Gaëlle Raffy
email: gaelle.raffy@ehesp.fr

Fabien Mercier

Philippe Glorennec

Corinne Mandin

Barbara Le Bot

Oral bioaccessibility of semi-volatile organic compounds (SVOCs) in settled dust: a review of measurement methods, data and influencing factors

Keywords: Human exposure, Indoor environment, Dust ingestion, Bioavailability, Pollutant

 Importance of considering bioaccessibility when assessing the exposure dose to SVOCs in dust  Need for simplification and harmonization of measurement methods  Main method parameters are inclusion of sorptive sink, bile concentration and fluid to dust ratio  Need for in-vivo validation of bioaccessibility data

Introduction

The last decade has seen raising awareness about the presence of semi-volatile organic compounds (SVOCs) in indoor environments [START_REF] Weschler | Semivolatile organic compounds in indoor environments[END_REF]. SVOCs are defined by their volatility (boiling point between 240 °C and 400 °C) and vapor pressure (from 1/10 14 to 1/10 4 atm) [START_REF] Weschler | Semivolatile organic compounds in indoor environments[END_REF][START_REF] Who | Indoor air quality: Organic pollutants[END_REF]. They include many different chemical families such as phthalates, polycyclic aromatic hydrocarbons (PAHs), polychlorobiphenyls (PCBs), polybromodiphenylethers (PBDEs), organophosphorus flame retardants (OPFRs), organophosphorus (OPs) and organochlorine (OCs) pesticides, pyrethroids, perfluorinated compounds (PFCs), synthetic musks, chlorinated paraffins (CPs), phenols, parabens, etc. [START_REF] Weschler | Semivolatile organic compounds in indoor environments[END_REF][START_REF] Bonvallot | Health ranking of ingested semi-volatile organic compounds in house dust: an application to France[END_REF]. Their presence in indoor environment is a matter of concern because many of these SVOCs are suspected of being toxic and/or endocrine disruptors, with effects on the reproductive tract development, the thyroid function, the nervous system and the development of metabolic diseases such as obesity and diabetes [START_REF] Bonvallot | Health ranking of ingested semi-volatile organic compounds in house dust: an application to France[END_REF][START_REF] Li | Exposure to environmental endocrine disruptors and human health[END_REF][START_REF] Giulivo | Human exposure to endocrine pilot study[END_REF][6]. In indoor environments, human exposure to SVOCs occurs through different pathways including air inhalation, ingestion of settled dust and dermal contact with surfaces, indoor air and settled dust. Dust ingestion is considered a major pathway of human exposure to several of these SVOCs including PBDEs [7-9], phthalates [9,10], OPFRs [11] and tetrabromobisphenol A (TBBP-A) [12]. Children are particularly concerned because their specific behavior, i.e., crawling on the floor, hand-to-mouth and object-to-mouth contacts, may contribute to a higher ingestion of dust. Moreover, they are more vulnerable to the harmful effects of pollutants because major systems of their organism are still immature [13].

To assess this risk, the SVOC intake by dust ingestion can be calculated according to the following equation [14]: The SVOC content in indoor settled dust has already been described in the scientific literature at an international level [15][16][17][START_REF] Wang | Levels of polychlorinated biphenyls in settled house dust from urban dwellings in China and their neurodevelopmental effects on preschool-aged children[END_REF][START_REF] Kademoglou | Legacy and alternative flame retardants in Norwegian and UK indoor environment: Implications of human exposure via dust ingestion[END_REF][START_REF] Ma | Spatiotemporal analysis and human exposure assessment on polycyclic aromatic hydrocarbons in indoor air, settled house dust, and diet: A review[END_REF]. However, for human exposure assessment, analyses have to be performed on the dust particle size that is adherent to human's hands and likely to be ingested.

Previous studies have shown that <100 µm are relevant to human exposure [START_REF] Cao | Mechanisms influencing the BFR distribution patterns in office dust and implications for estimating human exposure[END_REF][START_REF] Cao | Particle size: a missing factor in risk assessment of human exposure to toxic chemicals in settled indoor dust[END_REF]. Along with the dust particle size, exposure assessment studies must also consider the bioavailability of chemicals. The evaluation of the human risks associated with SVOC in dust often considers 100% of the SVOC content as the exposure concentration, potentially leading to an overestimated risk. Actually, only a fraction may effectively be absorbed by the body, and this fraction may differ between dust and the matrix that was used in the toxicity tests used for health risk assessment. To refine the exposure dose and establish the link between dust contamination and human exposure via dust ingestion, the oral bioavailability of a SVOC, defined as the fraction of a contaminant reaching the digestive system and absorbed into the systemic circulation should be known. However bioavailability is difficult to assess, mainly because of ethical reasons, as it needs to be measured in vivo. In this context, the notion of bioaccessibility was then considered. Oral bioaccessibility was defined in 2011 as the fraction of a compound that is soluble in the gastrointestinal tract and is therefore available for absorption [START_REF] Rostami | Assessment of Persistent Organic Pollutant (POP) Bioavailability and Bioaccessibility for Human Health Exposure Assessment: A Critical Review[END_REF]. It was further defined in 2015 as "the maximal amount of contaminant released from the test matrix in a synthetic gastrointestinal system" [START_REF] Collins | Towards a unified approach for the determination of the bioaccessibility of organic pollutants[END_REF] thus implying two additional conditions to the original definition: (i) bioaccessibility is assessed by synthetic systems and (ii) the bioaccessibility should be measured in a conservative way ("maximal amount"). Oral bioaccessibility is equal or greater than bioavailability as it does not include losses due to the passage across the intestinal wall and It is therefore a conservative measurement of bioavailability that can be measured with ethically friendly synthetic systems. For substances where the major pathway of exposure is dust ingestion, taking oral bioaccessibility into account is important to refine risk assessment and to improve epidemiological studies. Actually the inclusion of oral bioaccessibility allows a better characterization of the participants' exposure to the SVOCs contained in the dust they are exposed to, which is beneficial for the establishment of epidemiological associations between environmental exposures and health outcomes.

The present work is a review of the existing literature related to the in vitro assessment of SVOC oral bioaccessibility in indoor dust. It includes (i) the measurement methods used, (ii) the existing bioaccessibility data, which cover 96 substances from 6 chemical families, i.e.

organophosphorus and brominated flame retardants, PCBs, phthalates, pesticides, and HAPs, and (iii) a discussion on the factors influencing oral bioaccessibility.

Materials and Methods

A review of the literature was performed using the key words « dust » and « *accessib*» in the title and abstract fields of Science Direct, Pub Med and Web of Science search engines. All years were included. To ensure that no hit was missed, no mention of chemical substance was made in the search because SVOCs cover many individual substances and families of substances, which in addition can be spelt in different ways. The search then resulted in 142, 95, and 156 hits for Science Direct, Pub Med and Web of Science respectively and included many articles related to the bioaccessibility of inorganic elements which has been more studied so far [START_REF] Turner | Oral bioaccessibility of trace metals in household dust: A review[END_REF].

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After all irrelevant hits were removed, 20 relevant articles, published from 2011 to automn 2017, were considered for the purpose of this review.

Results & Discussion

Measurements methods

The ingestion and digestion of food through the human digestive tract follow four main processes (Figure 1): (i) in the mouth, thanks to mastication, food particles are reduced in size and mixed with saliva to produce a bolus; (ii) in the stomach, this bolus is subject to the gastric process which mainly consists in acidic and enzymatic hydrolysis; (iii) in the small intestine further enzymatic hydrolysis and absorption of the nutrients take place; and (iv) in the colon, occurs the large intestine process, which is mainly fermentation and water removal [START_REF] Boland | Human digestion -a processing perspective[END_REF].

In vitro methods have been developed for simulating human digestion in three different fields, related to the ingestion of food, soil and dust, respectively. They can be highly sophisticated, like the gastrointestinal dynamic digestion systems, which include stomach and intestinal compartments, equipped with temperature, pH and redox sensors, variable speed pumps to control the flow of meal and digestive secretions and the possibility to work under anaerobic conditions, within a software controlled environment [START_REF] Ménard | Validation of a new in vitro dynamic system to simulate infant digestion[END_REF][START_REF] Minekus | Huis in 't Veld, A multicompartmental dynamic computer-controlled model simulating the stomach and small Intestine[END_REF]. A 5-step multi-chamber reactor was developed to simulate the human intestinal microbial ecosystem in the small and large intestines [START_REF] Molly | Development of a 5-step multi-chamber reactor as a simulation of the human intestinal microbial ecosystem[END_REF]. On line coupling was implemented between a physiologically relevant bioaccessibility system and inductively coupled plasma spectrometry [START_REF] Herrera | On-line coupling of physiologically relevant bioaccessibility testing to inductively coupled plasma spectrometry: Proof of concept for fast assessment of gastrointestinal bioaccessibility of micronutrients from soybeans[END_REF]. A bioaccessibility test was developed by the BioAccessibility Research Group of Europe (BARGE) for the measurement of metals and metalloids in soils and is known as the Unified BARGE Method (UBM) [START_REF] Denys | In Vivo Validation of the Unified BARGE Method to Assess the Bioaccessibility of Arsenic, Antimony, Cadmium, and Lead in Soils[END_REF]. Less method [START_REF] Cui | Advances in in vitro methods to evaluate oral bioaccessibility of PAHs and PBDEs in environmental matrices[END_REF]. Three standards were documented for soils: the German guideline DIN 19738 [START_REF]Soil quality -Bioaccessibility of organic and inorganic pollutants from contaminated soil material[END_REF],

the ISO 17402 [START_REF] Nf En | Soil quality: Requirements and guidance for the selection and application of methods for the assessment of bioavailability of contaminants in soil and soil materials[END_REF], and the ISO 16751 [START_REF]Soil quality -Environmental availability of non-polar compounds -Determination of the potential bioavailable fraction and the non-bioavailable fraction using a strong adsorbent or complexing agent[END_REF].

