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Assessing human exposure to phthalates, alternative plasticizers and organophosphate esters
Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
2017 (English)Doctoral thesis, comprehensive summary (Other academic) [Artistic work]
Abstract [en]

Phthalate esters (PEs) and organophosphate esters (OPEs) are common indoor pollutants frequently detected in environmental (dust, air), personal (hand wipes, diet) and human matrices (urine, serum etc.). In this thesis, mathematical models were used to establish links between intake and body burden for a comprehensive dataset based on a Norwegian study population. Also, the relative importance of different PE uptake pathways was assessed and discussed. Furthermore, the suitability of human nails as an alternative, non-invasive biomonitoring matrix for PEs was investigated. Additionally, information regarding alternative plasticizers to PEs was collected and presented extensively. Results showed that for PEs (paper II), daily intakes based on external exposure media agree with back-calculations using urinary metabolite concentrations, leading to the conclusion that human exposure for the general adult population is well understood and that the most important uptake routes were captured. Overall intake levels are comparable or lower than level presented in recent comprehensive studies and hazard quotients were well below 1 (low risk). As expected, diet was found to be the most important uptake route for all PEs. For lower molecular weight PEs, inhalation becomes a strong contributing pathway whereas for higher molecular weight PEs, dust ingestion was also important. Daily intake based on hand wipes was found to be much lower than the estimated total dermal intake based on air, dust and personal care products, questioning the relevance of hand wipes to represent total dermal exposure. Human nails were found to be unsuitable for replacing urine as a biomonitoring matrix for PEs as internal intake (from blood) cannot explain measured nail concentrations and uptake from air is too slow to reach observed concentrations within a realistic time frame (paper III). Hence, the kinetic links between intake and nail concentrations could not be established. Although exposure to traditional PEs is decreasing, use and body burden of some alternatives are increasing (paper I). Fortunately, most alternative plasticizers have favorable toxicological properties, resulting in low risk for humans. In contrast to PEs, OPEs still remain a group of poorly studied substances in terms of human exposure (paper IV). Due to lack of information regarding human metabolism, reliable links between intake and concentrations in serum and urine could not be established. Modelling results showed that concentrations in serum, and to some extent, urine, were underestimated for 2 compounds. It is likely that a combination of missing intake and suboptimal biomarkers were the cause for this under-prediction. Because of this, further studies regarding human metabolism should be performed for OPEs and potentially more specific biomarkers identified in the future. For PEs, there is a need for more comprehensive datasets to study exposure for high risk groups such as infants and children. Furthermore, dermal uptake remains poorly understood and the uptake of PEs into human nails should be studied in more detail to establish the kinetic links between exposure and body burden.

Place, publisher, year, edition, pages
Stockholm: Department of Environmental Science and Analytical Chemistry, Stockholm University , 2017. , p. 59
Keywords [en]
Human exposure, phthalates, organophosphates, plasticizers, flame retardants, modelling
National Category
Environmental Sciences
Research subject
Applied Environmental Science
Identifiers
URN: urn:nbn:se:su:diva-141808ISBN: 978-91-7649-698-5 (print)ISBN: 978-91-7649-699-2 (electronic)OAI: oai:DiVA.org:su-141808DiVA, id: diva2:1089101
Public defence
2017-06-01, William-Olssonsalen, Geovetenskapens hus, Svante Arrhenius väg 14, Stockholm, 13:00 (English)
Opponent
Supervisors
Funder
EU, FP7, Seventh Framework Programme, 316665
Note

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 2: Manuscript. Paper 4: Manuscript.

Available from: 2017-05-09 Created: 2017-04-18 Last updated: 2017-05-10Bibliographically approved
List of papers
1. Human exposure, hazard and risk of alternative plasticizers to phthalate esters
Open this publication in new window or tab >>Human exposure, hazard and risk of alternative plasticizers to phthalate esters
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2016 (English)In: Science of the Total Environment, ISSN 0048-9697, E-ISSN 1879-1026, Vol. 541, p. 451-467Article in journal (Refereed) Published
Abstract [en]

