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Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 Cross-Mediterranean Environment and Health Network CROME–LIFE The CROME method Prof. Denis Sarigiannis – Project coordinator Environmental Engineering Laboratory Department of Chemical Engineering, Aristotle University of Thessaloniki GR-54124, Thessaloniki, Greece Chair of Environmental Health Engineering, Institute of Advanced Study, Pavia 27100, Italy CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 1 LIFE12 ENV/GR/001040 Project consortium Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Lead Beneficiary: Aristotle University of Thessaloniki (AUTH) - Greece AUTH coordinates the scientific/technical and administrative/financial aspects of the project Project manager: Prof. Dimosthenis Sarigiannis Associated beneficiaries: – Agencia Estatal Consejo Superior de Investigaciones Cientificas (CSIC) – Spain – Principal investigator: Prof. Joan Grimalt – Istituto Superiore di Sanità (ISS) – Italy Principal investigator: Dr. Gemma Calamandrei – Jožef Stefan Institute (JSI) – Slovenia Principal investigator: Prof. Milena Horvat CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 2 What is Exposome? Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 • The record of all exposures, both internal and external, an individual receives over his or her lifetime, from conception onward. These exposures range from chemicals in the environment to the body’s response to infection or psychological stress (C. Wild, IARC, 2005) • It is important to keep an unbiased (agnostic) stance to coupling chemical exposure to health status S M Rappaport, M T Smith Science 2010;330:460-461 CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 3 LIFE12 ENV/GR/001040 What is the exposome? Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Rappaport et al., 2014. Environmental Health Perspectives122: 769-774. CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 4 Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki The connectivity paradigm LIFE12 ENV/GR/001040 Environmental sensors Remote sensing Exposure modelling metabol ite formati on GI tract – portal vein Environmental modeling / data management GI tract – portal vein L i v e r L i v e r H e a r t H e a r t B r a i n B r a i n M u s c l e s S k i n M u s c l e s S k i n K i d n e y A s d i p o s e B o n e s K i d n e y A s d i p o s e B o n e s B r e a s t Uterus - gonads A r t e r i a l b l o o d L u n g s EWAS B r e a s t Uterus - gonads V e n o u s b l o o d A r t e r i a l b l o o d L u n g s V e n o u s b l o o d Community Effects / Cohorts Systems Effects / Individual exposome Environmental analysis Epigenetics Cellular/tissue effects Human biosampling Molecular initiating events Metabolomics Agent based modelling Ubiquitous personal sensors Fluxomics (dynamic flux balance analysis) Transcriptomics CROME LIFE+ Closing Conference December 20, 2016 Bioinformatics / systems biology Athens, Greece Pathway analysis 5 CROME towards new E & H paradigm Main technical innovation proposed LIFE12 ENV/GR/001040 Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki CROME facilitated the new E & H paradigm, proposing targeted innovation steps that include: 1. the operational use and demonstration of the validity of biology-based modeling tools that allow to mechanistically link environmental exposure to biomonitoring and epidemiological data. This will be done by: (a) linking environmental exposure to the biologically effective dose (BED) of xenobiotics at the main target tissues; (b) linking biomarker levels in biological fluids to the BED at target tissues; and (c) linking target tissue BED with health outcomes. In this way, environment-wide associations with adverse health effects or physiological perturbations will be established and mechanistic hypotheses regarding the mode and/or mechanism of action can be investigated. 2. the operational use of an integrated approach to biomonitoring that combines the use of state-of the-art biomarkers with reverse dosimetry and environmental data to reconstruct the effective dose human population is exposed to. The results will allow moving towards an improved environmental health risk assessment in the EU and the world. 