Among these existing methods, three were used for measuring SVOC bioaccessibility in dust: the PBET, the FOREhST and the DIN 19738. These methods often come from the experiences gained on soil [START_REF] Wragg | An inter-laboratory trial of the unified BARGE bioaccessibility method for arsenic, cadmium and lead in soil[END_REF][START_REF] Dean | Approaches to assess the oral bioaccessibility of persistent organic pollutants: A critical review[END_REF] and replicate part or all of the four processes involved in human digestion through in vitro simulations.

Mouth in vitro process. The simulation of the action of saliva is implemented in the BARGE protocol [START_REF] Barge | UBM procedure for the measurement of inorganic contaminant bioaccessibility from solid matrices[END_REF], the German standard DIN 19738 [START_REF] Ertl | Bioaccessibility of pesticides and polychlorinated biphenyls from house dust: in-vitro methods and human exposure assessment[END_REF][START_REF] Starr | Using paired soil and house dust samples in an in vitro assay to assess the post ingestion bioaccessibility of sorbed fipronil[END_REF], and the FOREhST [START_REF] Quintana | Invitro estimation of bioaccessibility of chlorinated organophosphate flame retardants in indoor dust by fasting and fed physiologically relevant extraction tests[END_REF]. It consists in extracting the dust in a pH neutral aqueous solution containing salts (NaCl, NaSCN or KSCN, Na 2 SO 4 , NaHCO 3 , NaOH, KCl, KH 2 PO 4 or NaH 2 PO 4 , CaCl 2 ), proteins (mucin, α-amylase), urea and uric acid, and food (whole milk, skimmed milk and denatured skimmed milk [START_REF] Ertl | Bioaccessibility of pesticides and polychlorinated biphenyls from house dust: in-vitro methods and human exposure assessment[END_REF] or organic creamy infant food, baby milk powder, and sunflower oil [START_REF] Quintana | Invitro estimation of bioaccessibility of chlorinated organophosphate flame retardants in indoor dust by fasting and fed physiologically relevant extraction tests[END_REF]). The solution is stirred for up to 30 minutes at 37 °C. This first process is sometimes considered of limited interest because the extraction time, which should not exceed 2 minutes to be physiological relevant, and the neutral pH do not have much impact on the dissolution of SVOCs, compared to the following processes [START_REF] Collins | Towards a unified approach for the determination of the bioaccessibility of organic pollutants[END_REF][START_REF] Dean | Approaches to assess the oral bioaccessibility of persistent organic pollutants: A critical review[END_REF].

Stomach in vitro process. The gastric process is present in all models reported in the literature.

The dust is introduced in an acidic (pH < 2.5) synthetic gastric fluid containing pepsin, the [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF][START_REF] Kang | Risk Assessment of Human Exposure to Bioaccessible Phthalate Esters via Indoor Dust around the Pearl River Delta[END_REF][START_REF] Wang | Risk assessment of bioaccessible organochlorine pesticides exposure via indoor and outdoor dust[END_REF][START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF][START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF], or mucin (protein responsible for the gel texture) [START_REF] Yu | Optimization of an in vitro method to measure the bioaccessibility of polybrominated diphenyl ethers in dust using response surface methodology[END_REF]. At this stage, food components (starch, yeast extract, casein, pectin, xylan, arabinogalactan, etc.) can be added to simulate the fed state [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF][START_REF] Kademoglou | Bioaccessibility of PBDEs present in indoor dust: A novel dialysis membrane method with a Tenax TA® absorption sink[END_REF]. The solutions are then stirred for 1 to 2 hours at 37 °C.

Small intestine in vitro process is also present in all the models reported in the literature. In physiological terms, this process is of a particular importance for bioaccessibility because of the long incubation time and because it is where the absorption through the intestinal wall takes place. In this process, the dust is brought into contact with the intestinal juice at a neutral pH (between 6.5 and 8), either following neutralization of the pH of the preceding gastric solution or after centrifugation, recovery of the dust and introduction in a freshly prepared intestinal solution. In most models, neutralization of the solution is obtained via the addition of bicarbonate, as bicarbonate is the ion secreted in the human body to neutralize gastric secretion in the lumen [START_REF] Mudie | Physiological Parameters for Oral Delivery and in Vitro Testing[END_REF]. Intestinal solutions always include pancreatin (a mixture of digestive enzymes produced by the pancreas) and bile salts (produced by the liver, intended for lipid digestion and promoting absorption in the small intestine). Various other salts are also added, as well as urea and albumin [START_REF] Barge | UBM procedure for the measurement of inorganic contaminant bioaccessibility from solid matrices[END_REF] and lipase [START_REF] Barge | UBM procedure for the measurement of inorganic contaminant bioaccessibility from solid matrices[END_REF][START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF]. Again at this stage, dietary components can be added [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF][START_REF] Kademoglou | Bioaccessibility of PBDEs present in indoor dust: A novel dialysis membrane method with a Tenax TA® absorption sink[END_REF]. Some authors also add an adsorbent to capture the compounds as they are released in the digestive fluids, thus mimicking the passage of compounds through the intestinal wall [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF][START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF][START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF]. The solutions are stirred 4 to 7 hours at 37 °C.

After incubation, dust is separated from the digestive fluid by centrifugation. However, if foam

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particles, originating from product weathering, are present in dust, separation is achieved by filtering the digestive fluid through glass wool [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF].

Because of the presence of bile, which promotes the solubilization of hydrophobic organic compounds through the formation of micelles, the fraction of intestinal bioaccessibility is often greater than the fraction of gastric bioaccessibility [START_REF] Kang | In vitro digestion and absorption of BDE-28, -47, -99 and -153 in indooor dust and its implication in risk assessemnt[END_REF][START_REF] Pan | Comparison of in vitro digestion model with in vivo relative bioavailability of BDE-209 in indoor dust and combination of in vitro digestion/Caco-2 cell model to estimate the daily intake of BDE-209 via indoor dust[END_REF]. This was experimentally demonstrated, as shown in Figure 2, where the distribution of bioaccessible SVOC is on average 35% in the gastric fluid and 65 % in the small intestine fluid.

Colon in vitro process. The inclusion of the large intestine process (colon extended PBET) was reported by Abdallah et al. [START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF], Fang and Stapleton [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF], and Kademoglou et al. [START_REF] Kademoglou | Bioaccessibility of PBDEs present in indoor dust: A novel dialysis membrane method with a Tenax TA® absorption sink[END_REF]. Indeed, according to Tilston et al. [START_REF] Tilston | Colon Extended Physiologically Based Extraction Test (CE-PBET) Increases Bioaccessibility of Soil-Bound PAH[END_REF], there could be absorption at the level of the colon, along with water removal. The inclusion of this process is above all a conservative approach because the prolonged incubation time and the presence of carbohydrates in the colon could increase the bioaccessibility of persistent organic pollutants [START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF], although this was not always confirmed [START_REF] Zhang | Bioaccessibility of PAHs in Fuel Soot Assessed by an in Vitro Digestive Model with Absorptive Sink: Effect of Food Ingestion[END_REF]. The synthetic solution, at a nearly neutral pH, contains salts, mucin, cysteine hydrochloride (a reducing agent used to promote anaerobic conditions [START_REF] Tilston | Colon Extended Physiologically Based Extraction Test (CE-PBET) Increases Bioaccessibility of Soil-Bound PAH[END_REF]), bile salts, haemin and food components. The solutions are kept at 37 °C for 8 to 16 hours. For flame retardants, the additional bioaccessibility provided by the colon incubation ranged from 11 to 32% of the total bioaccessibility [START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF], as shown in Figure 3.

Microbial activity. The SHIME (Simulator of Human Intestinal Microbial Ecosystem) simulates

the GI tract form stomach to colon including enzymatic and microbial activities and has mostly been used for studying the interactions between food and microbiota [START_REF] Guerra | Relevance and challenges in modeling human gastric and small intestinal digestion[END_REF]. Siciliano et al. used both the SHIME and a sterile in vitro digestion method to assess the bioaccessibility of PAHs in

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They concluded that the release of PAHs in digestive fluids was not influenced by microbial activities [START_REF] Siciliano | Polycyclic aromatic hydrocarbons are enriched but bioaccessibility reduced in brownfield soils adhered to human hands[END_REF], which can explain why SHIME was never further used with dust samples.

Physiological parameters. Authors always seek to produce physiologically relevant methods.

The temperature of the human body, 37 °C, is respected by all authors. The pH values, close to 6.5 for saliva, close to neutrality in the small intestine and colon compartments, and acidic (pH <2.5) in the gastric medium are physiologically relevant [START_REF] Guerra | Relevance and challenges in modeling human gastric and small intestinal digestion[END_REF]. Authors used relevant incubation times, except for the mouth compartment with long incubation times of up to 30 minutes [START_REF] Ertl | Bioaccessibility of pesticides and polychlorinated biphenyls from house dust: in-vitro methods and human exposure assessment[END_REF][START_REF] Starr | Using paired soil and house dust samples in an in vitro assay to assess the post ingestion bioaccessibility of sorbed fipronil[END_REF]. All authors also apply shaking to their system to simulate the peristaltic movements of human digestion.

