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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.
  • As described in the previous slide, the first compartment of our methodology is the link of emission sources to indoor concentrations.Firstly, to estimate emissions, we use the data regarding the use of consumer products (e.g. air fresheners) / existing materials and the specific release rate for the contaminants under consideration. After constructing the emission inventory from the indoor sources, we need to estimate indoor concentrations. For estimating concentrations, we take into account indoor/outdoor air interaction, as well as the parameters such as room volumes and air exchange rates, that they present a wide variability between the several geographic locations. For the purposes of the INTERA, we decided that a dual box model is sufficient. In general, box models assume that the concentration within the examined indoor location is uniform, which is a valid assumption for residential locations, since there are no strong emission sources, neither strong ventilation systems (as in occupational settings). Thus, we avoided the use of CFD models which they demand very high computational cost, without to derive any significant refinement in the exposure assessment process of the current application.
  • As discussed earlier, beside inhalation, oral non-dietary and dermal exposure will be taken also into account. For dermal exposure, the plausible exposure scenarios constituteinstant and repeated application (e.g. an insect repellent), rubbing off (e.g. scanning dust from a desk surface with the forearm) and migration (e.g. contact with a cloth). It is important to clarify, that this is a 2 stage calculation; firstly we need to estimate what is called potential dose. The potential dose represents the dose that is in contact with the biological barriers of the human body (e.g., digestive tract, lungs and skin), while the absorbed dose constitutes the quantity of the compound that effectively passes across them and reaches the systemic blood circulation and internal organs. Similarly for non-dietary ingestion, the employed exposure mechanisms soil and dust ingestion, hand to mouth behavior and object to mouth behavior, the later being more important for children.
  • The next step after estimating exposure is the calculation of internal dose, meaning the concentration of the compound of interest within human tissues. To accomplish this task, we use Physiology Based Pharmacokinetic models. Physiologically based pharmacokinetic models (PBPK) are modelling tools which describe the mechanisms of absorption, distribution, metabolism and elimination (ADME) of chemicals in the body resulting from acute and/or chronic exposure regimes. They are independent structural models, comprising the tissues and organs of the body with each perfused by, and connected via, the blood circulatory system. In PBPK models the organism is frequently represented as a network of tissue compartments (e.g., liver, fat, slowly perfused tissues, and richly perfused tissues) interconnected by systemic circulation.
  • The importance for the use of internal dose models arise from the need to realistically describe the actual internal exposure variability. In this figure we can see that by monitoring only concentrations or exposure we can’t fully capture the dynamics of actual exposure, as in the case of benzene presented herein. Since benzene toxicity arise from its toxic metabolites, we need to be able to capture that time hysteresis between external and internal exposure.In addition, aggregation of multiple routes and pathways does not occur by just summing up the concentrations; contribution of each exposure route to the systemic circulation is estimated in a biologically plausible manner. In this way, differences in the absorption rate and in the overall bioavailability are taken into account and unnecessary overestimations occurring by summing up the externaldoses are avoided.
  • Dehp

    1. 1. SOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 IS INDOOR EXPOSURE TO DEHP A HEALTH RISK? D.A. Sarigiannis S.P. Karakitsios A. Gotti 1AristotleUniversity of Thessaloniki, Department of Chemical Engineering, Environmental Engineering Laboratory, Thessaloniki, 54124, Greece; 2Centre for Research and Technology Hellas (CE.R.T.H.), Thessaloniki, 57001,Greece
    2. 2. RationaleSOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 DEHP is used as plasticizer in PVC plastics, including personal care products, packaging materials, toys, building materials,…. As DEHP is not chemically bound to PVC it can leach, migrate or evaporate into indoor air, dust, foodstuff, other materials,… Consequently, DEHP is ubiquitous in our environment systemic health effects local health effects (inhalation) Threshold Threshold value Health effect – ref value local ref systemic local effects ? effect Reproductive 50 µg/kg bw/day effects (CSTEE, (20 µg/kg bw/day)* inhalation; 1998;ECB, (Bornehag et DEHP Developmental (25 µg/kg increased asthma ? 2008;EFSA, al., 2004)) effects bw/day)** risk in children 2005a)
    3. 3. Methodological concept of the approachSOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 GI tract – portal vein GI tract – portal vein Liver Liver Heart Heart SOURCES Brain Brain Muscles Muscles Skin Skin Kidneys Kidneys Adipose Adipose Bones Bones Breast Breast Uterus - gonads Uterus - gonads Arterial Lungs Venous Arterial Lungs Venous blood blood blood blood
