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Ecotoxicology and Human Environmental Health

In vitro inhalation bioaccessibility of phthalate esters and alternative plasticisers present in indoor dust using artificial lung fluids Katerina Kademoglou, Georgios Giovanoulis, Anna Palm-Cousins, Juan Antonio Padilla-Sánchez, Jörgen Magnér, Cynthia A. de Wit, and Christopher D. Collins Environ. Sci. Technol. Lett., Just Accepted Manuscript • DOI: 10.1021/acs.estlett.8b00113 • Publication Date (Web): 20 Apr 2018 Downloaded from http://pubs.acs.org on April 23, 2018

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Environmental Science & Technology Letters

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In Vitro Inhalation Bioaccessibility Of Phthalate Esters And Alternative Plasticisers Present In

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Indoor Dust Using Artificial Lung Fluids

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Katerina Kademoglou a, b*, Georgios Giovanoulis c , Anna Palm-Cousins c, Juan Antonio

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Padilla-Sanchez d, Jörgen Magnér c, Cynthia A. de Wit e, Christopher D. Collins a**

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a

Soil Research Centre, University of Reading, Reading, RG6 6DW, UK

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b

RECETOX, Masaryk University, Kamenice 753/5, pavilion A29, 62500 Brno, Czech

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Republic

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c

IVL Swedish Environmental Research Institute, SE-100 31, Stockholm, Sweden

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d

Domain of Infection Control and Environmental Health, Norwegian Institute of Public

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Health (NIPH), P.O. Box 4404, Nydalen, 0403 Oslo, Norway

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e

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University, SE-106 91, Stockholm, Sweden

Department of Environmental Science and Analytical Chemistry (ACES), Stockholm

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* - Corresponding authors: Katerina Kademoglou: [email protected] &

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[email protected] ; **Christopher D. Collins: [email protected]

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1 ACS Paragon Plus Environment


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Abstract

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Phthalate esters (PEs) are used as plasticisers in consumer products. Their low migration

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stability has resulted into the classification of PEs as major indoor contaminants. Due to PE’s

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ubiquitous character and adverse health effects to humans and especially children, non-

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phthalate alternative plasticisers have been introduced into the market. This is the first study

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on in vitro inhalation bioaccessibility of PEs (e.g. DMP, DEP, DEHP) and alternative

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plasticisers (e.g. DEHT and DINCH) via indoor dust to assess inhalation as an alternative

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route of exposure. Two artificial lung fluids were used, mimicking two distinctively different

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pulmonary environments: 1) artificial lysosomal fluid (ALF, pH = 4.5) representing the

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intracellular acidic lung fluid inhaled particles contact after phagocytosis by alveolar

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macrophages and 2) Gamble’s solution (pH = 7.4), the extracellular healthy fluid for deep

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lung deposition of dust. DMP and DEP were highly bioaccessible (> 75 %), whereas highly

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hydrophobic compounds such as DEHP, DINCH and DEHT were < 5 % bioaccessible via

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both artificial lung fluids. Our findings show that the inhalation bioaccessibility of PEs is

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primarily governed by their hydrophobicity and water solubility. Further research is necessary

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towards unified and biologically relevant inhalation bioaccessibility tests, employed within

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the human risk assessment for volatile and semi-volatile organic pollutants.

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Keywords: bioaccessibility, inhalation, phthalate esters, indoor dust, artificial lysosomal fluid,

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DINCH

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Introduction

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Phthalate esters (PEs) are plasticiser additives enhancing durability, elasticity and flexibility

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in consumer and polymeric products 1. Low molecular weight (LMW) PEs such as dimethyl

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phthalate (DMP) and diethyl phthalate (DEP) are added as synthetic stabilisers to industrial

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solvents and personal care products and used as colouring or fragrance additives 2,3. High MW

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(HMW) PEs such as di-(2-ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP)

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are primarily used in polyvinyl chloride (PVC) products including floor polishing, wall

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coatings, children’s toys, medical products and food packaging 4–6. Their low migration

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stability and vapour pressure influence PE release to the indoor environment, resulting in their

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classification as major indoor organic contaminants 7,8. Consequently, high levels of PEs have

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been found in indoor dust worldwide 5,9–13. Human exposure to PEs in the indoor environment

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is of growing concern due to the potentially adverse health effects of PEs such as DEHP, di-n-

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butyl phthalate (DnBP) and di-iso-butyl phthalate (DiBP) in adults. These include disrupted

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endocrine and thyroid homeostasis, reduced fertility and reproduction 3,14,15. The US and the

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EU have partly restricted the use of DiBP, DnBP, and DEHP in toys and childcare products

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16,17

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(i.e. alternative plasticisers) in consumer products in the early 2000s, such as di-isononyl-

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cyclohexane-1,2-dicarboxylate (DINCH; DEHP and DiNP replacement) and bis(2-ethylhexyl)

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terephthalate (DEHT), a structural isomer of DEHP 18–21. However, due to their dominant use

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and rapid substitution, considerable levels of DINCH and DEHT have been reported in the

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indoor environment, raising concerns about their potential effects on humans 22–25.

