Development of a generic lifelong physiologically based biokinetic model for exposome studies.

The current study within the frame of the HEALS project aims at the development of a lifelong physiologically based biokinetic (PBBK) model for exposome studies. The aim was to deliver a comprehensive modelling framework for addressing a large chemical space. Towards this aim, the delivered model can easily adapt parameters from existing ad-hoc models or complete the missing compound specific parameters using advanced quantitative structure activity relationship (QSAR). All major human organs are included, as well as arterial, venous, and portal blood compartments. Xenobiotics and their metabolites are linked through the metabolizing tissues. This is mainly the liver, but also other sites of metabolism might be considered (intestine, brain, skin, placenta) based on the presence or not of the enzymes involved in the metabolism of the compound of interest. Each tissue is described by three mass balance equations for (a) red blood cells, (b) plasma and interstitial tissue and (c) cells respectively. The anthropometric parameters of the models are time dependent, so as to provide a lifetime internal dose assessment, as well as to describe the continuously changing physiology of the mother and the developing fetus. An additional component of flexibility is that the biokinetic processes that relate to metabolism are related with either Michaelis-Menten kinetics, as well as intrinsic clearance kinetics. The capability of the model is demonstrated in the assessment of internal exposure and the prediction of expected biomonitored levels in urine for three major compounds within the HEALS project, namely bisphenol A (BPA), Bis(2-ethylhexyl) phthalate (DEHP) and cadmium (Cd). The results indicated that the predicted urinary levels fit very well with the ones from human biomonitoring (HBM) studies; internal exposure to plasticizers is very low (in the range of ng/L), while internal exposure to Cd is in the range of µg/L.

A dual mixture of persistent organic pollutants modifies carbohydrate metabolism in the human hepatic cell line HepaRG.

Individuals as well as entire ecosystems are exposed to mixtures of Persistent Organic Pollutants (POPs). Previously, we showed, by a non-targeted approach, that the expression of several genes involved in carbohydrate metabolism was almost completely inhibited in the human hepatic cell line HepaRG following exposure to a mixture of the organochlorine insecticide alpha-endosulfan and 2,3,7,8 tetrachlorodibenzo-p-dioxin. In this European HEALS project, which studies the effects of the exposome on human health, we used a Physiologically Based BioKinetic model to compare the concentrations previously used in vitro with in vivo exposures for humans. We investigated the effects of these POPs on the levels of proteins, on glycogen content, glucose production and the oxidation of glucose into CO2 and correlated them to the expression of genes involved in carbohydrate metabolism as measured by RT-qPCR. Exposure to individual POPs and the mixture decreased the expression of the proteins investigated as well as glucose output (up to 82%), glucose oxidation (up to 29%) and glycogen content (up to 48%). siRNAs that specifically inhibit the expression of several xenobiotic receptors were used to assess receptor involvement in the effects of the POPs. In the HepaRG model, we demonstrate that the effects are mediated by the aryl hydrocarbon receptor and the estrogen receptor alpha, but not the pregnane X receptor or the constitutive androstane receptor. These results provide evidence that exposure to combinations of POPs, acting through different signaling pathways, may affect, more profoundly than single pollutants alone, metabolic pathways such as carbohydrate/energy metabolism and play a potential role in pollutant associated metabolic disorders.

Risk characterization of bisphenol-A in the Slovenian population starting from human biomonitoring data.

The current study aims to characterize exposure and risk associated to bisphenol-A (BPA) exposure in Slovenia, starting from biomonitoring data. Based on the urinary data, daily intake for the individuals was back-calculated using a physiology based biokinetic (PBBK) model properly parameterized for BPA, coupled with an exposure reconstruction algorithm. Re-running the PBBK model in forward mode allowed the estimation of biologically effective dose (free plasma BPA) and the respective daily area under the curve (AUC). Finally, risk characterization ratio was derived using both external and internal dose metrics. The urinary BPA levels were found low, with GM of 0.79, 1.51 and 0.20 µg/g creatinine for mothers, children and fathers respectively, similar to the levels of other European countries. Based on the above and accounting for the dynamics of exposure and biokinetics, daily intake was estimated, median exposure levels have been estimated equal to 0.019, 0.035 and 0.005 µg/kg_bw/d for mothers, fathers and children respectively. The highest estimated intake level was found in a child, equal to 0.87 µg/kg_bw/d, while the maximum intake for mothers and fathers were 0.7 and 0.8 µg/kg_bw/d respectively. The respective RCR levels using the EFSA t-TDI of 4 µg/kg_bw/d were 2 magnitudes of order lower below 1, independently of the selected method. It has to be noted that had daily intake been estimated solely based on the urinary concentrations mass balance, the estimated intake would be lower, as a result of the oversimplification on exposure and elimination time dynamics. This highlights the importance for using PBBK modelling based exposure reconstruction schemes for rapidly metabolized and excreted compounds such as BPA, as well as the study design of efficient sampling for rapidly metabolized compounds.

