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What contributes to human body burdens of phthalate esters?: An experimental approach
Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.ORCID iD: 0000-0003-4473-2345
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Phthalate esters (PEs) and alternative plasticizers used as additives in numerous consumer products are continuously released into the environment leading to subsequent human exposure. The ubiquitous presence and potential adverse health effects (e.g. endocrine disruption and reproductive toxicity) of some PEs are responsible for their bans or restrictions. This has led to increasing use of alternative plasticizers, especially cyclohexane-1,2-dicarboxylic acid diisononyl ester (DINCH). Human exposure data on alternative plasticizers are lacking and clear evidence for human exposure has previously only been found for di(2-ethylhexyl) terephthalate (DEHTP) and DINCH, with increasing trends in body burdens. In this thesis, a study population of 61 adults (age: 20–66; gender: 16 males and 45 females) living in the Oslo area (Norway) was studied for their exposure to plasticizers. Information on sociodemographic and lifestyle characteristics that potentially affect the concentrations of PE and DINCH metabolites in adults was collected by questionnaires. Using the human biomonitoring approach, we evaluated the internal exposure to PEs and DINCH by measuring concentrations of their metabolites in urine (where metabolism and excretion are well understood) and using these data to back-calculate daily intakes. Metabolite levels in finger nails were also determined. Since reference standards of human metabolites for other important alternative plasticizers apart from DINCH (e.g. DEHTP, di(2-propylheptyl) phthalate (DPHP), di(2-ethylhexyl) adipate (DEHA) and acetyl tributyl citrate (ATBC)) are not commercially available, we further investigated the urine and finger nail samples by Q Exactive Orbitrap LC-MS to identify specific metabolites, which can be used as appropriate biomarkers of human exposure. Many metabolites of alternative plasticizers that were present in in vitro extracts were further identified in vivo in urine and finger nail samples. Hence, we concluded that in vitro assays can reliably mimic the in vivo processes. Also, finger nails may be a useful non-invasive matrix for human biomonitoring of specific organic contaminants, but further validation is needed. Concentrations of PEs and DINCH were also measured in duplicate diet, air, dust and hand wipes. External exposure, estimated based on dietary intake, air inhalation, dust ingestion and dermal uptake, was higher or equal to the back-calculated internal intake. By comparing these, we were able to explain the relative importance of different exposure pathways for the Norwegian study population. Dietary intake was the predominant exposure route for all analyzed substances. Inhalation was important only for lower molecular weight PEs, while dust ingestion was important for higher molecular weight PEs and DINCH. Dermal uptake based on hand wipes was much lower than the total dermal uptake calculated via air, dust and personal care products, but still several research gaps remain for this exposure pathway. Based on calculated intakes, the exposure risk for the Norwegian participants to the PEs and DINCH did not exceed the established tolerable daily intake and reference doses, and the cumulative risk assessment for combined exposure to plasticizers with similar toxic endpoints indicated no health concerns for the selected population. Nevertheless, exposure to alternative plasticizers, such as DPHP and DINCH, is expected to increase in the future and continuous monitoring is required. Findings through uni- and multivariate analysis suggested that age, smoking, use of personal care products and many other everyday habits, such as washing hands or eating food from plastic packages are possible contributors to plasticizer exposure.

Place, publisher, year, edition, pages
Stockholm: Department of Environmental Science and Analytical Chemistry, Stockholm University , 2017. , 55 p.
Keyword [en]
Phthalates, Alternative plasticizers, DINCH, In vivo screening, Urine, Nails, Air, Dust, Hand wipes, Duplicate diet, Predictors of exposure
National Category
Environmental Sciences
Research subject
Applied Environmental Science
Identifiers
URN: urn:nbn:se:su:diva-143147ISBN: 978-91-7649-874-3 (print)ISBN: 978-91-7649-875-0 (electronic)OAI: oai:DiVA.org:su-143147DiVA: diva2:1095745
Public defence
2017-09-01, Nordenskiöldsalen, Geovetenskapens hus, Svante Arrhenius väg 12, Stockholm, 10:00 (English)
Opponent
Supervisors
Note

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

Available from: 2017-06-08 Created: 2017-05-15 Last updated: 2017-05-30Bibliographically 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, 451-467 p.Article 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.