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Prenatal and childhood exposure to PEs via indoor dust and PVC materials have been linked

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with chronic respiratory problems such as allergies, asthma, bronchial hyperactivity and

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inflammation, as well as neurodevelopmental disorders manifesting in adulthood 26–31.

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Franken et al. (2017) reported the high occurrence of asthma in Belgian teenagers (especially

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girls) associated with high DEHP and DnBP exposure 32. DEHT and DINCH administration

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to rodents revealed no signs of DEHP-like toxicity 33–35. However, DINCH in utero exposure

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has been associated with signs of impaired liver metabolism and premature testicular aging

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such as decreased testosterone secretion, physical changes in seminal glands and testicular

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atrophy in rats and their young offspring 36. Thus, the debate regarding the safety of

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alternative plasticisers is ongoing, especially the effects of early-life exposure during critical

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developmental stages.

. Such actions paved the way for the introduction of less toxic, non-phthalate substitutes



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Physiologically-based extraction tests (PBET) have been employed to assess the oral

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bioaccessibility (i.e. uptake) of PEs via dust ingestion 37–39. PE gut bioaccessibility decreased

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as logKow increased; LMW PEs such as DMP and DEP were found to be 32 % and 26 %

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bioaccessible, respectively, while DEHP was only 10 % bioaccessible via the gut 38. In a

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comparative study between different dust size fractions and oral bioaccessibility, Wang et al.

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(2013) reported the highest gut uptake for LMW PEs in < 63 µm size fraction, compared to

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particles > 63 µm39. Dermal absorption of DEP and DnBP directly from air has been proposed

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by Weschler et al.40. Since no studies exist regarding the inhalation bioaccessibility of organic

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pollutants, this calls for their development 41.

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This is the first study we are aware of quantifying the inhalation bioaccessibility of PEs

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and alternative plasticisers employing two artificial lung fluids, mimicking two distinctively

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different interstitial lung conditions. Artificial pulmonary fluids have been previously

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employed in inhalation bioaccessibility studies of water-soluble metals and nanoparticles 42–46.

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Artificial lysosomal fluid (ALF, pH=4.5) represents the acidic (i.e. inflammatory) intracellular

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lung environment inhaled particles come into contact with after phagocytosis by alveolar and

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interstitial macrophages. Gamble’s solution (GMB, pH=7.4) is a surrogate fluid for deep lung

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deposition of particles within the interstitial (i.e. extracellular) environment under healthy

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conditions 43,46,47. The objectives of our study are to evaluate the in vitro inhalation

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bioaccessibility of PEs, DINCH and DEHT present in indoor dust by employing two different

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artificial pulmonary fluids, i.e. Gamble’s solution and ALF representing the healthy and

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inflammatory status of the tracheobronchial environment, respectively, and to assess possible

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factors influencing inhalation bioaccessibility of PEs, DINCH and DEHT.

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Materials and Methods

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Sampling and dust particle properties

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Details on the A-TEAM cohort sampling in Oslo, Norway, are given elsewhere48. Pre-existing

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vacuum cleaner dust samples (N=10) were passed through a methanol-washed, metallic sieve

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(< 63 µm) with respect to the inhalable aerodynamic particle cut off convention according to

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the International Organization for Standardization (ISO)49. Specific surface area and dust

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particle size were determined by laser diffraction spectroscopy (Mastersizer 3000, Malvern

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Ltd., UK), while total carbon (TC %) and nitrogen (TN %) contents were determined by


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Thermo Flash 2000 and organic matter content (OMC %) was determined by loss-on-ignition

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(LOI) as described elsewhere 50.

