Long-term exposure to elemental components of fine particulate matter and all-natural and cause-specific mortality in a Danish nationwide administrative cohort study.

BACKGROUND: Fine particulate matter (PM2.5) is a well-recognized risk factor for premature death. However, evidence on which PM2.5 components are most relevant is unclear. METHODS: We evaluated the associations between mortality and long-term exposure to eight PM2.5 elemental components [copper (Cu), iron (Fe), zinc (Zn), sulfur (S), nickel (Ni), vanadium (V), silicon (Si), and potassium (K)]. Studied outcomes included death from diabetes, chronic kidney disease (CKD), dementia, and psychiatric disorders as well as all-natural causes, cardiovascular disease (CVD), respiratory diseases (RD), and lung cancer. We followed all residents in Denmark (aged ≥30 years) from January 1, 2000 to December 31, 2017. We used European-wide land-use regression models at a 100 × 100 m scale to estimate the residential annual mean levels of exposure to PM2.5 components. The models were developed with supervised linear regression (SLR) and random forest (RF). The associations were evaluated by Cox proportional hazard models adjusting for individual- and area-level socioeconomic factors and total PM2.5 mass. RESULTS: Of 3,081,244 individuals, we observed 803,373 death from natural causes during follow-up. We found significant positive associations between all-natural mortality with Si and K from both exposure modeling approaches (hazard ratios; 95% confidence intervals per interquartile range increase): SLR-Si (1.04; 1.03-1.05), RF-Si (1.01; 1.00-1.02), SLR-K (1.03; 1.02-1.04), and RF-K (1.06; 1.05-1.07). Strong associations of K and Si were detected with most causes of mortality except CKD and K, and diabetes and Si (the strongest associations for psychiatric disorders mortality). In addition, Fe was relevant for mortality from RD, lung cancer, CKD, and psychiatric disorders; Zn with mortality from CKD, RD, and lung cancer, and; Ni and V with lung cancer mortality. CONCLUSIONS: We present novel results of the relevance of different PM2.5 components for different causes of death, with K and Si seeming to be most consistently associated with mortality in Denmark.

Health impact assessment should be based on correct methods.

The methodology of health impact assessment (HIA), originally proposed by WHO, is widely used to predict the potential health effects in a community living in a place in which a new project (e.g., an industrial plant) will be implemented. One of the key quantities to calculate the impact (i.e., the number of attributable cases) is the baseline (i.e., before the project implementation) rate of selected diseases in the community. In a recent paper on this journal, this methodology has been challenged. Specifically, the use of baseline rate has been questioned, proposing to use only the fraction of the baseline rate due to the exposures related to the project, and not the rate due to all risk factors for the disease. In this commentary, we argue that the proposal is logically and epidemiologically unsound, and devoid of scientific motivation. The conclusion that the traditional approach overestimates the health impact should be rejected as based on flawed assumptions. On the contrary, the proposal may produce a (seriously biased) underestimation of attributable cases.

[Health impact: considering only a plant assessment is not enough, an area assessment is also needed]. / Impatto sanitario: la valutazione del singolo impianto non è sufficiente, occorre anche una valutazione di area.

Environmental Impact Assessments (EIAs) often conclude with a "low" or at least "negligible" final health impact assessment (HIA) of the industrial plant under assessment. We explore the reasons for this - often simplistic - conclusion and offer suggestions on how to extend the assessment focus from just the plant to an appropriate impact area. For many assessments, the conclusions are easily predictable: the application of available risk functions to modest increases in pollution, in the presence of numerically small populations in the areas of greatest fallout and considering rather rare health outcomes, can only result in quantitatively modest health impacts. This is the classic situation of low sensitivity of the observation system due to the impossibility of containing the type II error (false negatives) since we cannot increase the exposed population at will. The risk is to give the green light to an industrial plant in which the apparently null or very limited damage is simply not properly detectable. There is hardly any trace of these elements in the HIA scoping phase. In environmental complex territories, the renewal or authorization of a new plant should consider not only the impact of the individual plant, but also the health profile of the population concerned and the context in which the industrial project is located. An 'HIA area' is therefore configured, aimed at the complex of environmental pressure factors that insist on the same area of impact of the plant. Epidemiology focuses on the exposed population, considers the 'current' state of health, hazard, and risk information from toxicology, and estimates individual exposure and the effects of exposure. The 'HIA area' can assess the impact of the complex of persistent emission sources, considering in the analysis the health status of the exposed population and the presence of specific vulnerabilities. The proposal is in line with what is already foreseen in the Essential levels of care and Environmental technical performance of the National Health Service.A basic condition is the establishment of functions dedicated to integrated environmental and health surveillance to update the health profile and carry out the 'HIA area' as an accompanying tool for local strategic planning. On these issues, the Italian Environment and Health Network (RIAS) has opened a discussion within the network and with any Italian regions.

