From emission sources to human tissues: modelling the exposure to per- and polyfluoroalkyl substances. Melissa Ines Gomis

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3 From emission sources to human tissues: modelling the exposure to per- and polyfluoroalkyl substances Melissa Ines Gomis

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5 From emission sources to human tissues: modelling the exposure to perand polyfluoroalkyl substances Melissa Ines Gomis

6 Melissa Ines Gomis, Stockholm University 2017 Cover illustration by Melissa Ines Gomis ISBN print ISBN PDF Printed in Sweden by US-AB, Stockholm 2017 Distributor: Department of Environmental Science and Analytical Chemistry (ACES)

7 A mi abuelo Olimpio.

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9 Contents Abstract... 1 Sammanfattning... 2 Sommaire... 3 Resumen... 5 List of papers Introduction Background The role of human exposure in the risk assessment of chemicals Knowledge gaps in the state-of-the-science Linking production changes with time trends in serum levels Direct versus indirect sources of human exposure Are fluorinated alternatives an improvement on legacy PFASs? Objectives Methods Predicting physicochemical properties of organic contaminants Environmental fate modelling Pharmacokinetic modelling Sensitivity and uncertainty analysis Results and discussion Past and current exposure to PFAAs Response of the body burden to exposure dynamics The elimination half-life as a determinant factor of body burden The lock-in problem of structurally similar replacements Persistence (P) and long-range transport potential (LRTP) Potency ranking of legacy PFCAs and alternatives Conclusion Future perspectives References Acknowledgements... 41

10 Abbreviations Acronym AUC ss CTD FTOH GenX K AW K OA K OW LFER PBT PFAA PFAS PFBS PFCA PFOA PFHxS PFOS PFSA pk a PBPK PK P OV QSAR QSPR REACH SSRW TE US EPA Definition Area under the curve at steady-state Characteristic travel distance Fluorotelomer alcohol Ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate Air water partition coefficient Octanol air partition coefficient Octanol water partition coefficient Linear free energy relationship Persistent, bioaccumulative, toxic Perfluoroalkyl acid Per- and polyfluoroalkyl substance Perfluorobutane sulfonic acid Perfluoroalkyl carboxylic acid Perfluorooctanoic acid Perfluorohexane sulfonic acid Perfluorooctane sulfonic acid Perfluoroalkyl sulfonic acid -log 10K a, where K a is the acid dissociation constant Physiologically-based pharmacokinetic Pharmacokinetic Overall persistence Quantitative structure activity relationships Quantitative structure property relationships Registration, Evaluation, Authorisation and Restriction of Chemicals Sum of squared residual weighted Transfer efficiency US Environmental Protection Agency

11 Abstract Produced since the 1950 s, per- and polyfluoroalkyl (PFASs) substances are persistent, bioaccumulative and toxic compounds that are ubiquitous in the environment. Being proteinophilic with a tendency to partition to protein-rich tissues, PFASs have been found in human serum worldwide and in wildlife with a predominance of long-chain perfluoroalkyl carboxilic acids (C 7-C 14 PFCAs) and perfluoroalkyl sulfonic acids (C 6-C 9 PFSAs). Due to rising concern regarding their hazardous properties, several regulatory actions and voluntary industrial phase-outs have been conducted since early 2000s, shifting the production towards other fluorinated alternatives. This thesis explores the human exposure to long-chain PFASs and their alternatives using different modelling methods and aims to 1) link comprehensively the past and current industrial production with the human body burden and 2) assess the potential hazardous properties of legacy PFASs replacements, on which information is very limited. In Paper I, the historical daily intakes in Australia and USA were reconstructed from cross-sectional biomonitoring data of perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and perfluorohexanesulfonic acid (PFHxS). The results indicate that humans experienced similar exposure levels and trends to PFOS and PFOA in both regions, suggesting a common historical exposure possibly dominated by consumer products. The model could not be fitted to PFHxS concentration in serum. In Paper II, the relative contribution of indirect (i.e. subsequent metabolism of precursors into legacy PFASs) versus direct exposure was evaluated on occupationally exposed ski wax technicians. The indirect exposure contributed by up to 45% to the total body burden of PFOA. In Paper III, the physicochemical properties, the persistence and the long-range transport of fluorinated alternatives were predicted using different in silico tools. Findings suggest that fluorinated alternatives are likely similar to their predecessors, in terms of physicochemical properties and environmental fate. Finally, Paper IV compares the toxic potency of PFOS, PFOA and their alternatives as a function of external and internal dose. While alternatives are less potent than their predecessors when considering the administered dose, they become similarly potent when the assessment is based on levels in the target tissue. This thesis demonstrates that pharmacokinetic models are effective tools to comprehensively reconnect the body burden to the exposure of phased-out chemicals. More importantly, the studies on fluorinated alternatives raise the necessity to provide more information and data on the potential hazard of these novel and emerging products. 1

12 Sammanfattning Per- och polyfluorerade (PFASs) ämnen är långlivade, bioackumulerande och toxiska ämnen som producerats sedan 1950-talet och återfinns överallt i miljön. Då de är proteinfila, har PFAS ämnen hittats i mänskligt serum i hela världen och i vilda djur, framförallt i form av långkedjade perfluoralkyl karboxylsyror (C 7-C 14 PFCAs) och perfluoralkyl sulfonsyror (C 6-C 9 PFSAs). På grund av den stigande oron gällande deras skadliga egenskaper har flera lagstiftningsåtgärder och frivilliga industriella utfasningar genomförts sedan början av 2000-talet, vilket skiftat produktionen mot andra fluorerande alternativ. Denna avhandling undersöker människors exponering för långkedjade PFASs ämnen och deras ersättare med hjälp av olika modelleringsmetoder och syftar till att 1) på ett omfattande sätt länka den tidigare och nuvarande industriella produktionen med mänsklig belastning och 2) bedöma de potentiellt skadliga egenskaperna hos äldre PFAS alternativ, om vilka kunskapen är väldigt begränsad. I Paper 1, har de historiska dagliga intagen i Australien och USA rekonstruerats från tvärsnitts, biologisk övervakningsdata av perfluoroktansulfonsyra (PFOS), perfluorkarboxylsyra (PFOA) och perfluorhexan sulfonat (PFHxS). Resultaten indikerar att människor har upplevt liknande exponeringsnivåer och trender för PFOS och PFOA i båda regionerna, vilket tyder på en gemensam historisk exponering potentiellt dominerad av konsumentprodukter. Modellen kunde inte anpassas till PFHxS koncentrationen i serum. I Paper ll, utvärderas bidraget av indirekt (dvs. efterföljande metabolism av prekursorer till äldre PFAS ämnen) kontra direkt exponering av yrkesexponerade skidvaxningstekniker. Den indirekta exponeringen bidrog med upp till 45 % av den totala kroppsbelastningen av PFOA. I Paper lll, förutsågs de fysikalisk-kemiska egenskaperna, persistensen, och långdistans transporten av fluorerade alternativ med hjälp av olika in silico verktyg. Resultaten tyder på att fluorerade alternativ sannolikt liknar sina föregångare när det gäller deras persistens och fysikalisk-kemiska egenskaper. Slutligen, Paper lv jämför toxisk potens av PFOS, PFOA och deras alternativ som en funktion av yttre och inre dos. Medan alternativen är mindre potenta än sina föregångare när man överväger den administrerade dosen, blir de lika potenta när bedömningen är baserad på nivåer i målvävnaden. Denna avhandling visar att farmakokinetiska modeller är effektiva verktyg för att på ett omfattande sätt återkoppla kroppsbelastning till exponering av avvecklade kemikalier. Ännu viktigare, studierna av de fluorerade alternativen belyser nödvändigheten av att ge mer information och data om den potentiella faran med dessa nya och framväxande produkter. 2

