WP4. Eological Epidemiology · 2020. 9. 9. · Task 4.3. Risk of thyroid cancer in the Milazzo area (Fabrizio Bianchi e Le’zia Pi^o) In the Milazzo PS, including the municipaly

PROGETTOCentro Internazionale di Studi Avanzati su Ambiente,

ecosistema e Salute umana [CISAS]

WP4.E+ologicalEpidemiology

To develop knowledge on the association between priority pollutants specific for each area and selected health conditions,

identified on the basis of environmental and epidemiological knowledge and relevance for research and innovation

FabrizioBianchi,HeadUnitofenvironmentalepidemiology,IFCCNR

Dipar'mentoScienzedelsistemaTerraetecnologieperl'ambiente

Background•  ForthePollutedSite(PS)ofMilazzoandPriolodataonmortality,incidenceandhospitaliza'onwereprovided(Pirastuetal.2012e2014).

•  ForthePSofCrotonemortalitydata1995-2002wereprovided(Pirastuetal2012),upgradedbyarecentanalysisondata2006-2012,providingdisaggregateddataforthemunicipali'esofCrotoneandCassano-Cerchiara(ISTISAN16/9).

•  InthethreePSsunderstudyseveralexcessesofhealthindicatorswereobserved.

Background

Environment characterization of target pollutants in 3 polluted sites of national interest

•  Augusta-Priolo(Sicily)–  Hg,Cd,Zn,Pb,PCDD,PCD,Esachlorobenzene,PAH,PCB,BTEX

•  Milazzo(Sicily)–  Pb,Hg,Ni,Cr,Cd,PAH,BTEX

•  Crotone(Calabria)–  Cd,Zn,As,Pb,Cu,Hg

AIMSofCISASWP4

•  Enhanceknowledgeonselectedindicatorsthroughthestudyofriskmarkersandpre-clinicalsignsinpopula+ongroupsatdifferentlevelsofexposure.

•  mergingenvironmental,epidemiologicalandresearchcriteria

•  Augusta-Priolo–  liveranddiabetes

•  Milazzo–  thyroid

•  Crotone– cardiovascular– urinary

Ac+vi+esplanned:•  BMsurveys(exposureBM)•  cohortstudies•  riskpercep+onsurveys•  linkagestudieswithmortality

andmorbiditydata•  Par+cipatoryandKTE

ini+a+ves

Target diseases and planned activities

Organiza+on

WP4consistsof5tasks:

Task 4.1 Coordination, analysis and monitoring (Fabrizio Bianchi) Task 4.2 Risk of liver cancer in the Priolo area (Amalia Gastaldelli) Task 4.3 Risk of thyroid cancer in the Milazzo area (Letizia Pitto) Task 4.4 Risk of cardiovascular biomarkers in the Crotone area

(Alessandro Pingitore e Francesco Faita) Task 4.5 Pilot study on renal function impairment and early kidney

damage in the Crotone area (Giovanni Tripepi e Davide Bolignano)

Task 4.6 Dissemination and scientific networking (Liliana Cori)

Task 4.1 Coordination, analysis and monitoring (Fabrizio Bianchi, IFC CNR)

ManagementProjectmanagementac'vi'es,coordina'onwithotherWP,epidemiologicaldesignandsta's'calanalysis,rela'onshipswithotherlocal,regional,na'onalbodies,monitoringandevalua'onofac'onsdevelopment.

LiteraturereviewCompleteliteraturereviewonenvironmentandhealthinthethreestudyareas(Augusta,MilazzoandCrotone)asstar'ngpointofthefieldwork(coopera'onproposaltoISS)

MonitoringandevaluaConAspecificlistofindicatorshavetobedefinedtomonitorandevaluatethetaskdevelopment,asabasicfunc'onofthemanagementac'vity

Task 4.2 Risk of liver cancer in the Priolo area (Amalia Gastaldelli, IFC-CNR)

ThePrioloPSischaracterizedbyadiffuseenvironmentalcontamina'onduetotoxic,persistentandbio-accumulablecompounds,suchasheavymetals,polychlorinatedbiphenyls(PCBs),dioxinsandpolycyclicaroma'chydrocarbons(PAHs)weredetectedandthepastandpresentexposuretovola'leorganiccompounds(VOCs)wasascertained.TheincidenceofallcancersshowedanexcessinbothgenderswithrespecttothepoolofcancerregistriesofcentralandsouthernItaly,inpar'cularneoplasmsinexcessincludedliverandpancreascancersandmesothelioma.