Specific human populations. Models used for the analysis of dust aim towards physiological

relevance, but they did not consider specific conditions relative to some human populations. In the field of food studies, however, where more sophisticated in vitro digestion models are applied, specific gastro-intestinal conditions of the infants and elderly can be simulated [START_REF] Levi | Extending in vitro digestion models to specific human populations: Perspectives, practical tools and bio-relevant information[END_REF]. For infants' gastric conditions, a limited stomach capacity, a relatively high gradient pH (3.2-6.5), and a reduced pepsin secretion are considered, as well as a lower bile salt concentration in the intestinal phase [START_REF] Levi | Extending in vitro digestion models to specific human populations: Perspectives, practical tools and bio-relevant information[END_REF]. These specific models could be applied for the evaluation of SVOC bioaccessibility in studies where the population of interest is mainly children.

A step towards the in vitro evaluation of bioavailability. Bioaccessible SVOCs are released in the GI tract while bioavailable SVOCs are those who reached the systemic circulation (Figure 1).

Bioaccessible SVOCs become bioavailable once they have crossed the intestinal wall and undergone presystemic metabolisms (both intestinal and hepatic) [58]. A step towards the evaluation of bioavailability can be reached in vitro using Caco-2 cells to mimic the transport They also emphasized the need to evaluate the toxicity of the investigated substance towards Caco-2 cells, before using them, because if the behavior of the Caco-2 cells is compromised, the transmembrane passage could be affected [START_REF] Cui | Advances in in vitro methods to evaluate oral bioaccessibility of PAHs and PBDEs in environmental matrices[END_REF]. Kang et al. attempted to measure the uptake by Caco-2 cells of BDE-28, -47, -99 and -153, respectively, and reported absorption rates of 30%, 26%, 41% and 59% respectively [START_REF] Kang | In vitro digestion and absorption of BDE-28, -47, -99 and -153 in indooor dust and its implication in risk assessemnt[END_REF]. Likewise, Pan et al. measured an absorption rate of 42%

for BDE-209 [START_REF] Pan | Comparison of in vitro digestion model with in vivo relative bioavailability of BDE-209 in indoor dust and combination of in vitro digestion/Caco-2 cell model to estimate the daily intake of BDE-209 via indoor dust[END_REF]. In both studies, authors only considered the cell uptake, ignoring the transfer between cells. They may therefore have underestimated the overall transfer across the Caco-2 cells monolayer. Still, using Caco-2 cells can help for a better assessment of a SVOC human internal dose. The relative bioavailability of PCBs (101, 138, 153 and 180) in soil was assessed by measuring concentrations found in swines' adipose tissue: values were all greater than 45%, independently of the investigated soil or PCB congener [START_REF] Delannoy | Impact of soil characteristics on relative bioavailability of NDL-PCBs in piglets[END_REF]. For PCBs 52 and 118 in soil, the relative bioavailability measured in rats' blood was greater than 87% and could not be linked to their bioaccessibility measured by PBET, which produced underestimated results (40% to 80%) [START_REF] Pu | Bioavailability of 2,3',4,4',5pentachlorobiphenyl (PCB118) and 2,2',5,5'-tetrachlorobiphenyl (PCB52) from soils using a rat model and a physiologically based extraction test[END_REF].

Method

Li et al. estimated the soil bioavailability of DDT and its metabolites (DDTr) by measuring their concentration in mice's adipose tissues after soil ingestion: values varied from 18% to 65% depending on the type of soil. They compared it to DDTr bioaccessibility using a PBET model with and without Tenax® TA as a sorptive sink. When adding Tenax® TA in the model, DDTr bioaccessibility increased up to 22 fold, and could then be linked by a linear regression to bioavailability (slope = 1.2, r² = 0.62, p=0.065) [START_REF] Li | Predicting the Relative Bioavailability of DDT and Its Metabolites in Historically Contaminated Soils Using a Tenax-Improved Physiologically Based Extraction Test (TI-PBET)[END_REF].

An in vivo/in vitro validation study was also undertaken for PFOA in food, and showed a good correlation (r=0.76, p<0.01) between PFOA bioaccessibility, assessed with the UBM method, and its bioavailability measured in rats' liver [START_REF] Li | In vivo bioavailability and in vitro bioaccessibility of perfluorooctanoic acid (PFOA) in food matrices: Correlation analysis and method development[END_REF].

Lack of data for bioavailability validation in dust studies are not only due to ethical concerns, but also practical difficulties. Actually, it can be difficult to have enough dust with a sufficient SVOC content so that consequent bioavailable concentrations measured after ingestion are meaningful. However, before bioaccessibility values can be relied upon in risk assessment and epidemiological studies, they must be validated versus in vivo studies and so more of these studies should be performed taking into account the metabolism and the fate of the substance

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in the body. Moreover, due caution should be applied when choosing the animal species for in vivo validation: Duan et al. showed that swine's and rat's bioavailability measurements of benzo[a]pyrene in soils were correlated, but bioavailability was underestimated by about a quarter in the rat study, which should be taken into account [START_REF] Duan | Comparison of oral bioavailability of benzo[a]pyrene in soils using rat and swine and the implications for human health risk assessment[END_REF]. While rats are more often considered for in vivo measurements, swines are recommended because their digestive system is comparable to that of children in terms of body size, gut physiology and genetic profile, and because they produce more conservative bioavailability estimates.

For optimal dust bioaccessibility measurements, advantage should be taken from the experience and feedback from validation studies performed in the field of outdoor soils. In addition, efforts should be made towards method simplification, so they can be applied on numerous samples with a minimal cost and be eventually used in epidemiological studies to establish refined associations between the presence of SVOCs indoor and health outcome in populations.

SVOC bioaccessibilities in dust reported in the literature

Bioaccessibility data related to SVOC in dust reported in the literature were compiled and are shown as percentages in Figure 4. Data comparison was limited by the differences in measurement methods, the nature of the dust (settled dust or dust collected from air conditioning filter) and its particle size (sieving fraction from 20-60 µm to < 250 µm). Some of these limitations (inclusion of food or adsorbent in the measurement method) are visually shown in Figure 4. tetrabromobisphenol A (TBBP-A) and hexabromocyclododecanes (HBCDs) [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF][START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF][START_REF] García-Alcega | Does the source migration pathway of HBCDs to household dust influence their bio-accessibility?[END_REF]). For PBDEs, valued ranged from 11 to 71% (median 37%) with the lowest bioaccessibilities observed for BDE-209 (11-63%, median 19%). For alternative BFRs, bioaccessibilities ranged from 12% to 94% (median 37%). Highest bioaccessibilities were observed for alternative BFRs, as determined by Abdallah, when using Tenax® TA in their CE-PBET model (72-94%) [START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF]. Data are reported in Table 1 and graphically displayed in Figure 4.

Brominated flame retardants (BFRs). The bioaccessibility of

Organophosphorus flame retardants. OPFR bioaccessibilities were only recently reported with 22 results published in 3 articles in 2014 [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF], 2015 [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF], and 2016 [START_REF] Quintana | Invitro estimation of bioaccessibility of chlorinated organophosphate flame retardants in indoor dust by fasting and fed physiologically relevant extraction tests[END_REF] for tris(2-chloroethyl) phosphate (TCEP), tris(1-chloro-2-propyl) phosphate (TCPP), tris(1,3-dichloro-2-propyl) phosphate (TDCPP), and triphenyl phosphate (TPHP). Reported bioaccessibilities, shown in Table 2 and in Figure 4, ranged from 8% to 103%, depending on the compound and the measurement method.

PCBs. Fifty-two values documenting the bioaccessibility of PCBs were published in three articles in 2012 [START_REF] Ertl | Bioaccessibility of pesticides and polychlorinated biphenyls from house dust: in-vitro methods and human exposure assessment[END_REF] and 2013 [START_REF] Wang | Exposure assessment and distribution of polychlorinated biphenyls (PCBs) contained in indoor and outdoor dusts and the impacts of particle size and bioaccessibility[END_REF][START_REF] Kang | Bioaccessibility of polychlorinated biphenyls in workplace dust and its implication for risk assessment[END_REF]. Overall, values ranged from 3% to 92% (median 22%), depending on the congener and the measurement method used (data shown in Table 3 and Figure 4). In the presence of food, valued ranged from 41 to 92% (median 74%, n=5) [START_REF] Ertl | Bioaccessibility of pesticides and polychlorinated biphenyls from house dust: in-vitro methods and human exposure assessment[END_REF]. Without food, bioaccessibility values, ranging from 3 to 46% (median 20%, n=42) [START_REF] Wang | Exposure assessment and distribution of polychlorinated biphenyls (PCBs) contained in indoor and outdoor dusts and the impacts of particle size and bioaccessibility[END_REF][START_REF] Kang | Bioaccessibility of polychlorinated biphenyls in workplace dust and its implication for risk assessment[END_REF], might have been underestimated.

