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Exposure to Chemical Mixtures and Associated Health Risks: Focusing on Endocrine Disruption and the Swedish General Population
Stockholm University, Faculty of Science, Department of Environmental Science.ORCID iD: 0000-0002-5277-6404
2025 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Humans are exposed to a wide range of environmental pollutants through multiple routes of exposure. Chemical exposure can result in endocrine-disrupting effects, manifesting at low concentrations, and are associated with several health problems, such as infertility, obesity, and autoimmune diseases. This thesis aims to evaluate the potential health effects of exposure to complex chemical mixtures. Two key objectives were to understand human chemical exposure and investigate whether the Swedish general population falls within the risk threshold for health effects related to this exposure. In Paper I, a literature review was conducted to investigate chemical exposure based on existing knowledge, compiling peer-reviewed literature on chemicals and their exposure levels in Swedish human blood. Additional chemicals were analyzed in Swedish human blood to examine exposure to chemicals currently used, such as per- and polyfluoroalkyl substances (PFAS, Paper II) and synthetic phenolic contaminants (Paper III). A 50-component chemical mixture was created based on human blood levels found in Papers I-III to better understand the potential endocrine-disrupting and developmental toxic effects. Persistent organic pollutants (POPs) were the most frequently studied and detected chemicals analyzed in human blood (Paper I), prompting the inclusion of four POP classes in the artificial mixture. New contaminants not previously found in Swedish samples were also identified, including hydrogen-substituted perfluoroalkyl carboxylic acids (Paper II) and synthetic phenolic antioxidants (SPAs) (Paper III). Some PFAS and SPAs were present in all individuals at high levels, motivating the addition of the SPAs into the chemical mixture. Mixture risk assessment strategies were employed to evaluate the potential adverse effects of exposure to POPs (Paper I) and PFAS (Paper II). The mixture comprises polychlorinated biphenyls (PCBs), brominated flame retardants, organochlorine pesticides, PFAS, SPAs, bisphenol A, and phthalates. The total mixture was tested as a whole and as six subgroup mixtures to identify the drivers of effect. The mixtures were evaluated using in vitro cell assays to screen for binding to estrogen receptor α, androgen receptor, and aryl hydrocarbon receptor (Paper IV). The developmental toxicity of the mixtures was examined using the zebrafish embryo toxicity (ZFET) test (Paper V). The effects associated with exposure to the total chemical mixture demonstrated estrogen and androgen activity at 10 and 15 times human blood concentration (xHBC), respectively, levels that fall within the human blood exposure range of the Swedish general population (Paper IV). Developmental effects were observed at 15 xHBC using the ZFET test (Paper V). This thesis identified that POPs, such as PFAS, chlorinated pesticides, and PCBs, continue to pose a health threat. Newly identified SPAs present a potential risk due to high exposure levels and need further investigation. The mixture risk assessment strategies employed in this thesis suggest that a risk of health impairments from known chemical exposure cannot be ruled out for the Swedish population. Although these risk assessments are only tentative, they add to the ever-growing body of evidence, showing that mixtures pose an unavoidable health concern to humans. Therefore, it is essential to manage and limit human exposure to the mixture of environmental pollutants to ensure the well-being of future generations.

