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. ...:,2011.532. ISBN9785917540948   . , , ,,. , . . , , 蠖. . , , , ,. ,, ,, , . ʠ614.878.086+504.75.05/.06 ISBN9785917540948 ..,..,..,2011 ͠ ,2011 FederalStateScientificInstitutionFederalScientificCenterforMedical andPreventiveHealthRiskManagementTechnologies ofFederalStateServiceonConsumersRightsProtection andHumanWellBeingSurveillance G.G.Onishchenko,N.V.Zaitseva, M.A.Zemlyanova IDENTIFICATIONOFHEALTHEFFECTSCAUSED BYENVIRONMENTALCHEMICAL EXPOSURE Monography EditedbyacademicianG.G.Onishchenko Perm2011 UDC614.878.086+504.75.05/.06 Reviewer MD,ProfessorV.A.Khoroshavin(OfficeRospotrebnadzorPermregion) Onishchenko,G.G. Identificationofhealtheffectscausedbyenvironmentalchemicalexposure/G.G.On ishchenko,N.V.Zaitseva,M.A.Zemlyanova;

underred.G.G.Onishchenko.Perm,2011. 532p. ISBN9785917540948 The monograph presents of specific characteristics of the identification and as sessmentofhealtheffectsofenvironmentalchemicalexposure. resentcomplexesofbiomarkersofexposure,biomarkersofeffectandtheiras sessmentcriteriaunderconditionsofpersistentenvironmentalexposureofhumansto heavy metals, chlororganic compounds, aromatic hydrocarbons, formaldehyde and its derivatives. Inthismonograph,wedeterminethespecificityofhealtheffectscausedbyexpo suretochemicalshavingmutagenicandreprotoxicactivityinmothersandfetuses,chil drenusingdataobtainedbyepidemiologicalstudiesandthoroughlaboratoryinvestiga tions. We scientifically substantiate and present an algorithm for organizing and per forming thorough investigations of chromosome aberrations in humans exposed to environmentalchemicalmutagens. The monograph considers advanced research directions aimed at substantiating fundamentallynewbiomolecularmarkersofeffectusingthesynthesisofpostgenomic technologies,i.e.proteomics,metabolomics,metabonomics,andcurrentanalyticalap proaches. We provide theoretical substantiation and show the application of methodical approaches to establishing standards for concentrations of hazardous chemical sub stances in human biological media. The use of allowable levels of toxic compounds in human biological media, the system of markers of effect, a causeandeffect systems analysisintendedinthepracticeofpublichealthsurveillanceandcontrolofhygienicre search,expertise. The materials are intended for use by agencies and organizations of Rospotreb nadzor, research institutes working in the field of preventive medicine, environmental healthofthemediumandconsumerprotection,whileincreasingtrainingofdoctorsof differentprofiles,teachingmedicalstudents. UDC614.878.086+504.75.05/.06 ISBN9785917540948 OnishchenkoG.G.,ZaitsevaN.V.,ZemlyanovaM.A.,2011 FSIFederalScientificCenterforMedical andPreventiveHealthRiskManagementTechnologies, 2011 Š .....................................................................................................11 ......................................................................................................................13 1.⠠ 頫ࠖ............................22 1.1.Π蠠 ..........22 1.2. ........................................29 2. ..........................38 2.1................................................................38 2.1.1. ..................................................................................38 2.1.2..............40 2.1.3.Π .......................................................................................42 2.1.4.蠠 .........46 2.2.....................................................................................71 2.2.1. , ,.............71 2.2.2.젠 頠 ........................................................................................77 2.2.3. ..........................108 2.2.4...........111 2.3..............................................................121 2.3.1 ...................................................................121 2.3.2. ...........................123 2.3.3.⠠ 蠠 ..................................134 2.3.4. ࠠ ...............................................................................145 2.3.5.頠 ..........168 5 2.4.,.......................177 2.4.1 .

