(200g) Integrated External and Internal Exposure to Chemicals: the Integra Computational Platform

Non-occupational exposure to chemical agents originates either from environmental contamination (air, water, soil, transfer through food chain), or from consumer products (food contact materials, construction materials, cosmetics, clothes, etc.) through multiple routes, namely inhalation, ingestion and dermal contact. Aggregate exposure, i.e. the quantitative exposure assessment to a single agent from all potential exposure pathways (the physical course taken by an agent as it moves from a source to a point of contact with a person) and the related exposure routes, poses specific questions that need to be addressed:

- Identification of contamination sources;

- Estimation of the different environmental media contamination including inter-media exchange;

- Exposure based on media concentrations and contact duration;

- Identification of exposure mechanisms (pathways and relevant routes);

- Internal dose in target tissue(s) based on temporal variation of exposure and contribution of exposure routes;

- Exposure distribution in relevance to the wider population or specific susceptible groups (e.g. infants);

- Identification of contribution of sources to exposure, or possible exposure patterns when biological indices of exposure (biomarkers) are measured (reverse modelling);

- Risk characterization based on worst case as well as to realistic exposure estimates; and

- Direct evaluation of available biomonitoring data to toxicological/legislative thresholds (Biomonitoring Equivalents)

Refined aggregate exposure assessment is data-intensive, requiring detailed information at every step of the source-to-dose pathway.

This requires

•           a methodology to allow calculating the aggregate exposure systematically; and

•           a computational platform to disaggregate the exposure into the different contributing sources.

Based on the needs described above, the objective of INTEGRA is to bring together all available information within a coherent methodological framework for assessing the source-to-dose continuum for the entire life cycle of substances covering an extensive chemical space. Hence, the major component of INTEGRA is a unified computational platform that integrates environmental fate, exposure and internal dose dynamically in time. In this way, the platform will be able to differentiate between biomonitoring data corresponding to steady exposure patterns as opposed to acute, one-off exposures. The platform will be largely validated using human biomonitoring data from Europe and the USA. The INTEGRA computational platform is based on the existing platform developed in the frame of the CEFIC-LRI INTERA and TAGS projects extending it to incorporate several advances:

1. Incorporation of ART (and its dermal exposure-integrated version, DART) for assessing occupational exposure, coupled to a generic PK model for linking exposure to internal dosimetry and estimating total body burden
2. Refinement of the TAGS multimedia model to account for multi-scale interactions affecting the environmental transport and fate of chemicals
3. Refinement of the TAGS/INTERA micro-environmental modeling for improved personal exposure assessment
4. Refinement of the TAGS/INTERA generic PBTK model so as to incorporate life stage changes and physiological and metabolic efficiency change over an individual’s lifetime (from conception till 80 years of age). The model will be able to cover perinatal exposure including exposure routes such as lactation, being practically a mother-fetus interaction model.
5. Inverse modeling for exposure reconstruction and HBM data assimilation.

To achieve this aim, a comprehensive work flow was followed, starting from the review of the current state of the art on aggregate exposure and internal dosimetry science (available models, data assimilation), identifying the availability of data for performing aggregate exposure and the relevant data gaps and evaluating the processes for the verification of aggregate exposure/internal dosimetry estimates. All the above methodological approaches was further enhanced by the experience obtained from the respective case studies, highlighting the needs of an integrative modelling framework needed for executing aggregate exposure and internal dosimetry calculations.

The development of the INTEGRA computational platform started with a review of the latest models and exposure assessment computational environments and databases available in the EU and the USA. This review guided us towards the development of a computational environment able to support effectively a comprehensive aggregate exposure assessment. This computational environment includes:

(a) A probabilistic or activity-based exposure scenario development module;

(b) A module for environmental fate modelling of chemicals;

(c) An exposure modelling module;

(d) An internal exposure modelling module using a PBTK/D platform to translate chemical exposure into internal dose to allow coupling exposure modelling with exposure biomarker measurements, including exposure reconstruction based on biomonitoring data; and

(e) A probabilistic exposure modelling module (using Monte Carlo simulation) to extend point estimates to population-relevant assessment based on Bayesian statistics.