Phthalates. The bioaccessibility of phthalates in dust was published in three articles in 2012 [START_REF] Kang | Risk Assessment of Human Exposure to Bioaccessible Phthalate Esters via Indoor Dust around the Pearl River Delta[END_REF], 2013 [START_REF] Wang | Size fraction effect on phthalate esters accumulation , bioaccessibility and in vitro cytotoxicity of indoor / outdoor dust , and risk assessment of human exposure[END_REF], and 2015 [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF]. Thirteen values were reported that ranged from 1% to 81% with a median of 13% (Table 4 and Figure 4). However, these values were obtained using a PBET Pesticides. The bioaccessibility of pesticides in dust was assessed in three articles published in 2012, 2013, and 2016. Investigated substances were mainly organochlorine pesticides [START_REF] Ertl | Bioaccessibility of pesticides and polychlorinated biphenyls from house dust: in-vitro methods and human exposure assessment[END_REF][START_REF] Wang | Risk assessment of bioaccessible organochlorine pesticides exposure via indoor and outdoor dust[END_REF],

fipronil [START_REF] Starr | Using paired soil and house dust samples in an in vitro assay to assess the post ingestion bioaccessibility of sorbed fipronil[END_REF], piperonyl butoxide [START_REF] Ertl | Bioaccessibility of pesticides and polychlorinated biphenyls from house dust: in-vitro methods and human exposure assessment[END_REF] and permethrine [START_REF] Ertl | Bioaccessibility of pesticides and polychlorinated biphenyls from house dust: in-vitro methods and human exposure assessment[END_REF]. Reported bioaccessibilities, shown in Table 5 and Figure 4, ranged from 6 to 52% (median 14%). In the absence of food they ranged from 6 to 40% (median 12%, n=14). They increased in the presence of food, from 29% to 52% (median 41%, n=5), thus showing again the conservative aspect of adding food to the model, as not to underestimate oral bioaccessibility.

PAHs. The bioaccessibility of PAHS was only reported in one article from 2011 on air conditioning filter dust [START_REF] Kang | Mutagenicity, genotoxicity and carcinogenic risk assessment of indoor dust from three major cities around the Pearl River Delta[END_REF], and ranged from 2% to 17% (median 7%). Reported values for PAHs are the lowest, compared to all other chemical families. These in vitro tests were performed without sorptive sink. In soil studies, the addition of a sorptive sink to the in vitro model caused an increase of PAHs bioaccessibility, by a factor of 1.2 to 2.8 [START_REF] Collins | Is there sufficient "sink" in current bioaccessibility determinations of organic pollutants in soils?[END_REF], or from 4-7 % to 16-31% [START_REF] Li | Tenax as sorption sink for in vitro bioaccessibility measurement of polycyclic aromatic hydrocarbons in soils[END_REF].

Even taking this increase into account, PAHs would remain among the less bioaccessible substances, and it is therefore even more important to take their bioaccessibility into account for a more accurate estimate of the exposure dose.

Discussion on the factors influencing oral bioaccessibility

A C C E P T E D M A N U S C R I P T
The oral bioaccessibility of SVOCs in dust is influenced by different factors that can be classified in three categories: (i) factors related to the measurement method, (ii) factors related to the dust as a matrix and (iii) factors related to the SVOC chemical properties (Table 7).

Influence of the measurement method

The results from the literature showed variations that could be attributed to the measurement method used for measuring bioaccessibility. A good understanding of the factors influencing SVOC bioaccessibility is necessary to progress towards a relevant and unified measurement method. These factors are listed below.

Presence of sorptive sink. Human digestion is a dynamic process where the equilibrium of the compounds' distribution between the matrix and the digestive fluids is constantly displaced because of the dilution created by fluids secretion and the passage of the compounds across the intestinal wall. To mimic this phenomena some authors used an adsorbent, i.e., Tenax® TA, for capturing the compounds as they are released in the digestive fluids [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF][START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF][START_REF] Kademoglou | Bioaccessibility of PBDEs present in indoor dust: A novel dialysis membrane method with a Tenax TA® absorption sink[END_REF][START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF]. By doing so, He et al. observed an increase of approximately 30% of the bioaccessibility of OPFRs after adding 2.5 g of Tenax® TA in their method [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF]. Similarly, the addition of 0.5 g of Tenax® TA increases the bioaccessibility of OPFR (+ 37% on average) and PBDE (+ 86% on average), which are thus close to the in vivo data measured in the rat after ingestion of SRM 2585 [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF]. The use of an adsorbent is therefore important for a more accurate measurement of SVOC bioaccessibility, and at least for avoiding underestimating its value. However, there are some practical difficulties with its use, and authors struggle to find easy to implement solutions for retrieving the adsorbent from the fluids and separating it from the dust. A novel method using dialysis membranes was proposed by Kademoglou et al. to solve this problem [START_REF] Kademoglou | Bioaccessibility of PBDEs present in indoor dust: A novel dialysis membrane method with a Tenax TA® absorption sink[END_REF]. In soil or fuel

A C C E P T E D M A N U S C R I P T
soot applications, authors attempted to use silicon cords [START_REF] Juhasz | Oral relative bioavailability of Dichlorodiphenyltrichloroethane (DDT) in contaminated soil and its prediction using in vitro strategies for exposure refinement[END_REF][START_REF] Gouliarmou | Sorptive physiologically based extraction of contaminated solid matrices: Incorporating silicone rod as absorption sink for hydrophobic organic contaminants[END_REF] or silicon sheets [START_REF] Zhang | Bioaccessibility of PAHs in Fuel Soot Assessed by an in Vitro Digestive Model with Absorptive Sink: Effect of Food Ingestion[END_REF]: these are easier to manipulate since the silicon can simply be removed from the fluids and rinsed.

However, substances do not adsorb on silicon; they are absorbed in the material, according to equilibrium equations between fluids and silicon that need to be assessed. Authors also attempted to use adsorption on activated carbon as a sink: while in this case there is no risk of the compounds being back-released in the fluids, SVOC can be hard to desorb from the activated carbon and it might only be possible to measure the non-bioaccessible content left in the dust [START_REF] Collins | Is there sufficient "sink" in current bioaccessibility determinations of organic pollutants in soils?[END_REF].

Presence of food.

An increase of about 30% of pesticides' and PCBs' bioaccessibility was measured in the presence of milk in the in vitro system. This increase was attributed to the presence of proteins, which are known to increase the solubility of organic substances [START_REF] Ertl | Bioaccessibility of pesticides and polychlorinated biphenyls from house dust: in-vitro methods and human exposure assessment[END_REF].

Such an increase was also observed for PAHs in soils in the presence of lyophilized milk and in fuel soot in the presence of soybean oil [START_REF] Guney | Bioaccessibility and other key parameters in assessing oral exposure to PAH-contaminated soils and dust: A critical review[END_REF]. However this increase was not confirmed for OPFRs with the FOREhST method. Quintana et al. even observed that the release of OPFRs in the intestinal fluid was higher in the absence of food. They hypothesized that it might be due to the binding of OPFRs to food components, that would then bind to dust particles, thus reducing

OPFRs bioaccessibility [START_REF] Quintana | Invitro estimation of bioaccessibility of chlorinated organophosphate flame retardants in indoor dust by fasting and fed physiologically relevant extraction tests[END_REF].

Concentration of bile salts. The biliary concentration of 1.78 g / L usually reported [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF][START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF][START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF][START_REF] Kademoglou | Bioaccessibility of PBDEs present in indoor dust: A novel dialysis membrane method with a Tenax TA® absorption sink[END_REF] has not been optimized since before 1993 [START_REF] Ruby | Development of an in-vitro screening-test to evaluate the in-vivo bioaccessibility of ingested mine-waste lead[END_REF]. However Yu et al. optimized the biliary concentration and concluded that it should be between 4.0 and 7.0 g/ L so as not to underestimate the bioaccessibility, but without physiological reference [START_REF] Yu | Optimization of an in vitro method to measure the bioaccessibility of polybrominated diphenyl ethers in dust using response surface methodology[END_REF]. The median concentration of bile salts in the intestines, as reported by Mudie et al. in their review of human

A C C E P T E D M A N U S C R I P T
physiological parameters, was 2.7 mM in the fasted state and ranged from 3.6 to 11.9 mM in the fed state [START_REF] Mudie | Physiological Parameters for Oral Delivery and in Vitro Testing[END_REF]. Considering a bile molecular weight of 408.6 g/mol, these concentrations are equivalent to 1.1 g/L for the fasted state and from 1.5 to 4.9 g/L in the fed state. Bile concentration is an important parameter to consider because it determines the formation of micelles. Indeed, micelles have a positive impact on bioaccessibility because they mobilized apolar substances thus enhancing their solubilization and making them bioaccessible. The influence of bile concentration varies according to the polarity of the substance: the less polar substances will rapidly be mobilized in the form of micelles while the more polar will remain solubilized in the water and can be readsorbed on the matrix, hence a greater variability of their bioaccessibility [START_REF] Cave | Comparison of batch mode and dynamic physiologically based bioaccessibility tests for PAHs in soil samples[END_REF]. In dust samples, increasing the quantity of bile salts in the in vitro model caused an increase of the bioaccessibility of OPFRs and phthalates [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF], PCBs [START_REF] Kang | Bioaccessibility of polychlorinated biphenyls in workplace dust and its implication for risk assessment[END_REF], and

PBDEs [START_REF] Yu | Optimization of an in vitro method to measure the bioaccessibility of polybrominated diphenyl ethers in dust using response surface methodology[END_REF]. The concentration of bile added to the in vitro system should therefore be physiologically relevant and not exceed 5g/L in the presence of food in the model.

Fluid to dust ratio. The massic ratio between synthetic fluid and dust is a parameter to consider because larger volumes of fluid will lead to a better migration of SVOCs towards digestive fluids.