..................................................................177 2.4.2.頠 .........................179 2.4.3.頠 .....................................................183 2.4.4.⠠ ,蠠 , ,,.......188 2.4.5.蠠 ............................................193 2.4.6....................228 3. ............................................253 3.1.ࠠ .........................253 3.2.젠 ...............................262 3.3.젠 ⠠ ................................................................272 3.4.  ,頠 .......................................................279 4. ..........................296 4.1. ࠠ ...............................................296 4.1.1.........297 4.1.2..................................................................304 4.1.3. ........310 4.1.4. 蠠 ⠠.....................................................313 4.1.5. ⠠ ............318 6 4.1.6.堠 ................................................327 4.1.7.젠 .................................................348 4.1.8.蠠  .....................................................................................351 4.2.ࠠ ....................................................................................................355 4.3. ....................................................................................................377 4.4.ࠠ ....................................................................................................396 5. .............................................................416 5.1.頠 ࠠ ..........................................................................416 5.2. ............................................419 6.堠 ...............................................434 6.1........434 6.2., ....................................445 6.3.頠 ࠠ .....................................450 7. ..................452 7.1.⠠ ,.........452 7.2....................................................................462 7.3.,蠠 .........................................471 7.4......................475 7.5. .........................................................................481 ......................................................................................489 ...............................................................................................................524 7 TABLEOFCONTENTS ListofAbbreviations......................................................................................................11 Introduction................................................................................................................... 18 Chapter1.Identificationofhealtheffectsintheproofsystemofenvironment healthcauseeffectrelationships..............................................................22 1.1.Onanincreasingnoninfectiousdiseaseincidenceandmortality ratesandchemicalhealthriskfactorsinRussia....................................22 1.2.Biomarkersasatoolfortheassessmentofhealtheffects ofchemicalexposure.............................................................................29 Chapter2.Identificationofhealtheffectscausedbyenvironmental chemicalexposure.......................................................................................38 2.1.Chlororganiccompounds........................................................................38 2.1.1.Chlororganiccompoundsasafactorofwaterpollution................38 2.1.2.Issuesofdrinkingwatersupplyinurbanareas..............................40 2.1.3.Onthemechanismoftoxicactionofchlororganiccompounds..........42 2.1.4.Biomarkersofeffectcausedbychronicdrinkingwater exposuretochlororganiccompounds.............................................46 2.2.Heavymetals...........................................................................................71 2.2.1.Heavymetalsasfactorsofpollutionofambientair, waterinpublicwatersupplysystems,urbansoil...........................71 2.2.2.Exposuretoheavymetalsandadversehealtheffectscaused bylongterminhalationexposure...................................................77 2.2.3.Identificationofhealtheffectsofinhalationexposure toheavymetals............................................................................108 2.2.4.Biomarkersofeffectinchildrenwiththeosteopenicsyndrome......111 2.3.Aromatichydrocarbons.........................................................................121 2.3.1Aromatichydrocarbonsasfactorsofambientairpollution.........121 2.3.2.Aromatichydrocarbonsandadversehealtheffects oflongtermenvironmentalexposure.........................................123 2.3.3.Identificationofadversehealtheffectsincaseofashortterm increaseinbenzeneandphenolconcentrationsinambientair.......134 2.3.4.Identificationofhealtheffectscausedbychronicinhalation exposuretobenzeneandhomologues.........................................145 2.3.5.Biomarkersofeffectinchildrenwithsomatoformautonomic dysfunctionasapredictorofcardiovasculardiseases..................168 2.4.Formaldehydeanditsderivatives,methylalcohol...............................177 2.4.1Formaldehydeanditsderivativesasfactorsofambientair pollution.......................................................................................177 2.4.2.Adversehealtheffectscausedbylongtermenvironmental exposuretoformaldehydeanditsderivatives..............................179 2.4.3.Adversehealtheffectscausedbylongtermenvironmental exposuretomethylalcohol...........................................................183 8 2.4.4.Identificationofhealtheffectsofmultimedia,combined exposuretoformaldehydeanditsderivatives,aromatic hydrocarbons,methylalcohol,heavymetals...............................188 2.4.5.Biomarkersofeffectinchildrenwithchronic gastroduodenaldiseases...............................................................193 2.4.6.Biomarkersofeffectinchildrenwithbronchialasthma..............228 Chapter3.Cytogeneticbiomarkersofeffectunderconditionsofenvironmental exposuretochemicalmutagensandreprotoxicants................................253 3.1.Chemicalmutagensandreprotoxicantsasriskfactorsfor cytogeneticdisordersinhumans..........................................................253 3.2.Cytogeneticbiomarkersofeffectinchildreninhalationallyexposed tochemicalmutagens.