Urinary bisphenol A in children, mothers and fathers from Slovenia: Overall results and determinants of exposure.

In the present study, urinary bisphenol A (BPA) levels were reported for the first time in the Slovenian general population and were evaluated with regard to dietary and non-dietary exposure sources, and compared according to age, gender and area of residence. First morning urine was collected from children (6-11 years), their mothers (30-52 years) and fathers (30-53 years), living in urban and rural areas of Slovenia. Besides basic questionnaire data on general population characteristics, socio-economic status and dietary habits, BPA-specific data was also collected, including consumption of food and beverages from plastic and canned containers, presence of white dental fillings, the use of specific consumer products and hormonal treatments. Urine samples were analysed for both free and conjugated BPA using GC-MS/MS. The urinary levels of total BPA in children, mothers and fathers were low, with geometric means of 1.51, 0.79, and 0.20 µg/g creatinine, respectively. The levels were comparable with the levels reported for other European countries and were all below the current health-based guidance values. In line with large-scale surveys, the data revealed age-dependant BPA urinary levels, with the highest levels in the youngest age group. In mothers, urinary levels of BPA were determined by hormonal interactions more than dietary sources, while a positive association between urinary BPA and diet was apparent in children (canned food/drink and food from plastic material) and fathers (canned food/drink). The study clearly shows that physiological and behavioural differences account for differences in levels of urinary BPA among study groups, a finding that sets the priorities for future research.

Addressing complexity of health impact assessment in industrially contaminated sites via the exposome paradigm.

BACKGROUND: this paper is based upon work from COST Action ICSHNet. Assessment of the health impacts related to industrially contaminated sites (ICSs) is a major scientific challenge with multiple societal implications. Most studies related to associations between ICSs and public health do not provide established mechanistic links between environmental exposure and disease burden, potentially resulting in suboptimal risk management measures. OBJECTIVES: to assess the potential of the exposome paradigm to overhaul ICS risk assessment and management leading to precision prevention and targeted interventions. METHODS: we selected the second largest waste landfill in Europe and the data collected in the frame of the HERACLES study on the exposome and health and analysed them together with clinical evidence of neurodevelopmental perturbations following the exposome-wide association study paradigm using the exposome analysis tools; briefly, these pertain to refined exposure assessment, internal dosimetry, and human biomonitoring, multi-omics/toxicity pathway analysis and advanced statistical tools for environment-wide association studies. Waste streams and the related contamination of environmental media are not viewed in isolation, but rather as components of the expotype, the vector of exposures an individual is exposed to over time. Thus, a multi-route and multi-pathway exposure estimation can be performed setting a realistic basis for integrated health risk and impact assessment. The study was located in the area around the landfill of Fili, outside Athens (Greece). Since 2012, 325 children were recruited and have been followed using a combination of human biomonitoring, advanced-omics analysis on biosamples, environmental monitoring for metals and organic contaminants, and dietary pattern information. The children were clinically tested for neurodevelopmental perturbations during different developmental stages and the results were analysed according to the exposome-wide association study methodology in conjunction with environmental exposure, but also socioeconomic, dietary, and metabolic determinants of internal exposure and health risk. RESULTS: using the exposome analysis tools, we confirmed that proximity to a landfill and the consequent soil contamination with metals are critical for children neurodevelopment. However, it was found that additional parameters such as parental education level, socioeconomic status, and nutrition contribute either positively or negatively on child neurodevelopment. CONCLUSIONS: the exposome concept comes to overhaul the nature vs. nurture paradigm and embraces a world of dynamic interactions between environmental exposures, endogenous exposures, and genetic expression in humans. In this context, the exposome paradigm provides a novel tool for holistic ICS health risk management. The effectiveness of the exposome approach is demonstrated in the case of Athens, the capital of Greece, where health effects associated to long term exposure to a major waste management facility (landfill) are presented.

