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TIERED AGGREGATE EXPOSURE ASSESSMENT: THE CASE OF BISPHENOL A

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A TIERED APPROACH FOR ASSESSMENT OF AGGREGATE EXPOSURE TO ENDOCRINE DISRUPTORS: THE CASE OF BISPHENOL-A …

A TIERED APPROACH FOR ASSESSMENT OF AGGREGATE EXPOSURE TO ENDOCRINE DISRUPTORS: THE CASE OF BISPHENOL-A

D.A. Sarigiannis1,2, S.P. Karakitsios1, A. Gotti1

1 Τμήμα Χημικών Μηχανικών, Αριστοτέλειο Πανεπιστήμιο Θεσσαλονίκης
2 ΕΚΕΤΑ/ΙΔΕΠ


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  • In this figure, it is graphically illustrated the methodological concept of the INTERA approach, following the source to dose continuum.Keeping in line to the source to dose assessment, we initiate by identifying the potential indoor sources of contamination, taking into account also outdoor contributions such as traffic. From emissions, we move to environmental media concentrations, thus meaning the concentrations in the indoor air from all type of sources. After estimating the concentrations, we need to calculate human exposure from all type of possible exposure pathways and routes. Thus, besides exposure from inhaling indoor air, exposure due to non-dietary oral exposure as well as dermal exposure will be taken into account.Following, we estimate internal dose. Internal dose is the actual exposure metric, and it might be referring either to the parent compound entering human body or to the product of metabolisms. Additional advantage from the implementation of internal dose arises from the possibility of use of biomarker data. Although INTERA project is focused on exposure, exposure data or internal dose data might be further used for assessing possible health risks or the margin of safety for the indoor locations under study. All the above methodological elements described above, are currently implemented within a computational platform, which is composed by individual models. In addition, the overall modelling platform derives dynamic source to dose calculations, meaning that we can track the temporal variability of the several intermediate outcomes.At this point, we need to address that the overall assessment does not always start from emissions, but the starting point might be indoor concentration or even inhalation exposure.
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    • 1. 1TIERED AGGREGATE EXPOSURE ASSESSMENT: THECASE OF BISPHENOL AD.A. Sarigiannis1,2, S.P. Karakitsios1,2, A. Gotti11Environmental Engineering Laboratory (EnvE-Lab), Department of Chemical Engineering, Aristotle University of Thessaloniki GR-54124, Thessaloniki, Greece2Natural Resources and Renewable Energy Laboratory, CPERI, Centre for Research and Technology - Hellas, GR-57001, Thermi-Thessaloniki, GreeceΣάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 1
    • 2. 2What is “aggregateexposure”?Aggregate exposure is defined as the quantitative exposure assessment to asingle agent from all potential exposure pathways and routesDo we always need to conduct an aggregate exposure assessment? And if yes, atwhat level of complexity?Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 2
    • 3. 3Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 3An exposure scenario is the set ofconditions that describe how thesubstance is manufactured or usedduring its life-cycle and how themanufacturer or importer controls, orrecommends others to control,exposures of humans and the environmentExposure scenarios shall be developed for:i) the manufacturing process andii) for identified uses including own uses by the M/I, and uses furtherdown the chemical supply chain and consumer uses,iii) life cycle stages resulting from manufacture and identified uses(article service life and waste life stages)Why we need to carry outexposure assessment?REACH regulationECHA guidance documents
    • 4. 4Why we need to refineexposure assessment?Increasingbenefit→Increasingcost→Social BenefitSocial costOptimalcost-benefitAcceptable riskExposure reduction →Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 4
