer registries (age group: 0-19 years) for six NPCSs; 666 cases where diagnosed in the age group 0-24 years, corresponding to an excess of 9%. The main contributions to this excess are from soft tissue sarcomas in children (aged 0-14 years), acute myeloid leukaemia in children (aged 0-14 years) and in the age group 0-29 years, non-Hodgkin lymphoma and testicular cancer in young adults (aged 20-29 years). In seven out of 15 NPCSs, an excess prevalence rate of overall congenital anomalies at birth was observed. Congenital anomalies excesses included the following sites: genital organs, heart, limbs, nervous system, digestive system, and urinary system., Conclusions: The main findings of SENTIERI Project have been the detection of excesses for the diseases which showed an a priori epidemiological evidence of a causal association with the environmental exposures specific for each considered NPCS. These observations are valuable within public health, because they contribute to priority health promotion activities. Looking ahead, the health benefits of an improved environmental quality might be appreciated in terms of reduction of the occurrence of adverse health effects attributable to each Site major pollutant agents. Due to the methodological approach of the present study, it was not possible to adjust for several confounding factors reported to be risk factors for the studied diseases (e.g., smoking, alcohol consumption, obesity). Even if excesses of mortality, hospitalization, cancer incidence, and prevalence of congenital anomalies were found in several NPCSs, the study design and the multifactorial aetiology of the considered diseases do not permit, for all of them, to draw conclusions in terms of causal links with environmental contamination. Moreover, it must be taken into consideration that economic factors and the availability of health services may also play a relevant role in a diseases outcome. A few observations regarding some methodological limitations of SENTIERI Project should be made. There is not a uniform environmental characterisation of the studied NPCSs in term of quality and detection of the pollutants, because this information is present in different databases which at present are not adequately connected. Moreover, the recognition of a contaminated site as a National Priority Site is based on soil and groundwater pollution, and the available information on air quality is currently sparse and not homogenous. Another limitation, in term of statistical power, is the small population size of many NPCSs and the low frequency of several health outcomes. A special caution must be paid in data interpretation when considering the correspondence between the contaminated areas and the municipality boundaries, as they do not always coincide perfectly: in some cases, a small municipality with a large industrial site, while in other settings only a part of the municipality is exposed to the sources of pollution. Furthermore, all available health information systems are currently accessible at municipality level. The real breakthrough is essentially comprised of the development and fostering of a networking system involving all local health authorities and regional environmental protection agencies operating in the areas under study. The possibility to integrate the geographic approach of SENTIERI Project with a set of ad hoc analytic epidemiological investigations, such as residential cohort studies, case control studies, children health surveys, biomonitoring surveys, and with socioepidemiological studies, might greatly contribute to the identification of health priorities for environmental remediation activities. Finally, as discussed in the last section of the report, there is a need to adopt, in each NPCS, a two-way oriented communication plan involving public health authorities, scientific community, and resident population, taking into account that the history, the cultural frame and the network of relationships specific of each local context play a major role in the risk perception perspective.

Background: this paper is based upon work from COST Action ICSHNet. Health risks related to living close to industrially contaminated sites (ICSs) are a public concern. Toxicology-based risk assessment of single contaminants is the main approach to assess health risks, but epidemiological studies which investigate the relationships between exposure and health directly in the affected population have contributed important evidence. Limitations in exposure assessment have substantially contributed to uncertainty about associations found in epidemiological studies., Objectives: to examine exposure assessment methods that have been used in epidemiological studies on ICSs and to provide recommendations for improved exposure assessment in epidemiological studies by comparing exposure assessment methods in epidemiological studies and risk assessments., Methods: after defining the multi-media framework of exposure related to ICSs, we discussed selected multi-media models applied in Europe. We provided an overview of exposure assessment in 54 epidemiological studies from a systematic review of hazardous waste sites; a systematic review of 41 epidemiological studies on incinerators and 52 additional studies on ICSs and health identified for this review., Results: we identified 10 multi-media models used in Europe primarily for risk assessment. Recent models incorporated estimation of internal biomarker levels. Predictions of the models differ particularly for the routes 'indoor air inhalation' and 'vegetable consumption'. Virtually all of the 54 hazardous waste studies used proximity indicators of exposure, based on municipality or zip code of residence (28 studies) or distance to a contaminated site (25 studies). One study used human biomonitoring. In virtually all epidemiological studies, actual land use was ignored. In the 52 additional studies on contaminated sites, proximity indicators were applied in 39 studies, air pollution dispersion modelling in 6 studies, and human biomonitoring in 9 studies. Exposure assessment in epidemiological studies on incinerators included indicators (presence of source in municipality and distance to the incinerator) and air dispersion modelling. Environmental multi-media modelling methods were not applied in any of the three groups of studies., Conclusions: recommendations for refined exposure assessment in epidemiological studies included the use of more sophisticated exposure metrics instead of simple proximity indicators where feasible, as distance from a source results in misclassification of exposure as it ignores key determinants of environmental fate and transport, source characteristics, land use, and human consumption behaviour. More validation studies using personal exposure or human biomonitoring are needed to assess misclassification of exposure. Exposure assessment should take more advantage of the detailed multi-media exposure assessment procedures developed for risk assessment. The use of indicators can be substantially improved by linking definition of zones of exposure to existing knowledge of extent of dispersion. Studies should incorporate more often land use and individual behaviour.