13 Sommaire Produites depuis les années 1950, les substances per- et polyfluorées (PFASs) sont des produits persistants, bioaccumulables, toxiques et omniprésents dans l'environnement. Etant protéinophiles avec une forte tendance à migrer dans les tissus riches en protéines, les PFASs se retrouvent, à l échelle mondiale, dans le sérum humain et dans la faune, principalement les acides carboxyliques perfluorés (PFCAs de 7 à 14 carbones) et les acides sulfoniques perfluorés (PFSAs de 6 à 9 carbones) possédant une longue chaîne carbonée. En raison de l'inquiétude grandissante suscitée par leurs propriétés dangereuses, plusieurs mesures réglementaires ainsi que l'élimination volontaire par les principaux producteurs ont été décidées depuis le début des années 2000, en orientant, entre autres, la production vers d'autres produits de remplacement fluorés. Cette thèse explore l'exposition humaine aux PFASs à longue chaîne carbonée et à leurs produits de remplacement en utilisant différentes méthodes de modélisation et vise à: 1) associer de façon exhaustive la production industrielle passée et actuelle à la concentration des PFASs dans le sang humain; et 2) évaluer les propriétés potentiellement dangereuses des produits chimiques fluorés remplaçant les PFASs sous règlementation, au sujet desquelles les informations demeurent très limitées. Dans l Article I, les expositions quotidiennes à l'acide perfluorooctanesulfonique (PFOS), à l'acide perfluorocarboxylique (PFOA) et à l'acide perfluorohexanesulfononique (PFHxS) subies précédemment par les populations australienne et états-unienne ont été estimées à partir de données annuelles sur la concentration dans le sang. Les résultats indiquent que les niveaux d'exposition au PFOS et PFOA ainsi que les tendances temporelles sont relativement similaires dans les deux régions géographiques, suggérant une exposition historique globalement commune, probablement dominée par l exposition aux produits de consommation. Le modèle n'a pas pu être appliqué au PFHxS. Dans l Article II, la contribution de l exposition indirecte (i.e. absorption de produits précurseurs suivie par leur métabolisme en PFCAs ou PFSAs) par rapport à l'exposition directe a été évaluée sur un groupe de techniciens farteurs de skis exposés au PFOA et à l un de ses précurseurs dans le cadre de leur travail. Jusqu'à 45% de la concentration de PFOA mesurée dans le sang a pu être attribuée à l exposition indirecte. Dans l Article III, les propriétés physicochimiques des produits de remplacement fluorés ainsi que leur persistance et leur propension à être transportés sur de longues distances ont été estimées à l'aide de différents modèles informatiques. Les résultats indiquent que les produits de remplacement fluorés sont 3

14 probablement semblables à leurs prédécesseurs, en termes de persistance, de comportement dans l environnement et de propriétés physicochimiques. Finalement, l Article IV compare le potentiel toxique de PFOS, de PFOA et de leurs remplacements en fonction de la dose externe et interne. Lorsque l analyse se base sur la dose administrée, les produits de remplacements ont un potentiel toxique moins élevé que leurs prédécesseurs. Cependant, leur potentiel toxique s égalise lorsque l'évaluation est basée sur la concentration dans le tissu cible. Cette thèse démontre que les modèles pharmacocinétiques sont des outils efficaces pour établir exhaustivement un lien connexe entre la concentration de PFASs dans le sang humain avec leur niveau d exposition. De plus, les études sur les produits de remplacement fluorés s accordent sur la nécessité de fournir rapidement plus d'informations et de données sur les risques potentiels de ces produits émergents. 4

15 Resumen Producidas desde la década de 1950, las sustancias per- e polifluoroalquilo (PFASs) son compuestos persistentes, bioacumulativos y tóxicos que son ubicuos en el medio ambiente. Al ser proteinófilico con tendencia a repartirse en tejidos ricos en proteínas, PFASs se han encontrado en el suero humano y en la fauna en todo el mundo, con un predominio de ácido perfluoroalkyl carboxílico de cadena larga (PFCAs con C 8 hasta C 14) y ácidos perfluoroalkyl sulfónicos (PFSAs con C 6 hasta C 9). Debido a la preocupación creciente por las propiedades nocivas de estos componentes, desde principios de la década del 2000, tanto la normativa adoptada oficialmente como las medidas voluntarias aplicadas por parte de la industria han desplazado la producción hacia otras alternativas fluoradas. Esta tesis explora la exposición humana a los PFASs de cadena larga y sus alternativas utilizando diferentes métodos de modelización y tiene como objetivo de 1) vincular integralmente la producción industrial pasada y actual con el nivel de PFASs en el cuerpo humano y 2) evaluar las potenciales propiedades peligrosas de las alternativas fluoradas reemplazando los PFASs bajo regulación, cuya información es muy limitada. En el Artículo I, se reconstruyeron la exposición diaria historica al ácido perfluorooctanosulfónico (PFOS), al ácido perfluorocarboxílico (PFOA) y al ácido perfluorohexanosulfónico (PFHxS) en Australia y en los Estados Unidos a partir de datos de corte transversal. Los resultados indican que los seres humanos experimentaron niveles similares de exposición al PFOS y PFOA en ambas regiones, lo que sugiere una exposición histórica común posiblemente dominada por el contacto con productos de consumo. El modelo no pudo ajustarse a las concentraciónes de PFHxS en el suero. En el Artículo II, se evaluó la contribución de la exposición indirecta (i.e. metabolismo de los precursores en los PFCAs y PFSAs) frente a la exposición directa en un grupo de especialistas en tratamientos con ceras a los esquís de alta competición expuestos por su profesión al PFOA y a uno de sus precursores. Hasta un 45% de la concentración de PFOA medida en el suero fue atribuida a la exposición indirecta. En el Artículo III, se predijeron las propiedades fisicoquímicas, la persistencia y el transporte de largo alcance de varias alternativas fluoradas utilizando diferentes metodos in silico. Los resultados sugieren que las alternativas fluoradas son probablemente similares a sus predecesores, en términos de su persistencia, transporte de largo alcance y propiedades físicoquímicas. Por último, el Artículo IV compara la potencia tóxica de PFOS, PFOA y sus alternativas en función de la dosis externa e interna. Aunque las alternativas son 5

16 menos potentes que sus predecesores al considerar la dosis administrada, se vuelven similarmente potentes cuando la evaluación se basa en los niveles obtenidos en el tejido objeto de estudio. Esta tesis demuestra que los modelos farmacocinéticos son herramientas eficaces para reconectar exhaustivamente el nivel de PFASs en el cuerpo humano con la exposición a productos químicos eliminados y regulados. Más importante aún, los estudios sobre las alternativas fluoradas plantean la necesidad de proveer más información y datos sobre el peligro potencial de estos productos emergentes. 6

