TIERED AGGREGATE EXPOSURE ASSESSMENT: THE CASE OF BISPHENOL A
- 1. 1 TIERED AGGREGATE EXPOSUREASSESSMENT: THE CASE OF BISPHENOL A D.A. Sarigiannis1,2, S.P. Karakitsios1,2, A. Gotti1 1Environmental Engineering Laboratory (EnvE-Lab), Department of Chemical Engineering, Aristotle University of Thessaloniki GR-54124, Thessaloniki, Greece 2Natural Resources and Renewable Energy Laboratory, CPERI, Centre for Research and Technology - Hellas, GR-57001, Thermi-Thessaloniki, Greece Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 1
- 2. 2 What is “aggregate exposure”? Aggregateexposure is defined as the quantitative exposure assessment to a single agent from all potential exposure pathways and routes Do we always need to conduct an aggregate exposure assessment? And if yes, at what level of complexity? Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 2
- 3. 3 Σάββαηο 25 Μαΐοσ2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 3 An exposure scenario is the set of conditions that describe how the substance is manufactured or used during its life-cycle and how the manufacturer or importer controls, or recommends others to control, exposures of humans and the environment Exposure scenarios shall be developed for: i) the manufacturing process and ii) for identified uses including own uses by the M/I, and uses further down 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 out exposure assessment? REACH regulation ECHA guidance documents
- 4. 4 Why we needto refine exposure assessment? Increasingbenefit→ Increasingcost→ Social Benefit Social cost Optimal cost-benefit Acceptable risk Exposure reduction → Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 4
- 5. 5 Decision Strategy forTiered Approach to Aggregated Exposure Assessment Aggregation “within” scenario Aggregation “across” scenario Define Exposure scenario (single source) Ignoring the magnitude of exposure is there a basis for aggregation across routes? Screening magnitude of exposure, is one route dominant and other routes negligible? YES SEA within Exposure scenario (Tier 1) AEA within Exposure scenario (Tier 1) SEA within Exposure scenario (Tier 2) AEA within Exposure scenario (Tier 2) NO NO TIER 0 TIER 1 TIER 2 Define Set of Relevant Exposure scenario (multiple sources and pathways) Ignoring the magnitude of exposure is there a basis for aggregation across scenarios Screening the magnitude of exposure, is one exposure scenario dominant? YES No AEA across Exposure scenario AEA across Exposure scenario (Tier 1) AEA across Exposure scenario (Tier 2) NO NO TIER 0 TIER 1 TIER 2 Develop a set for plausible scenario combinations Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 5
- 6. 6 Σάββαηο 25 Μαΐοσ2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 6 Methodological concept of the TAGS approach and computational platform Food contamination Drinking water contamination Water contamination Consumer products Indoor air Outdoor air Environmental - contamination Bioaccumulation Active smoking Oral exposure Dermal exposure Non-dietary oral exposure Direct skin application Agriculture In house building materials, objects and activities Inhalation exposure GI tract – portal vein Liver Heart Brain Muscles Skin Kidneys Adipose Bones Breast Uterus - gonads Lungs GI tract – portal vein Liver Heart Brain Muscles Skin Kidneys Adipose Bones Breast Uterus - gonads LungsArterial blood Venous blood Arterial blood Venous blood Multimedia environmental modeling Exposure modeling Internal dose modeling
- 7. 7 Σάββαηο 25 Μαΐοσ2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 7 _ _ _ _ _ _ _ _ _ _ _ _ _ _ chem gas chem gas ind out chem gas chem gas out chem PM chem gas p chem gas p PM chem dust dust d chem gas chem PM dust dC V E Q C C V dt C k C V r C V K C C m r C C V K _ _ _ _ _ _ chem PM chem PM p chem gas p PM chem PM ind out PM PM out PM dC C V r C V dt K C C Q C C V C _ _ _ _ _ _ chem dust chem dust dust d chem gas chem PM dust dC C m V r C C V dt K Gas phase mass equilibrium Particles phase mass equilibrium Dust phase mass equilibrium Multimedia/microenvironmental models
- 8. 8 Σάββαηο 25 Μαΐοσ2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής ‹#›
- 9. 9 Σάββαηο 25 Μαΐοσ2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 9 GI tract – portal vein Liver Heart Brain Muscles Skin Kidneys Adipose Bones Breast Uterus - gonads Lungs GI tract – portal vein Liver Heart Brain Muscles Skin Kidneys Adipose Bones Breast Uterus - gonads Lungs metabolite formation Arterial blood Venous blood Arterial blood Venous blood ( ) lim Pr ij i i j ij ij ij ij ij dC V Q CA CV Metab E Absorp Binding dt PBPK models serve three main purposes: - internal dose – Biologically Effective Dose (BED) assessment for refined exposure characterization (I) - the capability to derive an exposure conversion factor (ECF)/advanced exposure reconstruction for biomonitoring data assimilation (II) - the capability to derive Biomonitoring Equivalents (BEs) - link to BED for direct comparison to legislative/toxicological thresholds (III) Physiology Based PharmacoKinetic (PBPK) models are modeling tools that describe the mechanisms of absorption, distribution, metabolism and elimination (ADME) of chemicals in the body resulting from acute and/or chronic exposure regimes Internal dosimetry models