Background: this paper is based upon work from COST Action ICSHNet. Industrially contaminated sites (ICSs) are a serious problem worldwide and there is growing concern about their impacts on the environment and public health. Health risk assessment methods are used to characterize and quantify the health impacts on nearby populations and to guide public health interventions. However, heterogeneous methods and inconsistent reporting practices compromise comparability risk and impact estimates., Objectives: to review the literature on assessment of the adverse health effects of ICSs. Specifically, we: - collect published, peer-reviewed literature addressing health assessment of ICSs; - identified and evaluated the methods and tools for the assessment of health impacts related to ICSs; - analysed the methods and tools used in different conditions; - discussed the strengths and weaknesses of the identified approaches; - presented an up-to-date understanding of the available health risk and impact assessment in ICSs. In addition, the terminologies were described and harmonization was proposed., Methods: we systematically searched PubMed and Web of Science to identify peer-reviewed reviews and original studies from January 1989 to December 2017. We used a qualitative approach for analysing the different elements (type of ICSs, Country of research, active years of working, distance from sources, pollutants, affected population, methods and tools, health outcomes, main founding, method stage, dose-response assessment, risk characterization) of included studies. We divided risk assessment methods used in the papers into four stages: semi-quantitative, quantitative, health impact, and health burden stage., Results: a total of 92 relevant original papers at ICSs were found and analysed. In current practice, the health risks have been characterized mainly as hazard quotients or hazard indexes (23 studies), and as cancer risk probabilities (60 studies). Only 8 studies estimated the number of cases and one study evaluated years of life lost., Conclusion: hazard quotients and cancer probabilities are suitable for semi-quantitative and quantitative personal risk estimation, respectively. More comparable risk characterization on public health level requires specificity on the type of outcome and corresponding number of cases. Such data is needed for prioritization of action at low to medium risk sites. We found limited amount of studies that have quantified the health impact at industrially contaminated sites. Most of the studies have used semi-quantitative risk characterization approaches and the adopted methods are mostly of toxicological origin, while epidemiological analysis is almost lacking. There is a need to improve quantitative risk assessment and include health impact and environmental burden of disease assessments at ICSs.