A review of exposure assessment methods for epidemiological studies of health effects related to industrially contaminated sites.

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.

The use of structural alerts to avoid the toxicity of pharmaceuticals.

In order to identify compounds with potential toxicity problems, particular attention is paid to structural alerts, which are high chemical reactivity molecular fragments or fragments that can be transformed via bioactivation by human enzymes into fragments with high chemical reactivity. The concept has been introduced in order to reduce the likelihood that future candidate substances as pharmaceuticals will have undesirable toxic effects. A significant proportion (∼78-86%) of drugs characterized by residual toxicity contain structural alerts; there is also evidence indicating the formation of active metabolites as a causal factor for the toxicity of 62-69% of these molecules. On the other hand, the pharmacological action of certain drugs depends on the formation of reactive metabolites. Detailed assessment of the potential for the formation of active metabolites is recommended to characterize a biologically active compound. Although many prescribed drugs frequently contain structural alerts and form reactive metabolites, the vast majority of these drugs are administered in low daily doses. Avoiding structural alerts has become almost a norm in new drug design. An in-depth review of the biochemical reactivity of these structural alerts for new drug candidates is critical from a safety point of view and is currently being monitored in the discovery of drugs. The chemical strategies applied to structural alerts in molecules to limit the toxicity are: •partial replacement or full replacement of the structural alert;•reduction of electronic density;•introduction of a structural element of metabolic interest (metabolic switching);•multiple approaches. Therefore, chemical intervention strategies to eliminate bioactivation are often interactive processes; their success depends largely on a close working relationship between drug chemists, pharmacologists and researchers in metabolic science.

Biomarkers of exposure in environment-wide association studies - Opportunities to decode the exposome using human biomonitoring data.

BACKGROUND: The European Union's 7th Framework Programme (EU's FP7) project HEALS - Health and Environment-wide Associations based on Large Population Surveys - aims a refinement of the methodology to elucidate the human exposome. Human biomonitoring (HBM) provides a valuable tool for understanding the magnitude of human exposure from all pathways and sources. However, availability of specific biomarkers of exposure (BoE) is limited. OBJECTIVES: The objective was to summarize the availability of BoEs for a broad range of environmental stressors and exposure determinants and corresponding reference and exposure limit values and biomonitoring equivalents useful for unraveling the exposome using the framework of environment-wide association studies (EWAS). METHODS: In a face-to-face group discussion, scope, content, and structure of the HEALS deliverable "Guidelines for appropriate BoE selection for EWAS studies" were determined. An expert-driven, distributed, narrative review process involving around 30 individuals of the HEALS consortium made it possible to include extensive information targeted towards the specific characteristics of various environmental stressors and exposure determinants. From the resulting 265 page report, targeted information about BoE, corresponding reference values (e.g., 95th percentile or measures of central tendency), exposure limit values (e.g., the German HBM I and II values) and biomonitoring equivalents (BEs) were summarized and updated. RESULTS: 64 individual biological, chemical, physical, psychological and social environmental stressors or exposure determinants were included to fulfil the requirements of EWAS. The list of available BoEs is extensive with a number of 135; however, 12 of the stressors and exposure determinants considered do not leave any measurable specific substance in accessible body specimens. Opportunities to estimate the internal exposure stressors not (yet) detectable in human specimens were discussed. CONCLUSIONS: Data about internal exposures are useful to decode the exposome. The paper provides extensive information for EWAS. Information included serves as a guideline - snapshot in time without any claim to comprehensiveness - to interpret HBM data and offers opportunities to collect information about the internal exposure of stressors if no specific BoE is available.

Development of QSARs for parameterizing Physiology Based ToxicoKinetic models.