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Dust extraction and clean-up

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Details of the indoor dust extraction have been published previously 24,51. Briefly, 100 mg of

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dust (< 63 µm) were extracted with 10 mL acetone: n-hexane (1:1 v/v) using microwave-

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assisted extraction (MAE) under controlled pressure and temperature. Prior to extraction, 400

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ng ISTD mix prepared in n-hexane (DMP-d4, DnBP-d4 and DEHP-d4) were spiked into all

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samples. The dust extracts were concentrated to 0.5 ml under a gentle nitrogen (N2) stream

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which was filtered through a glass Pasteur pipette tip containing charcoal in order to eliminate

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any traces of external contamination and the solvent was exchanged to n-hexane. This

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solution was loaded onto an ENVI-Florisil cartridge (500 mg / 3 mL, Biotage Isolute,

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Uppsala, Sweden) and 9 mL of n-hexane were added as a cleaning elution step. During the

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second elution, all target analytes were eluted using 9 mL acetone: n-hexane (1:1) and the

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resulting eluate was concentrated to 1 ml with a gentle, charcoal-filtered N2 flow at room

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temperature. Finally, all extracts were transferred to GC vials and biphenyl (300 ng) was

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added as an injection recovery standard prior to GC-MS/MS analysis (Figure S1). Details

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about instrumental analysis are available in SI.

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Lung fluid extraction

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All lung fluid extractions were conducted in duplicate. Both fluids were freshly prepared 24 h

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before the initiation of each test in ultra-pure H2O (18.2 Ω) as described elsewhere43 (Table

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S3), pH-adjusted using HCl 1 M and NaOH 1 M, stored at 4°C and checked for background

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phthalate contamination prior to use. According to Boisa et al. (2014), the experimental

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volume for simulated lung fluid extraction tests should be equal to 20 mL, given the

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pulmonary fluid volume capacity of healthy non-smoking adults (0.3 mL / kg; 70 kg body

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mass)42. To avoid particle agglomeration due to dust overloading43, 0.2 g of indoor dust (< 63

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µm) were combined in glass test tubes with 20 mL of each artificial lung fluid separately,

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maintaining 1:100 solid-to-liquid (S/L) ratio between the incubated matrix and the pulmonary

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fluid 52 . All sample test tubes were covered with oven-baked aluminium foil to avoid

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background phthalate contamination, followed by continuous incubation inside a thermostatic

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chamber (60 rpm; 37 °C) for 96 h , a time point relevant to the human alveolar clearance

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capacity 45,53. After 96 h, the samples were separated by centrifugation (1500 rpm; 3 min) and

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the lung supernatants were subjected to liquid-liquid extraction (LLE) using 7 mL Hexane: 5 ACS Paragon Plus Environment


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MTBE 3:1 twice, while ultrasonication-assisted extraction was employed for the residual

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dusts twice for 10 min using 7 mL of Acetone: Hexane 1:1. Prior to all extractions, all

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samples were spiked with 400 ng ISTD mix prepared in n-hexane (DMP-d4, DnBP-d4 and

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DEHP-d4). To avoid any water residue and remove any gel-like emulsion formed during LLE,

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a sufficient amount of oven-baked Na2SO4 (powder) was added to all extracts, followed by 1

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min vortexing and organic phase collection after centrifugation (1500 rpm; 3 min). All

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extracts were combined, solvent was exchanged to n-hexane and concentrated to 1 ml under a

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gentle, charcoal-filtered N2 stream at room temperature. The residual dust extracts were

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cleaned-up using ENVI-Florisil SPE cartridges (500 mg / 3 mL, Biotage Isolute, Uppsala,

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Sweden), similarly to the dust extraction procedure described above. Briefly, the residual dust

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extracts were loaded onto the Florisil® columns, the first hexane eluate was discarded, while

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the second eluate was collected using 9 mL of MTBE. The resulting eluate was concentrated

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to 1 ml under a charcoal-filtered N2 flow at room temperature. Finally, all extracts were

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transferred to oven-baked GC vials and biphenyl (300 ng) was added as an injection recovery

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standard prior to GC-MS/MS analysis (Figure S2).

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Data analysis

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Inhalation bioaccessibility (IBAF) was determined using Eq. 1, where mass phthalate (lung

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supernatant) is the phthalate mass (ng) determined in the lung supernatant of the in vitro

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pulmonary system and mass phthalate (dust residual) is the mass (ng) determined in the dust

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residual collected after the 96 h-incubation of the in vitro pulmonary system which is

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considered as the non-bioaccessible fraction. IBAF%

ℎ ℎ = % 100 Eq. 1! ℎ ℎ lung supernatant! + ℎ ℎ # $#! 153 154

GraphPad Prism® version 7.00 for Windows, (GraphPad Software, La Jolla CA, USA) was

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used for statistical analysis. Prior to statistical analysis, all data were checked for normality

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using the Shapiro–Wilk test and not all data passed the normality test. All data were arc-sine

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transformed, as this mathematical transformation is necessary for statistical analysis of results

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set in percentages in order to equalise variances among treatments 54. Ordinary two-way

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ANOVA (Uncorrected Fisher’s test, p 4). This is

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similar to gut bioaccessibility, which is partly governed by a pollutant’s physico-chemical