17 List of Papers Paper I: Historical human exposure to perfluoroalkyl acids in the United States and Australia reconstructed from biomonitoring data using population-based pharmacokinetic modelling. Gomis, M. I., Vestergren, R., MacLeod, M., Mueller, J. F., Cousins, I. T. Manuscript, submitted. Paper II: Contribution of direct and indirect exposure to human serum concentrations of perfluorooctanoic acid in an occupationally exposed group of ski waxers. Gomis, M. I., Vestergren, R., Nilsson, H., Cousins, I. T. Environmental Science & Technology, 2016, 50(13), Reproduced with permission from American Chemical Society. Paper III: A modeling assessment of the physicochemical properties and environmental fate of emerging and novel per-and polyfluoroalkyl substances. Gomis, M. I., Wang, Z., Scheringer, M., & Cousins, I. T. Science of the Total Environment, 2015, 505, Reproduced with permission from Elsevier. Paper IV Comparing the potency in vivo of PFAS alternatives and their predecessors. Gomis, M. I., Vestergren, R., Borg, D., Cousins, I. T. Manuscript, not yet submitted. Statement of contribution I parametrized the models and performed all simulations in Paper I, II and IV. I carried out the uncertainty analyses with the help of M. MacLeod in Paper I and II. I generated the physicochemical properties together with Z. Wang and performed the environmental fate simulations in Paper III. I developed the study design together with I. Cousins and R. Vestergren for Paper II and with R. Vestergren for Paper IV. Interpretations of the results were made together with the co-authors for all four papers. I took the lead role in writing the four manuscripts. 7

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19 Because the fluorine-carbon bond is extremely stable and hardly polarizable, PFAAs are highly resistant to degradation under even extreme laboratory conditions (e.g. high temperature), and they display lower surface tensions compared to their non-fluorinated analogues. 2 Due to these unique physico-chemical properties, PFASs have been used in both industrial and commercial applications. Examples include surface treatment of textile, carpet, and food packaging, fire-fighting foams, cookware but also as processing aid in fluoropolymer manufacture, as mist suppressants for metal plating and in the production of semi-conductors. 3 The extensive use for over 5 decades coupled with the persistent nature of the perfluorinated moieties has resulted in the accumulation of PFASs in the environment and distribution to remote regions far away from emitting sources. 4 Despite that organofluorine compounds were detected already in human serum in the late 60 s, 5 the first compound-specific analysis of PFAAs in human serum occurred only in 2001, thanks to refined mass spectrometry methods. 6 Since then, PFASs, more specifically perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA) and longer chain PFCAs and PFSAs, have been globally measured in wildlife and humans, 7 10 highlighting their bioaccumulation potential. 11 Concerns over the possible hazard of these substances resulted in a joint effort by industry and regulatory authorities to gradually phase out long-chain PFCAs ( C 7), PFSAs ( C 6) and their precursors. As a result, 3M, the major PFOS and perfluorooctanesulfonyl fluoride (POSF)-derivative manufacturer, voluntarily discontinued the production and use of perfluorohexyl, -octanyl and -decyl chemistry in In 2006, eight major manufacturers made an agreement with the US Environmental Protection Agency (US EPA) to remove PFOA and long-chain PFCAs from their products and to eliminate point-source emissions by In 2009, PFOS was listed in Annex B (i.e. restricted use) of the Stockholm Convention on Persistent Organic Pollutants. 14 Additionally, PFOA, C 9, C 10, C 11-C 14 PFCAs and their sodium and ammonium salts were included in the Candidate List of Substances of Very High Concern for Authorisation under the European Chemicals Regulation on the Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH). 15 This shift in production initiated in the beginning of the 21 st century resulted in the replacement of the legacy PFAAs and their precursors with shorterchain homologues. The rationale behind these substitutions is motivated by the lower bioaccumulation potential and lower toxicity of shorter-chain PFCAs and PFSAs, 16 despite a similar tendency for environmental persistence. Other fluorinated substances (hereafter referred to as alternatives ) have been recently identified as being used as surrogates for PFOA and PFOS. 17 9

20 1.2 The role of human exposure in the risk assessment of chemicals Achieving performant products and cost-effective manufacturing processes are two important objectives of the chemical industry in terms of chemical design. Nevertheless, the chemical properties displaying unique performance capabilities can also be potentially hazardous and pose a risk for the environment, humans and animals, if exposure occurs. In terms of human health, the risk, defined as the probability of a hazardous chemical to cause harm, is characterized by 1) the potential toxicity of the chemical at a given concentration and 2) the magnitude of exposure experienced by the individual. Under REACH, a hazard assessment of industrial chemicals based on their persistence (P), bioaccumulation potential (B) and toxicity (T) is required. 18 However, since hazardous properties are inherent to the molecular structure, addressing the potential risk is usually done by reducing the exposure through phase-outs or mitigation actions. In this respect, comprehensively linking the chemical emissions and the human body burden is of paramount importance for introducing effective, preventive and mitigative steps. Assessing the human exposure should therefore integrate both the external (i.e. levels in the environmental media) and internal (i.e. levels in the human body) exposure. The external exposure aims to identify and quantify the sources and potential exposure pathways which, in the case of industrial chemicals, can be grouped in two categories, namely, the contact to consumer products containing the chemical or the contact to contaminated environmental media. The internal exposure is defined as the amount of chemical in the human body, from its total body burden to the concentration in target tissues, resulting from the external exposure and subsequent intake of a substance. 1.3 Knowledge gaps in the state-of-the-science Since their identification in human serum in 2001, the subsequent intense scientific attention on PFASs, especially long-chain PFCAs and PFSAs, has shed much light on the origins of human exposure. Nevertheless, the numerous fluorochemicals produced for various applications, 3 the historical and ongoing changes in production, the existence of multiple potential exposure pathways 22 combined with the scarcity of information provided by industry 23 makes exposure assessment of PFASs a challenging task. The following subsections introduce the state of the science and knowledge gaps in the field of human exposure to legacy PFAAs and their alternatives when this doctoral thesis work was initiated. 10

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22 the origin of PFOS and PFOA levels in serum prior to the phase out and their exceptionally rapid decline since the early 2000 s was still poorly understood Direct versus indirect sources of human exposure Some fluorochemicals, such as perfluoroalkylsulfonamidoalcohols and fluorotelomer alcohols, have been found to undergo abiotic and biotic degradtion into PFOS and PFOA. 33,34 This has led to a discussion of the presence of PFOS and PFOA in the environment in terms of the relative contribution of indirect (i.e. degraded precursors) versus direct emission sources. 35,36 A related debate has been ongoing concerning the body burden of PFOS and PFOA. Various species including rat, mice and trout have been found to metabolise FTOHs and polyfluoroalkyl phosphoric acids into PFOA, as well as perfluorooctanesulfonamide into PFOS, as the stable end-metabolites In vitro experiments also demonstrated the ability of human microsomes and hepatocytes to metabolise precursors. 41,43,44 These findings suggest that the biotransformation of precursors subsequent to their absorption (i.e. indirect exposure) could contribute to the total body burden of PFOS and PFOA in humans. The relative importance of indirect and direct exposure has however been widely debated in the scientific literature. 22,45 47 Several total intake studies using concentrations in exposure media as a point of departure (i.e. bottomup approach) combined with biotransformation factors estimated the contribution of indirect exposure. Values ranged between <1 and 27% for PFOA and 2-34% for PFOS, for low and intermediate exposure scenarios and up to 80% for PFOA and 55% for PFOS for high exposure scenario. 28,48,49 The difficulty in quantifying the indirect pathway for humans is partly due to the scarcity of data on precursor concentration in exposure media, the interspecies variability in metabolism rates (which increases uncertainty from extrapolation to humans), the lack of knowledge on the pharmacokinetics of precursors and, finally, the multiple exposure pathways that may contribute to the internal exposure. Precursors can be found in various consumer products such as food packaging, treated carpet and outdoor equipment, 47,50,51 and, as a consequence, human exposure can potentially occur. When this thesis work was initiated, there was a need to quantify accurately the contribution of indirect exposure in order to, if non-negligible, address this ongoing source of legacy PFAAs. By studying a highly exposed population with a well characterized external exposure it would be possible to better constrain the metabolism yield of precursor in human. 12