3. development of new and validation of existing biomarkers for environmental health risk assessment and environmental human biomonitoring Exposure source Transport fate CROME LIFE+ Closing Conference External contact Internal dose December 20, 2016 Biologically effective dose Early biological response Altered function Athens, Greece Clinical disease 6 Exposure modelling Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 Oral exposure – Non Dietary Oral exposure – Dietary Skin exposure Inhalation takes into account Dietary ingestion takes into account Object to mouth Hand to mouth - The chemical concentration of food category i in μg/g - The daily average consumption in g/d of food category i, age category j and gender category k Instant application Food residues are estimated - Through the food web (multimedia model) Inhalation exposure Migration from skin contact - The concentration from the several locations encountered during the exposure regimes - The intensity of activity, gender and age dependent inhalation rate For particles and the compounds adsorbed, deposition across the HRT is considered Soil and dust ingestion - Accounting also for migration through food contact materials Rubbing off Personal care products ingestion Constant rate CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 7 LIFE12 ENV/GR/001040 Biokinetic modeling Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Lifetime evolving parameters • • • Organ volumes Blood flows Age-dependent clearance Mother – Fetus interaction Breast feeding CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 8 LIFE12 ENV/GR/001040 Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Expanding the chemical space - use of QSARs According to Abraham’s solvation equation, a biological property SP can be described by the following equation log SP c r R2 s 2 a 2 b 2 v log Vx Where: R2 R2 is an excess molar refraction that can be determined simply from π2Η a knowledge of the compound refractive index π2Η is the compound dipolarity/polarizability Σα2Η is the solute effective or summation hydrogen-bond acidity Σβ2Η is the solute effective or summation hydrogen-bond basicity Vx is the McGowan characteristic volume 1 2 3 Σα2Η Σβ2Η n LogSP 4 Vx 5 6 Input layer CROME LIFE+ Closing Conference December 20, 2016 Hidden layer Athens, Greece Output layer 9 What does a spot sample represent? LIFE12 ENV/GR/001040 20 Concentration in human specimen (μg/L) Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki 16 Exposure scenario 1 Exposure scenario 2 Exposure scenario 3 12 Spot sampling 8 4 0 0 4 8 12 16 20 24 Time (h) CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 10 Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Exposure reconstruction LIFE12 ENV/GR/001040 Optimal methodological scheme for exposure Distribution of exposure reconstruction values consistent with biomarker data Potential exposure estimation Improved sampling En B*n PBTK model run with E*n input E3 B*3 E2 B*2 E1 PBTK model run with E*1 input Exposure model CROME LIFE+ Closing Conference Companion data B*1 Comparison with biomarker data Optimization algorithm Small proportion of rejected model simulations Biomarker data (Exposure related) December 20, 2016 Athens, Greece 11 LIFE12 ENV/GR/001040 CROME LIFE+ Closing Conference Application: reconstructing Arsenic exposure from HBM data Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki As → PROBE- Italy As → PHIME Slovenia December 20, 2016 Athens, Greece 12 LIFE12 ENV/GR/001040 CROME LIFE+ Closing Conference Application: reconstructing HCB and DDT exposure from HBM data Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki HCB → INMA - Spain DDT → INMA - Spain December 20, 2016 Athens, Greece 13 LIFE12 ENV/GR/001040 CROME LIFE+ Closing Conference Application: reconstructing MeHg exposure from HBM data Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki MeHg → PHIME - Croatia MeHg → PHIME - Slovenia December 20, 2016 Athens, Greece 14 LIFE12 ENV/GR/001040 • • Association of biomonitoring data to health effects Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki To estimate the health impact we will use a statistical approach based on survey-weighted logistic multivariate regression adjusted for different covariates (age, sex, socio-economic status (SES) etc.) linking internal doses with health effect considering the interdependence of the covariates (using as metric an analogy of the “linkage disequilibrium” metric used in genome-wide association studies). The general formulation of the approach is based on the following mathematical linkage of health end points (expressed in terms of odds ratio, p) with different covariates (age sex, SES etc.) and the internal dose in the target tissue (XFactor): where cov represents the different covariates used in the model and α and β are the regression coefficients which take into account the interdependence between the covariates. CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 15 LIFE12 ENV/GR/001040 CROME LIFE+ Closing Conference Association of biomonitoring data to health effects December 20, 2016 Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Athens, Greece 16 Explore causality in EWAS Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 17 LIFE12 ENV/GR/001040 Explore causality in EWAS using linkage disequilibrium Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Red: positive Blue: negative Thickness: | | CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 18 LIFE12 ENV/GR/001040 Name Country/Region INMA Spain (Valencian Community) Available cohort data Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Questionnaires available People targeted HBM matrices Health end-points Chemicals 500 mother-infant pairs venous blood serum, cord blood serum Bayley test for infant development Mercury, Organochlorine compounds, polybromodiphenyl ethers (including decabromodiphenyl ether) yes venous blood serum, cord blood serum McCarthy Scales of Children’s Abilities. Tests for the California Mercury, organochlorine Preschool Social compounds, polybromodiphenyl Competence Scale ethers and Attention-Deficit Hyperactivity Disorder (ADHD) yes 480 cord blood 300 blood at 4 years INMA Spain (Menorca) JSI Slovenia – 12 regions included in the national human 600 pairs, mother-child, biomonitoring survey, man including rural, urban and contaminated sites Breast milk, blood, urine, hair Reproductive and neurodevelopmental toxicity and effects of endocrine disruptors BPA, phthalates, pesticides, PCBs, metals and As yes PHIME Slovenia Brest milk, bllood urine, hair neurodevelopmental toxicity and effects of endocrine disruptors BPA, phthalates, pesticides, PCBs, Hg and other metals and As yes PROBE Italy - various Regions 1500 adults 500 Latium for adolescents adolescents HM (focus on Arsenic) yes CROME LIFE+ Closing Conference 225 mother-child pairs Blood and serum December 20, 2016 Athens, Greece 19 LIFE12 ENV/GR/001040 Additional data Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki The CROME-LIFE Cross-Mediterranean study (or Common case study) is a follow up study of pre-existing Children Mediterranean cohorts based on: PHIME, involving Slovenia, Croatia, Italy, Greece INMA (Environment and Childhood), Spain Aim: to find those gene polymorphisms that could modulate the effects of metals, particularly Hg, at low exposure in the Mediterranean cohort: glutathione-related genes metal binding protein genes genes involved in scavenging of ROS genes implicated in brain development others, identified by GWAS CROME LIFE+ Closing Conference December 20, 2016 MERCURY MINING Athens, Greece 20 Additional case studies - Greece Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 Greece – Aspropyrgos plastic recycling plant fire → PCDDs / PCDFs Greece – Asopos basin → Cr+6 Greece – Biomass burning in large cities → PM / PAHs CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 21 LIFE12 ENV/GR/001040 Asopos region – Cr(VI) Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Health impact A total of 474 deaths were observed over an 11-year period (1999 - 2009). The standardized mortality ratios (SMR) for all cause mortality was 98 (95% CI 89107) and for all cancer mortality 114 (95% CI 94-136). The SMR for primary liver cancer was 1104 (95% CI 405-2403, p-value < 0.001). Statistically significantly higher SMRs were identified for lung cancer (SMR = 145, 95% CI 100-203, p-value = 0.047) and cancer of the kidney and other genitourinary organs among women (SMR = 368, 95% CI 119-858, p-value = 0.025). Elevated SMRs for several other cancers were also noted (lip, oral cavity and pharynx 344, stomach 121, female breast 134, prostate 128, and leukaemias 168), but these did not reach statistical significance. In addition, increased morbidity related to asthma and allergies have been observed *Linos et al (2011). Oral ingestion of hexavalent chromium through drinking water and cancer mortality in an industrial area of Greece - An ecological study. Environ. Health. 10. CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 22 Cr(VI) in water Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 1,000 5%-95% Cr(VI) in water Median Εξασθενές χρώμιο (μg/L) Mean 100 10 1 0 Tap water CROME LIFE+ Closing Conference December 20, 2016 Underground water Athens, Greece 23 Exposure biomarkers Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 5 Total Cr 5%-95% Median Urine (μg/L) / Hair (μg/g) 4 Mean 3 2 1 0 Childrern Adults Urine CROME LIFE+ Closing Conference Childrern Adults Hair December 20, 2016 Athens, Greece 24 LIFE12 ENV/GR/001040 Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Biomarkers analysis Integrated biology workflow LC-MS/MS GC-MS/MS MassHunter Qual/Quant ChemStation AMDIS Microarrays Feature Extraction NGS CROME LIFE+ Closing Conference GeneSpring Platform Biological Pathways Alignment to Reference Genome December 20, 2016 Athens, Greece 25 LIFE12 ENV/GR/001040 Biomarkers analysis Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Cancer CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 26 LIFE12 ENV/GR/001040 Biomarkers analysis Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Allergies and asthma CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 27 Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 Health risks of recycling The case of Aspropyrgos recycling plant fire – dioxin/furan release CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 28 Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki Recycling plant accidental event LIFE12 ENV/GR/001040 10,000 Concentration (fg/m3) 1,000 5%-95% Median PCDDs and PCDFs (TEQ) 100 10 1 Rural areas City centre Industrial area Landfield fires Aspropyrgos fire 24 Conc. (pg/g lipid_TEQ) 20 16 12 Background levels 8 4 0 8 6 7 8 9 6 11 8 9 10 7 6 9 11 9 273841552941324225394231293942255836474930364924342936483839443842274449344148534953483934 Children Adults Individuals age (years) 5%-95% Median Risk Cancer risk 1.E-06 1.E-07 1.E-08 Background risk CROME LIFE+ Closing Conference December 20, 2016 Post-accidental risk / Post-accidental risk / Post-accidental risk / adults neonates breast fed Athens, Greece 29 Metabolomics and pathway analysis Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 Increased levels of unsaturated vs saturated fatty acids, compared to controls → cholesterol homeostasis perturbation → AhR deregulation CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 30 LIFE12 ENV/GR/001040 Biomass smoke Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki The environmental problem In Greece, the use of biomass for space heating was introduced in 2011 as a CO2-neutral means to foster global warming mitigation However, a series of austerity measures combined with the excessive rise in the taxation of light heating diesel, resulted in irrational use of biomass for residential heating in the winter of 2012-2013 This was followed by a significant increase of ambient and indoor air levels and, as a result of the lack of technological readiness of Greek households to use biomass for space heating; the vast majority of the appliances included use of open fireplaces or woodstoves CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 31 Study design Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki – integrating detailed environmental information into enhanced exposure and health impact assessment LIFE12 ENV/GR/001040 25 20 15 15 Indoor concentrations Index Meteorological parameters prediction Lung cancer risk 25 20 Index Temperature Humidity Wind speed Wind direction Precipitation Region specific oxidative potential index 10 10 5 5 0 0 Nasopharyng eal Trach eo bro nchial Pulmonary bronchioles Nasopharyng eal Traffic Trach eo bro nchial Pulmonary bronchioles Nasopharyng eal Trach eo bro nchial Traffic Urban backgroun d Pulmonary bronchioles Nasopharyng eal Trach eo bro nchial Pulmonary bronchioles Urban backgroun d 1 Dynamics in time 2 PM PM day before Forecasted ANN Ambient air PM HRT deposition + INTERA comp. platform Measured Population exposure n Ambient air PM monitoring network Database Health impact Training loop 150 Urban background Anthropometric data Time activity data Housing data Other sources Biomass Chemical analysis • Source apportionment (e.g. Levoglucosan, BC, metals) • Refined risk assessment (e.g. PAHs analysis, redox activity) Monetary impact 120 90 60 30 0 Sarigiannis et al. Total exposure to airborne particulate matter in cities: The effect of biomass