    • 5. 5Decision Strategy for Tiered Approachto Aggregated Exposure AssessmentAggregation “within” scenario Aggregation “across” scenarioDefine Exposurescenario (singlesource)Ignoring themagnitude ofexposure is therea basis foraggregationacross routes?Screeningmagnitude ofexposure, is oneroute dominantand other routesnegligible?YESSEAwithinExposurescenario(Tier 1)AEAwithinExposurescenario(Tier 1)SEAwithinExposurescenario(Tier 2)AEAwithinExposurescenario(Tier 2)NONOTIER 0TIER 1TIER 2Define Set ofRelevantExposurescenario (multiplesources andpathways)Ignoring themagnitude ofexposure is therea basis foraggregationacross scenariosScreening themagnitude ofexposure, is oneexposure scenariodominant?YESNo AEAacrossExposurescenarioAEAacrossExposurescenario(Tier 1)AEAacrossExposurescenario(Tier 2)NONOTIER 0TIER 1TIER 2Develop a set forplausible scenariocombinationsΣάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 5
    • 6. 6Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 6Methodological concept of theTAGS approach and computational platformFoodcontaminationDrinking watercontaminationWatercontaminationConsumer productsIndoor airOutdoor airEnvironmental - contaminationBioaccumulationActive smokingOral exposureDermal exposureNon-dietaryoral exposureDirect skin applicationAgricultureIn house buildingmaterials, objects andactivitiesInhalation exposureGI tract – portal veinLiverHeartBrainMusclesSkinKidneysAdiposeBonesBreastUterus - gonadsLungsGI tract – portal veinLiverHeartBrainMusclesSkinKidneysAdiposeBonesBreastUterus - gonadsLungsArterialbloodVenousbloodArterialbloodVenousbloodMultimedia environmental modeling Exposure modeling Internal dose modeling
    • 7. 7Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 7__ _ _ _ ___ __ __ __chem gaschem gas ind out chem gas chem gas outchem PMchem gas p chem gasp PMchem dust dustd chem gas chem PMdustdCV E Q C C VdtCk C V r C VK CC mr C C VK_ ____ _chem PM chem PMp chem gasp PMchem PMind out PM PM outPMdC CV r C Vdt K CCQ C C VC_ _ __ __chem dust chem dust dustd chem gas chem PMdustdC C mV r C C Vdt KGas phase mass equilibriumParticles phase mass equilibriumDust phase mass equilibriumMultimedia/microenvironmentalmodels
    • 8. 8Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής ‹#›
    • 9. 9Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 9GI tract – portal veinLiverHeartBrainMusclesSkinKidneysAdiposeBonesBreastUterus - gonadsLungsGI tract – portal veinLiverHeartBrainMusclesSkinKidneysAdiposeBonesBreastUterus - gonadsLungsmetaboliteformationArterialbloodVenousbloodArterialbloodVenousblood( ) lim Priji i j ij ij ij ij ijdCV Q CA CV Metab E Absorp BindingdtPBPK models serve three main purposes:- internal dose – Biologically Effective Dose (BED) assessmentfor refined exposure characterization (I)- the capability to derive an exposure conversion factor(ECF)/advanced exposure reconstruction for biomonitoringdata assimilation (II)- the capability to derive Biomonitoring Equivalents (BEs) - linkto BED for direct comparison to legislative/toxicologicalthresholds (III)Physiology Based PharmacoKinetic (PBPK) models aremodeling tools that describe the mechanisms ofabsorption, distribution, metabolism and elimination (ADME)of chemicals in the body resulting from acute and/or chronicexposure regimesInternal dosimetry models
    • 10. 10Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 10Multiplemodel runs Model to estimate exposure( , , )EXPOSURE f A B CParameter A Parameter B Parameter CProbabilitydistribution based onaccumulated outputresultsProbabilityExposureModel predictionDistribution of input values for parameters A, B and CUncertainty and variabilityimplementation
    • 11. 11Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 11Testing the TAGS methodology –The Bisphenol A (BPA) case studyApplication Tonnes/year Information SourceBPA production 1150000 PlasticsEurope (1) Figures for BPA production and polycarbonate use areestimated volumesFigures for other use categories are calculated fromestimated percentage increase/decrease since 2003figures as provided by relevant industry group.Information sources:PlasticsEurope (1) Polycarbonate / Bisphenol A GroupPlasticsEurope (2) Epoxy Resins CommitteeCefic (1) Unsaturated Polyester Resin CommitteeCefic (2) ESPA European Stabiliser Producers AssociationCefic(3) European Council