..........................................................................262 3.3.Cytogeneticbiomarkersofeffectunderconditionsofenvironmental exposureofmothersandfetusestochemicalmutagens andreprotoxicantsaccordingtoepidemiologicalandthorough laboratoryinvestigations......................................................................272 3.4.Organizationofthoroughlaboratoryinvestigationsofcytogenetic disordersinhumansexposedtochemicalshavingmutagenic andreprotoxicactivity..........................................................................279 Chapter4.Substantiationofmaximumallowableconcentrationsofhazardous chemicalsubstancesinhumanbiologicalmedia......................................296 4.1.Themethodologyforthesubstantiationofmaximumallowable concentrationsofhazardouschemicalsubstancesinhuman biologicalmediaforchronicexposure..................................................296 4.1.1.Planningandperforminginvestigations......................................297 4.1.2.Subjectsofinvestigations.............................................................304 4.1.3.Criteriaforchoosingbiologicalsubstratesforthesubstantiation ofmaximumallowableconcentrationsofchemicalsubstances.......310 4.1.4.Samplingcriteriaforinvestigationsforthesubstantiation ofmaximumallowableconcentrationsofchemicalsubstances inblood..........................................................................................313 4.1.5.Analgorithmofinvestigationsforthesubstantiation ofmaximumallowableconcentrationsofchemicalsubstances inbloodunderconditionsofchronicenvironmentalexposure........318 4.1.6.Investigatingresponsereactionsofthehumanbody toachronicimpactofabiomarkerofexposure...........................327 4.1.7.Thesubstantiationofbiomarkersofeffectunderconditions ofchronicchemicalexposure........................................................348 4.1.8.Calculationofdailymaximumallowableconcentrations ofachemicalsubstanceinbloodforchronicexposure................351 4.2.Thesubstantiationofthemaximumallowableconcentration ofchromiuminblood............................................................................355 4.3.Thesubstantiationofthemaximumallowableconcentration ofnickelinblood...................................................................................377 9 4.4.Thesubstantiationofthemaximumallowableconcentration ofmanganeseinblood..........................................................................396 Chapter5.Scientificandmethodicalsupportofassessmentsandlaboratory investigationsoftheimpactofobjectsofsurveillance onhumanhealth........................................................................................416 5.1.Generalapproachestoperforminginvestigationsoftheimpact ofobjectsofsanitationandhygienesurveillance onhumanhealth...................................................................................416 5.2.Theprogrammeofinvestigationsoftheimpactproduced byobjectsofsurveillanceonhumanhealth.........................................419 Chapter6.Thesubstantiationofbiomolecularmarkersofeffectbased onproteomicandmetabolonictechnologies...........................................434 6.1.Proteomictechnologiesandanalysisofbiomarkermolecules.............434 6.2.Thedevelopmentofmetabolomic,metabonomicanalyses inbiomolecularinvestigations..............................................................445 6.3.Theapplicationpotentialofpostgenomictechnologies andstateoftheartanalyticalapproachestoimprove theefficiencyofsubstantiatingbiomarkersofeffectcaused bychemicalriskfactors.........................................................................450 Chapter7.Possiblehealthhazardsofmanufacturingandapplication ofnanomaterialsandnanotechnologies...................................................452 7.1.Issuesconcerningpossiblehazardsofnanomaterialsandproducts manufacturedusingnanotechnologies................................................452 7.2.Generalcharacteristicsofnanoparticlesandnanomaterials................462 7.3.Characteristicsofbiologicalactivity,toxicityandbehavior ofnanoparticlesandnanomaterialsintheenvironment andhumanbiologicalmedia................................................................. 7.4.Thespecificityoftoxicityofnanomaterials...........................................475 7.5.Assessingpossiblehazardsofpowders inpowderfireextinguishers.................................................................481 References...................................................................................................................489 Appendices..................................................................................................................524 10 Ѡ Ҡ /Ԡ / Ϡ Р Ġ ՠ Πࠠ ʠࠠ ݠ Ѡ European Chemical Industry EcologyToxicology Research Centre ( ,) Ҡࠠ Ϡ Ϡ ʠʠ Ѡ ̠ נ Ѡ ʠ ˠ ݠ 3頠 4頠 11 4.