23 1.3.3 Are fluorinated alternatives an improvement on legacy PFASs? Historical examples of chemical substitution with structurally similar products have demonstrated that, by keeping the similar desired functionalities, the hazardous and adverse properties are often maintained, leading to a lock-in problem in the substitution process. 52 Because industry-generated data are often classified as confidential business information, vital information concerning the identity of fluorinated alternatives, their properties, their toxicological profile, their production and their emissions are often unavailable in the public domain, which hinders risk assessment. Though their physicochemical properties and production volumes are unknown, Wang et al. (2013) identified more than 20 novel and emerging fluorinated alternatives, among which, functionalized perfluoropolyethers. 17 Despite the claim of a lower bioaccumulation potential for many fluorinated alternatives, screening of 2930 chemicals highlighted the general tendency of poly- and perfluorinated structures to be PBT. 18 Perfluoroalkyl moieties are not expected to degrade in the environment. Furthermore, according to several toxicity studies on rats, fluorinated alternatives have a lower toxic potency, a parameter that allows the comparison of substances according to their ability in triggering a specific effect, compared to their predecessors However, the potency ranking is usually based on the administered dose (i.e. the need of a lower dose to trigger a toxic effect indicates a higher potency), which integrates the toxicokinetics of the substance within the toxic response. The affinity of PFASs to proteins, 56 which appeared to increase with chain-length, 57,58 plays an important role in their distribution and elimination. It is therefore not clear to what extent of the toxicity of short-chain alternatives is confounded by their distribution and fast elimination kinetics Due to this lack of transparency and the limited knowledge about the environment and the human health risk, the scientific community, through the Helsingør and Madrid statement, brought attention to the potential issues linked to the extensive use of fluorinated chemicals. 63,64 Similar to long-chain PFCAs and PFSAs in the past, some of these alternatives have recently been detected in American, German and Chinese rivers, leading to a potential exposure source for humans As a result, it is urgent to generate data and properly analyse them to facilitate the assessment of the environmental fate and toxicity of these alternatives and to evaluate if the hazard has been reduced compared to the legacy PFASs that they replace. 1.4 Objectives This thesis is a model-based exposure assessment of PFASs that aims to connect comprehensively the industrial production to the human body burden of 13

24 legacy PFAAs, as well as to fill current knowledge gaps in the human exposure of these legacy substances and their replacements. The following questions on human exposure to PFASs were addressed in four studies, which directly reflect the knowledge gaps in the state of the science outlined in section 1.3: 1) How did the human exposure to legacy PFAAs globally and historically evolve? (Paper I) 2) What is the relative contribution of direct and indirect (i.e. metabolized precursors) exposure to the human body burden for PFAAs? (Paper II) 3) Are the fluorinated alternatives less hazardous than their predecessors? (Paper III) 4) Are PFOS and PFOA replacements less potent than their predecessors? (Paper IV) The thesis explores various modelling methods, including quantum-chemistry based models, linear free energy-based models and pharmacokinetic (PK) models to investigate the different questions. The specific objectives of each paper are listed below. Paper I The main objective of this study was to recreate the historical intake of legacy PFAAs (PFOS, PFOA and PFHxS) in the American and Australian population by fitting a population PK model to cross-sectional biomonitoring data. The secondary objectives were to estimate their elimination half-lives and investigate the contribution of menstruation as an additional elimination pathway for women. Paper II This paper aimed to investigate the contribution of direct (i.e. exposure to PFOA) and indirect (i.e. exposure to 8:2 fluorotelomer alcohol (8:2 FTOH) further metabolised into PFOA) exposure in occupationally exposed ski waxers. The metabolism yield, as a measure of the amount of PFOA originating from 8:2 FTOH, was estimated using a dynamic one-compartment PK model. The elimination half-life of PFOA was also estimated. Paper III The primary objective of this project was to predict the physicochemical properties of 16 emerging and novel fluorinated alternatives using in-silico tools. In a second step, the likely environmental fate, characterised by the overall 14

25 persistence and long-range transport potential, was predicted using a multimedia environmental fate model. Paper IV The primary objective was to assess the potency of legacy PFAAs and their replacements by comparing dose-response curves from sub-chronic oral toxicity studies in male rats with the doses expressed as 1) administered dose, 2) serum concentrations and 3) liver concentrations. A dynamic one-compartment PK model was used to convert administered doses into the corresponding concentrations in serum and measured liver:serum concentration ratios were used to convert the estimated concentration in serum into concentrations in liver. 15

26 2 Methods 2.1 Predicting physicochemical properties of organic contaminants Determining the physicochemical properties of contaminants is essential as a preliminary step toward the identification of a potential hazard. In terms of environmental fate, physicochemical properties control the partitioning behaviour and thus the transport and the degradation of the chemical once it is released in the environment. In this respect, they are often used as input parameters in environmental fate models. In addition, comparing chemicals on the basis of their physicochemical properties allow the identification of potential structural and functional similarities. This becomes crucial when assessing the reduction of inherent hazard between legacy industrial contaminants and their replacements. Because experimental data are often not available, especially for novel and emerging contaminants, the physicochemical properties have to be predicted using in silico tools. Several quantitative or qualitative structure-based predictive methods exist such as quantitative structure property/activity relationships (QSPRs/QSARs), linear free energy relationships (LFERs) and quantum-chemistry based models. Selecting the proper method depends on its applicability to the chemical considered but also on the availability of predictive tools. In Paper III, two predictive models were used to estimate the physicochemical properties of legacy PFASs and their replacements. First, the quantumchemistry based model, COSMOtherm, was used to estimate the air water, octanol water, and octanol air partition coefficients (K AW, K OW and K OA), which determine the preferential distribution of the chemical between two different phases. Briefly, energetically favoured conformers were predicted with COSMOconf from the chemical structure of interest (Figure 3). Their surface charge densities were then converted into chemical potential in different bulk phases (i.e. octanol, water, gas) which were further used to calculate the K AW, K OW and K OA of each conformer. The final coefficient value corresponded to the weighted average of all conformers, based on their probability of occurrence. Second, the LFER-based model SPARC was used to predict the acid dissociation constant (pk a) of PFOS, PFOA and the acidic fluorinated alternatives. 16

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28 Tool predicts the overall environmental persistence under steady-state conditions (P OV, in days), which corresponds to the overall lifetime of the substance under consideration in the unit world, and two long range transport potential indicators, namely, the characteristic travel distance (CTD, in km) and the transfer efficiency (TE, in %). CTD represents the distance at which the chemical concentration at the source has dropped by 63% and TE is the targeted transfer of the chemical from the air compartment into the soil or water compartment. The input parameters required were K AW and K OW, estimated with COS- MOtherm (see section 2.1), and the degradation half-life (t 1/2, in hours) in air, water and soil. The degradation parameters were estimated using the EPISuite package applying QSPR/QSAR methods. Because the deprotonated form of acidic PFASs influences their environmental fate, K AW and K OW, which could only be predicted for the neutral forms, were adapted to represent the air water and octanol water distribution ratios of the corresponding anion. This manipulation could not be carried out for the estimated degradation half-lives. 2.3 Pharmacokinetic modelling PK models describe in a relatively simple way complex physiological processes that control the absorption, distribution, metabolism and excretion of exogenous chemicals in an organism. Initially developed to characterize the fate of therapeutic drugs in animals and humans, this mathematical approach, when combined with biomonitoring data, has been successfully used in the exposure assessment of organic contaminants The type of biomonitoring data, namely cross-sectional (i.e. various individuals are monitored at one point in time) and longitudinal (i.e. the same individual is monitored over time) determine the nature of information that can be assessed. With crosssectional data from various points in time, the past and contemporary intake trends of PFASs within a population can be back-calculated by a PK model, that is, in this case, referred as population-based PK model. In contrast, longitudinal data give a better insight on the physiological response to a specific exposure over time. Two main categories of PK model exists: the one-compartment models, where the organism is described as one central reservoir, and the multi-compartment models (known as physiologically-based (PB)PK models), where the central compartment is connected to one or several peripheral compartments representing organs. Despite being more descriptive than one-compartment PK models, PBPK models are more complex and require a proportionally larger number of kinetic input parameters, which, if they are not well constrained, increase the uncertainty of the predicted results. For Paper I, II and IV, a parsimonious one-compartment PK model was favoured and its applicability within the objectives of the papers was justified by the following reasons: 18