Keyword
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. Evaluation of exposure to phthalate esters and DINCH in urine and nails from a Norwegian study population
Open this publication in new window or tab >>Evaluation of exposure to phthalate esters and DINCH in urine and nails from a Norwegian study population
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2016 (English)In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 151, 80-90 p.Article in journal (Refereed) Published
Abstract [en]

Phthalate esters (PEs) and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) used as additives in numerous consumer products are continuously released into the environment, leading to subsequent human exposure which might cause adverse health effects. The human biomonitoring approach allows the detection of PEs and DINCH in specific populations, by taking into account all possible routes of exposure (e.g. inhalation, transdermal and oral) and all relevant sources (e.g. air, dust, personal care products, diet). We have investigated the presence of nine PE and two DINCH metabolites and their exposure determinants in 61 adult residents of the Oslo area (Norway). Three urine spots and fingernails were collected from each participant according to established sampling protocols. Metabolite analysis was performed by LC-MS/MS. Metabolite levels in urine were used to back-calculate the total exposure to their corresponding parent compound. The primary monoesters, such as monomethyl phthalate (MMP, geometric mean 89.7 ng/g), monoethyl phthalate (MEP, 104.8 ng/g) and mono-n-butyl phthalate (MnBP, 893 ng/g) were observed in higher levels in nails, whereas the secondary bis(2-ethylhexyl) phthalate (DEHP) and DINCH oxidative metabolites were more abundant in urine (detection frequency 84-100%). The estimated daily intakes of PEs and DINCH for this Norwegian population did not exceed the established tolerable daily intake and reference doses, and the cumulative risk assessment for combined exposure to plasticizers with similar toxic endpoints indicated no health concerns for the selected population. We found a moderate positive correlation between MEP levels in 3 urine spots and nails (range: 0.56-0.68). Higher frequency of personal care products use was associated with greater MEP concentrations in both urine and nail samples. Increased age, smoking, wearing plastic gloves during house cleaning, consuming food with plastic packaging and eating with hands were associated with higher levels in urine and nails for some of the metabolites. In contrast, frequent hair and hand washing was associated with lower urinary levels of monoisobutyl phthalate (MiBP) and mono(2-ethyl-5-hydroxyhexyl) phthalate (5-OH-MEHP), respectively.

Keyword
Phthalates, DINCH, Biomonitoring, Urine, Nails
National Category
Earth and Related Environmental Sciences Environmental Health and Occupational Health
Research subject
Applied Environmental Science
Identifiers
urn:nbn:se:su:diva-136277 (URN)10.1016/j.envres.2016.07.025 (DOI)000386413600010 ()27466754 (PubMedID)
Available from: 2016-12-05 Created: 2016-12-01 Last updated: 2017-05-17Bibliographically approved
3. Case Study on Screening Emerging Pollutants in Urine and Nails
Open this publication in new window or tab >>Case Study on Screening Emerging Pollutants in Urine and Nails
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2017 (English)In: Environmental Science and Technology, ISSN 0013-936X, E-ISSN 1520-5851, Vol. 51, no 7, 4046-4053 p.Article in journal (Refereed) Published
Abstract [en]

Alternative plasticizers and flame retardants (FRs) have been introduced as replacements for banned or restricted chemicals, but much is still unknown about their metabolism and occurrence in humans. We identified the metabolites formed in vitro for four alternative plasticizers (acetyltributyl citrate (ATBC), bis(2-propylheptyl) phthalate (DPHP), bis(2-ethylhexyl) terephthalate (DEHTP), bis(2ethylhexyl) adipate (DEHA)), and one FR (2,2-bis (chloromethyl)-propane-1,3-diyltetrakis(2-chloroethyl) bisphosphate (V6)). Further, these compounds and their metabolites were investigated by LC/ESI-Orbitrap-MS in urine and finger nails collected from a Norwegian cohort. Primary and secondary ATBC metabolites had detection frequencies (% DF) in finger nails ranging from 46 to 95%. V6 was identified for the first time in finger nails, suggesting that this matrix may also indicate past exposure to FRs as well as alternative plasticizers. Two isomeric forms of DEHTP primary metabolite were highly detected in urine (97% DF) and identified in finger nails, while no DPHP metabolites were detected in vivo. Primary and secondary DEHA metabolites were identified in both matrices, and the relative proportion of the secondary metabolites was higher in urine than in finger nails; the opposite was observed for the primary metabolites. As many of the metabolites present in in vitro extracts were further identified in vivo in urine and finger nail samples, this suggests that in vitro assays can reliably mimic the in vivo processes. Finger nails may be a useful noninvasive matrix for human biomonitoring of specific organic contaminants, but further validation is needed.

National Category
Environmental Engineering Earth and Related Environmental Sciences
Research subject
Applied Environmental Science
Identifiers
urn:nbn:se:su:diva-142381 (URN)10.1021/acs.est.6b05661 (DOI)000398646500051 ()28293951 (PubMedID)
Available from: 2017-05-04 Created: 2017-05-04 Last updated: 2017-05-17Bibliographically approved
4. 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.

Keyword
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

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