Place, publisher, year, edition, pages
Stockholm: Department of Environmental Science, Stockholm University , 2025. , p. 73
Keywords [en]
Chemical mixtures, Human blood, Chemical exposure, Sweden, Human health, Synthetic phenolic antioxidants (SPAs), PFAS, Persistent organic pollutants, Mixture risk assessments, Endocrine disruption, in vitro, zebrafish embryo toxicity (ZFET) test
National Category
Environmental Sciences Analytical Chemistry Occupational Health and Environmental Health
Research subject
Environmental Sciences
Identifiers
URN: urn:nbn:se:su:diva-239371ISBN: 978-91-8107-114-6 (print)ISBN: 978-91-8107-115-3 (electronic)OAI: oai:DiVA.org:su-239371DiVA, id: diva2:1936583
Public defence
2025-03-28, De Geer-salen, Geovetenskapens hus, Svante Arrhenius väg 14 and online via Zoom, public link is available at the department website, Stockholm, 10:00 (English)
Opponent
Supervisors
Funder
Swedish Research Council Formas, 2018-02264Available from: 2025-03-05 Created: 2025-02-11 Last updated: 2025-02-21Bibliographically approved
List of papers
1. Anthropogenic Organic Contaminants Analysed in Human Blood and Combined Risk
Open this publication in new window or tab >>Anthropogenic Organic Contaminants Analysed in Human Blood and Combined Risk
2023 (English)In: Exposure and Health, ISSN 2451-9766 , E-ISSN 2451-9685, Vol. 15, no 3, p. 551-565Article, review/survey (Refereed) Published
Abstract [en]

The number of chemicals in the anthroposphere is increasing and some of them end up in humans. A literature search was made to assess which anthropogenic organic contaminants (OCs) that have been analysed in blood from the general population. The reviewed articles were used to create a database of studies [human blood database (HBDB), containing 559 OCs] reporting blood analyses made worldwide. All studies analysing blood from the Swedish population were compiled into a second database [Swedish exposure database (SEDB), containing 166 OCs] listing blood concentrations of OCs. Data from the SEDB showed decreasing levels of regulated chemicals in blood over time, indicating that regulation had made an impact. The Hazard Index (HI) approach was used as a qualitative mixture risk assessment of the OCs with established human biomonitoring guidance values (HBM-GVs) and blood levels in the SEDB. Nine HBM-GVs were found and the HI of the corresponding OCs/groups of OCs showed that a risk of adverse effects in the general population could not be excluded, which is a cause for concern considering that only a fraction of the analysed OCs in the SEDB were included. This study presents the OCs identified in human blood and concentration time trends. The study highlights the lack of HBM-GVs needed for mixture risk assessments to assess the combined risk of chemical exposure to the general population. 

Keywords
Anthropogenic organic contaminants, Blood analysis, Chemical exposure, Mixture risk assessment
National Category
Occupational Health and Environmental Health Environmental Sciences
Identifiers
urn:nbn:se:su:diva-210265 (URN)10.1007/s12403-022-00507-y (DOI)000859753800002 ()2-s2.0-85138782745 (Scopus ID)
Available from: 2022-10-12 Created: 2022-10-12 Last updated: 2025-02-11Bibliographically approved
2. An extended PFAS profiling of a Swedish subpopulation and mixture risk assessments using multiple approaches
Open this publication in new window or tab >>An extended PFAS profiling of a Swedish subpopulation and mixture risk assessments using multiple approaches
2025 (English)In: Environment International, ISSN 0160-4120, E-ISSN 1873-6750, Vol. 195, article id 109214Article in journal (Refereed) Published
Abstract [en]

Per- and polyfluoroalkyl substances (PFAS) have been detected worldwide, from the deep seas to polar regions. A previous review showed that PFAS are risk drivers of the chemical mixture present in human blood. This study focused on establishing the PFAS exposure of a Swedish subpopulation and investigated whether the exposure poses a risk of adverse health effects. Human serum from 60 blood donors in Stockholm, Sweden, was analyzed. A target method including 32 PFAS analytes and over 270 suspect features was used to detect and quantify PFAS. Twenty-six PFAS were quantified, and 7 suspect PFAS features (6 H-PFCAs and PFECHS) were semi-quantified. Nine mixture risk assessment (MRA) strategies were used to assess the risk of health outcomes. Fifteen effect levels were derived and used, along with 15 already established values. The certainty of various derivation techniques was discussed. The MRAs showed that the entire studied population exceeded some of the risk thresholds, with effects including high cholesterol and immune suppression. However, the certainty was lower when deriving these two effect levels. The MRA, using human biomonitoring guidance values (high certainty), concluded that for 63 % of the individuals, a risk for adverse health effects cannot be excluded. This study has demonstrated that there is a reason for concern regarding PFAS exposure in the general population of Sweden. To our knowledge, this is the first time the H-PFCAs have been semi-quantified in human blood using a reference standard.