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30 Following this model definition, the mass balance of an individual exposed to a specific PFAS can be generally expressed as a first-order differential equation (Eq. 1): 20 [1] Where C serum (ng/ml) is the concentration of PFAS in serum, I (ng/day) is the intake of PFASs, E a (dimensionless) is the absorption efficiency dependent on the uptake route considered (i.e. oral, inhalation, dermal), V d (ml/kg) is the volume of distribution, B W (kg) is the body weight of the individual and k e (1/day) is the elimination rate calculated from the elimination half-life (i.e. k e = ln(2)/t 1/2). For the three studies, the equation was solved under dynamic conditions to integrate in the predictions the frequency (Papers II and IV) and change in magnitude (Papers I and II) of intake over time. Depending on the objective of the study, the model as presented in Eq. 1 required further parametrization and assumptions to improve the accuracy of the output results. In Paper I, modelling the exposure in a population required the implementation of age- and gender-dependent factors influencing the body burden of PFASs, such as the intake from breast feeding, mother-to-foetus chemical transfer and elimination from growth dilution and menstruation. Paper II dealt with longitudinal data obtained from an occupational exposure study that provided detailed quantitative information about the exposure. Therefore, The PK model included the working hours, to characterize the extent of exposure, as well as the inhalation and ingestion exposure of dust. Paper IV differed from the two other studies as the model was applied to rats and required to predict accurately the concentrations in rat serum under sub-chronic exposure conditions. In this respect, biphasic trends in serum, where the decline of concentration in serum after dosing is first attributable to the distribution of the chemical into peripherical tissues, and second, when steady state is reached, to elimination, had to be considered in the parametrization of the model. After parametrization, the models were fitted to the biomonitoring data to obtain, for Paper I, the reference adult daily intake and the elimination half-life, and, for Paper II, the metabolism yield of 8:2 FTOH and the elimination halflife. The least-square optimization method 71 was used to minimize the sum of squared residual weighted (SSRW), with the best estimate corresponding to the simulation with the closest coefficient of determination (= 1-SSRW) to 1. In contrast with the two other studies, in Paper IV the model predicted the concentration in serum with the objective to estimate the internal exposure in in vivo subchronic experiments. The predicted results were expressed as area under the serum concentration curve (AUC ss) calculated at the interval between two doses when steady-state was reached. In addition, the internal exposure in liver was also calculated from liver:serum concentration ratios. Table 1 summarizes the type of biomonitoring data and model used in the three studies as well as the PFASs and outputs that were assessed.

31 Table 1: Summary of the modelling approach in Paper I, II and IV. Paper I Paper II Paper IV PFASs PFOS / PFHxS / PFOA PFOA / 8:2 FTOH C5-C9 PFCAs /GenX / PFOS / PFBS Data Cross-sectional Longitudinal Longitudinal Model Output Dynamic one-compartment population-based PK model Fitted adult daily intake Fitted elimination halflife Dynamic one-compartment PK model Fitted metabolism yield Fitted elimination halflife Dynamic one-compartment PK model Predicted AUCss in serum 2.4 Sensitivity and uncertainty analysis The sensitivity analysis of the model identifies which input parameter has the highest impact on the predicted results. The uncertainty analysis quantifies the uncertainty propagated in the output results by the error in the input parameters. Conducting both analyses systematically is encouraged for a better understanding of model limitations and for a more transparent communication of the results. 78 Several methods were used in this thesis. In Paper III, due to the nature of the predictive tool used and the lack of validation data, the uncertainty of the predictions was qualitatively evaluated and discussed based the potential application domain of the tools on perfluorinated chemical structures. In Paper I and IV, the sensitivity and uncertainty analysis was carried out by applying the Monte Carlo method. Briefly, the technique consists in running numerous simulations based on input data that are randomly varied along a defined distribution. In Paper II, the first-order analytical sensitivity and error propagation method proposed by MacLeod et al. (2002) was used to calculate the margin of error of the fitted results

32 3 Results and discussion 3.1 Past and current exposure to PFAAs The American and Australian adult daily intakes for PFOS estimated in Paper I peaked in the 1980 s in both regions and reached levels of 4.5 and 4.0 ng/kgbw/day, respectively. The intakes started to decrease in the second half of 1990 s with a halving-time of 2.3 years for USA and 4.5 years for Australia. For PFOA, the peak occurred later, in 1992 (3.6 ng/kg-bw/day) for Australia and 1995 (1.1 ng/kg-bw/day) in USA and started to decline in 1995 with a halving time of 5.9 years for Australia and in 2000 with a halving time of 5.8 years for USA. Even though the predictive power for PFOA in USA was weaker compared to the other simulations, the similar time-trends observed in both regions for PFOS and PFOA suggest a common historical exposure source. Since levels in the environment are higher in the Northern compared to the Southern hemisphere, 21,80 the results converge towards an exposure linked to consumer products rather than environmental exposure. In addition, the decline of the fitted daily intakes in the 1990 s before the phase out coincides with the drastic decrease in concentrations of several POSF-derivatives around year 1998 measured in food packaging materials. 81 These results corroborate the hypothesis of Vestergren and Cousins (2009) 32 stating the historical existence of an exposure pathway dominated by consumer products (see Figure 2). While the model was successfully applied to PFOS and PFOA, the model could not be fitted to PFHxS concentrations in serum of both the American and Australian population. The biomonitoring data of PFHxS suggest a potential age-dependent exposure pattern, with a higher intake for individuals below 20 years old. Specific age-dependent exposure such as dust intake for toddlers and kids was not considered in the model. Furthermore, exposure to PFHxS appears to still be ongoing at a similar magnitude to the pre-phase out exposure conditions, even though, like PFOA and PFOS, it was phased-out by the 3M Company in Since the phase out, emissions of precursors may have become more important. 82 Exposure to precursors and subsequent metabolism (i.e. indirect exposure) has been hypothesised as a potential exposure route for PFOA and PFOS, but has never been investigated on a human cohort. 49,83 In Paper II, the metabolism yield (Y meta) of 8:2 FTOH to PFOA was estimated as a quantitative measure of indirect exposure on six ski wax technicians highly ex- 22