for Plasticisers and IntermediatesETPA European Thermal Paper AssociationECVM European Council of Vinyl ManufacturersEuPC European Plastics ConvertersBPA usesPolycarbonate 865000 PlasticsEurope (1)Epoxy resins 191520 PlasticsEurope (2)– can coatings 2755 PlasticsEurope (2)– ethoxylated BPA 2260 PlasticsEurope (2)Phenoplast cast resin processing 8800Unsaturated polyesters 3600 Cefic (1)Thermal paper 1890 ETPAPVC – polymerisation 0 ECVM- stabiliser packages 450 ECVM, Cefic (2), (3), EuPC- phthalate plasticisers 900 ECVM, Cefic (2), (3), EuPC- direct stabilisation 450 ECVM, Cefic (2), (3), EuPCOthers 7245Net exports 65000 PlasticsEurope (1)Total consumption 1149870
    • 12. 12Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 12Testing the TAGS methodology –The Bisphenol A (BPA) case studyo Comparison of aggregated dose to EFSA TDI (50 μg/kg-bw/day)o Identification of the exposure scenarios across the several population groups (data from scientificliterature, RAR reports based on contamination and biomonitoring data) using worst case estimateso Aggregation across (if eligible) scenarios and within scenarioso Identification of the exposure scenarios across the several population groups (data from scientificliterature, RAR reports from several regulatory bodies)o Aggregation across scenarios (if eligible……) and within scenarios at (a) external exposure (b) at internaldose levelso Comparison of internal dose derived by the several exposure scenarios to (a) EFSA TDI (50 μg/kg-bw/day)and (b) the equivalent internal doseTier 1Tier 2o Environmental contamination through Emission Release Categories based on process categories (tonnagefractions)o Environmental contamination through actual releases for each process category
    • 13. 130.000.200.400.600.801.001.20RCRRCR - InhalationRCR - DermalRCR - Oral1Considering that Infant formula is diluted with water in a proportion 1:3.5, instead of 1:7 which is the intended use2Premature infants are fed enterically and parenterically. In the first case they are also exposed to the amount of BPA from infant formula21Tier 1 assessment(routes contribution)Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 13
    • 14. 14TIER 2a outcome(routes contribution based onaverage values)0.000.050.100.150.200.250.30RCRRCR - InhalationRCR - DermalRCR - OralΣάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 14
    • 15. 15TIER 2a outcome(variability assessment)0.000.100.200.300.400.500.600.70RCR95%MaximumMinimum5%Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 15
    • 16. 16Mother –Fetus interactionBreast feeding linkb dV a T c T eOrgan volumes (V) and blood flows (Q) were takenfrom the ICRP (2002) report and the obtained datawere fitted to time (T) in order to excludecontinuous time depended non lineal polynomialformulas in the form of:0.75__ __tissue childtissue child tissue adulttissue adultVPS PSVThe permeability parameters PS were scaledaccording to the formula:ADME processes( ) lim Priji i j ij ij ij ij ijdCV Q CA CV Metab E Absorp Bindingdt__ _ _ _ _uterus_M uterus Muterus M art M d uter pla placenta uterus MuterusQ CF C K C Ct P_ _ _ __ _ _placenta placentad uter pla placenta uterus M placenta_B art Bplacentaplacentad pla amniot placenta amniot m placenta placentaamniotQ CK C C F Ct PPK C C K CP_ __ _ _int__breast breastcell breast breast excrbreastdC CV PS fu C Ldt K__ _ /_breastexcr milk milk bloodbreastCL Q PK_ __ /_ _ow tissue tissuemilk bloodow blood bloodK Fl FwPK Fl Fw_ _ _ _ __ _ _ _ _placentaamniotd pla amniot placenta amniot e gut B gut Bamniote bile B liver B a amniot B amniotPQK C C K Ct PK C K CGI tract – portal veinLiverHeartBrainMusclesSkinKidneysAdiposeBonesBreastUterus - gonadsLungsGI tract – portal veinLiverHeartBrainMusclesSkinKidneysAdiposeBonesBreastUterus - gonadsLungsBPA - Glu &BPA – SulfformationPlacentaPlacentaArterial blood Arterial blood Venous bloodGI tract – portal veinLiverHeartBrainMusclesSkinKidneysAdiposeBonesGonadsLungsGI tract – portal veinLiverHeartBrainMusclesSkinKidneysAdiposeBonesGonadsLungsBPA - Glu &BPA – SulfformationArterial blood Arterial blood Venous blood/ow tissue tissuetissue bloodow blood bloodK Fl FwPK Fl FwThe blood/tissue partition coefficients arecontaminant specific and are estimated by thetissue lipids content and the octanol/water partitioncoefficient of the contaminant by the followingformulaSarigiannis, D.A., Karakitsios, S.P. A dynamic physiology basedpharmacokinetic model for assessing lifelong internal dose. In AIChE2012, Pittsburgh, PA.Additional considerations Very strong plasma proteins binding Reduced clearance during earlydevelopmental stages (ontogeny of relatedenzymes) Route specific bioavailability differencesThe Bisphenol-Atwo-generation PBPK modelΣάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 16