[Covid-19 and clinical-epidemiological research in Italy: proposal of a research agenda on priority topics by the Italian association of epidemiology]. / Covid-19 e ricerca clinico-epidemiologica in Italia: proposta di un'agenda di ricerca su temi prioritari da parte dell'Associazione italiana di epidemiologia.

BACKGROUND: the Covid-19 pandemic has provoked a huge of clinical and epidemiological research initiatives, especially in the most involved countries. However, this very large effort was characterized by several methodological weaknesses, both in the field of discovering effective treatments (with too many small and uncontrolled trials) and in the field of identifying preventable risks and prognostic factors (with too few large, representative and well-designed cohorts or case-control studies). OBJECTIVES: in response to the fragmented and uncoordinated research production on Covid-19, the   italian Association of Epidemiology (AIE) stimulated the formation of a working group (WG) with the aims of identifying the most important gaps in knowledge and to propose a structured research agenda of clinical and epidemiological studies considered at high priority on Covid-19, including recommendations on the preferable methodology. METHODS: the WG was composed by 25 subjects, mainly epidemiologists, statisticians, and other experts in specific fields, who have voluntarily agreed to the proposal. The agreement on a list of main research questions and on the structure of the specific documents to be produced were defined through few meetings and cycles of document exchanges. RESULTS: twelve main research questions on Covid-19 were identified, covering aetiology, prognosis, interventions, follow-up and impact on general and specific populations (children, pregnant women). For each of them, a two-page form was developed, structured in: background, main topics, methods (with recommendations on preferred study design and warnings for bias prevention) and an essential bibliography. CONCLUSIONS: this research agenda represents an initial contribution to direct clinical and epidemiological research efforts on high priority topics with a focus on methodological aspects. Further development and refinements of this agenda by Public Health Authorities are encouraged.

[Exposure assessment to air pollutants: dispersion models versus human biomonitoring]. / La valutazione dell'esposizione a contaminanti ambientali: modelli di dispersione e biomonitoraggio umano.

BACKGROUND: the assessment of individual exposure to toxicants in industrially contaminated areas is difficult when multiple productions are actively close to residential areas. Two thermoelectric power plants (one recently converted to coal) and a large harbour have been operating since the Sixties in the area of Civitavecchia (North of Rome, Lazio Region, Central Italy). Detailed exposure assessment of pollutants from industrial sources, heating (biomass combustion), and urban traffic were not available. OBJECTIVES: to assess the individual exposure of residents by using both dispersion models and human biomonitoring. DESIGN: cross-sectional study. SETTING AND PARTICIPANTS: residents in the area of Civitavecchia since 2001 aged 35-69 years were enrolled and their addresses were geocoded. Exposure assessment to power plants emissions (PM10), traffic (NOx), harbour (PM10), and biomass burning (PM10) was performed at individual residential address using Lagrangian dispersion models. The "Ambiente e Biomarcatori a Civitavecchia" study (Environment and biomarkers in Civitavecchia - ABC study) made available urinary concentrations of metals (i.e., Cd, Pt, W, Pd, Hg, Tl, Cr, Pd, Ni, As) in a sample of residents, while information on personal characteristics, lifestyles, work history, clinical history, and use of drugs was collected by interview. MAIN OUTCOME MEASURES: for each metal, a linear regression analysis was implemented to study the association between its log-transformed values (adjusted for urinary creatinine) and the linear terms of the estimated pollutants concentrations, adjusted for age, gender, period, and other risk factors (i.e., educational level, smoking habit, alcohol, BMI). Geometric Mean Ratios (GMR) and the corresponding confidence intervals (95%CI) were computed. RESULTS: in the ABC sample of 1,141 residents (42% male, mean age 53.5 years, SD 9.7), there was a positive association between PM10 from power plants and urinary cadmium (Cd) (GMR: 1.12; 95%CI 1.00-1.25), traffic pollution (NOx) and platinum (Pt) (GMR: 1.17; 95%CI 1.00-1.38), PM10 from biomass burning and Cd (GMR: 1.14; 95%CI 1.05-1.24), and tungsten (W) (GMR: 1.19; 95%CI 1.03-1.37) and palladium (Pd) (GMR: 1.11; 95%CI 1.00-1.23). Other associations observed did not reach statistical significance. CONCLUSIONS: although it may not be said that dispersion models can replace biomonitoring studies, they certainly represent an excellent tool for exposure assessment and, therefore, they may be used for the estimation of the individual exposure of populations living in industrially contaminated areas.