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34 at steady state. Considering the current PFOA levels in serum of the background population, that average 2 ng/ml (range ng/ml), 91 the contribution of indirect exposure, in the case of 8:2 FTOH, is likely negligible. It should be however noted that Y meta has been extrapolated on two individuals only, which does not provide a high level of confidence in the estimated value. 3.2 Response of the body burden to exposure dynamics As a result of their long elimination half-lives, the body burden of bioaccumulative chemicals such as PFAAs keeps a memory of the past exposure conditions and displays a slower response to changes in the magnitude of exposure compared to more readily-excreted contaminants. Paper I and II provide good examples to illustrate the impact of exposure dynamics on the human body burden of PFAAs. As mentioned in section 3.1, the six ski wax technicians displayed different PFOA levels and sensitivity to the ongoing exposure: while the PFOA body burden of technicians with low concentrations was building up over time, technicians with high concentrations were depurating. Simulating the past and future concentration time trends in serum of both technician groups helps to understand the general connection between body burden and exposure (Figure 7). When a sudden shift in exposure occurs, the concentration in serum needs to readjust to reach steady state with the new exposure conditions. For individuals who experience a reduced exposure, which could be illustrated by the use of protective equipment for ski wax technicians or by a phase-out event for the general population (Paper I), the concentration in serum decreases over time. In turn, for individuals for which the exposure levels shift upwards, the concentration in serum increases. As shown in Figure 7, if the exposure level is constant over a certain period of time, the concentration in serum at steady state will be the same in all technicians. Therefore, the duration of exposure combined with higher past occupational exposure conditions likely lead to the discrepancies in PFOA body burden. 92,93 24

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36 3.4 The lock-in problem of structurally similar replacements Since the desired performance and properties of a chemical are obtained from its chemical structure, replacing phased-out products with structurally similar ones is a common practice to maintain the requirements of industry. Nevertheless, hazardous properties are also inherent to the chemical structure and substitution with similar products may, therefore, pose the same risk as their predecessors. 103,104 Paper III and IV provide a preliminary assessment on the similarity between PFOS, PFOA and 8:2 FTOH and their alternatives in terms of physicochemical properties, environmental fate and toxicity Persistence (P) and long-range transport potential (LRTP) Despite some limitations, the modelling methods presented in Paper III allowed a preliminary comparative assessment between PFOS, PFOA, 8:2 FTOH and their replacements based on their predicted physicochemical properties, persistence and long-range transport. Overall, estimated log K aw values differed by less than 1.6 log unit. Estimated log K ow values between PFOS and its replacements were less than 0.6 log units apart, while for PFOA, four of the six replacement had log K ow within less than 2 log units. For 8:2 FTOH replacements as well as two PFOA replacements, log K ow values were different by 4 log units compared to the legacy PFASs. Hydrophobicity is likely linked to the molecular sizes since bigger molecules require higher energy to create a cavity among strongly-bonded water molecules. The inclusion of ether linkage(s) appeared to have a steric effect on the perfluorinated molecules, but had a negligible impact on its polarity. Concerning their behaviour in the environment, only two replacements were predicted to be less persistent (P OV<1030 days) and mobile (CTD <1700km) than PFOS and PFOA and 8:2 FTOH replacements were estimated to be less persistent (P OV<350days) but more mobile (CTD>1900km) than 8:2 FTOH. These results suggest similar properties and environmental fate between the alternatives and their predecessors Potency ranking of legacy PFCAs and alternatives The rationale behind the use of shorter chain homologues and other fluorinated alternatives to replace PFOA is based on a lower B and T. 105 In terms of potency, the following ranking has been established based on administered dose and its effect on the liver weight of male rats: PFNA>PFOA>GenX> PFBA>PFHxA (see Figure 8). Paper IV investigated to what extent this ranking is attributed to differences in pharmacokinetics among the substances. As shown in Figure 8, the ranking changes to PFNA GenX>PFOA>PFHxA>PFBA when considering serum AUC ss and 26

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38 4 Conclusion This work provides an insight on different aspects of the broad field of human exposure to PFASs. The past and current exposure to legacy PFASs as well as the propensity of novel and emerging PFASs to be hazardous were investigated. In Paper I, the daily intakes of PFOS and PFOA were successfully estimated from cross-sectional data of two geographically distant populations. The timetrends in exposure were, within the uncertainty range, similar in both regions, suggesting a common historical exposure dominated by consumer products and, upon removal, replaced nowadays by a lower but dominating diet exposure. Furthermore, the declining daily intake prior to 2000 suggests that the industry phase out could have been initiated earlier than the official announcement in Finally, the relatively fast response to the shift in production reinforces the idea of a direct correlation between the industrial phase-out actions and the decline in serum concentrations. In Paper II, the metabolism yield, representing the amount of 8:2 FTOH absorbed that is metabolised to PFOA, was successfully fitted to longitudinal biomonitoring data of occupationally exposed ski wax technicians. However, while the contribution of indirect exposure to the body burden of PFOA was important for ski waxers, it is probably a negligible exposure pathway for the general population. Nevertheless, this study could only investigate the exposure to 8:2 FTOH and, therefore, the same conclusions might not stand for other precursors. In Paper III, the physicochemical properties including the persistence and long-range transport of fluorinated alternatives were predicted using different in silico tools, and compared with the legacy PFASs they are currently replacing. Despite different molecular structures (e.g. inclusions of new atomic moieties), a majority of fluorinated alternatives displayed similar properties, persistence and long-range transport as their predecessors. This implies that the hazardous characteristics of legacy PFASs could also be inherent to some fluorinated alternatives. In Paper IV, the potency ranking among the legacy PFAAs and their alternatives was gradually disappearing as when concentrations closer to the target tissues were used for the assessment. This indicated that toxicokinetics are an important factor in determining the toxicity of PFAAs. 28

39 5 Future perspectives Despite the decrease in production of legacy PFASs, (bi)annual biomonitoring of the population should be maintained in the future, especially for long-chain PFCAs, for which serum concentrations are still increasing despite the recent regulation. Every additional year further away from the phase-out brings new insights on the exposure and depuration trends (e.g. estimated elimination half-lives). Furthermore, we may be able to perform population-scale PKmodelling on the longer-chain PFCAs in the future, which could not be studied in this thesis since population-based model are suited for declining chemical body burden. If possible in the future, it would be an opportunity to estimate the elimination half-lives of long-chain PFCAs, which are currently unknown but expected to be long. Furthermore, future research should investigate the potential age-dependency in exposure to PFHxS, especially for toddlers and kids. To date, the apparent elimination half-life of PFHxS in humans has been estimated only once. 96 Additional biomonitoring, cross-sections in the future could help establishing the intrinsic elimination half-life of PFHxS. Overall, even though the long-chain PFASs are now regulated, research towards investigating the link between their emissions and their body burden should continue with the objective to identify the effectiveness of chemical phase-outs and production shifts. Recent biomonitoring studies have shown that humans are being exposed to a wide range of organofluorine compounds, with increasing ratios of unidentified ones. As non-target analytical methods identify novel PFASs in human serum there may be further candidates for long-term human biomonitoring. 24 The exposure study on exposed ski waxers was a unique opportunity to study the relative contribution of indirect versus direct exposure. Because occupational exposure studies raise awareness of working conditions and promote the use of protective equipment, future work on ski waxer exposure is likely to be of limited value. Ski waxers now wear protective face masks and work in highly ventilated workspaces, which has likely reduced their exposure. Even though precursors are being regulated along with their predecessors in Europe and USA, high exposure to precursors could still occur regionally in other production centres such as China and Brazil. 108 Occupational cohorts in these regions could provide elevated exposure conditions to further study the indirect exposure to other volatile precursors. There can, however, be political 29