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properties including MW and log Kow 57,58. DiBP bioaccessibility was 15.5 % and 12 %, in

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Gamble’s solution and ALF, respectively, whereas DnBP and HMW PEs were 10 % and < 5

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% bioaccessible in both fluids, including DEHP and its alternatives, DEHT and DINCH

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(Figure 1). Compared to lung uptake, HMW PEs were more bioaccessible via the gut 38,39,

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strongly influenced by their hydrophobic character and low water solubility, alongside the

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lipid-rich gut environment which facilitates higher desorption rates 6,23,38. However, no

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consensus exists regarding pulmonary fluid composition for inhalation bioaccessibility studies

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of organics. Employing modified lung fluid formulations with the addition of biologically

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relevant pulmonary surfactants such as albumin, mucin and dipalmitoylphosphatidylcholine

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(DPCC) have been proposed 41,42,59. The case of DPCC makes biological sense and it should

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be thus systematically investigated along with other test parameters including diffusion

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mechanisms, S/L ratio, incubation duration and dust particle diameter 41,60, aiming towards a

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unified testing approach similar to gut bioaccessibility57.


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Method performance using SRM 2585

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The selected inhalation bioaccessibility parameters were assessed using SRM 2585, a well-

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characterised and homogenous dust sample. IBAF > 75 % was found for LMW PEs, while

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highly hydrophobic DEHP and DiNP were the least bioaccessible (IBAF < 5 %) (Table 1),

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similar to the Norwegian house dust IBAF results. The SRM 2585 batch purchased in our

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study was prepared using a pool of U.S. dust samples collected during mid to late 1990s.

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Thus, DINCH and DPHP were not detected, since they were introduced in the market after

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2000 18,61.

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In this study we proposed an in vitro method to assess the inhalation bioaccessibility of PEs

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and alternatives plasticisers via indoor dust. Low MW PEs such as DMP and DEP were found

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to be highly bioaccessible in both pulmonary fluids (> 75 %), regardless of the fluid’s pH and

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composition. Unlike DEP, which presented similar bioaccessibility in both fluids, DMP was

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more readily absorbed through ALF than Gamble’s solution. HMW PEs, along with DEHP

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alternatives, DEHT and DINCH, did not exceed 5 % bioaccessibility. Hence, inhalation may

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be a considerable route of exposure for LMW and less hydrophobic PEs. Our results show

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that inhalation bioaccessibility of organic pollutants is primarily governed by hydrophobicity

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and water solubility (Table S10). Therefore, the pulmonary uptake for compounds with

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comparable physico-chemical properties, e.g. LMW polycyclic aromatic hydrocarbons

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(PAHs) or organophosphates (PFRs) should be considered. Future research should therefore

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aim towards unified and biologically relevant in vitro inhalation bioaccessibility tests for

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organics related to lung dust deposition and diffusion mechanisms, human lung function and

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inflammation alongside animal studies, necessary for the in vitro method validation.

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Conflict of interest The authors declare no conflict of interest.

Supporting information

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Detailed information is available regarding chemicals and reagents, instrumental analysis,

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sample preparation for dust extraction, composition of pulmonary fluids, method accuracy,

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method limits of detections and concentrations of target analytes in dust.



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Acknowledgments

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The research leading to these results has received funding from the European Union Seventh

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Framework Programme FP7/2007–2013 under grant agreement n° 316665 (A-TEAM

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project). Katerina Kademoglou and Georgios Giovanoulis would like to thank Dr. Yolanda

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Hedberg from KTH (Sweden) for her help and useful guidance during the experimental

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design. We acknowledge Dr. Eleni Papadopoulou from NIPH (Norway) for her help during

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the ATEAM sampling campaign. This research was supported by the Ministry of Education,

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Youth and Sports of the Czech Republic (LO1214) and the RECETOX Research

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Infrastructure (LM2015051 and CZ.02.1.01/0.0/0.0/16_013/0001761). Katerina Kademoglou

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would like to thank Dr. Shovonal Roy (UoR) and Prof Adrian C. Williams (UoR) for their

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useful comments on the manuscript and acknowledge the financial support from the

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Mediterranean Scientific Association of Environmental Protection (MESAEP) during her PhD

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studies by means of the Emmanuel Lahaniatis award for young scientists.

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Figures and tables

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Figure 1 – In vitro inhalation bioaccessibility (IBAF%) of phthalate esters and alternative plasticisers present in indoor dust samples (N=10), using two different simulated lung fluids, namely Gamble’s solution (GMB) and artificial lysosomal fluid (ALF). Statistically significant differences shown here (*; p

1 In Vitro Inhalation Bioaccessibility Of Phthalate ... - ACS Publications

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