Conversely, in Yu et al. study, an increase of the solid phase, or a decrease of the liquid phase caused the partition equilibrium of PBDEs to shift towards the solid phase, thus leading to the decrease of their bioaccessibility [START_REF] Yu | Optimization of an in vitro method to measure the bioaccessibility of polybrominated diphenyl ethers in dust using response surface methodology[END_REF]. The mean gastric and intestinal volumes reported by Mudie et al. were < 30 mL and from 81 to 165 mL, respectively, for the fasted state and from 250 to 664 mL and from 47 to 590 mL, respectively, for the fed state [START_REF] Mudie | Physiological Parameters for Oral Delivery and in Vitro Testing[END_REF]. Even if the upper percentile for daily dust intake of 100 mg recommended by the US EPA [START_REF] Epa | Exposure Factors Handbook: 2011 Edition[END_REF] was ingested in one single intake, ratios would go from 300:1 (for gastric volume in fasted state) to 6640:1 (for max Collins et al. recommend a minimum ratio of 100:1, even though they appreciate that a higher ratio may be more realistic, but would lead to detection problems [START_REF] Collins | Towards a unified approach for the determination of the bioaccessibility of organic pollutants[END_REF]. Besides, in their review of bioaccessibility in soil, Rostami and Juhasz reported that little difference was observed in metal bioaccessibility in soil when fluid:soil ratios varied from 100:1 to 5000:1 [START_REF] Rostami | Assessment of Persistent Organic Pollutant (POP) Bioavailability and Bioaccessibility for Human Health Exposure Assessment: A Critical Review[END_REF]. The fluid:dust ratio should therefore not fall below 100:1, as a compromise between physiological relevance and analytical feasibility.

Calculation of bioaccessibility.

There are two different approaches for the calculation of bioaccessibility. The first one, more widely used [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF][START_REF] Wang | Risk assessment of bioaccessible organochlorine pesticides exposure via indoor and outdoor dust[END_REF][START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF][START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF][START_REF] Kang | In vitro digestion and absorption of BDE-28, -47, -99 and -153 in indooor dust and its implication in risk assessemnt[END_REF][START_REF] Pan | Comparison of in vitro digestion model with in vivo relative bioavailability of BDE-209 in indoor dust and combination of in vitro digestion/Caco-2 cell model to estimate the daily intake of BDE-209 via indoor dust[END_REF][START_REF] Wang | Exposure assessment and distribution of polychlorinated biphenyls (PCBs) contained in indoor and outdoor dusts and the impacts of particle size and bioaccessibility[END_REF][START_REF] Kang | Bioaccessibility of polychlorinated biphenyls in workplace dust and its implication for risk assessment[END_REF][START_REF] Wang | Size fraction effect on phthalate esters accumulation , bioaccessibility and in vitro cytotoxicity of indoor / outdoor dust , and risk assessment of human exposure[END_REF][START_REF] Kang | Mutagenicity, genotoxicity and carcinogenic risk assessment of indoor dust from three major cities around the Pearl River Delta[END_REF], is based on the ratio between bioaccessible SVOCs and total SVOC concentration, originally present in dust:

𝑏𝑖𝑜𝑎𝑐𝑐𝑒𝑠𝑠𝑖𝑏𝑖𝑙𝑖𝑡𝑦 (%) = [𝑏𝑖𝑜𝑎𝑐𝑐𝑒𝑠𝑠𝑖𝑏𝑙𝑒 𝑆𝑉𝑂𝐶𝑠] [𝑡𝑜𝑡𝑎𝑙 𝑆𝑉𝑂𝐶𝑠] 𝑥100

The second approach considers the ratio between bioaccessible SVOCs and the sum of bioaccessible SVOCs and non-bioaccessible SVOCs, measured in the residual dust pellet left after the in vitro test [START_REF] Yu | Optimization of an in vitro method to measure the bioaccessibility of polybrominated diphenyl ethers in dust using response surface methodology[END_REF][START_REF] Kademoglou | Bioaccessibility of PBDEs present in indoor dust: A novel dialysis membrane method with a Tenax TA® absorption sink[END_REF][START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF][START_REF] García-Alcega | Does the source migration pathway of HBCDs to household dust influence their bio-accessibility?[END_REF]:

𝑏𝑖𝑜𝑎𝑐𝑐𝑒𝑠𝑠𝑖𝑏𝑖𝑙𝑖𝑡𝑦 (%) = [𝑏𝑖𝑜𝑎𝑐𝑐𝑒𝑠𝑠𝑖𝑏𝑙𝑒 𝑆𝑉𝑂𝐶𝑠] [𝑏𝑖𝑜𝑎𝑐𝑐𝑒𝑠𝑠𝑖𝑏𝑙𝑒 𝑆𝑉𝑂𝐶𝑠] + [𝑛𝑜𝑛 -𝑏𝑖𝑜𝑎𝑐𝑐𝑒𝑠𝑠𝑖𝑏𝑙𝑒 𝑆𝑉𝑂𝐶𝑠] 𝑥100
The two approaches would give the same results if Collins et al. suggested an harmonized protocol where most of the above parameters, i.e., colon simulation, dietary components and an sorptive sink, are considered [START_REF] Collins | Towards a unified approach for the determination of the bioaccessibility of organic pollutants[END_REF]. This harmonization protocol should be applied in further bioaccessibility studies, and an effort should be made toward the simplification of the method. Even though bioaccessibility studies will always be simpler to implement than bioavailability assessment studies, they remain long and tedious and

have not yet been applied on many samples in large-scale studies. A simpler method, based on Collins et al. recommendations, physiologically relevant in terms of body temperature and pH should be developed. Efforts should be concentrated on the main influencing factors, ie inclusion of a sorption sink, concentration of bile salts, and fluid:dust ratio. The method should be validated versus in vivo studies, as it was done with the UBM for metals, and eventually included in an ISO standard.

Influence of dust as a matrix.

The second category of factors influencing the bioaccessibility of SVOC in dust are those related to dust as a matrix. In 2003, Morawska and Salthammer described dust as "an undefined matrix, the composition of which is essentially dependent on the type of indoor fittings, the general behavior and standard hygiene of the room occupants, and the possibility of introducing dirt, soil and sand from the surroundings of the indoor environment" [START_REF] Morawska | Fundamentals of Indoor Particles and Settled Dust[END_REF]. Dust is made of human fragments, mainly skin flakes containing squalene and cholesterol, cellulose and petrochemical fibers, microplastics, particles originating from the abrasion of fabrics, furniture and surfaces,

A C C E P T E D M A N U S C R I P T
pollen, living organisms (bacteria, fungi), fuel soot as well as inorganic particle made of quartz, albite, calcite, dolomite, etc.) [START_REF] Zhang | Bioaccessibility of PAHs in Fuel Soot Assessed by an in Vitro Digestive Model with Absorptive Sink: Effect of Food Ingestion[END_REF][START_REF] Macher | Review of methods to collect settled dust and isolate culturable microorganisms[END_REF][START_REF] Gyntelberg | Dust and the Sick Building Syndrome[END_REF][START_REF] Weschler | Squalene and cholesterol in dust from danish homes and daycare centers[END_REF][START_REF] Dris | A first overview of textile fibers, including microplastics, in indoor and outdoor environments[END_REF][START_REF] Yang | A comparative study on physicochemical characteristics of household dust from a metropolitan city and a remote village in China[END_REF][START_REF] Butte | Pollutants in house dust as indicators of indoor contamination[END_REF]. Moreover, dust particles were reported as having different morphologies (micro-aggregates, spherical, angular, etc.) [START_REF] Yang | A comparative study on physicochemical characteristics of household dust from a metropolitan city and a remote village in China[END_REF]. Dust is therefore a complex matrix that can bind with SVOCs and retain them in its pores, thus influencing their bioaccessibility in a varying extent depending on dust chemical and physical characteristics.

Carbon or organic matter content. The amount of organic matter (OM) contained in dust may vary from 5 to 95% percent [START_REF] Butte | Pollutants in house dust as indicators of indoor contamination[END_REF], although a narrower range (8% -61%) was described in the literature [START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF][START_REF] Kang | In vitro digestion and absorption of BDE-28, -47, -99 and -153 in indooor dust and its implication in risk assessemnt[END_REF][START_REF] Pan | Comparison of in vitro digestion model with in vivo relative bioavailability of BDE-209 in indoor dust and combination of in vitro digestion/Caco-2 cell model to estimate the daily intake of BDE-209 via indoor dust[END_REF][START_REF] Yu | Concentrations and seasonal variations of polybrominated diphenyl ethers (PBDEs) in in-and out-house dust and human daily intake via dust ingestion corrected with bioaccessibility of PBDEs[END_REF]. The effect of an increase of carbon or organic matter was investigated:

while no effect could be observed for flame retardants [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF], PBDEs [START_REF] Kang | Assessment of relative bioavailability of heavy metals in soil using in vivo mouse model and its implication for risk assessment compared with bioaccessibility using in vitro assay[END_REF], and the less hydrophobic OPFRs and phthalates [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF], a decrease of the average bioaccessibility of PBDEs [START_REF] Yu | Concentrations and seasonal variations of polybrominated diphenyl ethers (PBDEs) in in-and out-house dust and human daily intake via dust ingestion corrected with bioaccessibility of PBDEs[END_REF], tri-to hepta-BDEs [START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF], BDE-209 [START_REF] Pan | Comparison of in vitro digestion model with in vivo relative bioavailability of BDE-209 in indoor dust and combination of in vitro digestion/Caco-2 cell model to estimate the daily intake of BDE-209 via indoor dust[END_REF], the more hydrophobic OPFRs and phtalates [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF],

and fipronil [START_REF] Starr | Using paired soil and house dust samples in an in vitro assay to assess the post ingestion bioaccessibility of sorbed fipronil[END_REF] was observed. Similar effects were also observed in soils, for example for phenanthrene [64] and PCBs [START_REF] Delannoy | Impact of soil characteristics on relative bioavailability of NDL-PCBs in piglets[END_REF][START_REF] Delannoy | Effects of standard humic materials on relative bioavailability of NDL-PCBs in juvenile swine[END_REF]. Delannoy et al. also compared different types of organic matter in soil and found that the reducing effect of OM on PCBs' bioaccessibility increased as following: fulvic acid > sphagnum peat ≥ sphagnum peat and activated carbon ≥ humic acid >> activated carbon. Yu et al. tried to better characterize OM in dust by assessing its aromaticity (using the H/C ratio: the lower the ratio, the higher the aromaticity) and its polarity (using the N/C ratio: the higher the ratio, the higher the polarity), and their impact on the bioaccessibility of tri-to hepta-BDE. Their bioaccessibility increased with decreasing OM aromaticity, while increased with increasing OM polarity [START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF]. The effect of OM on bioaccessibility is therefore not only due to the OM content but also to the complexity of its nature.