Task4.2 RiskoflivercancerinthePrioloarea AmaliaGastaldelli,IFC-CNR

h^p://www.who.int/phe/news/march2016/en/

ModifiedbyInt.J.Mol.Sci.2013,14,22052-22066

Increasedchemicalproduc+onhasbeenassociatedwithincreasedprevalenceofDiabetes,CVD,FaYyLiver,Cancer

Neel B A , and Sargis R M Diabetes 2011;60:1838-1848

Nonpersistantpollutantsactasendocrinedisruptors

Hepatocellular carcinoma (HCC) is the main type of primary liver cancer, it is the sixth most commonly occurring cancer in the world and the second largest contributor to cancer mortality.

Themechanisms for thedevelopmentofHCCares'llunknownbut itmightbeduetoaltera'onsof lipidmetabolism.Infact,theriskfactorsforHCCarerepresentednotonlybyviralinfec'ons(HCVandHBV)andexcessalcoholbutalsobyexposure topollutants thatactasendocrinedisruptorsandproducemetabolicaltera'ons.

Age-adjusted incidences per 100,000 of livercancer among men and women by region,2003-2007.Age-adjustedtoworldstandard.

HypothesisMostofthepollutantsarelipidsolubleandoncetheyaccumulateinadipose'ssueandlivertheymightpromotecelllipotoxicity,increaselipolysis,denovolipogenesis(DNL)andsynthesisofsaturatedfa^yacids,inpar'cularpalmi'cacid(PALM)andotherclassesoflipidsuchasceramides,di-andtri-acylglycerols(DAGandTAG).

FaYyacids(FA)arerequiredforenergystorage,membraneprolifera+on,andthegenera+onofsignalingmoleculesandaltera+onsinFAmetabolismmaybeinvolvedintheinduc+onofthecancerogenesisevent.

Proposedmechanisms

Aimofthestudy

Toiden'fyifsubjectslivingintheexposedarea:Ø  displayincreasedlevelsofestablishedriskfactorsand

poten'albiomarkersofliverdiseaseandHCC

Ø  display specific disease-related metabolic pathwaysresponsible of the altera'on in lipidmetabolism abletopromoteliverdiseaseandHCCdevelopment

Experimentaldesignofthestudy

1stgroup(n=220):withoutlivercancerlivinginexposedarea

2ndgroup(n=220):withoutlivercancerlivinginunexposedarea

3rdgroup:subjectswithHCCwillbeaskedtopar'cipatePlasmaandurine

samples

•  DNLindexescalculatedasthera'opalmi'c/linoleicacid(16:0/18:2)

•  Freefa^yacid(FFA)concentra'onandcomposi'on

Theseparameterswillmeasureinplasma,bygaschromatographymassspectrometry(GC/MS)

•  Lipidomicprofile(e.g.ceramides,di-andtri-acylglycerols)willbemeasuredinplasmasamplesbyliquidchromatographymassspectrometryLC-MSQ-TOF

•  clinicalandbiochemicalparameters

•  fa^yliverindex(FLI)•  fibro'cliverindexes•  inflammatorymarkers•  adipocytehormone

lep'nandthepancrea'chormoneinsulin

Ø  Toiden'fyclassesoftoxiclipidsthat,duetothehighconcentra'onsofenvironmentalpollutantsinthePrioloarea,canpromoteands'mulatealtera'onsoflipidandfa^yacidmetabolismthatmaybeinvolvedinthedevelopmentofhepatocellularcarcinoma.

Ø  Toiden'fypoten'albiomarkersinvolvedinspecificmetabolic

pathwaysthatcouldbeusedastargettoprevent/treathepatocellularcarcinoma.