    4. 4. ConcentrationsSOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 Gas phase mass equilibrium dCchem _ gas V Echem _ gas Qind _ out Cchem _ gas Cchem _ gas _ out V dt Echem_gas : chemical emission rate Cchem _ PM k Cchem _ gas V rp Cchem _ gas V Qint_out : Indoor/outdoor air exchange rate K p CPM K : chemical decay coefficient Cchem _ dust m_ dust rd Cchem _ gas Cchem _ PM V KP : gas/particles partition coefficient K _ dust Kdust : gas/dust partitioning coefficient Particles phase mass equilibrium rP, rd : partitioning kinetics dCchem _ PM Cchem _ PM V : location volume V rp Cchem _ gas V dt K p CPM CPM : PM concentration indoors Qind _ out CPM CPM _ out Cchem _ PM V CPM_out : PM concentration outdoors CPM CDEHP_gas : chemical concentration in gas phase Dust phase mass equilibrium CDEHP_PM : chemical concentration in PM phase dCchem _ dust Cchem _ dust m_ dust CDEHP_dusts : chemical concentration in dust phase V rd Cchem _ gas Cchem _ PM V dt K _ dust m_dust : mass of dust in the location
    5. 5. SOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013
    6. 6. Internal exposure (PBPK) modelingSOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 dCij Vi Qi (CAj CVij ) Metabij E limij Absorpij Pr Bindingij dt GI tract – portal vein GI tract – portal vein GI tract – portal vein GI tract – portal vein Liver Liver Liver Liver Heart Heart Heart Heart Brain Brain Brain Brain Muscles Muscles Muscles Muscles Skin Skin Skin Skin Kidneys Kidneys Kidneys Kidneys Adipose Adipose Adipose Adipose Bones Bones Bones Bones Breast Breast Breast Breast Uterus - gonads Uterus - gonads Uterus - gonads Uterus - gonads Arterial blood Lungs Venous blood Arterial blood Lungs Venous blood Arterial blood Lungs Venous blood Arterial blood Lungs Venous blood DEHP MEHP 5-OH MEHP 5- oxo - MEHP
    7. 7. The vinyl floor caseSOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 DEHP is emitted from electronic equipment and vinyl flooring. Lets assume a typical scenario of a common residential dwelling (size of 270 m2 and air exchange rate equal to 0.5) characterized by total DEHP gaseous emissions of 200 μg/h (vinyl flooring and other plastic equipment) Exposure pathways considered:  Exposure through inhalation: - gas phase - particles phase  Exposure through skin: - Rubbing of dust (0.01 g/day)  Exposure through ingestion - Dust ingestion through hand to mouth behavior Female Female Male Infants Toddlers Children Teens Male Teens Adults Adults House dust ingestion (g/day) 0.05 0.05 0.01 0.001 0.001 0.001 0.001
    8. 8. DEHP concentration in different mediaSOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 6 4000 3500 Gas/partcles phase concentration (μg/m3) 5 Dust phase concentration (μg/g dust) 3000 Concentration in EU indoor locations 4 Gas + particles (μg/m3) Dust (μg/g_dust) Study 2500 0.13 626 Weschler et al, 2008 3 3214 Clausen et al. 2003 2000 970 Butte et al., 2008 604 Abb et al., 2009 1500 2 540 Langer et al. 2010 1000 1 gas particles 500 dust 0 0 1 49 97 145 193 241 289 337 385 433 481 Time (h)
    9. 9. DEHP internal exposureSOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 0.07 5.0 Venous - mothers milk concentration (μg/L) 0.06 Adipose tissue concentration (μg/L) 4.0 0.05 0.04 3.0 Adipose tissue 0.03 2.0 Venous blood Milk 0.02 1.0 0.01 0.0 0 1 49 97 145 193 241 289 337 385 433 481 Time (h)
    10. 10. DEHP and major metabolites internal exposureSOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 0.9 0.8 Venous blood concentration (μg/L) 0.7 0.6 0.5 MEHP 0.4 DEHP 5-OH-MEHP 0.3 5-oxo-MEHP 0.2 0.1 0 1 49 97 145 193 241 289 337 385 433 481 Time (h)
    11. 11. Major metabolites urine concentrationsSOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 8 7 Urine concentration (μg/gCr) 6 5 4 3 2 5-OH-MEHP 1 MEHP 5-oxo-MEHP 0 1 49 97 145 193 241 289 337 385 433 481 Time (h)
    12. 12. DEHP daily uptake per routeSOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 1.4 Adults 1.2 Kids Uptake (μg/kg_bw/d) 1.0 0.8 0.6 0.4 0.2 0.0 Inhalation Oral Skin Route
    13. 13. ConclusionsSOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 • Linking Emissions, Concentrations, Exposure and Internal dose within a “continuous” mathematical frame allows us to couple environmental and biological processes efficiently • Capturing jointly toxicokinetics, toxicodynamics and exposure dynamics allowed us to incorporate mechanistic knowledge in exposure assessment and thus improve the validity and relevance of the risk characterization outcome • It also allowed the identification of exposure scenarios that could pose health risk • Integrated external and internal exposure assessment for DEHP highlights the fact that the current health risk from human exposure to DEHP indoors is very low. • Sum of urinary DEHP metabolites one order of magnitude lower than the BE (660 ug/g creatinine) • Daily uptake is higher for children than for adults. • Oral and skin uptake are important routes for children, but negligible for adults.
    14. 14. SOT’s 52nd Annual Meeting San Antonio, Texas March 10th –14th 2013 Thank you for your kind attention A new perspective to environment-related processes