    • 17. 17BPA pharmacokineticconsiderations- BPA-GLU de-conjugates to BPA in the placenta, increasingthe actual dose during pregnancy- BPA-GLU de-conjugates to BPA in the stomach, increasingthe actual dose during breast feeding, thus, the sum of BPAand BPA-GLU needs to be taken into account as BPA doseduring breast feeding- Very strong plasma protein and RBC binding- Strong inter individual variability regarding glucuronidationcapacity (significantly lower clearance for neonates/infants)- First-pass metabolism decisive for clearance – widebioavailability differences are expected from routes beyondoral (up to six times higher internal dose concentrations forinhalation compared to oral)0.144 0.152 0.160 0.167 0.175 0.183Free plasma BPA (μg/L)Adult EFSA TDI dose(50 μg/kg-bw/d) biomonitoringequivalentΣάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 17
    • 18. 18TIER 2b outcome(routes contribution based onaverage values)0.00.10.20.30.40.50.60.70.80.91.0RCRRCR - InhalationRCR - DermalRCR - OralΣάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 18
    • 19. 190.00.51.01.52.02.5RCR95%MaximumMinimum5%TIER 2b outcome(variability assessment)Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 19
    • 20. 20The optimum combination of human protection against exposure to chemicals from multiplesources is ensured by a well constructed and targeted Tiered approachLinking Emissions, Concentrations, Exposure and Internal dose within a “continuous”mathematical frame allows the exploration of alternative scenarios and the explicit incorporationof uncertainty and variability in the overall assessmentTier 2b assessment always gives higher 95th percentiles and maximum values compared to Tier2, due to the incorporation of inter-individual differences in the metabolismA cost-efficient methodology for assessing aggregate exposure is neededConclusionsTier 2b assessment is recommended when Tier 2a RCR is above 0.1 and large bioavailabilitydifferences are expected (ontogeny of the related enzymes employed for the metabolism, routedepended differences). In any case, the overall actual increasing RCR factor will be less than thedefault UF uncertainty factor for inter-individual differences which is equal to 10, resulting tomost cost-efficient risk management and identification of the actual problematic scenarios.Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 20
    • 21. 21Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 21Conclusions –The role of chemical engineerGI tract – portal veinLiverHeartBrainMusclesSkinKidneysAdiposeBonesBreastUterus - gonadsLungsGI tract – portal veinLiverHeartBrainMusclesSkinKidneysAdiposeBonesBreastUterus - gonadsLungsmetaboliteformationArterialbloodVenousbloodArterialbloodVenousbloodGI tract – portal veinLiverHeartBrainMusclesSkinKidneysAdiposeBonesBreastUterus - gonadsLungsGI tract – portal veinLiverHeartBrainMusclesSkinKidneysAdiposeBonesBreastUterus - gonadsLungsmetaboliteformationArterialbloodVenousbloodArterialbloodVenousbloodAnimal PBPK model(supplementary) Human PBPK modelMOA ?Environmental fateHazardassessmentExposure assessmentQSARsRiskcharacterizationPhysico-chemicalpropertiesFoodchainConsumerproductsBiomonitoringdataBPAD → Human BED → Human BEPredictivetoxicologyin vitro/alternativeomicsNew chemical:• Uses• Structure/physico-chemicalproperties
    • 22. 22Thank you for your kindattentionΣάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 22Acknowledgments:The current study was carried out under the project B5: Realistic estimationof exposure to substances from multiple sources (TAGS), granted by theEuropean Chemical Industry Council (CEFIC)