ExpectedResults

Task4.3.RiskofthyroidcancerintheMilazzoarea(FabrizioBianchieLe'ziaPiô)IntheMilazzoPS, includingthemunicipalyofMilazzo,PacedelMelaeSanFilippodelMela,the incidenceofthyroidcancer(TC) in2003-2010hasbeenreportedinexcess (not sta's'cally significant) among men andwomen (24%and 40% increases rispec'vely), and thehospitaliza'onforTCin2005-2010showedsta's'callysignifican excess of 55% amongman and 24% amongwomen.(Pirastuetal.2014)

Task4.3.RiskofthyroidcancerintheMilazzoarea(FabrizioBianchieLe'ziaPiô)ExcessesofmortalityandmorbiditywereobservedinseveralPSsinaddi'ontoMilazzo(Brescia-Caffaro,MantuaLakes,Sassuolo-Scandiano,Taranto),inbothgenders(Pirastuetal.2014)Sincelong'meiswellknownthecri'calroleofthethyroidglandinthedevelopment/cellulardifferen'a'on,andfetal'ssue,inthecontrolmetabolichomeostasisandfunc'onofthemajorityoforgansandsystems(cardiovascularandcentralnervoussystemfirstofall),includingtheremainingendocrineorgansandthereproduc'vesystem.

Task4.3.RiskofthyroidcancerintheMilazzoarea(FabrizioBianchieLe'ziaPiô)Thisroleisemphasizedbytherelief,clinicalandexperimental,thatevenminimalchangeinthyroidfunc+onwithcircula'nglevelsofhormoneswhiles'llresul'nginthereferencerangeofnormality'(so-calledhyperorhypothyroidismpreclinical)areabletogeneratenega+veconsequences,par+cularlyatfetalandneurologicallevel.Hormone-likemoleculesmime+cPCB,Bisphenolandothersiswellrecognized,whiletheroleofheavymetals,suchasmercury,lead,cadmium,islessknown.

Task4.3.RiskofthyroidcancerintheMilazzoarea(FabrizioBianchieLe'ziaPiô)Subtask3.1EpidemiologicalinvesCgaConToexaminepoten'almechanismsoftoxicac'ononthyroidfunc'onofmercury,lead,cadmium,andotherheavymetalswithanintegratedapproachthatincludestheuseofananimalmodelwidelyusedandvalidatedfortoxicologicalwhichzebrafish.Theprimaryaimistoiden'fyifsubjectslivingintheexposedareadisplayincreasedlevelsofestablishedriskfactorsandbiomarkersoffunc'on/thyroidcarcinogenesis.

Task4.3.RiskofthyroidcancerintheMilazzoarea(FabrizioBianchieLe'ziaPiô)Subtask3.1EpidemiologicalinvesCgaConThesecondaryaimistodiscoverifsubjectslivingintheexposedareadisplayaltera'oninmetabolismthatcanpromotethyroidcancer.Subjects:wewillstudysubjectswithoutknownthyroidcancer,aged18-44years,recruitedintheMilazzoareaandinanotherareawithoutcontamina'on.

Task4.3.RiskofthyroidcancerintheMilazzoarea(FabrizioBianchieLe'ziaPiô)Subtask3.1EpidemiologicalinvesCgaConInallsubjectswewillcollectplasmaandurinesamples,andthefollowingparameterswillbemeasured:TSH,FT3,FT4,urinaryorbloodlevelsofvariousheavymetalsofinterest,adjustedforcrea'ninuria.Athyroidsonographicmeasurements(glandularvolume)willbedoneineachsubject.

Zebrafisharewidelyusedintoxicologicalresearchbecauseofitssmallsize,easyculture,highreproduc+veperformance,rapidorganogenesisandsensi+vitytotheharmfulchemicals.Recently, zebrafish studies have led to important insights into thyroiddevelopment,andhavebeenusedtomodelendocrinecancer.The thyroid system in zebrafish is similar tomammalian,which can provide avaluablereferenceforhumanbeings.

Subtask3.2Experimentalmodel

Zebrafish an in-vivo model to investigate the effects of environmental pollutants on Thyroid function and on occurrence of thyroid carcinoma

84%ofgenesknowntobeassociatedwithhumandiseasehavezebrafishcounterparts

Inthepresentstudy,zebrafishwillbeusedforelucida'ngtheeffectsofseveralenvironmentalpollutantsiden'fiedintheareaofinterestofMilazzo,ondisrup'onofthyroidfunc'onandexpressionandoninsurgenceofthyroidcarcinoma.

Fishcrossing

andeggsfer+liza+on

1

Arrayedembryos 2 3 xenobio+caddi+on

Thislineallowsliveimagingofthyroiddevelopmentinembryosfrombuddingstagethroughoutforma'onoffunc'onalthyroidfollicles.

AnslysisofDio1andDio2,TR-αandTR-β,tsh-βgene,theiodinetransporterslc5a5gene,thethyroglobulinandtransthyre+n.