A Quantitative Structure Activity Relationship (QSAR) model was developed in order to predict physicochemical and biochemical properties of industrial chemicals of various groups. This model was based on the solvation equation, originally proposed by Abraham. In this work Abraham's solvation model got parameterized using artificial intelligence techniques such as artificial neural networks (ANNs) for the prediction of partitioning into kidney, heart, adipose, liver, muscle, brain and lung for the estimation of the bodyweight-normalized maximal metabolic velocity (Vmax) and the Michaelis - Menten constant (Km). Model parameterization using ANNs was compared to the use of non-linear regression (NLR) for organic chemicals. The coupling of ANNs with Abraham's solvation equation resulted in a model with strong predictive power (R2 up to 0.95) for both partitioning and biokinetic parameters. The proposed model outperformed other QSAR models found in the literature, especially with regard to the estimation and prediction of key biokinetic parameters such as Km. The results show that the physicochemical descriptors used in the model successfully describe the complex interactions of the micro-processes governing chemical distribution and metabolism in human tissues. Moreover, ANNs provide a flexible mathematical framework to capture the non-linear biochemical and biological interactions compared to less flexible regression techniques.

Integrated exposure and risk characterization of bisphenol-A in Europe.

The current study aims at a comprehensive risk characterization of bisphenol A (BPA) supported by an integrated exposure modelling framework that comprises far field and near field exposure modelling coupled to a dynamic lifetime PBTK model. Exposure analysis was done on European data of BPA food residues and human biomonitoring (HBM). The latter were further assimilated through an advanced exposure reconstruction modelling framework to estimate the corresponding external and internal systemic dose of BPA and its metabolites. Special attention was paid on the assessment of exposure to BPA during critical developmental stages such as gestation by modelling the mother-fetus toxicokinetic interaction. Our findings showed that current exposure levels in Europe are below the temporary Tolerable Daily Intake (t-TDI) of 4 µg/kg_bw/d proposed by the European Food Safety Authority. Taking into account age-dependent bioavailability differences, internal exposure of premature neonates hosted in intensive care units was reckoned close to the biologically effective dose (BED) resulting from translating the EFSA temporary total daily intake (t-TDI) into equivalent internal dose. Use of the ToxCast21 Biological Pathway Altering Dose (BPAD) as an alternative internal exposure reference value, resulted in increased margins of safety compared to the conventional exposure/risk characterization scheme.

Public health impacts of city policies to reduce climate change: findings from the URGENCHE EU-China project.

BACKGROUND: Climate change is a global threat to health and wellbeing. Here we provide findings of an international research project investigating the health and wellbeing impacts of policies to reduce greenhouse gas emissions in urban environments. METHODS: Five European and two Chinese city authorities and partner academic organisations formed the project consortium. The methodology involved modelling the impact of adopted urban climate-change mitigation transport, buildings and energy policy scenarios, usually for the year 2020 and comparing them with business as usual (BAU) scenarios (where policies had not been adopted). Carbon dioxide emissions, health impacting exposures (air pollution, noise and physical activity), health (cardiovascular, respiratory, cancer and leukaemia) and wellbeing (including noise related wellbeing, overall wellbeing, economic wellbeing and inequalities) were modelled. The scenarios were developed from corresponding known levels in 2010 and pre-existing exposure response functions. Additionally there were literature reviews, three longitudinal observational studies and two cross sectional surveys. RESULTS: There are four key findings. Firstly introduction of electric cars may confer some small health benefits but it would be unwise for a city to invest in electric vehicles unless their power generation fuel mix generates fewer emissions than petrol and diesel. Second, adopting policies to reduce private car use may have benefits for carbon dioxide reduction and positive health impacts through reduced noise and increased physical activity. Third, the benefits of carbon dioxide reduction from increasing housing efficiency are likely to be minor and co-benefits for health and wellbeing are dependent on good air exchange. Fourthly, although heating dwellings by in-home biomass burning may reduce carbon dioxide emissions, consequences for health and wellbeing were negative with the technology in use in the cities studied. CONCLUSIONS: The climate-change reduction policies reduced CO2 emissions (the most common greenhouse gas) from cities but impact on global emissions of CO2 would be more limited due to some displacement of emissions. The health and wellbeing impacts varied and were often limited reflecting existing relatively high quality of life and environmental standards in most of the participating cities; the greatest potential for future health benefit occurs in less developed or developing countries.

Size-segregated emissions and metal content of vehicle-emitted particles as a function of mileage: Implications to population exposure.