Alternative plasticizers to phthalate esters have been used for over a decade, but data regarding emissions, human exposure and health effects are limited. Here we review 20 alternative plasticizers in current use and their human exposure, hazard and risk. Physicochemical properties are collated for these diverse alternatives and log K-OW values range over 15 orders of magnitude and log K-AW and log K-OA values over about 9 orders of magnitude. Most substances are hydrophobic with low volatility and are produced in high volumes for use in multiple applications. There is an increasing trend in the total use of alternative plasticizers in Sweden compared to common phthalate esters in the last 10 years, especially for DINCH. Evaluative indoor fate modeling reveals that most alternatives are distributed to vertical surfaces (e.g. walls or ceilings). Only TXIB and GTA are predicted to be predominantly distributed to indoor air. Human exposure data are lacking and clear evidence for human exposure only exists for DEHT and DINCH, which show increasing trends in body burdens. Human intake rates are collected and compared with limit values with resulting risk ratios below 1 except for infant's exposure to ESBO. PBT properties of the alternatives indicate mostly no reasons for concern, except that TEHPA is estimated to be persistent and TCP toxic. A caveat is that non-standard toxicological endpoint results are not available and, similar to phthalate esters, the alternatives are likely pseudo-persistent. Keydata gaps for more comprehensive risk assessment are identified and include: analytical methods to measure metabolites in biological fluids and tissues, toxicological information regarding non-standard endpoints such as endocrine disruption and a further refined exposure assessment in order to consider high risk groups such as infants, toddlers and children.

Keywords
Alternative plasticizer, Human exposure, Risk assessment, PBT property, Indoor fate
National Category
Earth and Related Environmental Sciences
Research subject
Applied Environmental Science
Identifiers
urn:nbn:se:su:diva-125634 (URN)10.1016/j.scitotenv.2015.09.036 (DOI)000365289300049 ()26410720 (PubMedID)
Available from: 2016-01-19 Created: 2016-01-15 Last updated: 2017-05-15Bibliographically approved
2. Multi-pathway human exposure assessment of phthalate esters and DINCH
Open this publication in new window or tab >>Multi-pathway human exposure assessment of phthalate esters and DINCH
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Phthalate esters are substances mainly used as plasticizers in various applications. Some have been restricted and phased out due to their adverse health effects and ubiquitous presence, leading to the introduction of alternative plasticizers, such as DINCH. Using a comprehensive dataset from a Norwegian study population, human exposure to DMP, DEP, DnBP, DiBP, BBzP, DEHP, DINP, DIDP, DPHP and DINCH was assessed by measuring their presence in external exposure media, allowing an estimation of the total intake, as well as the relative importance of different uptake pathways. Intake via different uptake routes, in particular inhalation, dermal absorption, and oral uptake was estimated and total intake based on all uptake pathways was compared to the back-calculated intake from biomonitoring data. Hand wipe results were used to determine dermal uptake and compared to other exposure sources such as air, dust and personal care products. Results showed that the calculated total intakes were similar, but slightly higher than those based on biomonitoring methods by 1.1 to 2.8 times (median), indicating a good understanding of important uptake pathways. The relative importance of different uptake pathways was comparable to other studies, where inhalation was important for lower molecular weight phthalates, and negligible for the higher molecular weight phthalates and DINCH. Dietary intake was the predominant exposure route for all analyzed substances. The dermal uptake assessed by hand wipes was much lower (median up to 2000 times) than the sum of dermal uptake via air, dust and personal care products and unlikely represents an integrative dermal exposure. Dermal uptake is not a well-studied exposure pathway and several research gaps (e.g. absorption fractions) remain. Based on calculated intakes, the exposure risk for the Norwegian participants to the phthalates and DINCH was lower than health based limit values. Nevertheless, exposure to alternative plasticizers, such as DPHP and DINCH, is expected to increase in the future and continuous monitoring is required.