Quan+ta+onanalysisofthyroidregula+nggenesbyQuan+ta+veRealTimePCR.

Morphologicalstudiesusingofthetransgeniclinetg(tg:mCherry)

T3,T4quan+fica+onbyElisaKit

4Embryodevelopmentinthepresenceofxenobio+cs

Investigation on the impact of pollutants on thyroid metabolism

Toevaluatethegenotoxiceffectofthepollutantsunderstudies,differentexposureprotocolswillbeu'lizedonthetransgenictg(tg:mCherry)lineandonthemutantp53-/-linewhichlackingofthetumorsuppressorp53genewillresultinanincreaseoftheneoplasiafrequenciesmakingeasierthegenera'onoftumorfreecurves.

8weeksPF16weeksPF20weeksPF24weeksPF36weeksPF

Genotoxicantexposure

-Morphological analysis -Histopatological studies: hematoxylin and eosin staining for neoplastic lesion identification .

2 Treatmentoftg(tg:mCherry)juvenilefishes

p53-/-3 Treatmentofp53-/-juvenilefishes

Genotoxicantexposure

- Morphological analysis -Histopatological studies Generation of tumor free curves. Tu

mor-freecurve -p53-/-fishes

p53-/-+pollutants

1620242832weeksPF

8weeksPF16weeksPF20weeksPF24weeksPF28weeksPF32weeksPF36weeksPF

3daysPF9daysPF15daysPFGenotoxicantexposure

qRAPDandAFLPassaysforgenomicinstabilityquan+fica+on

FACSsor'ngoffluorescentthyroidcellsforoncogeneanalysisbyQRTPCR

1 Treatmentoftg(tg:mCherry)embryos

Investigation on the impact of pollutants on thyroid neoplasia

Task4.4.RiskofcardiovascularbiomarkersintheCrotonearea Background

IntheCrotoneareahighconcentra'onofheavymetalswasreported(Troisietal2002).TheStudySENTIERIon1995-2002mortalitydata,showedanexcessforcircolatorydiseasesamongmales(+13%)(Pirastu2012)Mortalityforkidneytumorswasobservedinexcessamongmalesandfemales(+105%and+37%rispec'vely),whileanexcessofurinarytractandnephrosiskidneyfailureemergedamongfemales(+43%).Hospitaladmissionduetoischemicheartdisease,acuteischemicdiseases,nephri+s,nephro+csyndromeandnephrosisshowedexcessesforbothgenders(+42-68%),forkidneycancersamongmales(+49%).(ISTISAN16/9)

Background Heavy metals and CardioVascular Diseases: a true relationship

“…4 metals having no role in the human body (xenobiotic), mercury, lead, cadmium, and arsenic, have epidemiological and mechanicistic links to atheroslclerosis and CVD.”

Solenkova NV et al. Am Heart J 2014 (Review) “Blood lead and calcium, at levels well below current safety standards, were associated with an increased prevalence of peripheral arterial disease…”

Navas-Acien A et al. Circulation 2004 “Urine cadmium … was associated with increased cardiovascular mortality…”

Tellez-Plaza et al. Epidemiology 2013 “Long-term exposure to low to moderate arsenic levels was associated with cardiovascular disease incidence…”

Moon KA et al. Ann Intern Med 2013

Task4.4.RiskofcardiovascularbiomarkersinCrotone

Oxidative stress and inflammation

“The overall vascular effect of mercury include increased oxidative stress and inflammation, reduced oxidative defense, thrombosis, vascular smooth muscle dysfunction, endothelial dysfunction, dyslipidemia, and immune and mithocondrial dysfunction.”

Houston MC J Clin Hypertens 2011 “The potential association between chronic heavy metal exposure, like arsenic, lead, cadmium, mercury, and CVD has been less well defined. The mechanism through which heavy metals act …..may still remains unknown, although impaired antioxidants metabolism and oxidative stress may play a role.”

Alissa EM et al. J Toxicol 2011


Effects on cv biomarkers

11 12 ? 13-14 stiff

“…mercury is associated with increasing BP and pulse pressure … after considering the effect of fish nutrients … and other confounders.”

Valera B et al. Hypertension 2009 “The results of this study suggest a deleterious impact of mercury on BP and HRV in adults.”

Valera B et al. Environ Health 2008 “Mercury exposure was significantly associated with increased BP and IMT”

Choi Al et al. Environ Health Perspect 2009 “An association has been shown between exposure to high levels of arsenic and cardiovascular risk factors such as … subclinical carotid atherosclerosis.”