The study aims at investigating the characteristics (size distribution, active surface and metal content) of particles emitted by cars as a function of mileage using a novel methodology for characterizing particulate emissions captured by Exhaust Gas Suspension (EGS). EGS was obtained by passing the exhaust gases through a container of deionized water. EGS analysis was performed using laser granulometry, electron scanning microscopy, and high resolution mass spectrometry. Implications of the differences in key features of the emitted particles on population exposure were investigated using numerical simulation for estimating size-segregated PM deposition across human respiratory tract (HRT). It was found that vehicle mileage, age and the respective emissions class have almost no effect on the size distribution of the exhaust gas particulate released into the environment; about half of the examined vehicles with low mileage were found to release particles of aerodynamic diameter above 10 µm. The exhaust gas particulate detected in the EGS of all cars can be classified into three major size classes: (1) 0.1-5 µm - soot and ash particles, metals (Au, Pt, Pd, Ir); (2) 10-30 µm - metal (Cr, Fe, Cu, Zr, Ni) and ash particles; (3) 400-1,000 µm - metal (Fe, Cr, Pb) and ash particles. Newer vehicles with low mileage are substantial sources of soot and metal particles with median diameter of 200 nm with a higher surface area (up to 89,871.16 cm(2)/cm(3)). These tend to deposit in the lower part of the human respiratory tract.

Health impact and monetary cost of exposure to particulate matter emitted from biomass burning in large cities.

The study deals with the assessment of health impact and the respective economic cost attributed to particulate matter (PM) emitted into the atmosphere from biomass burning for space heating, focusing on the differences between the warm and cold seasons in 2011-2012 and 2012-2013 in Thessaloniki (Greece). Health impact was assessed based on estimated exposure levels and the use of established WHO concentration-response functions (CRFs) for all-cause mortality, infant mortality, new chronic bronchitis cases, respiratory and cardiac hospital admissions. Monetary cost was based on the valuation of the willingness-to-pay/accept (WTP/WTA), to avoid or compensate for the loss of welfare associated with illness. Results showed that long term mortality during the 2012-2013 winter increased by 200 excess deaths in a city of almost 900,000 inhabitants or 3540 years of life lost, corresponding to an economic cost of almost 200-250m€. New chronic bronchitis cases dominate morbidity estimates (490 additional new cases corresponding to a monetary cost of 30m€). Estimated health and monetary impacts are more severe during the cold season, despite its smaller duration (4 months). Considering that the increased ambient air concentrations (and the integral of outdoor/indoor exposure) are explained by shifting from oil to biomass for domestic heating purposes, several alternative scenarios were evaluated. Policy scenario analysis revealed that significant public health and monetary benefits (up to 2b€ in avoided mortality and 130m€ in avoided illness) might be obtained by limiting the biomass share in the domestic heat energy mix. Fiscal policy affecting fuels/technologies used for domestic heating needs to be reconsidered urgently, since the net tax loss from avoided oil taxation due to reduced consumption was further compounded by the public health cost of increased mid-term morbidity and mortality.

Lung cancer risk from PAHs emitted from biomass combustion.

This study deals with the assessment of the cancer risk attributable to PAH exposure, attributable to the increased use of biomass for space heating in Greece in the winter of 2012-2013. Three fractions of particulates (PM1, PM2.5 and PM10) were measured in two sampling sites (urban/residential and traffic-influenced) followed by chemical analysis of 19 PAHs and levoglucosan (used as a biomarker tracer). PAH-induced lung cancer risk was estimated by a comprehensive methodology that incorporated human respiratory tract deposition modelling in order to estimate the toxic equivalent concentration (TEQ) at each target tissue. This allowed us to further differentiate internal exposure and risk by age groups. Results showed that all PM fractions are higher in Greece during the cold months of the year, mainly due to biomass use for space heating. PAH and levoglucosan levels were highly correlated, indicating that particles emitted from biomass combustion are more toxic than PM emitted from other sources. The estimated lung cancer risk was non-negligible for residents close to the urban background monitoring site. Higher risk was estimated for infants and children, due to the higher bodyweight normalized dose and the human respiratory tract (HRT) physiology. HRT structure and physiology in youngsters favor deposition of particles that are smaller and more toxic per unit mass. In all cases, the estimated risk (5.7E-07 and 1.4E-06 for the urban background site and 1.4E-07 to 5.0E-07 for the traffic site) was lower to the one estimated by the conventional methodology (2.8E-06 and 9.7E-07 for the urban background and the traffic site respectively) that is based on Inhalation Unit Risk; the latter assumes that all PAHs adsorbed on particles are taken up by humans. With the methodology proposed herein, the estimated risk presents a 5-7 times difference between the two sampling sites (depending on the age group). These differences could not have been identified had we relied only on conventional risk assessment method. Consequently, the actual cancer risk attributable to PAHs on PM emitted from biomass burning would have been significantly underestimated.