Background: this paper is based upon work from COST Action ICSHNet. Children's environmental health is on the 2030 Agenda for Sustainable Development. The incidence of childhood cancer is increasing worldwide and in Europe. Yet, the aetiology of most childhood cancers, including the role of environmental carcinogens, is still largely unknown. Contaminated areas, especially of industrial origin, are of high concern due to complex mix of hazardous pollutants and their potential health impacts on human populations, notably in children., Objectives: to describe cancer risk in children and young adults (YA) residing in national priority contaminated sites (NPCSs) in Italy and to provide a suitable framework for a development of cancer surveillance in industrially contaminated sites (ICSs) in Europe., Methods: this study is based on a collaborative work of the Italian Institute of Health (ISS) and the Italian Association of Cancer Registries (AIRTUM), in the context of the SENTIERI project (Epidemiological study of residents in National Priority Contaminated Sites). Incidence rates were standardised according to the European standard population. The number of observed cases was compared to the expected cases derived from the age-, sex-, and cancer-specific incidence rates of the national pool of AIRTUM registries for the period 2006-2013. Standardized incidence ratios (SIRs) and 90% confidence intervals (CIs) were computed. The study reports the cancer profile in all combined 28 NPCSs covered by 22 cancer registries., Results: 1,050 cases of malignant tumours (MTs) were recorded among 3,161,786 person-years in people aged 0-29 years in 28 NPCSs (SIR: 1.03; 90%CI 0.98-1.09), with an age-standardised incidence rate of 317 per million. Excess risks were observed for: MT of the central nervous system in the age-group <1 year (SIR: 3.2; 90%CI 1.4-6.3); soft tissue sarcoma in the age-group 0-14 years (SIR: 1.6; 90%CI 1.1-2.3); acute myeloid leukaemia in the agegroup 0-14 years (SIR: 1.7; 90%CI 1.1-2.4); non-Hodgkin lymphoma in the age-group 20-24 years (SIR 1.5; 90%CI 1.1-2.1), and germ cell tumours of male gonads in the age-group 20-29 years (SIR: 1.33; 90%CI 1.1-1.5). A deficit of cases was observed for Hodgkin lymphomas in the age-group 20-29 years (SIR 0.8; 90%CI 0.6-1.0)., Discussion: this study, which is based on standardized methods and accredited information sources, supports the hypothesis that living in an NPCS increases the risk of some cancer types in children and young adults. Further work will concern groups of NPCSs characterised by common sources of contamination/key carcinogenic pollutants. In fact, in a novel project proposal we aim to monitor the cancer profile in children living in ICSs in Europe. The new project, based on the SENTIERI-AIRTUM methodology, will build on the networking activities of the COST Action on Industrially Contaminated Sites and Health Networking (ICSHNet) and childhood cancer studies coordinated by the International Agency for research on Cancer (IARC).

Background: this paper is based upon work from COST Action ICSHNet. Industrial contaminated sites (ICSs) are of high concern since industrial plants have produced widespread contamination potentially affecting the health of local population OBJECTIVES: to assess the types of epidemiological designs applied in studies of health effects related to ICSs according to time periods, type of ICS, and geography., Methods: a literature search was conducted in Medline (OVID) through June 30th, 2018, using MeSH and customized terms, and no restrictions on publication year or language. We included all studies throughout the world where a potential contamination of industrial origin occurred, an epidemiological approach (including biomonitoring, HBM) was applied, and health outcomes or exposure biomarkers among residents were investigated. Data on publication year, geographical localization and ICS characterization, study design (systematic reviews, cohort, case-control, temporal changes, cross-sectional, ecological, descriptive - area-level, case-series, narrative reviews, and HBM), and health outcomes were extracted from the abstracts. To check the sensitivity of the main search strategy, a case-study on Italy was conducted applying an ad-hoc search., Results: from a literature search capturing 5,485 studies, 655 studies on resident populations were identified. The review includes more than 376 different ICSs, 86% from Europe, North America, and Asia combined, mostly dealing with nuclear sites and mining industries, waste and petrochemical activities. Most of the studies were descriptive (32.5%), cross-sectional (16.3%), or narrative review (14.8%), while analytical studies - case-control and cohort studies (9.6% and 8.4%, respectively) - were rarer; HBM were only 6.9%. A total of 235 studies, conducted mostly in Asia (34.5%), Europe (25.5%), and North America (22.3%), included children. The most frequently studied outcome was cancer (33.7%), followed by respiratory diseases (11.4%), and reproductive health (11.4%). The ad-hoc strategy greatly increased the number of detected papers (+122%)., Conclusions: future research should adopt the most valid and suitable study design, according to the area-specific social and environmental context, also in areas of the world which are less studied, but with very high environmental worries of the resident population suffering the industrial contamination. Involvement of local experts on ICSs and local inventories are recommended to improve the coverage of the present inventory.

The cohort study aims to test the hypothesis of an association between specific exposure/s and adverse health outcomes. The cohorts include the subjects who experience the exposure/s and are followed up over time to ascertain the health outcomes. This contribution presents the database for the analysis of mortality studies which is made available for public institutions carrying out cohort studies in Italy. The rates were computed from official mortality data from ISTAT. The database contains 141 causes or groups of causes for the years 1970-2012 ensuring correspondence with subsequent editions of ICD (International Classification of Diseases) VIII, IX and X.