Stea F at el. Environ Sci Pollut Res Int 2014 “… the increase of IMT with age was higher than that observed in the healthy population ...”

Stea F et al. Environ Sci Pollut Res Int 2016 “… THU ameliorates cadmium-induced hypertension, vascular dysfunction , and arterial stiffness …”

Sangartit W et al. PLoS One 2014 “Acute exposure to diesel exhaust is associated with an immediate and transient increase in arterial stiffness.”

Lundback M et al. Part Fibre Toxicol 2009


Task4.4.RiskofcardiovascularbiomarkersintheCrotonearea

StudydesignandSubject

•  300subjectsaged40-70yearswithoutpreviouscardiovasculardiseasesandwithorwithoutknownconven'onalCVriskfactors.Selectedaccordingtotheresidenceatlowmiddleandhighlevelofenvironmentalpollu'on

•  CVriskscore,FraminghamorEuroScore,willbeassessedforeachsubject

•  Aplajormwillbeusedprovidinganintegratedandmul'purposecomputer-basedprogramforCVriskassessment

•  Ques'onnairesonlife-stylehabitsandpsychosocialparameterswillbeconducted

The Multiple Arsenic Pathways to Cardiovascular Disease

Cosselman K et al. Nat Rev Cardiol 2015

Vitamin K is the essential co-factor for activation of matrix Gla-protein (MGP), the natural inhibitor of tissue

calcification. Biologically inactive, desphospho-uncarboxylated MGP (dp-ucMGP) is a marker of vascular

vitamin K status

The key finding of our study was that elevated dp-ucMGP concentrations were associated with higher cardiovascular

and total mortality in stable patients with manifest vascular disease.

Mayer O et al. Atherosclerosis 2015

Heavy Metals Accumulation Affects Bone Microarchitecture

Scimeca M et al. Environ Toxicol 2016

the presence of heavy metals into bone shed new light on the comprehension of the pathogenesis of osteoporosis since these elements could play a non redundant role in the development of osteoporosis at cellular/molecular and epigenetic level

OA = pts with osteoarthritis OP = pts with osteoporosis and femoral fracture

Task4.4.RiskofcardiovascularbiomarkersintheCrotoneareaCardiovascular analysis

Caro+dfemoralPulseWaveVelocityandCentralBloodPressure:•  PulsePen(Diatecne,Italy)device•  Arteriograph(Tensiomed,Hungary)device•  PWVcf,Pc,AIx,PWVao

Localcaro+dassessement:•  Caro+dechocardiography•  Caro+dStudio(Quipu,Italy)device•  PulsePen(Diatecne,Italy)device•  IMT,CS

Characteriza+onofcaro+datherosclero+cplaques:•  Caro+dechocardiographywithDoppler•  Customdesignedtextureanalysissohware

Endothelialfunc+on:•  BrachialechocardiographywithDoppler•  FMDStudio(Quipu,Italy)device•  EndoPat(Itamar,Israel)device•  FMD,PVA,RHI



Cardiovascular analysis

Electrocardiogram(ECG)analysis:•  CustomdesigneddeviceforECGacquisi+on•  CustomdesignedsohwareforECGanalisys•  HR,QT,HRV

Biohumoraltests:•  Inflammatorymarkers•  Oxida+vestressmarkers•  NT-proBNP,tPa,CD40•  Bonehealthmarkers

-Thereisnowconsiderableevidencepoin'ngattheroleofenvironmentalpollu'onasaprominentae'ologicalfactorofCKDofmul'factorialorunknownorigin(CKDmfo/CKDu)

-Severalmechanis'candexperimentalstudieshavedefinedtheroleofions,heavymetalsandfluoridesaskeydeterminantsofearlyglomerularandtubulardamage,whichusuallyan'cipatethefrankimpairmentofrenalfunc'on,leadingtoEnd-StageKidneyDisease(ESKD)

Task4.5.Pilotstudyonrenalfunc+onimpairmentandearlykidneydamageintheCrotonearea(GiovanniTripepieDavideBolignano)

-Theincidenceandprevalenceofchronickidneydisease(CKD)haverisenconstantlyoverthelast3decades,becomingnowagrowingpublichealthproblem.