- 10. 10 Σάββαηο 25 Μαΐοσ2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 10 Multiple model runs Model to estimate exposure ( , , )EXPOSURE f A B C Parameter A Parameter B Parameter C Probability distribution based on accumulated output results Probability Exposure Model prediction Distribution of input values for parameters A, B and C Uncertainty and variability implementation
- 11. 11 Σάββαηο 25 Μαΐοσ2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 11 Testing the TAGS methodology – The Bisphenol A (BPA) case study Application Tonnes/year Information Source BPA production 1150000 PlasticsEurope (1) Figures for BPA production and polycarbonate use are estimated volumes Figures for other use categories are calculated from estimated percentage increase/decrease since 2003 figures as provided by relevant industry group. Information sources: PlasticsEurope (1) Polycarbonate / Bisphenol A Group PlasticsEurope (2) Epoxy Resins Committee Cefic (1) Unsaturated Polyester Resin Committee Cefic (2) ESPA European Stabiliser Producers Association Cefic(3) European Council for Plasticisers and Intermediates ETPA European Thermal Paper Association ECVM European Council of Vinyl Manufacturers EuPC European Plastics Converters BPA uses Polycarbonate 865000 PlasticsEurope (1) Epoxy resins 191520 PlasticsEurope (2) – can coatings 2755 PlasticsEurope (2) – ethoxylated BPA 2260 PlasticsEurope (2) Phenoplast cast resin processing 8800 Unsaturated polyesters 3600 Cefic (1) Thermal paper 1890 ETPA PVC – 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), EuPC Others 7245 Net exports 65000 PlasticsEurope (1) Total consumption 1149870
- 12. 12 Σάββαηο 25 Μαΐοσ2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 12 Testing the TAGS methodology – The Bisphenol A (BPA) case study o 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 scientific literature, RAR reports based on contamination and biomonitoring data) using worst case estimates o Aggregation across (if eligible) scenarios and within scenarios o Identification of the exposure scenarios across the several population groups (data from scientific literature, RAR reports from several regulatory bodies) o Aggregation across scenarios (if eligible……) and within scenarios at (a) external exposure (b) at internal dose levels o Comparison of internal dose derived by the several exposure scenarios to (a) EFSA TDI (50 μg/kg-bw/day) and (b) the equivalent internal dose Tier 1 Tier 2 o Environmental contamination through Emission Release Categories based on process categories (tonnage fractions) o Environmental contamination through actual releases for each process category
- 13. 13 0.00 0.20 0.40 0.60 0.80 1.00 1.20 RCR RCR - Inhalation RCR- Dermal RCR - Oral 1Considering that Infant formula is diluted with water in a proportion 1:3.5, instead of 1:7 which is the intended use 2Premature infants are fed enterically and parenterically. In the first case they are also exposed to the amount of BPA from infant formula 2 1 Tier 1 assessment (routes contribution) Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 13
- 14. 14 TIER 2a outcome (routescontribution based on average values) 0.00 0.05 0.10 0.15 0.20 0.25 0.30 RCR RCR - Inhalation RCR - Dermal RCR - Oral Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 14
- 15. 15 TIER 2a outcome (variabilityassessment) 0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70 RCR 95% Maximum Minimum 5% Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 15
- 16. 16 Mother –Fetus interaction Breastfeeding link b d V a T c T e Organ volumes (V) and blood flows (Q) were taken from the ICRP (2002) report and the obtained data were fitted to time (T) in order to exclude continuous time depended non lineal polynomial formulas in the form of: 0.75 _ _ _ _ tissue child tissue child tissue adult tissue adult V PS PS V The permeability parameters PS were scaled according to the formula: ADME processes ( ) lim Pr ij i i j ij ij ij ij ij dC V Q CA CV Metab E Absorp Binding dt _ _ _ _ _ _ uterus_M uterus M uterus M art M d uter pla placenta uterus M uterus Q C F C K C C t P _ _ _ _ _ _ _ placenta placenta d uter pla placenta uterus M placenta_B art B placenta placenta d pla amniot placenta amniot m placenta placenta amniot Q C K C C F C t P P K C C K C P _ _ _ _ _int_ _ breast breast cell breast breast excr breast dC C V PS fu C L dt K _ _ _ / _ breast excr milk milk blood breast C L Q P K _ _ _ / _ _ ow tissue tissue milk blood ow blood blood K Fl Fw P K Fl Fw _ _ _ _ _ _ _ _ _ _ placentaamniot d pla amniot placenta amniot e gut B gut B amniot e bile B liver B a amniot B amniot PQ K C C K C t P K C K C GI tract – portal vein Liver Heart Brain Muscles Skin Kidneys Adipose Bones Breast Uterus - gonads Lungs GI tract – portal vein