A C C E P T E D M A N U S C R I P T
Dust particle size and pore volumes. An increase of SVOC bioaccessibility associated to the decrease of dust particles was observed for PAHs [START_REF] Wang | Risk assessments of PAHs and Hg exposure via settled house dust and street dust, linking with their correlations in human hair[END_REF], PBDEs [START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF], OCPs [START_REF] Wang | Risk assessment of bioaccessible organochlorine pesticides exposure via indoor and outdoor dust[END_REF], and phthalates [START_REF] Wang | Size fraction effect on phthalate esters accumulation , bioaccessibility and in vitro cytotoxicity of indoor / outdoor dust , and risk assessment of human exposure[END_REF]. These observations are expected because smaller dust particles have larger specific surface area per mass unit, allowing better contact and dissolution in digestive fluids. Therefore, the right particle size to be analyzed has to be chosen for relevant human exposure assessment: not only will this have an impact on total concentration of SVOCs in dust, but also on their bioaccessibility. Similarly to smaller particle size, larger pore volumes were associated with higher bioaccessibility because they also offer a larger specific area more easily accessible to digestive fluids [START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF].

Sample aging.

In soils, the bioaccessibility of persistent organic pollutants (POPs) decreases when their residence time increases, through the aging process which allows POPs to be absorbed in organic matter and diffuse into the matrix nanopores [START_REF] Rostami | Assessment of Persistent Organic Pollutant (POP) Bioavailability and Bioaccessibility for Human Health Exposure Assessment: A Critical Review[END_REF]. Fang and Stapleton compared the bioaccessibility of OPFRs and BDEs in two series of samples, sampled in 2006 and 2010, respectively [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF]. Except for BDE-209, the 2006 bioaccessibility serie was significantly lower than the 2010's, thus confirming the observations made on soils. BDE-209 might be present in the dust, not only via sorption on dust surface, but also within the fibers, via materials abrasion, and would therefore be less concerned by the aging process (see also "Influence of the SVOC migration pathway" below).

The bioaccessibility of SVOC could be predicted based on a knowledge of the matrix and the total SVOC content, which are easier to measure than the bioaccessibility itself. To this end, the matrix influence parameters need to be ranked depending on their respective impact on bioaccessibility. Yu et al. compared the different parameters, i.e., OM content, polarity and

A C C E P T E D M A N U S C R I P T
aromaticity of OM, particle size, surface area, and pore volume of dust, using multiple linear regression [START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF]. Only OM content and pore volume remained in the statistical model. The bioaccessibility of tri-to hepta-BDEs could thus be calculated according to the equation: bioaccessibility (%) = 45.05 -0.49 x OM% + 1.79 x pore volume [START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF]. For the same reasons as stated above, BDE-209 measurements did not fit this equation. Further studies should be undertaken to integrate the aging process and the way the SVOC integrated dust in the model and a more comprehensive equation proposed.

Influence of the SVOC's chemical properties

The third category of factors that influence the bioaccessibility are those related to the SVOC chemical properties, such as the octanol/water partition coefficient (K OW ) that could be used to predict the propensity of SVOCs to migrate from dust to digestive fluids.

Kow. SVOCs with higher K OW are more hydrophobic and less likely to solubilize in aqueous digestive fluids. A decreasing trend in bioaccessibility was thereby observed with increasing log K ow for OPFRs [START_REF] Quintana | Invitro estimation of bioaccessibility of chlorinated organophosphate flame retardants in indoor dust by fasting and fed physiologically relevant extraction tests[END_REF][START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF], BFRs [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF][START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF][START_REF] Kademoglou | Bioaccessibility of PBDEs present in indoor dust: A novel dialysis membrane method with a Tenax TA® absorption sink[END_REF], PCBs [START_REF] Wang | Exposure assessment and distribution of polychlorinated biphenyls (PCBs) contained in indoor and outdoor dusts and the impacts of particle size and bioaccessibility[END_REF][START_REF] Kang | Bioaccessibility of polychlorinated biphenyls in workplace dust and its implication for risk assessment[END_REF], phthalates [START_REF] Kang | Risk Assessment of Human Exposure to Bioaccessible Phthalate Esters via Indoor Dust around the Pearl River Delta[END_REF], and PAHs [START_REF] Kang | Mutagenicity, genotoxicity and carcinogenic risk assessment of indoor dust from three major cities around the Pearl River Delta[END_REF], although this trend could not be confirmed in two others studies related to PBDEs [START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF][START_REF] Kang | In vitro digestion and absorption of BDE-28, -47, -99 and -153 in indooor dust and its implication in risk assessemnt[END_REF][START_REF] Yu | Concentrations and seasonal variations of polybrominated diphenyl ethers (PBDEs) in in-and out-house dust and human daily intake via dust ingestion corrected with bioaccessibility of PBDEs[END_REF], showing that other parameters are also to consider.

SVOC migration pathway.

The presence of SVOC in indoor dust can arise through three mechanisms: (i) via volatilization and re-condensation of the SVOC on dust particles (air mediated transfer), (ii) via direct transfer from horizontal surfaces to dust, and (iii) via weathering or abrasion of polymers [START_REF] Webster | Identifying Transfer Mechanisms and Sources of Environments Using Environmental Forensic Microscopy[END_REF][97][98]. In the first two cases, the SVOC is sorbed onto the surfaces of dust particles, whereas in the third case, the SVOC is a constituent of dust particles when trying to explain the lower bioaccessibility of BDE-209 in their dust samples [START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF].

However, in a more recent study, an experimental chamber was used to compare the bioaccessibility of HBCDs in a pre-characterized dust that had been enriched by HBCDs originating from treated textile via the two migration pathway: HBCDs bioaccessibility in dust contaminated via volatilization (35%) was greater than in dust contaminated by abrasion (15%) [START_REF] García-Alcega | Does the source migration pathway of HBCDs to household dust influence their bio-accessibility?[END_REF]. This study confirms the general tendency of sorbed compounds being more bioaccessible than constitutive ones, although more studies need to be performed with other SVOCs sources.

Level of SVOC concentration. A variation of the amount of SVOC present in dust before it is submitted to bioaccessibility test showed no impact of the SVOC concentration [START_REF] Yu | Optimization of an in vitro method to measure the bioaccessibility of polybrominated diphenyl ethers in dust using response surface methodology[END_REF][START_REF] Yu | Concentrations and seasonal variations of polybrominated diphenyl ethers (PBDEs) in in-and out-house dust and human daily intake via dust ingestion corrected with bioaccessibility of PBDEs[END_REF]. main HBCDs diastereoisomers (α, β, and γ), but this does not preclude the existence of an effect on their bioavailability [START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF].

A summary of the influencing factors related to the measurement method, the matrix and the SVOC is shown in Table 7.

Conclusion

SVOC bioaccessibilities show large variations, from 1 to 100 %. It is therefore important to take bioaccessibility into account for a better assessment of human exposure. It is particularly relevant for PAHs, which is the chemical family displaying the lowest bioaccessibilities and would therefore be more prone to exposure assessment errors. It is also important for phthalates, because the high concentrations measured in indoor dust could be put into perspective knowing their bioaccessibility. Bioaccessibility studies are easier to implement than bioavailability studies. However existing methods need to be (i) simplified, based on their most influencing parameters: inclusion of a sorptive sink and/or food, bile concentration and fluid:dust ratio, (ii) harmonized via interlaboratory calibrations, and (iii) validated versus in-vivo studies, preferably using swine. Predictions of the bioaccessible fraction could be made for compounds mainly concerned by the adsorption migration pathways, based on a knowledge of the SVOC content of the dust, its organic matter content and its pore sizes. Within a chemical family, further equations could be established based on their K ow . However, more bioaccessibility data need to be acquired, on many different dust samples, for building and validating such models. Moreover, the bioaccessibility of SVOCs in dust has been assessed for

Effect on SVOC bioaccessibility

Factor related to the measurement method: Presence of a sorptive sink ↗ (OPFRs [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF][START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF], PBDEs [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF][START_REF] Kademoglou | Bioaccessibility of PBDEs present in indoor dust: A novel dialysis membrane method with a Tenax TA® absorption sink[END_REF])