Global estimates of mortality associated with long-term exposure to outdoor fine particulate matter.

Exposure to ambient fine particulate matter (PM2.5) is a major global health concern. Quantitative estimates of attributable mortality are based on disease-specific hazard ratio models that incorporate risk information from multiple PM2.5 sources (outdoor and indoor air pollution from use of solid fuels and secondhand and active smoking), requiring assumptions about equivalent exposure and toxicity. We relax these contentious assumptions by constructing a PM2.5-mortality hazard ratio function based only on cohort studies of outdoor air pollution that covers the global exposure range. We modeled the shape of the association between PM2.5 and nonaccidental mortality using data from 41 cohorts from 16 countries-the Global Exposure Mortality Model (GEMM). We then constructed GEMMs for five specific causes of death examined by the global burden of disease (GBD). The GEMM predicts 8.9 million [95% confidence interval (CI): 7.5-10.3] deaths in 2015, a figure 30% larger than that predicted by the sum of deaths among the five specific causes (6.9; 95% CI: 4.9-8.5) and 120% larger than the risk function used in the GBD (4.0; 95% CI: 3.3-4.8). Differences between the GEMM and GBD risk functions are larger for a 20% reduction in concentrations, with the GEMM predicting 220% higher excess deaths. These results suggest that PM2.5 exposure may be related to additional causes of death than the five considered by the GBD and that incorporation of risk information from other, nonoutdoor, particle sources leads to underestimation of disease burden, especially at higher concentrations.

Assessing the recent estimates of the global burden of disease for ambient air pollution: Methodological changes and implications for low- and middle-income countries.

The Global Burden of Disease (GBD) is a comparative assessment of the health impact of the major and well-established risk factors, including ambient air pollution (AAP) assessed by concentrations of PM2.5 (particles less than 2.5 µm) and ozone. Over the last two decades, major improvements have emerged for two important inputs in the methodology for estimating the impacts of PM2.5: the assessment of global exposure to PM2.5 and the development of integrated exposure risk models (IERs) that relate the entire range of global exposures of PM2.5 to cause-specific mortality. As a result, the estimated annual mortality attributed to AAP increased from less than 1 million in 2000 to roughly 3 million for GBD in years 2010 and 2013, to 4.2 million for GBD 2015. However, the magnitude of the recent change and uncertainty regarding its rationale have resulted, in some cases, in skepticism and reduced confidence in the overall estimates. To understand the underlying reasons for the change in mortality, we examined the estimates for the years 2013 and 2015 to determine the quantitative implications of alternative model input assumptions. We calculated that the year 2013 estimates increased by 8% after applying the updated exposure data used in GBD 2015, and increased by 23% with the application of the updated IERs from GBD 2015. The application of both upgraded methodologies together increased the GBD 2013 estimates by 35%, or about one million deaths. We also quantified the impact of the changes in demographics and the assumed threshold level. Since the global estimates of air pollution-related deaths will continue to change over time, a clear documentation of the modifications in the methodology and their impacts is necessary. In addition, there is need for additional monitoring and epidemiological studies to reduce uncertainties in the estimates for low- and medium-income countries, which contribute to about one-half of the mortality.

A survey on lifestyle and level of biomarkers of environmental exposure in residents in Civitavecchia (Italy).