40 and industry resistance to conduct such studies in these emerging economic regions where chemical regulation is currently lower than in Europe. One of the major findings of this thesis was, despite some uncertainties, the similarities between legacy PFAAs and their fluorinated alternatives in terms of properties, environmental fate and potency (albeit only for one toxic endpoint). These preliminary hazard assessments should be refined in the future as more information and monitoring data become available. Nevertheless, future research should be efficiently structured and organised to first prioritise the important data gaps and provide comparable data. A more precautionary approach that would limit the necessity of further research on the >3000 PFASs in society would be to follow the recommendation of the Madrid Statement, and eliminate PFASs from non-essential uses. In parallel to such strict regulation of PFASs, sustainable non-pfas alternatives that are both functional and non-hazardous should be developed. Regardless of how strictly PFAS are regulated in the future, resource-effective methods to regulate the large number of PFASs are needed. Society cannot afford to continue to research and regulate each PFAS individually and therefore grouping PFASs according to their similarities (e.g. toxic mode of action) 109 may be a feasible alternative that deserves future consideration. 30

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47 Sci. Technol. 2015, 49 (24), (70) Wegmann, F.; Cavin, L.; MacLeod, M.; Scheringer, M.; Hungerbühler, K. The OECD Software Tool for Screening Chemicals for Persistence and Long- Range Transport Potential. Environ. Model. Softw. 2009, 24 (2), (71) Ritter, R.; Scheringer, M.; MacLeod, M.; Moeckel, C.; Jones, K. C.; Hungerbühler, K. Intrinsic Human Elimination Half-Lives of Polychlorinated Biphenyls Derived from the Temporal Evolution of Cross-Sectional Biomonitoring Data from the United Kingdom. Environ. Health Perspect. 2011, 119 (2), (72) Gyalpo, T.; Toms, L.-M.; Mueller, J. F.; Harden, F. A.; Scheringer, M.; Hungerbühler, K. Insights into PBDE Uptake, Body Burden, and Elimination Gained from Australian Age-Concentration Trends Observed Shortly after Peak Exposure. Environ. Health Perspect. 2015, 123 (10), (73) Lorber, M.; Egeghy, P. P. Simple Intake and Pharmacokinetic Modeling to Characterize Exposure of Americans to Perfluoroctanoic Acid, PFOA. Environ. Sci. Technol. 2011, 45 (19), (74) Andersen, M. E.; Clewell, H. J.; Tan, Y.-M.; Butenhoff, J. L.; Olsen, G. W. Pharmacokinetic Modeling of Saturable, Renal Resorption of Perfluoroalkylacids in Monkeys--Probing the Determinants of Long Plasma Half-Lives. Toxicology 2006, 227 (1 2), (75) Seacat, A. M.; Thomford, P. J.; Hansen, K. J.; Olsen, G. W.; Case, M. T.; Butenhoff, J. L. Subchronic Toxicity Studies on Perfluorooctanesulfonate Potassium Salt in Cynomolgus Monkeys. Toxicol. Sci. 2002, 68 (1), (76) Loccisano, A. E.; Campbell, J. L.; Andersen, M. E.; Clewell, H. J. Evaluation and Prediction of Pharmacokinetics of PFOA and PFOS in the Monkey and Human Using a PBPK Model. Regul. Toxicol. Pharmacol. 2011, 59 (1), (77) Han, X.; Snow, T. A.; Kemper, R. A.; Jepson, G. W. Binding of Perfluorooctanoic Acid to Rat and Human Plasma Proteins. Chem. Res. Toxicol. 2003, 16 (6), (78) Buser, A. M.; MacLeod, M.; Scheringer, M.; Mackay, D.; Bonnell, M.; Russell, M. H.; DePinto, J. V; Hungerbühler, K. Good Modeling Practice Guidelines for Applying Multimedia Models in Chemical Assessments. Integr. Environ. Assess. Manag. 2012, 8 (4), (79) MacLeod, M.; Fraser, A. J.; Mackay, D. Evaluating and Expressing the Propagation of Uncertainty in Chemical Fate and Bioaccumulation Models. Environ. Toxicol. Chem. 2002, 21 (4), (80) Prevedouros, K.; Cousins, I. T.; Buck, R. C.; Korzeniowski, S. H. Sources, Fate and Transport of Perfluorocarboxylates. Environ. Sci. Technol. 2006, 40 (1), (81) Tittlemier, S. A.; Pepper, K.; Seymour, C.; Moisey, J.; Bronson, R.; Cao, X.- 37

48 L.; Dabeka, R. W. Dietary Exposure of Canadians to Perfluorinated Carboxylates and Perfluorooctane Sulfonate via Consumption of Meat, Fish, Fast Foods, and Food Items Prepared in Their Packaging. J. Agric. Food Chem. 2007, 55 (8), (82) Wang, Z.; Cousins, I. T.; Scheringer, M.; Buck, R. C.; Hungerbühler, K. Global Emission Inventories for C 4 C 14 Perfluoroalkyl Carboxylic Acid (PFCA) Homologues from 1951 to 2030, Part II: The Remaining Pieces of the Puzzle. Environ. Int. 2014, 69, (83) D eon, J. C.; Mabury, S. A. Exploring Indirect Sources of Human Exposure to Perfluoroalkyl Carboxylates (PFCAs): Evaluating Uptake, Elimination, and Biotransformation of Polyfluoroalkyl Phosphate Esters (PAPs) in the Rat. Environ. Health Perspect. 2011, 119 (3), 344. (84) Himmelstein, M. W.; Serex, T. L.; Buck, R. C.; Weinberg, J. T.; Mawn, M. P.; Russell, M. H. 8:2 Fluorotelomer Alcohol: A One-Day Nose-Only Inhalation Toxicokinetic Study in the Sprague-Dawley Rat with Application to Risk Assessment. Toxicology 2012, 291 (1 3), (85) Martin, J. W.; Mabury, S. A.; O Brien, P. J. Metabolic Products and Pathways of Fluorotelomer Alcohols in Isolated Rat Hepatocytes. Chem. Biol. Interact. 2005, 155 (3), (86) Nilsson, H.; Kärrman, A.; Westberg, H.; Rotander, A.; Van Bavel, B.; Lindström, G. A Time Trend Study of Significantly Elevated Perfluorocarboxylate Levels in Humans after Using Fluorinated Ski Wax. Environ. Sci. Technol. 2010, 44 (6), (87) Langer, V.; Dreyer, A.; Ebinghaus, R. Polyfluorinated Compounds in Residential and Nonresidential Indoor Air. Environ. Sci. Technol. 2010, 44 (21), (88) Barber, J. L.; Berger, U.; Chaemfa, C.; Huber, S.; Jahnke, A.; Temme, C.; Jones, K. C. Analysis of per-and Polyfluorinated Alkyl Substances in Air Samples from Northwest Europe. J. Environ. Monit. 2007, 9 (6), (89) Shoeib, M.; Harner, T.; Lee, S. C.; Lane, D.; Zhu, J. Sorbent-Impregnated Polyurethane Foam Disk for Passive Air Sampling of Volatile Fluorinated Chemicals. Anal. Chem. 2008, 80 (3), (90) Schlummer, M.; Gruber, L.; Fiedler, D.; Kizlauskas, M.; Müller, J. Detection of Fluorotelomer Alcohols in Indoor Environments and Their Relevance for Human Exposure. Environ. Int. 2013, 57, (91) Lewis, R. C.; Johns, L. E.; Meeker, J. D. Serum Biomarkers of Exposure to Perfluoroalkyl Substances in Relation to Serum Testosterone and Measures of Thyroid Function among Adults and Adolescents from NHANES Int. J. Environ. Res. Public Health 2015, 12 (6), (92) Freberg, B. I.; Haug, L. S.; Olsen, R.; Daae, H. L.; Hersson, M.; Thomsen, C.; Thorud, S.; Becher, G.; Molander, P.; Ellingsen, D. G. Occupational Exposure to Airborne Perfluorinated Compounds during Professional Ski Waxing. 38