Presence of food ↗ (pesticides and PCBs [START_REF] Ertl | Bioaccessibility of pesticides and polychlorinated biphenyls from house dust: in-vitro methods and human exposure assessment[END_REF]) ↘ (OPFRs [START_REF] Quintana | Invitro estimation of bioaccessibility of chlorinated organophosphate flame retardants in indoor dust by fasting and fed physiologically relevant extraction tests[END_REF])

Concentration of bile salts ↗ ↗ (OPFRs and phthalates [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF], PCBs [START_REF] Kang | Bioaccessibility of polychlorinated biphenyls in workplace dust and its implication for risk assessment[END_REF], PBDEs [START_REF] Yu | Optimization of an in vitro method to measure the bioaccessibility of polybrominated diphenyl ethers in dust using response surface methodology[END_REF])

Fluid :dust ratio ↗ ↗ (PBDEs [START_REF] Yu | Optimization of an in vitro method to measure the bioaccessibility of polybrominated diphenyl ethers in dust using response surface methodology[END_REF])

Factor related to the matrix:

Dust organic matter ↗ ↘ (PBDEs [START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF][START_REF] Pan | Comparison of in vitro digestion model with in vivo relative bioavailability of BDE-209 in indoor dust and combination of in vitro digestion/Caco-2 cell model to estimate the daily intake of BDE-209 via indoor dust[END_REF][START_REF] Yu | Concentrations and seasonal variations of polybrominated diphenyl ethers (PBDEs) in in-and out-house dust and human daily intake via dust ingestion corrected with bioaccessibility of PBDEs[END_REF], fipronil [START_REF] Starr | Using paired soil and house dust samples in an in vitro assay to assess the post ingestion bioaccessibility of sorbed fipronil[END_REF], and the more hydrophobic OPFRs and phthalates [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF]) → (FRs [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF], PBDEs [START_REF] Kang | Assessment of relative bioavailability of heavy metals in soil using in vivo mouse model and its implication for risk assessment compared with bioaccessibility using in vitro assay[END_REF], and the less hydrophobic OPFRs and phthalates [START_REF] He | Organophosphorus flame retardants and phthalate esters in indoor dust from different microenvironments: Bioaccessibility and risk assessment[END_REF])

Dust particle ↗ ↘ (PAHs [START_REF] Wang | Risk assessments of PAHs and Hg exposure via settled house dust and street dust, linking with their correlations in human hair[END_REF], PBDEs [START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF], OCs [START_REF] Wang | Risk assessment of bioaccessible organochlorine pesticides exposure via indoor and outdoor dust[END_REF], and phthalates [START_REF] Wang | Size fraction effect on phthalate esters accumulation , bioaccessibility and in vitro cytotoxicity of indoor / outdoor dust , and risk assessment of human exposure[END_REF])

Factor related to SVOC characteristics: K OW ↗ ↘ (OPFRs [START_REF] Quintana | Invitro estimation of bioaccessibility of chlorinated organophosphate flame retardants in indoor dust by fasting and fed physiologically relevant extraction tests[END_REF][START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF], BFRs [START_REF] Fang | Evaluating the bioaccessibility of flame retardants in house dust using an in vitro Tenax bead-assisted sorptive physiologically based method[END_REF][START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF], PCBs [START_REF] Wang | Exposure assessment and distribution of polychlorinated biphenyls (PCBs) contained in indoor and outdoor dusts and the impacts of particle size and bioaccessibility[END_REF][START_REF] Kang | Bioaccessibility of polychlorinated biphenyls in workplace dust and its implication for risk assessment[END_REF], phthalates [START_REF] Kang | Risk Assessment of Human Exposure to Bioaccessible Phthalate Esters via Indoor Dust around the Pearl River Delta[END_REF], and PAHs [START_REF] Kang | Mutagenicity, genotoxicity and carcinogenic risk assessment of indoor dust from three major cities around the Pearl River Delta[END_REF]) → (PBDEs [START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF][START_REF] Kang | In vitro digestion and absorption of BDE-28, -47, -99 and -153 in indooor dust and its implication in risk assessemnt[END_REF][START_REF] Yu | Concentrations and seasonal variations of polybrominated diphenyl ethers (PBDEs) in in-and out-house dust and human daily intake via dust ingestion corrected with bioaccessibility of PBDEs[END_REF]) SVOC migration pathway (sorption → abrasion)

↘

(PBDEs [START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF] and HBCDs [START_REF] García-Alcega | Does the source migration pathway of HBCDs to household dust influence their bio-accessibility?[END_REF]) → (PBDEs [START_REF] Abdallah | In vitro assessment of the bioaccessibility of brominated flame retardants in indoor dust using a colon extended model of the human gastrointestinal tract[END_REF]) Level of SVOC concentration ↗ → (PBDEs [START_REF] Yu | Optimization of an in vitro method to measure the bioaccessibility of polybrominated diphenyl ethers in dust using response surface methodology[END_REF][START_REF] Yu | Concentrations and seasonal variations of polybrominated diphenyl ethers (PBDEs) in in-and out-house dust and human daily intake via dust ingestion corrected with bioaccessibility of PBDEs[END_REF])

  𝑆𝑉𝑂𝐶 𝑑𝑎𝑖𝑙𝑦 𝑖𝑛𝑡𝑎𝑘𝑒 𝑏𝑦 𝑑𝑢𝑠𝑡 𝑖𝑛𝑔𝑒𝑠𝑡𝑖𝑜𝑛 = 𝑆𝑉𝑂𝐶 𝑐𝑜𝑛𝑡𝑒𝑛𝑡 𝑖𝑛 𝑑𝑢𝑠𝑡 * 𝑚𝑎𝑠𝑠 𝑜𝑓 𝑑𝑎𝑖𝑙𝑦 𝑖𝑛𝑔𝑒𝑠𝑡𝑒𝑑 𝑑𝑢𝑠𝑡 𝑏𝑜𝑑𝑦 𝑤𝑒𝑖𝑔ℎ𝑡

  sophisticated methods have also been developed, such as the physiologically-based extraction test (PBET), the simulator of the human intestinal microbial ecosystem (SHIME), the method from the Dutch National Institute for Public Health and the environment (RIVM), the Fed ORganic estimation human Simulation Test (FOREhST), and the in vitro gastrointestinal (IVG)

  across the intestinal epithelium. Indeed, Caco-2 cells can be cultivated as monolayers on semipermeable membrane where they develop the morphologic characteristics of epithelium cells, possessing a brush border and tight junctions between adjacent cells [59,60]. In their review, Cui et al. mentioned that HT29-MTX goblet cells are sometimes cultured with Caco-2 cells, because they can produce the mucus that otherwise lacks to Caco-2 cells monolayers.

  validation. The validation of a SVOC bioaccessibility assessment method involves two major steps. From an analytical point of view, the extraction of the digestive fluids and of any adsorbent included to the model, and the instrumental analysis of the extracted SVOCs, must be performed using quality control steps, as proposed by Rodríguez-Navas et al [61]. Once this analytical validation is achieved, then the bioaccessibility data produced by the method should be validated by comparison to bioavailability data measured in vivo, taking into account the metabolism and the fate of the substance in the body. However, in vivo data related to the bioavailability in dust are really scarce. Huwe et al. produced data for the bioavailability of in rats that had ingested a reference dust material, the SRM 2585, with known SVOC contents [62]. Pan et al. found a correlation between the bioaccessibility of BDE-209 in dust, measured with a PBET method and its relative bioavailability measured in rats' blood (slope 0.63; r² 0.73, p = 0.031) [52]. Plichta and Fromme produced bioavailability data for phthalates by measuring the urine concentrations of piglets that had ingested contaminated dust [63].This lack of data on SVOC bioavailability in dust led us to extend our review to soil studies, where more bioavailability tests were conducted. In 2004, Pu et al. measured the absolute bioavailability of phenanthrene in the blood of rats that had ingested contaminated soils, and its bioaccessibility in the same soils using a PBET method. Depending on the type of soil investigated, bioavailability varied between 15% and 49%, whereas bioaccessibilities varied between 18% and 89%. The authors found a linear relationship between bioaccessibility and bioavailability (r² = 0.53, p < 0.05), thus encouraging the use of bioaccessibility to predict bioavailability but also emphasizing the need for more studies, covering more chemicals and more types of soils[64]. More recently, James et al. assessed the PAH bioavailability in juvenile swines, by measuring their blood concentrations after the ingestion of contaminated soils.Bioavailability varied from 0 to 40% according to the PAH and the soil. In this study, however, no relationship could be established between partition coefficients into simulated intestinal fluids and bioavailability[START_REF] James | Predicting Polycyclic Aromatic Hydrocarbon Bioavailability to Mammals from Incidentally Ingested Soils Using Partitioning and Fugacity[END_REF]. However in a previous study, James et al. had added a C18 membranes to simulate lipid sinks and had then found a linear relationship between the bioaccessibility of PAHs in soils, measured with an in vitro digestion model (IVD) in the presence of a C18 A C C E P T E D M A N U S C R I P T membrane, and their bioavailability, measured in swines' blood serum (slope = 0.85, r² = 0.42, p < 0.07) [66].

  BFRs has been the most widely documented with 162 results (143 for PBDEs [45-47,50-52,72] and 19 for alternative BFRs (2-ethylhexyl-tetrabromo-benzoate (EH-TBB), bis(2-ethylhexyl) tetrabromophthalate (BEH-TEBP),

  method without sorbent and might have been underestimated (see discussion below). A right evaluation of the bioaccessibility of phthalates is nevertheless crucial, with respect to the high contamination levels found in indoor dust.

  gastric volume in fed state). In the methods used for the measurements of dust bioaccessibility, the fluid:dust ratio ranged from 20 to 133 for gastric fluids and from 67 to 300 for intestinal fluids. Yu et al. studied this ratio and concluded that it should be between 150 and 200[START_REF] Yu | Optimization of an in vitro method to measure the bioaccessibility of polybrominated diphenyl ethers in dust using response surface methodology[END_REF].