BACKGROUND: The assessment of individual exposure to toxicants in industrially contaminated areas is difficult when multiple productions are active close to residential areas. Two thermoelectric power plants and a large harbor have been operating since the '60s in the area of Civitavecchia (North of Rome). METHODS: The ABC (Ambiente e Biomonitoraggio nell'area di Civitavecchia, Environment and Biomonitoring in Civitavecchia) program involved, in the period 2013-2014, residents in Civitavecchia and in the nearby municipalities (Santa Marinella, Allumiere, Tolfa and Tarquinia). They were randomly selected from the Municipal Register's data and their residence addresses were geocoded using GIS techniques. Biomonitoring of the following urinary metals, Sb, Be, Mo, Cd, Sn, W, Ir, Pt, Hg, Tl, V, Cr, Mn, Co, Ni, Cu, Zn, Rh, Pd, As were performed. Glucose and lipid metabolism, liver, renal, and endocrine function were evaluated through blood laboratory tests. Tests of lung functionwere also carried out as well as saturometry (oxygen rate in the blood with an illuminated sensor placed on the fingertip), anthropometric and blood pressure measurements. Information on individual characteristics, histories of exposure, such as the consumption of local food, occupational history, lifestyle and medical history were collected through a validated questionnaire. Samples of nails and hair were also collected. The biological material (blood, urine, nails and hair) was stored in a biobank for future analysis related to the possible mechanisms of biological damage. The study protocol received the approval of the local ethics committee. RESULTS: A total of 1177 residents were enrolled (58% female, 60% with a secondary or graduate school degree). No particular differences in metal concentrations based on the municipality of residence were observed. For arsenic, mercury, lead, and tungsten some differences between the two geographical areas were observed, probably due to different diet, lifestyle (e.g., alcohol consumption, smoking, use of jewelry and piercings, tattoos, physical activity, hormonal and mineral supplements, and drugs), and occupational exposure. CONCLUSIONS: The undergoing study on the association between biomarkers concentration and pollutants concentrations - estimated using a dispersion modeling approach, and adjusting for personal characteristics and concomitant other environmental exposure - could clarify the individual exposure of the residents in this industrial area.

Does chronic exposure to high levels of nitrogen dioxide exacerbate the short-term effects of airborne particles?

BACKGROUND: Long-term exposure to air pollutants has been hypothesised as a factor in susceptibility to short-term exposure to particulate matter (PM), but results are not coherent. We studied the short-term effects of PM10 on mortality and assessed whether long-term exposure to nitrogen dioxide (NO2) modifies this association. METHODS: We used a case-crossover design to evaluate daily PM10-related mortality among 124 432 35+ year-old participants who died in Rome between 2001 and 2010 and maintained the same address for at least 5 years before death. Modification of PM10-related mortality by long-term NO2 exposure was determined by two-way interaction, while a three-way interaction was used to assess effect modification of high NO2 levels in population groups defined by sociodemographic position and pre-existing diseases. RESULTS: Mortality increased by 0.82% (0.23-1.41%) for each 10 µg/m3 increase in PM10. Mortality rose by 1.22% (0.17-2.38%) in participants exposed to NO2 levels ≥50 µg/m3 and by 0.69% (0.03-1.34%) in those exposed to levels <50 µg/m3 with no effect modification (p-interaction 0.378). A suggestion of effect modification was seen in 85+-year-olds (3.10%; p-interaction 0.043), as well as in those with a pre-existing arrhythmia (3.26%; p-interaction 0.014) and chronic obstructive pulmonary disease (3.52%; p-interaction 0.042). CONCLUSIONS: Long-term exposure to NO2 is not likely to induce susceptibility to short-term PM10 exposure in the overall population. However, an effect modification of NO2 is probable in the elderly and in those suffering from arrhythmias and chronic obstructive pulmonary disease.

Education and Mortality in the Rome Longitudinal Study.

BACKGROUND: A large body of evidence supports an inverse association between socioeconomic status and mortality. We analysed data from a large cohort of residents in Rome followed-up between 2001 and 2012 to assess the relationship between individual education and mortality. We distinguished five causes of death and investigated the role of age, gender, and birthplace. METHODS: From the Municipal Register we enrolled residents of Rome on October 21st 2001 and collected information on educational level attained from the 2001 Census. We selected Italian citizens aged 30-74 years and followed-up their vital status until 2012 (n = 1,283,767), identifying the cause of death from the Regional Mortality Registry. We calculated hazard ratios (HRs) for overall and cause-specific mortality in relation to education. We used age, gender, and birthplace for adjusted or stratified analyses. We used the inverse probability weighting approach to account for right censoring due to emigration. RESULTS: We observed an inverse association between education (none vs. post-secondary+ level) and overall mortality (HRs(95%CIs): 2.1(1.98-2.17), males; 1.5(1.46-1.59), females) varying according to demographic characteristics. Cause-specific analysis also indicated an inverse association with education, in particular for respiratory, digestive or circulatory system related-mortality, and the youngest people seemed to be more vulnerable to low education. CONCLUSION: Our results confirm the inverse association between education and overall or cause-specific mortality and show differentials particularly marked among young people compared to the elderly. The findings provide further evidence from the Mediterranean area, and may contribute to national and cross-country comparisons in Europe to understand the mechanisms generating socioeconomic differentials especially during the current recession period.