combustion. Science of the Total Environment 2014; 493: 795-805. Sarigiannis et al. Lung cancer risk from PAHs emitted from biomass combustion. Environmental Research 2015; 137: 147-156. Sarigiannis et al. Health impact and monetary cost of exposure to particulate matter emitted from biomass burning in large cities. Science of the Total Environment 2015; 524-525: 319-330. CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 32 Biomass contribution to PM10 LIFE12 ENV/GR/001040 150 150 Traffic site PM concentration (μg/m3) Urban background Other sources Other sources Biomass Biomass 120 120 90 90 60 60 30 30 0 0 CROME LIFE+ Closing Conference Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki December 20, 2016 Athens, Greece 33 ICR among age groups LIFE12 ENV/GR/001040 1.E-04 Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki 5%-95% Median Mean Lung cancer risk Lung cancer risk 1.E-05 1.E-06 3 7 1.E-07 1.E-08 0-3 3-23 23m.-3 3-8 months months years years 8-14 years 14-18 years 18-21 years Adult Urban background Lower SES area CROME LIFE+ Closing Conference December 20, 2016 IUR 0-3 3-23 23m.-3 3-8 months months years years 8-14 years 14-18 years 18-21 years Adult IUR Traffic Higher SES area Athens, Greece 34 CROME related interventions Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 A tiered measure strategy was proposed and adopted by the Hellenic government in the form of a Joint Ministerial Decree (KYA 3272, 23/12/2013) under the title “Short-term action plans to address air pollution by particulate matter” among Ministries of Health, Financial, Internal Affairs, Development And Competitiveness, Education And Religious, Administrative Reform And Government - Wellness Infrastructure, Transport And Networks - Environment, Energy And Climate Change - Public Order And Protection Citizen - Shipping And Islands - Information of the public - Reducing exposure of susceptible groups - Avoiding intensive exercise - Avoiding effort….. - Actions for restricting emissions - Reducing traffic emissions - Use of telematics systems – routes optimization - Speed limits - More passengers per vehicles - Restricted zones…….. - Reducing industrial emissions - Shifting into less polluting activities - Use of alternative fuels - Reducing activity and electricity production - Reducing household emissions - Reducing energy consumption - Use of cleaner energy CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 35 0 CROME LIFE+ Closing Conference December 20, 2016 2/8/2014 Athens, Greece 2/22/2014 2/20/2014 2/18/2014 2/16/2014 2/14/2014 2/12/2014 2/10/2014 125 2/6/2014 150 2/4/2014 -26% 2/2/2014 1/31/2014 1/29/2014 1/27/2014 1/25/2014 PM10 : 92.3 PM2.5: 70.7 1/23/2014 1/21/2014 1/19/2014 1/17/2014 1/15/2014 1/13/2014 1/11/2014 1/9/2014 1/7/2014 1/5/2014 1/3/2014 1/1/2014 12/30/2013 12/28/2013 Date of intervention PM10 : 68.6 PM2.5: 51.3 PM10 Urban background 20 PM10 Traffic Precipitation (mm) T (0C) Wind speed (km/h) 15 100 75 10 50 5 25 0 T (0C) - Wind speed (km/h) - Precipitation (mm) 200 12/26/2013 12/24/2013 12/22/2013 12/20/2013 12/18/2013 12/16/2013 12/14/2013 175 12/12/2013 12/10/2013 12/8/2013 12/6/2013 PM concentration (μg/m3) CROME related interventions Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 25 36 CONCLUDING REMARKS Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 The methodology applied in CROME - Takes stock of biomonitoring data in the health impact assessment process - Accounts for the internal dosimetry in the target tissues, setting the biological basis for understanding the interaction between environmental exposure and disease - Demonstrates in real-life environmental-health problems, what the targeted interventions should be for improving public health and protecting vulnerable groups CROME outcomes, will be disseminated as follows: • Transferring the outcomes (practices and technologies) of the project to the rest of the EU Member States. • Informing all stakeholders and general public of the demonstration sites on the resulted benefits. • Promoting the adopted practices and protocols to the key stakeholders. CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 37 Department of Chemical Engineering School of Engineering Aristotle University of Thessaloniki LIFE12 ENV/GR/001040 Thank you for your kind attention www.enve-lab.eu A new perspective to environment-health interactions CROME LIFE+ Closing Conference December 20, 2016 Athens, Greece 38