-  To assess the entity of renal function impairment and early tubular damage in a sample of subjects geographically exposed to a different gradient of environmental pollution by heavy metals

-  This will be achieved by: 1)  identifying the overall prevalence of CKDmfo/CKDu in this

population 2)  quantifying the entity of early renal damage by measuring tubular

biomarkers in individuals with apparently normal renal function.


We expect to find a significantly increased proportion of subjects presenting with CKDmfo/CKDu or altered (increased) levels of tubular biomarkers of early renal damage according to a geographical gradient of environmental pollution.

-  100adultswithnohistoryofrenaldiseasewillbeenrolled.Thesesubjectswillbesharedaccordingtotheplaceatlowmiddleandhighlevelofenvironmentalpollu'on.

-Renalfunc+onwillbees'matedasglomerularfiltra'onrate(eGFR)byusingtheCockcrol-GaultandtheMDRDformulabyassessingindividualserumcrea'ninelevels.Serumcysta+n-Cwillalsobeanalyzedandimplementedincysta'n-Cbasedformulasforimprovinges'ma'onprecisionofrenalfunc'on

-Biomarkersoftubulardamage,includingNAG,β2-MG,KIM-1,NGALandL-FABP,willbemeasuredinurinesamplesusingELISAcommercialavailablekitsandindexedbyurinarycrea'nineexcre'onlevels.


Task4.6.Dissemina+on&scien+ficnetworkingLilianaCori(IFCCNR)ThetaskwillbedevelopedintheframeworkoftheWP4ac'vi'es,incoordina'onwiththegeneralcommunica'onplan(WP1).

Threedifferentstudiesinvolvinghumansubjectsareplannedinareasdefinedatriskforenvironmentalpollu'on.

Ineachstudyàques'onnairetoinves'gatepastandcurrentrisks,informa'onreceivedconcerningenvironmentandhealth,riskpercep'on.

Task4.6.Dissemina+onandscien+ficnetworkingLilianaCori(IFCCNR)

Themainactorsdirectlyinvolved•  Par'cipa'ngsubjects(donors)•  LocalGeneralPrac''oners(LGP)•  LocalHealthAuthori'es(LHA)andEthicalCommiêes•  PublicAdministratorinHealthandEnvironmentsectorsThemainactorsindirectlyinvolved•  Scien'ficcommunity•  Localmediapeople•  Localstakeholders

Task4.6.Dissemina+onandscien+ficnetworkingLilianaCori(IFCCNR)DisseminaFonandscienFficnetworkingacFviFesA.  InternalcirculaConofinformaConB.  PreparatoryacCviCesC.  LegallybindingacCviCesD.  TrainingE.  CirculaConofresultswithintheScienCficCommunityF.  DisseminaConofresults

ERA-ENVHEALTH network – GA meeting – 16-17 June 2014

ww

w.e

ra-e

nvhe

alth

.eu

Coordination of national environment and health research programmes - Environment and Health ERA-NET Grant agreement number 219337

GeneralAssemblymee+ngBilthoven,October27,2016HostedbyRIVM


ww

w.e

ra-e

nvhe

alth

.eu


LareteERA-ENVHEALTHhafinanziatoprogemdiricercasuambienteesalute:marzo2008sonosta'finanzia'dueprogen:• RiskassesmentoftheimpactofclimatechangeonHumanhealth• ENHanCE:WellbeingeEnvironmentalchangeandrisingdoctrends:implica'onsforpublichealthgennaio2012progeôACCEPTED:Assessmentofchangingcondi'ons,environmentalpolicies,'me-ac'vi'es,exposureanddisease.


ww

w.e

ra-e

nvhe

alth

.eu


Dal2013lareteproseguea'tolovolontario(Roma,Stoccolma,Bruxelles,Bilthoven)Traleanvitàprincipalidelprogeô:•  RETEDIESPERTI

•  BRINGINGTHEGAPBETWEENSCIENCE&POLICY


ww

w.e

ra-e

nvhe

alth

.eu


COSTproject–TwinningandotherproposalNewsflashß2voltel’annoGAannualmee+ng2017àITALYSixthWHOEuropeMinisterialConferenceonEnvironmentandHealth:13-15June2017inOstrava,CzechRepublic

Jointac+vi+espromo+on

Documents

WP4. Eological Epidemiology · 2020. 9. 9. · Task 4.3. Risk of thyroid cancer in the Milazzo area (Fabrizio Bianchi e Le’zia Pi^o) In the Milazzo PS, including the municipaly