Quantifying the health impacts of ambient air pollutants: recommendations of a WHO/Europe project.

OBJECTIVE: Quantitative estimates of air pollution health impacts have become an increasingly critical input to policy decisions. The WHO project "Health risks of air pollution in Europe--HRAPIE" was implemented to provide the evidence-based concentration-response functions for quantifying air pollution health impacts to support the 2013 revision of the air quality policy for the European Union (EU). METHODS: A group of experts convened by WHO Regional Office for Europe reviewed the accumulated primary research evidence together with some commissioned reviews and recommended concentration-response functions for air pollutant-health outcome pairs for which there was sufficient evidence for a causal association. RESULTS: The concentration-response functions link several indicators of mortality and morbidity with short- and long-term exposure to particulate matter, ozone and nitrogen dioxide. The project also provides guidance on the use of these functions and associated baseline health information in the cost-benefit analysis. CONCLUSIONS: The project results provide the scientific basis for formulating policy actions to improve air quality and thereby reduce the burden of disease associated with air pollution in Europe.

[Health impact assessment of policies for municipal solid waste management: findings of the SESPIR Project]. / Impatto sulla salute delle politiche di gestione dei rifiuti solidi urbani: i risultati del Progetto SESPIR.

The SESPIR Project (Epidemiological Surveillance of Health Status of Resident Population Around the Waste Treatment Plants) assessed the impact on health of residents nearby incinerators, landfills and mechanical biological treatment plants in five Italian regions (Emilia-Romagna, Piedmont, Lazio, Campania, and Sicily). The assessment procedure took into account the available knowledge on health effects of waste disposal facilities. Analyses were related to three different scenarios: a Baseline scenario, referred to plants active in 2008-2009; the regional future scenario, with plants expected in the waste regional plans; a virtuous scenario (Green 2020), based on a policy management of municipal solid waste (MSW) through the reduction of production and an intense recovery policy. Facing with a total population of around 24 million for the 5 regions, the residents nearby the plants were more than 380,000 people at Baseline. Such a population is reduced to approximately 330.000 inhabitants and 170.000 inhabitants in the regional and Green 2020 scenarios, respectively. The health impact was assessed for the period 2008-2040. At Baseline, 1-2 cases per year of cancer attributable to MSW plants were estimated, as well as 26 cases per year of adverse pregnancy outcomes (including low birth weight and birth defects), 102 persons with respiratory symptoms, and about a thousand affected from annoyance caused by odours. These annual estimates are translated into 2,725 years of life with disability (DALYs) estimated for the entire period. The DALYs are reduced by approximately 20% and 80% in the two future scenarios. Even in these cases, health impact is given by the greater effects on pregnancy and the annoyance associated with the odours of plants. In spite of the limitations due to the inevitable assumptions required by the present exercise, the proposed methodology is suitable for a first approach to assess different policies that can be adopted in regional planning in the field of waste management. The greatest reduction in health impact is achieved with a virtuous policy of reducing waste production and a significant increase in the collection and recycling of waste.

[Methods for health impact assessment of policies for municipal solid waste management: the SESPIR Project]. / Metodologia di valutazione degli impatti sulla salute delle politiche di gestione dei rifiuti solidi urbani: il Progetto SESPIR.