頠 ̠ à ʠ Π Ġ Ѡ Ѡ Р ACGIHAmericanConferenceofGovernmentalIndustrialHygienists ( () ( )) EFSA European Food Safety Authority ( ) FDA Food & Drag Administration ( ,) HI IEC International Electrotechnical Commission ( ,) ILSIInternationalLifeSciencesInstitute( ) OECD Organization for Economic Cooperation and Development () ppbpartsperbillion() ppmpartspermillion() ZnĠZn 12 Š , , [167, 175, 194, 222, 205]. ,, , . , , .  , [185]. 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17 Introduction INTRODUCTION Issues concerning strategic and tactical approaches to human health improvementinvariouscountriesincludingRussiaarebecomingmoreur gentnowadays[167,175,194,222,205].Oneofthemostimportantpre sentday crossdisciplinary scientific issues which is both theoretical, fun damental and applied is an opportunity and of human health control by meansoftargetedmeasures.Undoubtedly,amongsuchmechanismsisen vironmentalqualitymanagement.InthePresidentsAnnualMessagetothe FederalAssemblyoftheRussianFederation,itisindicatedthattheprogress ofthesocietyrequiresincreasingeffortstoenhanceenvironmentalquality andpromotehumanhealth[185].Fromthestandpointofscience,suchef forts include not only the prediction of potential environmental problems butalsoanincreaseinthesignificanceofhealthmanagementbydevelop ing and improving the methodology for health effects assessment under adverseenvironmentalimpactsaspartofhealthriskassessment. Inthiscontext,scientificsubstantiationofapproachestotheapplica tionofhealthimprovementprinciplesinregionsthatarecharacterizedby significant environmental problems and environmentrelated health disor dersbecomesparticularlyurgent. TheefficiencyoftheactivityperformedbytheFederalServiceonCus tomersRightsProtectionandHumanWellBeingSurveillanceaimedatim plementingadministrativeandbudgetreforms,takingresultorientedcom prehensivemanagementmeasures,ensuringhumanrightsforhealthpro tection and environment is dependent on adequate scientific and methodicalsupportofthedecisionmakingsystem. Today,theactivityofinstitutionsoftheFederalServiceonCustomers RightsProtectionandHumanWellBeingSurveillanceinthefieldofhealth effects assessment in case of environmental chemical exposure gains methodological support from basic and applied research carried out by leading scientific institutions of the Russian Academy of Sciences, Federal Service on Customers Rights Protection and Human WellBeing Surveil lanceandtheirscientificschools. 18 Introduction Inordertoprovidemethodicalsupportofbasicandappliedresearch, specialists of FSI Federal Scientific Center for Medical and Preventive HealthRiskManagementTechnologies,theFederalServiceonCustomers Rights Protection and Human WellBeing Surveillance, have developed a newsystemofhighlysensitiveandselectivemethodsforthedetermination of 60 chemical compounds including heavy metals, trace elements, aro matic hydrocarbons, aliphatic aldehydes, aliphatic alcohols, chlororganic compounds,etc.intheenvironmentandhumanbiologicalmedia.Theme thodical developments are based on the employment of stateofthe artphysicochemical analytical methods, i.e. gas chromatography, high performance liquid chromatography, atomic absorption analysis, induc tively coupled plasma mass spectrometry (ICPMS), chromatographymass spectrometry. New analytical methods are developed for environmental qualityassessmenttoimprovethesensitivityandselectivityofdetermina tioninthereferenceconcentrationrangeallowingadequateevaluationof concentrationsofsomehighlytoxiccompounds. Thedevelopmentofhighlysensitivemethodsforthequantification of environmental pollutants in human biological media is closely con nectedwiththeidentificationandsubstantiationofefficientbiomarkers of effect. The performed investigations resulted in the substantiation and implementation of 40 biochemical, immunological and molecular genetic biomarkers of effect and their assessment criteria reflecting pathomorphismofenvironmentallyinducedblood,respiratory,gastroin testinal, cardiovascular and endocrine diseases, genetic and chromo some aberrations under conditions of persistent environmental expo sureofhumanstochemicalriskfactors(morethan30substances). Methods for indentifying biomarkers of immunological homeostasis, cellulartechnologiesbasedonflowcytofluorometry,determinationoflym phocyte subpopulations characterizing immune deficiency conditions (CD3+, CD3+CD4+, CD3+CD8+, CD19+, CD16+CD56+, CD3+CD25+, CD3+CD95+);