Total exposure to airborne particulate matter in cities: the effect of biomass combustion.

The study deals with the seasonal variability of PM exposure and the effect that biomass combustion has upon it in the urban environment. The study is based on measurements, chemical analyses and modeling results performed in Thessaloniki (Greece). The measurements campaign included the assessment of outdoor and indoor air quality and the evaluation of biomass use for domestic heating. The outdoor measurements highlighted a significant increase of PM10 (from 30.1 to 73.1 µg/m(3)) and PM2.5 (from 19.4 to 62.7 µg/m(3)) concentrations during the transition from the warm to the cold period of the year 2012 compared to 2011. The increase in ambient air PM during the winter was attributed to the use of biomass burning for space heating. The latter was verified by the presence of levoglucosan in the PM (concentrations up to 8 µg/m(3)), especially for samples taken from the urban background site. Outdoor PM concentrations were also modeled using an artificial neural network model taking into account major meteorological parameters; the latter explained more than 90% of PM10 and PM2.5 day-to-day variability. Indoor concentrations followed a similar pattern, while in the case of fireplace use, average daily concentrations rise to 10 µg/m(3) and 14 µg/m(3) for PM2.5 and PM10 respectively. Indoor air concentrations were affected the most by the ambient air particle infiltration. Indoor air quality went down after 3h of open fire biomass combustion for space heating. Personal exposure was significantly determined by overall indoor air quality. Yet, dynamic exposure analysis revealed that peaks of intake do not correspond to peaks of ambient air PM concentrations altering thus total exposure patterns. Thus, cost-effective public health protection has to aim at reducing the exposure profile of susceptible population sub-groups combining awareness raising, emission reduction measures and financial incentives to influence the choice of space heating systems.

A methodological frame for assessing benzene induced leukemia risk mitigation due to policy measures.

The study relies on the development of a methodology for assessing the determinants that comprise the overall leukemia risk due to benzene exposure and how these are affected by outdoor and indoor air quality regulation. An integrated modeling environment was constructed comprising traffic emissions, dispersion models, human exposure models and a coupled internal dose/biology-based dose-response risk assessment model, in order to assess the benzene imposed leukemia risk, as much as the impact of traffic fleet renewal and smoking banning to these levels. Regarding traffic fleet renewal, several "what if" scenarios were tested. The detailed full-chain methodology was applied in a South-Eastern European urban setting in Greece and a limited version of the methodology in Helsinki. Non-smoking population runs an average risk equal to 4.1·10(-5) compared to 23.4·10(-5) for smokers. The estimated lifetime risk for the examined occupational groups was higher than the one estimated for the general public by 10-20%. Active smoking constitutes a dominant parameter for benzene-attributable leukemia risk, much stronger than any related activity, occupational or not. From the assessment of mitigation policies it was found that the associated leukemia risk in the optimum traffic fleet scenario could be reduced by up to 85% for non-smokers and up to 8% for smokers. On the contrary, smoking banning provided smaller gains for (7% for non-smokers, 1% for smokers), while for Helsinki, smoking policies were found to be more efficient than traffic fleet renewal. The methodology proposed above provides a general framework for assessing aggregated exposure and the consequent leukemia risk from benzene (incorporating mechanistic data), capturing exposure and internal dosimetry dynamics, translating changes in exposure determinants to actual changes in population risk, providing a valuable tool for risk management evaluation and consequently to policy support.

Exposure to major volatile organic compounds and carbonyls in European indoor environments and associated health risk.

