The study area includes the Municipalities of Gela, Niscemi and Butera located in the South of Sicily, Italy. In 1990 it was declared Area at High Risk of Environmental Crisis. In 2000 part of it was designated as Gela Reclamation Site of National Interest, RSNI. The site includes a private industrial area, public and marine areas, for a total of 51 km(2). Gela populationin 2008 was 77,145 (54,774 in 1961). Sea level:46 m. Total area: 276 km(2). Grid reference: 37 degrees 4' 0" N, 14 degrees 15' 0" E. Niscemi and Butera are located border to Gela. Populations are respectively 26,541 and 5,063. Sea level respectively: 332 m and 402 m. Close to the city of Gela, the industrial area, operating since 1962, includes chemical production plants, a power station and an oil refinery plant, one of the larger in Europe, refining 5 millions tons of crude per year. From the beginning the workforces decreased from 7,000 to the current 3,000 units. Over the years, these industrial activities have been a major source of environmental pollution. Extremely high levels of toxic, persistent and bio-accumulating chemical pollutants have been documented. Many relevant environmental and health data are available. Prior to the studies described in the present publication, their use in order to identify environmental pressures on health has been limited. Nevertheless, since several years different epidemiological studies have provided evidence of the occurrence of health outcomes significantly higher than in neighbouring areas and compared to regional data. In 2007 a Multidisciplinary Working Group has been established, to analyze the existing data on pollution-exposure-effect and to complete current knowledge on the cycle of pollutants, from migration in the environment to health impact. The present publication is a collection of contribution of this group of experts, supported by the following projects: Evaluation of environmental health impact and estimation of economic costs at of National Interest Remediation Sites coordinated by the Italian National Institute of Health on behalf of the Ministry for the Environment and Technical Assistance of WHO Health and Environment Centre to the Sicilian Region to develop plans for environmental remediation. Results describe the state of contamination of a variety of environmental matrices in the area. Other contributions are addressed to understanding action mechanisms of main pollutants and their environmental pathways, as well as to identifying crucial knowledge to be used for studying the environment-health relations. A specific attention has been paid to pollutants migration in the environment and to the potential exposure of the population. Appropriate markers of exposure and physiological changes are described and referred to the chemical substances identified in the environment in Gela. Details are given about the genotoxic and endocrine disrupting potential, and about the potential association between markers of exposure and diseases observed in excess in the same area. Indications to develop specific biomarkers for Index Substances and human biomonitoring surveys for populations exposed to environmental risk are presented and discussed. A specific multiple-exposure risk assessment procedure is proposed for Index Substances. Epidemiological studies useful to describe the health status of Gela population are summarized. One report deals with the occupational and residential analyses of male petrochemical workers, born in Sicily, employed from 1960 to the end of 1993, followed up for mortality from 1960 to 2002. Major findings were amarked healthy worker effect and an increased lung cancer risk for residence in Gela. The analyses of death certificates from 1995 to 2002 and of hospital discharge records from 2001 to 2007 confirm the potentialities of these current statistics for ecological studies: they depict the poor health conditions of Gela residents compared to other neighbouring municipalities in a 40-km range. Infact, the overall mortality rate for tumor and non-tumor causes in Gela is significantly higher for both sexes, and this is shown also in the Municipality of Niscemi, especially among the male population. Hospital discharge records for tumor causes, but especially for non-tumor ones, exceeded expectations in both genders and must be analysed taking into consideration the attraction exerted on the surrounding areas by the Gela hospital. Data analysis according to 5 ten-year birth cohorts, from 1915 to 1964, shows a decreasing mortality trend, whereas the increase of hospital admissions is confirmed in the younger generations. The issue of birth defects is recurrent in this area: a suitable register is lacking so that updated figures cannot be presented. However, data previously published showed excesses of prevalence rates of several specific birth defects, mainly urinary tract and genital anomalies. The same is worth in the incidence of new cancer cases since the development of a proper register is yet in progress. Tools and methodologies that should be applied in Gela to study environment-health relations are proposed, like Life Cycle Analysis, dispersion patterns and an air-quality monitoring system. A conceptual model considering all pollution sources and different exposure patterns present in Gela, developed by the Multidisciplinary Working Group, is presented. Among the activities carried out by regional authorities, two Reports on the Regional Environment Protection Agency monitoring activity and on the EU Program SEARCH, School Environment And Respiratory Health in Children, are included. A section is devoted to understanding what is necessary to build an epidemiological monitoring system specifically designed for this area, in order to keep under permanent control environment-related health outcomes. This includes a systematic and continuative collection, storage and analysis of environmental-induced diseases, exposure and risk factors, as well as a timely dissemination of those information to the decision-makers. The final article describes the research activities carried out to design and implement a human biomonitoring survey in the area. These activities included relation-building with local communities, information collection, meetings, involvement of stake-holders. This experience will reach its climax when the community-exposure data feedback will be provided, because it will mark the consolidation of present knowledge and its possible processing into public health action plans. The present publication can represent an important tool and a model for all interest-bearers to assess environmental pollution impacts on human health in contaminated areas. A local system to assess the relation between environmental pollution and population health is therefore urgently needed to provide risk managers with ad-hoc tools to improve environmental protection and prevent further risks for local communities.