Liver Heart Brain Muscles Skin Kidneys Adipose Bones Breast Uterus - gonads Lungs BPA - Glu & BPA – Sulf formation Placenta Placenta Arterial blood Arterial blood Venous blood GI tract – portal vein Liver Heart Brain Muscles Skin Kidneys Adipose Bones Gonads Lungs GI tract – portal vein Liver Heart Brain Muscles Skin Kidneys Adipose Bones Gonads Lungs BPA - Glu & BPA – Sulf formation Arterial blood Arterial blood Venous blood / ow tissue tissue tissue blood ow blood blood K Fl Fw P K Fl Fw The blood/tissue partition coefficients are contaminant specific and are estimated by the tissue lipids content and the octanol/water partition coefficient of the contaminant by the following formula Sarigiannis, D.A., Karakitsios, S.P. A dynamic physiology based pharmacokinetic model for assessing lifelong internal dose. In AIChE 2012, Pittsburgh, PA. Additional considerations Very strong plasma proteins binding Reduced clearance during early developmental stages (ontogeny of related enzymes) Route specific bioavailability differences The Bisphenol-A two-generation PBPK model Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 16
- 17. 17 BPA pharmacokinetic considerations - BPA-GLUde-conjugates to BPA in the placenta, increasing the actual dose during pregnancy - BPA-GLU de-conjugates to BPA in the stomach, increasing the actual dose during breast feeding, thus, the sum of BPA and BPA-GLU needs to be taken into account as BPA dose during breast feeding - Very strong plasma protein and RBC binding - Strong inter individual variability regarding glucuronidation capacity (significantly lower clearance for neonates/infants) - First-pass metabolism decisive for clearance – wide bioavailability differences are expected from routes beyond oral (up to six times higher internal dose concentrations for inhalation compared to oral) 0.144 0.152 0.160 0.167 0.175 0.183 Free plasma BPA (μg/L) Adult EFSA TDI dose (50 μg/kg-bw/d) biomonitoring equivalent Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 17
- 18. 18 TIER 2b outcome (routescontribution based on average values) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 RCR RCR - Inhalation RCR - Dermal RCR - Oral Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 18
- 19. 19 0.0 0.5 1.0 1.5 2.0 2.5 RCR 95% Maximum Minimum 5% TIER 2b outcome (variabilityassessment) Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 19
- 20. 20 The optimum combinationof human protection against exposure to chemicals from multiple sources is ensured by a well constructed and targeted Tiered approach Linking Emissions, Concentrations, Exposure and Internal dose within a “continuous” mathematical frame allows the exploration of alternative scenarios and the explicit incorporation of uncertainty and variability in the overall assessment Tier 2b assessment always gives higher 95th percentiles and maximum values compared to Tier 2, due to the incorporation of inter-individual differences in the metabolism A cost-efficient methodology for assessing aggregate exposure is needed Conclusions Tier 2b assessment is recommended when Tier 2a RCR is above 0.1 and large bioavailability differences are expected (ontogeny of the related enzymes employed for the metabolism, route depended differences). In any case, the overall actual increasing RCR factor will be less than the default UF uncertainty factor for inter-individual differences which is equal to 10, resulting to most cost-efficient risk management and identification of the actual problematic scenarios. Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 20
- 21. 21 Σάββαηο 25 Μαΐοσ2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 21 Conclusions – The role of chemical engineer GI tract – portal vein Liver Heart Brain Muscles Skin Kidneys Adipose Bones Breast Uterus - gonads Lungs GI tract – portal vein Liver Heart Brain Muscles Skin Kidneys Adipose Bones Breast Uterus - gonads Lungs metabolite formation Arterial blood Venous blood Arterial blood Venous blood GI tract – portal vein Liver Heart Brain Muscles Skin Kidneys Adipose Bones Breast Uterus - gonads Lungs GI tract – portal vein Liver Heart Brain Muscles Skin Kidneys Adipose Bones Breast Uterus - gonads Lungs metabolite formation Arterial blood Venous blood Arterial blood Venous blood Animal PBPK model (supplementary) Human PBPK model MOA ? Environmental fate Hazardassessment Exposure assessment QSARs Riskcharacterization Physico-chemical properties Food chain Consumer products Biomonitoringdata BPAD → Human BED → Human BE Predictive toxicology in vitro/alternative omics New chemical: • Uses • Structure/physico-chemical properties
- 22. 22 Thank you foryour kind attention Σάββαηο 25 Μαΐοσ 2013, Αθήνα 9ο Πανελλήνιο Επιζηημονικό Σσνέδριο Χημικής Μητανικής 22 Acknowledgments: The current study was carried out under the project B5: Realistic estimation of exposure to substances from multiple sources (TAGS), granted by the European Chemical Industry Council (CEFIC)
Editor's Notes
- #3 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.