This paper summarizes recent data on the occurrence of major organic compounds (benzene, toluene, xylenes, styrene, acetaldehyde, formaldehyde, naphthalene, limonene, α-pinene and ammonia, classified by the European Commission's INDEX strategy report as the priority pollutants to be regulated) and evaluates accordingly cancer and non-cancer risks posed by indoor exposure in dwellings and public buildings in European Union (EU) countries. The review process indicated that significant differences in indoor air quality exist within and among the countries where data were available, indicating corresponding differences in sources and emission strength of airborne chemicals, identified or not. Conservative exposure limits were not exceeded for non-carcinogenic effects, except for formaldehyde; for carcinogenic agents the estimated risks were up to three orders of magnitude higher than the one (10(-6)) proposed as acceptable by risk management bodies. However, the risk assessment evaluation process faces crucial difficulties, either due to the relative paucity of indoor air quality measurements in many EU countries, or by the lack of sampling consistency in the already existing studies, indicating the need for additional measurements of indoor air quality following a harmonized sampling and analytical protocol. Additionally, uncertainties embodied in the cancer potency factors and exposure limit values impose further difficulties in substance prioritization and risk management.

Measurements of benzene and formaldehyde in a medium sized urban environment. Indoor/outdoor health risk implications on special population groups.

In the present study, the results of a measurement campaign aiming to assess cancer risk among two special groups of population: policemen and laboratory technicians exposed to the toxic substances, benzene and formaldehyde are presented. The exposure is compared to general population risk. The results show that policemen working outdoor (traffic regulation, patrol on foot or in vehicles, etc.) are exposed at a significantly higher benzene concentration (3-5 times) than the general population, while the exposure to carbonyls is in general lower. The laboratory technicians appear to be highly exposed to formaldehyde while no significant variation of benzene exposure in comparison to the general population is recorded. The assessment revealed that laboratory technicians and policemen run a 20% and 1% higher cancer risk respectively compared to the general population. Indoor working place air quality is more significant in assessing cancer risk in these two categories of professionals, due to the higher Inhalation Unit Risk (IUR) of formaldehyde compared to benzene. Since the origin of the danger to laboratory technicians is clear (use of chemicals necessary for the experiments), in policemen the presence of carbonyls in indoor air concentrations due to smoking or used materials constitute a danger equal to the exposure to traffic originated air pollutants.

Bayesian algorithm implementation in a real time exposure assessment model on benzene with calculation of associated cancer risks.

The objective of the current study was the development of a reliable modeling platform to calculate in real time the personal exposure and the associated health risk for filling station employees evaluating current environmental parameters (traffic, meteorological and amount of fuel traded) determined by the appropriate sensor network. A set of Artificial Neural Networks (ANNs) was developed to predict benzene exposure pattern for the filling station employees. Furthermore, a Physiology Based Pharmaco-Kinetic (PBPK) risk assessment model was developed in order to calculate the lifetime probability distribution of leukemia to the employees, fed by data obtained by the ANN model. Bayesian algorithm was involved in crucial points of both model sub compartments. The application was evaluated in two filling stations (one urban and one rural). Among several algorithms available for the development of the ANN exposure model, Bayesian regularization provided the best results and seemed to be a promising technique for prediction of the exposure pattern of that occupational population group. On assessing the estimated leukemia risk under the scope of providing a distribution curve based on the exposure levels and the different susceptibility of the population, the Bayesian algorithm was a prerequisite of the Monte Carlo approach, which is integrated in the PBPK-based risk model. In conclusion, the modeling system described herein is capable of exploiting the information collected by the environmental sensors in order to estimate in real time the personal exposure and the resulting health risk for employees of gasoline filling stations.

A methodology to estimate benzene concentrations in a town through a traffic model.

In this work an approach is presented that describes the changes of benzene concentration in the air, in relation with the special traffic characteristics of a road. The dominant input parameters of the model are traffic density and the vehicle's type distribution according to seven main categories characterized by different emission factors. The dispersion approach used is a semi-empirical relationship that apart from emission rates requires also wind speed and the direction, as well as the geometrical characteristics of the road. The methodology was validated for Ioannina, a Greek medium sized town with special traffic and geographic characteristics presenting high atmospheric pollution values. It is found that the benzene concentrations estimated by the methodology are in a very good agreement with the measurements.