The Project Epidemiological Surveillance of Health Status of Resident Population Around the Waste Treatment Plants (SESPIR) included five Italian regions (Emilia-Romagna, Piedmont, Lazio, Campania, and Sicily) and the National Institute of Health in the period 2010-2013. SESPIR was funded by the Ministry of Health as part of the National centre for diseases prevention and control (CCM) programme of 2010 with the general objective to provide methods and operational tools for the implementation of surveillance systems for waste and health, aimed at assessing the impact of the municipal solid waste (MSW) treatment cycle on the health of the population. The specific objective was to assess health impacts resulting from the presence of disposal facilities related to different regional scenarios of waste management. Suitable tools for analysis of integrated assessment of environmental and health impact were developed and applied, using current demographic, environmental and health data. In this article, the methodology used for the quantitative estimation of the impact on the health of populations living nearby incinerators, landfills and mechanical biological treatment plants is showed, as well as the analysis of three different temporal scenarios: the first related to the existing plants in the period 2008-2009 (baseline), the second based on regional plans, the latter referring to MSW virtuous policy management based on reduction of produced waste and an intense recovery policy.

[Health impact assessment of airport noise on people living nearby six Italian airports]. / Valutazione dell'impatto del rumore aeroportuale sulla salute della popolazione residente nelle vicinanze di sei aeroporti italiani.

BACKGROUND: aircraft noise has been associated with several health effects. Because of the great success of low-cost flights, small airports have been turned into international airports thus exposing nearby residents to an increase in noise levels and potential disturbances and health disorders. OBJECTIVE: to estimate the exposure levels and evaluate the health impact of aircraft noise on residents nearby six airports in Italy (Rome: Ciampino; Milan: Linate and Malpensa; Pisa; Turin; Venice) focusing on hypertension, acute myocardial infarction (AMI), annoyance and sleep disturbances. METHODS: residents in the local Municipalities considered at 31.12.2010 were included in the study and their addresses were geocoded. Aircraft noise exposure in 2011 was defined using the Integrated Noise Model linked to each participant's address. Lden (<55, 55-60, 61-65, 65-70 dB), Lnight, Leq (day and night) were calculated. Available exposure-response relationships were used to estimate the number of additional cases of hypertension, AMI, annoyance and sleep disturbances in the local population. RESULTS: 73,272 persons exposed to aircraft noise levels >55dB were considered: 55,915 (76.3%) were exposed to 55-60 dB; 16,562 (22.6%) to 60-65 dB; 795 (1.2%) to 65-70 dB. Exposure to aircraft noise levels above 55 dB was estimated to be responsible each year of 4,607 (95%CI 0-9,923) additional cases of hypertension; 3.4 (95%CI 0-10.7) cases of AMI; 9,789 (95%CI 6,895-11,962) cases of annoyance; 5,084 (95%CI 1,894-10,509) cases of sleep disturbances. CONCLUSIONS: a significant impact of airport noise on the health of residents nearby six Italian airports was estimated. Epidemiological evaluation and noise mitigation measures should be introduced to protect the health of residents.

Piccolipiù, a multicenter birth cohort in Italy: protocol of the study.

BACKGROUND: The fetal and infant life are periods of rapid development, characterized by high susceptibility to exposures. Birth cohorts provide unique opportunities to study early-life exposures in association with child development and health, as well as, with longer follow-up, the early life origin of adult diseases. Piccolipiù is an Italian birth cohort recently set up to investigate the effects of environmental exposures, parental conditions and social factors acting during pre-natal and early post-natal life on infant and child health and development. We describe here its main characteristics. METHODS/DESIGN: Piccolipiù is a prospective cohort of expected 3000 newborns, who will be recruiting in six maternity units of five Italian cities (Florence, Rome, Trieste, Turin and Viareggio) since October 2011. Mothers are contacted during pregnancy or at delivery and are offered to participate in the study. Upon acceptance, their newborns are recruited at birth and followed up until at least 18 years of age. At recruitment, the mothers donate a blood sample and complete a baseline questionnaire. Umbilical cord blood, pieces of umbilical cord and heel blood spots are also collected. Postnatal follow-up currently occurs at 6, 12, and 24 months of age using on-line or postal self administered questionnaire; further questionnaires and medical examinations are envisaged. Questionnaires collect information on several factors, including mother's and/or child's environmental exposures, anthropometric measures, reproductive factors, diet, supplements, medical history, cognitive development, mental health and socioeconomic factors. Health promotion materials are also offered to parents. DISCUSSION: Piccolipiù will broaden our understanding of the contribution of early-life factors to infant and child health and development. Several hypotheses on the developmental origins of health can be tested or piloted using the data collected from the Piccolipiù cohort. By pooling these data with those collected by other existing birth cohorts it will be possible to validate previous findings and to study rare exposures and outcomes.