Within the frame of INTEGRA, (Bis(2-ethylhexyl)phthalate) DEHP was chosen as a test compound related to consumer exposure, due to the increased scientific and regulatory interest of the recent years. The aim of the study was the identification of potential exposure scenarios (or combinations) among intended uses of DEHP. DEHP is used as plasticizer in PVC plastics. Benefits of these additions are increased flexibility, transparency, durability, and longevity of the products. Consequently, many consumer products and building materials contain DEHP (packaging materials, toys, building materials, like personal care product).  As DEHP is not chemically bound to plastics, it can leach, migrate or evaporate into indoor air, dust, foodstuff and other materials. As a result DEHP is ubiquitous in today’s environment. Due its boiling point DEHP belongs to the SVOCs (semi volatile organic compounds) category. These substances are essentially adsorbed to solids. Given the multitude of DEHP sources in the indoor environment, its usage patterns and routes of exposure, an aggregate, multi-pathway exposure approach is needed for the evaluation of systemic health effects.

The magnitude of exposure scenarios was estimated based on extensive literature review in DEHP manufacturing and processes for intended uses, residues in food and existing biomonitoring data. Indented uses of DEHP include building and construction materials, (wallpaper, flooring, sealing, wire and cable insulation), car interior (vinyl upholstery), clothing (footwear, raincoats), food packaging, children’s products (toys, grip bumpers), gloves, medical devices, PCPs and cosmetics. However, considering that the use of phthalates in toys and childcare items has been restricted in the European Union since December 1999, scenarios related to the overall cycle assessment of DEHP in building materials seems to be of excessive interest, DEHP in vinil flooring being dominant among them. .

To study the toxicokinetic behavior of DEHP, the generic PBTK model developed and incorporated into the INTEGRA platform was parameterized properly so as to capture the biokinetics of DEHP. After DEHP enters in human body, is subjected to extensive and rapid metabolism of Phase I and II reactions, and the major metabolites produced are MEHP, 5-OH-MEHP and 5-oxo-MEHP. This multi-compartmental PBTK model takes into account interactions like plasma protein and red blood cells binding, is age and gender depended and incorporates uptake from multiples routes of exposure. A major concern with regard to emerging pollutants such as DEHP is the maternal transfer through lactation. Excretion via lactation is described as an output from the mammary tissue compartment through a partitioning process between mammary tissue and milk, and milk withdrawal by suckling, as described for PCBs in rats and further adopted for humans.

The overall life cycle assessment of vinyl flooring manufacturing showed that environmental contribution to overall aggregate exposure to DEHP is negligible (either to ambient air contamination or due to food transfer). Thus, aggregate exposure to DEHP is attributed to the pathways involved due to vinyl flooring emissions. Under a typical scenario in a common residential dwelling (surface area of 270 m² and air exchange rate of 0.5hr-1) characterized by DEHP gaseous emissions of 200 μg/h (vinyl flooring and other plastic materials), the concentrations of DEHP in the gaseous, particles and dust phase are equal to 1.5 μg/m³, 21 μg/m³ and 4400 μg/g settled dust. Overall daily intake varies between 0.2 to 10 μg/kg-bw, depending on the exposure scenarios considered. The latter are age-dependent: adults are exposed mostly through inhalation and infants through non-dietary ingestion. For a common repeated aggregate exposure scenario of 2 μg/kg-bw, the DEHP internal dose in venous blood and in adipose tissue (where bioaccumulation is clearly observed) reach a quasi-state equilibrium of 0.07 and 0.4 μg/L respectively. The expected urinary concentrations of MEHP, 5-OH MEHP and 5oxo-MEHP are 3.1, 16 and 8 μg/gCr respectively. These findings are in good accordance to existing biomonitoring data from NHANES. They are also one order of magnitude below the recommended Biomonitoring Equivalent value of 660 μg/gCr for the sum of all DEHP metabolites measured in urine showing that DEHP concentrations in dwellings do not pose any significant health risk.