  [total SVOCs] = [bioaccessible SVOCs] + [non bioaccessible SVOCs], but this might not be true, depending on the efficiency of the extraction protocols. Moreover, the first equation assumes that the dust is homogeneous, and that the test samples used for the determination of [total SVOCs] and [bioaccessible SVOCs] are might not be true, particularly if the sieving fraction is high (>250 µm). The second equation should therefore be favored when possible in the study design.

  [START_REF] Webster | Identifying Transfer Mechanisms and Sources of Environments Using Environmental Forensic Microscopy[END_REF]. These migration pathways could lead to different bioaccessibilities, and sorbed SVOCs could be more bioaccessible than constitutive SVOCs. Yu et al. hypothesized that these different migration pathways could explain the lower PBDEs bioaccessibility in indoor dust than in outdoor dust since indoor dust is more likely to contain fragments of materials than outdoor dust[START_REF] Yu | Concentrations and seasonal variations of polybrominated diphenyl ethers (PBDEs) in in-and out-house dust and human daily intake via dust ingestion corrected with bioaccessibility of PBDEs[END_REF]. In their next study, they compared the bioaccessibility of PBDE-spiked dust versus unspiked dust and observed no change in the bioaccessibility of tri-to hepta-BDEs whereas BDE-209 bioaccessibility was higher in the spiked dust, thus confirming a different behavior of BDE-209, that could originate from material abrasion[START_REF] Yu | Factors influencing on the bioaccessibility of polybrominated diphenyl ethers in size-specific dust from air conditioner filters[END_REF]. Indeed, Webster et al. observed that the repartition of bromine of highly BDE-209 contaminated dust was heterogeneous in house dust and concentrated in scattered highly contaminated particles, suggesting an abrasion origin of BDE-209 in dust[START_REF] Webster | Identifying Transfer Mechanisms and Sources of Environments Using Environmental Forensic Microscopy[END_REF], although Abdallah et al. did not observe this heterogeneous repartition

  Enantiomeric form of the SVOC. No difference was observed in the bioaccessibility of the 3

Figure 1 :Figure 1 Figure 2 :

 112 Figures:

Figure 4 :

 4 Figure 4: Published (20011-2017) SVOC bioaccessibility data in indoor settled dust according to measurement design. Each dot represents the median value for one compound in one study OPFRs: organophosphorus flame retardants, BFRs: brominated flame retardants PCBs: polychlorobiphenyls, PAHs: polycyclic aromatic hydrocarbons, respectively

Figure 4

 4 Figure 4 also supplied as a separate TIFF file

  enzyme for the degradation of proteins. Salts (NaCl, KCl, KH 2 PO 4 or NaH 2 PO 4 , CaCl 2 , NH 4 Cl) are added in the BARGE and DIN 19737 methods. The authors applying PBET methods add different types of salts (sodium malate and tri-sodium citrate) and acids (lactic and acetic)

	U S C R I P T
	N
	A
	M
	C C E P T E D
	A

  PAH, phthalate, and DDT data are from the work of Wang et al.[START_REF] Wang | Risk assessment of bioaccessible organochlorine pesticides exposure via indoor and outdoor dust[END_REF][START_REF] Wang | Size fraction effect on phthalate esters accumulation , bioaccessibility and in vitro cytotoxicity of indoor / outdoor dust , and risk assessment of human exposure[END_REF][START_REF] Wang | Risk assessments of PAHs and Hg exposure via settled house dust and street dust, linking with their correlations in human hair[END_REF]. PCB data are from the work of Kang et al.[START_REF] Kang | Bioaccessibility of polychlorinated biphenyls in workplace dust and its implication for risk assessment[END_REF].

	90% 100% bioaccessibility (%)
	80%
	40% 70% 60% 50%	100		 no food, no sorbent  with food  with sorbent
	0% 10% 20% 30%	Nap Acy Ace Fl N=22 Phe OPFRs 0 50	Ant Flu Pyr BaA Chr B(b+k)F BaP PCB28 PCB77 PCB114 PCB118 PCB153 PCB157 PCB183 PCB194 DMP DEP DPRP DIBP DBP DMEP DHP BBP DEHP DCHP DnOP DNP+DiDP DDTs Stomach Small intestine N=162 N=52 N=35 N=21 N=42 N BFRs PCBs Phthalates Pesticides PAHs U max median S C R I P T min
				A
			M
	0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% C C E P T E D
	A
			Stomach+Small intestine	Colon

Nap: naphthalene, Acy: acenaphthylene, Ace acenaphthene, Fl: fluorene, Phe phenanthrenes, Ant: anthracene, Flu: fluoranthene, Pyr: pyrene, BaA: benzo(a) anthracene, Chr: chrysene, B(b + k)F: benzo(b + k)fluoranthene, BaP: Benzo(a)Pyrene, DMP: dimethyl phthalate, DEP: diethyl phthalate, DPRP: di-n-propyl phthalate, DiBP: diisobutyl phthalate, DBP: di-n-butyl phthalate, DMEP: bis (2-methoxyethyl) phthalate, DHP: di-n-hexyl phthalate, BBP: butyl benzyl phthalate, DEHP: di-2-ethylhexyl phthalate, DCHP: dicyclohexyl phthalate, DnOP: di-n-octyl phthalate, DNP: dinonyl phthalate, DiDP: di-iso-decyl phthalate, DDT: dichlorodiphenyltrichloroethane.

Figure 3: Partition of in vitro evaluation of SVOC absorption between stomach+small intestine and colon. Data are from the work of Abdallah et al. [46]. HBCD: hexabromocyclododecane, TBBP: tetrabromobisphenol, BDE: bromodiphenylether.

Table 1 : Bioaccessibility (% )of brominated flame retardants in indoor settled dust

 1 a pooled dust samples not enriched, b pooled dust samples enriched by volatilization, c pooled dust samples enriched by abrasion, d Spring, e Summer, f Autumn, g Winter, h home, i laboratory, j office, 1 k air conditionner

	U S C R I P T
	N
	A
	M
	C C E P T E D
	A

PBET: physiologically-based extraction test, CE: colon-extended, BEH-TEBP: bis(2-ethylhexyl) tetrabromophthalate, HBCD: hexabromocyclododecane, TBBP-A: tetrabromobisphenol A, BDE: bromodiphenyl ether

Table 2 : Bioaccessibility (%) of organophosphate flame retardants in indoor settled dust

 2 UBM: Unified BioAccessibility Research Group of Europe (BARGE) Method, FOREhST: Fed ORganic estimation human Simulation Test, PBET: physiologically-based extraction test, TCEP: tris(2-chloroethyl) phosphate, TCPP: tris(2-chloroisopropyl) phosphate, TDCPP: tris(1,3-dichloro-2-propyl) phosphate, TPP: triphenylphosphate.

	U S C R I P T
	A
	M
	C C E P T E D
	A

Table 3 : Bioaccessibility (%) of polychlorobiphenyls (PCBs) in indoor settled dust

 3

	U S C R I P T
	N
	A
	M
	C C E P T E D
	A
	PBET: physiologically-based extraction test

Table 4 : Bioaccessibility (%) of phthalates in indoor settled dust

 4 PBET: physiologically-based extraction test, DMP: dimethyl phthalate, DEP: diethyl phthalate, DPRP: di-npropylphthalate, DiBP: diisobutyl phthalate, DBP: dibutyl phthalate, DMEP: bis (2-methoxyethyl) phthalate, DHP: din-hexyl phthalate, BBP: butyl benzyl phthalate, DEHP: di-2-ethylhexyl phthalate, DCHP: dicyclohexyl phthalate, DnOP: di-n-octyl phthalate, DNP: dinonyl phthalate, DiDP: di-isodecyl phthalate (DiDP)

	U S C R I P T
	N
	A
	M
	C C E P T E D
	A

Table 5 : Bioaccessibility (%) of pesticides in indoor settled dust

 5 PBET: physiologically-based extraction test, DDTs: dichlorodiphenyltrichloroethanes ( a p,p'-DDT), HCHs: hexachlorocyclohexane( b Lindane), CHLs: Heptachlor, transchlordane, cis-chlordane, trans-nonachlor, and cisnonachlor, Drins: aldrin, dieldrin and endrin, HCB: hexachlorobenzene, PCP: pentachlorophenol, PBO: piperonyl butoxide

	U S C R I P T
	N
	A
	M
	C C E P T E D
	A

Table 6 : Bioaccessibility (%) of PAHs in indoor settled dust and air conditioning filter dust

 6 a air conditionning filter dust from commercial offices, b air conditionning filter dust from secondary schools, c air conditionning filter dust from shopping malls, d air conditionning filter dust from hospitals, e air conditionning filter dust from electronic factories, f air conditionning filter dust from commercial manufacturing plants, g house floor settled dust

Table 7 : Summary of the main factors influencing SVOC bioaccessibility in dust

 7

OPFRs: organophosphate flame retardants, PBDEs: polybromodiphenylethers, PCBs: polychlorobiphenyls, FRs: flame retardants, PAHs: polycyclic aromatic hydrocarbons, OCs: organochlorine pesticides, and HBCDs: hexabromocyclododecanes

Acknowledgments

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of interest: none.

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