immunogenetic investigations using PCR, allergy diagnostics, determination of levels lymphocyte apoptosis, reg cells suppressing the immuneresponse(cancerproliferation,autoimmunity,reproductivehealth disorders),etc.areactivelyimplementedtoday. 19 Introduction Scientific analysis also estimates a system of causeandeffect rela tionships.Withintheanalysis,morethanfivethousandmathematicalsimu lations of allowable levels of 10 biomarkers of exposure in children's bio logicalmediawerescientificallysubstantiatedasbiomonitoringcriteriafor assessmentsandmanagementdecisionmaking.Theinvestigationsresulted intheimplementationof30criteriaforbiochemical,cytoandimmunoge netic biomarkers for biomonitoring;

10 biomarker diagnostic test systems forthemonitoringof30healthindicatorsinscreeningandthoroughlabo ratoryinvestigations. Themainadvancedresearchdirectionsarestudiesofhumangenomic, proteomic,metabolomicprofileandconsequencesofintramolecularinterac tions(interactomics)underconditionsofenvironmentalandoccupationalex posuretorisk factors.Forthis direction, highlysensitive and highly selective biomolecularmethodsbasedonhybridtechnologiesallowingidentificationof fundamentally new direct target biomarkers related to the pathological process and, therefore, indicating early stages of health disorders are devel opedandimplemented. Theresultsofapplyinghealtheffectsassessmentmethodologyunder conditionsofadverseenvironmentalexposureusingepidemiologicalanaly sis and diagnostics of unfavorable environmental conditions have been employedasbasisforthedevelopmentandestimationoftheefficiencyof medical and preventive technologies which are recommended for the im plementationasefficienthealthriskmanagementmethods.Wedeveloped andsuccessfullyappliedathreestageorganizationalandfunctionalmodel ofspecializedhealthcareprovidedtochildrenwithenvironmentallymodi fied course of respiratory (allergic bronchitis, bronchial asthma), digestive (gastroduodenal,hepatobiliarydiseases),cardiovascular,nervousandsen sory diseases (somatoform autonomic dysfunction, nervous system dys function), skin and its appendages diseases (atopic dermatitis, alopecia, etc.), musculoskeletal diseases (osteomyelitis, osteoporosis), endocrine (endemicgoiter,obesity,etc.)andotherdiseases. Based on comprehensive studies carried out using a wide range of clinicalandfunctionalmethodsaswellasmoderndiagnosticandtreatment equipment,wehavegainedsignificantexperienceinthefieldoforganizing 20 Introduction diagnostic, correction and preventive measures, and have developed ap propriatestandardsandprotocols. Along with performing research investigations, specialists of FSI FederalScientificCenterforMedicalandPreventiveHealthRiskManage ment Technologies, the Federal Service on Customers Rights Protection and Human WellBeing Surveillance, actively participate in such means of riskmanagementasthedevelopmentandimprovementoftheregulatory system. The main activities in this field are the harmonization of the na tionalstandardswithcurrentinternationalstandardsandnorms(wehave proposed28harmonizedaveragedailyandannualMACsofhazardoussub stances in ambient air);

the development of regional standards (regional averagedailystandardsforthelevelsofhazardoussubstancesin ambient air),thesubstantiationofmaximumallowableconcentrationsofhazardous substancesinhumanbiologicalsamples(blood,urine,hair,bile,etc.). Furtherimprovementofscientificandmethodicalsupportoftheac tivity of the federal sanitation and epidemiology service including that basedonsystemsmodelingandhealthriskmanagementoptimizationwill enhancethesubstantiationandefficiencyofdevelopingandimplementing national functions (services) in the sphere of customers rights protection andhumanwellbeing. TheauthorswouldliketothanktheircolleaguesatFSIFederalScientificCen ter for Medical and Preventive Health Risk Management Technologies, the Federal Service on Customers Rights Protection and Human WellBeing Surveillance: Prof. O.Yu.Ustinova,PhD,Prof.O.V.Dolgikh,PhD,Prof.I.V.May,PhD,Prof.P.Z.Shur,PhD, Prof.V.B.Alexeev,PhD,Prof.T.S.Ulanova,PhD,Dr.D.A.Kiryanovfortheirassistance inthepreparationofthismonography. 21 1. … 1 ߠߠ   Š  ՠɠ Ż 1.1.Π 蠠 ࠠ , . ( 75%) [161]. . . 58%, 42%. 仠 (11%), (9%),(9%)[68]. 22 1.1.  ࠫ. , ;

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