National Category
Environmental Sciences
Identifiers
urn:nbn:se:su:diva-239366 (URN)10.1016/j.envint.2024.109214 (DOI)001392864100001 ()39705977 (PubMedID)2-s2.0-85212390242 (Scopus ID)
Funder
Stockholm UniversitySwedish Research Council Formas, 2018-02264
Available from: 2025-02-11 Created: 2025-02-11 Last updated: 2025-02-17Bibliographically approved
3. Multi-target analysis of synthetic phenolic compounds in human blood
Open this publication in new window or tab >>Multi-target analysis of synthetic phenolic compounds in human blood
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Synthetic phenolic compounds are widely used in plastics and personal care products, leading to potential high human exposure. This study aimed to develop two multi-target analytical methods to quantify phenolic compounds in human serum, including free and conjugated synthetic phenolic antioxidants (SPAs), bisphenols, parabens, and UV filters. The two methods were applied to 30 human serum samples from young adults (15 females and 15 males) living in Stockholm, Sweden. An average recovery of 73 % (range 36-125 %) and good reproducibility (RSD <30 %) were established for 37 target analytes, and another four analytes were semi-quantified. Twenty-one target analytes were found above quantification levels. Notable, five SPAs, namely 2,2'-methylenebis(4-methyl-6-tert-butylphenol) (AO2246), 4,4'-methylenebis(2,6-di-tert-butylphenol) (AO4426), 4-tert octylphenol (4-tOP), butylade hydroxyanisole (BHA), butylated hydroxytoluene (BHT) were quantified in >93 % of samples, and with median concentrations between 1.4 (BHA) and 520 ng/g (AO2246). Other compounds quantified in the samples were bisphenol B (quantification frequency 57 %) and methylparaben (quantification frequency 87 %), with median concentrations of 0.38 and 1.6 ng/g respectively. Additionally, two features were semi-quantified using suspect screening: Fenozan (an SPA metabolite, 3-(3,5-Di-tert-butyl-4-hydroxyphenyl)propionic acid) and benzophenone-4 (a UV filter, 5-benzoyl-4-hydroxy-2-methoxybenzenesulfonic acid). To the best of our knowledge, this is the first time AO4426, 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHT-COOH), 2-tert-butylbenzene-1,4-diol (TBHQ), bisphenol B, and Fenozan have been found in human blood. The finding of SPAs in human blood indicates high human exposure and needs further investigation.

National Category
Environmental Sciences
Identifiers
urn:nbn:se:su:diva-239367 (URN)10.1016/j.talanta.2025.127899 (DOI)
Funder
Swedish Research Council Formas, 2018-02264
Available from: 2025-02-11 Created: 2025-02-11 Last updated: 2025-03-05
4. Evaluating the endocrine-disrupting and oxidative stress potential of a 50-component human-relevant complex chemical mixture using in vitro tests
Open this publication in new window or tab >>Evaluating the endocrine-disrupting and oxidative stress potential of a 50-component human-relevant complex chemical mixture using in vitro tests
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Environmental Sciences
Identifiers
urn:nbn:se:su:diva-239368 (URN)
Funder
Swedish Research Council Formas, 2018-02264Knowledge Foundation, 20190098
Available from: 2025-02-11 Created: 2025-02-11 Last updated: 2025-02-11
5. Toxicity assessment of a 50-component human-relevant chemical mixture using zebrafish embryos (Danio rerio)
Open this publication in new window or tab >>Toxicity assessment of a 50-component human-relevant chemical mixture using zebrafish embryos (Danio rerio)
(English)Manuscript (preprint) (Other academic)
National Category
Environmental Sciences
Identifiers
urn:nbn:se:su:diva-239370 (URN)
Funder
Swedish Research Council Formas, 2018-02264
Available from: 2025-02-11 Created: 2025-02-11 Last updated: 2025-02-11

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