49 Environ. Sci. Technol. 2010, 44 (19), (93) Nilsson, H.; Kärrman, A.; Rotander, A.; van Bavel, B.; Lindström, G.; Westberg, H. Inhalation Exposure to Fluorotelomer Alcohols Yield Perfluorocarboxylates in Human Blood? Environ. Sci. Technol. 2010, 44 (19), (94) Nilsson, H.; Kärrman, A.; Rotander, A.; van Bavel, B.; Lindström, G.; Westberg, H. Biotransformation of Fluorotelomer Compound to Perfluorocarboxylates in Humans. Environ. Int. 2013, 51, (95) Bartell, S. M.; Calafat, A. M.; Lyu, C.; Kato, K.; Ryan, P. B.; Steenland, K. Rate of Decline in Serum PFOA Concentrations after Granular Activated Carbon Filtration at Two Public Water Systems in Ohio and West Virginia. Environ. Health Perspect. 2010, 118 (2), (96) Olsen, G.; Burris, J. Half-Life of Serum Elimination of Perfluorooctanesulfonate, Perfluorohexanesulfonate, and Perfluorooctanoate in Retired Fluorochemical Production Workers. Environ. Sci. Technol. 2007, 115 (9), (97) Spliethoff, H. M.; Tao, L.; Shaver, S. M.; Aldous, K. M.; Pass, K. A.; Kannan, K.; Eadon, G. A. Use of Newborn Screening Program Blood Spots for Exposure Assessment: Declining Levels of Perfluorinated Compounds in New York State Infants. Environ. Sci. Technol. 2008, 42 (14), (98) Wong, F.; MacLeod, M.; Mueller, J. F.; Cousins, I. T. Enhanced Elimination of Perfluorooctane Sulfonic Acid by Menstruating Women: Evidence from Population-Based Pharmacokinetic Modeling. Environ. Sci. Technol. 2014, 48 (15), (99) Russell, M. H.; Waterland, R. L.; Wong, F. Calculation of Chemical Elimination Half-Life from Blood with an Ongoing Exposure Source: The Example of Perfluorooctanoic Acid (PFOA). Chemosphere 2015, 129, (100) Lau, C.; Anitole, K.; Hodes, C.; Lai, D.; Pfahles-Hutchens, A.; Seed, J. Perfluoroalkyl Acids: A Review of Monitoring and Toxicological Findings. Toxicol. Sci. 2007, No. 99, (101) Harada, K.; Saito, N.; Inoue, K.; Yoshinaga, T.; Watanabe, T.; Sasaki, S.; Kamiyama, S.; Koizumi, A. The Influence of Time, Sex and Geographic Factors on Levels of Perfluorooctane Sulfonate and Perfluorooctanoate in Human Serum over the Last 25 Years. J. Occup. Health 2004, 46 (2), (102) Fromme, H.; Midasch, O.; Twardella, D.; Angerer, J.; Boehmer, S.; Liebl, B. Occurrence of Perfluorinated Substances in an Adult German Population in Southern Bavaria. Int. Arch. Occup. Environ. Health 2007, 80 (4), (103) Fantke, P.; Weber, R.; Scheringer, M. From Incremental to Fundamental Substitution in Chemical Alternatives Assessment. Sustain. Chem. Pharm. 2015, 1,

50 (104) Tickner, J. A.; Schifano, J. N.; Blake, A.; Rudisill, C.; Mulvihill, M. J. Advancing Safer Alternatives Through Functional Substitution. Environ. Sci. Technol. 2015, 49 (2), (105) Bowman, J. S. Fluorotechnology Is Critical to Modern Life: The FluoroCouncil Counterpoint to the Madrid Statement. Environ. Health Perspect. 2015, 123 (5), A112 A113. (106) Perkins, R. G.; Butenhoff, J. L.; Kennedy Jr, G. L.; Palazzolo, M. J. Drug and Chemical Toxicology 13 Week Dietary Toxicity Study of Ammonium Perfluorooctanoate (APFO) in Male Rats 13-Week Dietary Toxicity Study of Ammonium Perfluorooctanoate (APFO) in Male Rats. Palazzolo Drug Chem. Toxicol. DRUG Chem. Toxicol. 2004, 274 (4), (107) Beekman, M.; Zweers, P.; Zeilmaker, M.; Muller, Q.; de Vries, W.; Janssen, P. Evaluation of Substances Used in the GenX Technology by Chemours, Dordrecht; (108) Heydebreck, F.; Tang, J.; Xie, Z.; Ebinghaus, R. Emissions of Per- and Polyfluoroalkyl Substances in a Textile Manufacturing Plant in China and Their Relevance for Workers Exposure. Environ. Sci. Technol. 2016, 50 (19), (109) Wang, Z.; DeWitt, J. C.; Higgins, C. P.; Cousins, I. T. A Never-Ending Story of Per- and Polyfluoroalkyl Substances (PFASs)? Environ. Sci. Technol. 2017, 51 (5),

51 7 Acknowledgements This piece of work could not have been achieved without the direct or indirect support of a significant number of individuals. And because this thesis took me roughly 1460 days to write, I will take the necessary amount of pages to express my gratitude to each one of them (haters gonna hate). First of all, thanks to my two main supervisors, Ian and Robin, who provided me with the tools to get through the world of scientific research. Together, we have achieved interesting projects even though the path was sometimes sinuous. I learnt to be wrong and less stubborn (Hello, Paper II ) which is a good thing, I guess. Robin, you were of a great mental support during the darkest periods of this entire process. Thanks to Matt, the patience you had towards my questions on the mathematical aspect of my models and the uncertainty analyses is laudable. Thanks also to my co-authors and their valuable inputs. Then, part of the credit goes to my friends and colleagues, from far and close. Starting with my all-time favourite officemate, Stathis. The amount of shared stories and adventures would require an entire book to be told. So, for now I will just mention our Friday s dance-like-no-one-is-watching sessions in the office to release the frustration from our code errors and this: Oh! Get me away from here I'm dying / Play me a song to set me free. A gigantic thank to Kim, my life coach, you made it possible in the most genuine ways, countless times. Another huge one to Kerstin, my partner in crime for one million things, you know which ones. Also to Lisa, for your listening, your coolness but above all for your cakes: food for the soul and fuel for the brain. Credit goes also to Berit, Lara and Maria, by my side for the fun and less fun moments. Thank you girls! To the former and current AcesO gang, who made parties, gatherings and lunch discussions memorable: Dimi, Jana, Steffen, Anton, Lukas, Dämien, Li, Malte, Marko, Giannis, Anne, Raed, Bo, Claudia, Stella. Thanks to Fiona, for her scientific input in Paper I and Wouter for being my PFASs informer (GenX did not escape Paper IV, thanks to you). AcesX s Joao, Ellen, Mafalda and Zandra. To Anita and her bimonthly massages, attempting as best as one can to remove the muscle knots caused by my science. To the A-TEAMers, Lura, Andreia, Kate(rina), Somru, Joo Hui, Fenix, GG, Ana, Lila, Juan, Gopal and Claudio. Many unforgettable moments, especially in Madrid, B-gham, A-dam and S-holm. Special thanks 41

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