Keywords
Phthalate esters, DPHP, DINCH, plasticizers, exposure assessment
National Category
Environmental Sciences
Research subject
Applied Environmental Science
Identifiers
urn:nbn:se:su:diva-141806 (URN)
Funder
EU, FP7, Seventh Framework Programme, 316665
Available from: 2017-04-18 Created: 2017-04-18 Last updated: 2017-05-17Bibliographically approved
3. Estimating uptake of phthalate ester metabolites into the human nail plate using pharmacokinetic modelling
Open this publication in new window or tab >>Estimating uptake of phthalate ester metabolites into the human nail plate using pharmacokinetic modelling
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2017 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 100, p. 148-155Article in journal (Refereed) Published
Abstract [en]

There is a lack of knowledge regarding uptake of phthalate esters (PEs) and other chemicals into the human nail plate and thus, clarity concerning the suitability of human nails as a valid alternative matrix for monitoring longterm exposure. In particular, the relative importance of internal uptake of phthalate metabolites (from e.g. blood) compared to external uptake pathways is unknown. This study provides first insights into the partitioning of phthalate-metabolites between blood and nail using pharmacokinetic (PK) modelling and biomonitoring data from a Norwegian cohort. A previously published PK model (Lorber PK model) was used in combination with measured urine data to predict serum concentrations of DEHP and DnBP/DiBP metabolites at steady state. Then, partitioning between blood and nail was assessed assuming equilibrium conditions and treating the nail plate as a tissue, assuming a fixed lipid and water content. Although calculated as a worst-case scenario at equilibrium, the predicted nail concentrations of metabolites were lower than the biomonitoring data by factors of 44 to 1300 depending on the metabolite. It is therefore concluded that internal uptake of phthalate metabolites from blood into nail is a negligible pathway and does not explain the observed nail concentrations. Ingtead, external uptake pathways are more likely to dominate, possibly through deposition of phthalates onto the skin/nail and subsequent metabolism. Modelling gaseous diffusive uptake of PEs from air to nail revealed that this pathway is unlikely to be important. Experimental quantification of internal and external uptake pathways of phthalates and their metabolites into the human nail plate is needed to verify these modelling results. However, based on this model, human nails are not a good indicator of internal human exposure for the phthalate esters studied.

Keywords
Human nail, Phthalates, Pharmacoldnetic modelling, partitioning
National Category
Earth and Related Environmental Sciences
Research subject
Applied Environmental Science
Identifiers
urn:nbn:se:su:diva-141220 (URN)10.1016/j.envint.2017.01.007 (DOI)000394076900010 ()28089278 (PubMedID)
Available from: 2017-04-20 Created: 2017-04-20 Last updated: 2017-04-27Bibliographically approved
4. Probing the relationship between external and internal human exposure of organophosphate flame retardants using pharmacokinetic modelling
Open this publication in new window or tab >>Probing the relationship between external and internal human exposure of organophosphate flame retardants using pharmacokinetic modelling
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Human external exposure (i.e. intake) of organophosphate flame retardants (PFRs) has recently been quantified, but no link has yet been established between external and internal exposure. In this study, we used a pharmacokinetic (PK) model to probe the relationship between external and internal exposure data for three PFRs (EHDPHP, TNBP and TPHP) available for a Norwegian cohort of 61 individuals from 61 different households. Using current literature on metabolism of PFRs, we predicted the human body burden and compared it to the measured serum and urine data for the PFRs metabolites. Unavailable parameters were estimated using a model fitting approach (least squares method) after assigning reasonable constraints on the ranges of fitted parameters. Results showed an acceptable comparison between PK model estimates and measurements (< 10-fold deviation) for EHDPHP. However, a deviation of 10-1000 was observed between PK model estimates and measurements for TNBP and TPHP. Sensitivity and uncertainty analysis on the PK model revealed that EHDPHP results showed higher uncertainty than TNBP or TPHP. However, there are indications that (1) current biomarkers of exposure (i.e. assumed metabolites) for TNBP and TPHP chemicals might not be specific and ultimately affecting the outcome of the modeling, (2) some exposure pathways might be missing. Further research, such as in vivo laboratory metabolism experiments of PFRs including identification of better biomarkers will reduce uncertainties in human exposure assessment.

Keywords
flame retardants, human exposure, pharmacokinetic modelling, metabolism
National Category
Environmental Sciences
Identifiers
urn:nbn:se:su:diva-141807 (URN)
Funder
EU, FP7, Seventh Framework Programme, 316665
Available from: 2017-04-18 Created: 2017-04-18 Last updated: 2017-04-27Bibliographically approved

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