Perfluoroalkyl substances (PFASs) are widely utilized manmade chemicals. Their properties have made them highly appreciated in a variety of industrial and consumer product applications, including fire-fighting foams, hydraulic fluids, as well as in cookware and food contact papers. However, some of the PFASs are highly persistent in the environment and their toxicological profiles are of concern. Voluntary and regulatory efforts have been taken to reduce the environmental levels of PFASs. These actions have resulted in a reduction of PFASs in human milk from Stockholm as presented in this thesis. The radiosyntheses of 35S-PFOS, 35S-PFBS, and 14C-PFOA presented herein were applied for distribution studies in mice but also for solubility and adhesion experiments of common laboratory solvents and buffers. The radiosynthesis employed reactive Grignard reagents, perfluoroalkyliodides, and 35S-sulfur dioxide or 14C-carbon dioxide. The distribution studies were performed with 35S-PFOS on both pregnant mice and their offspring as well as on male mice. The mice were subjected to whole-body autoradiography and the tissues were analyzed by liquid scintillation counting. Liver and lungs were the target organs for 35S-PFOS in the dams. The fetuses and pups had remarkable high levels of 35S-PFOS in their lungs as well as in the brain. The male mice were given a high dose and a more environmental relevant dose of 35S-PFOS. PFOS was transferred from the blood to the tissues as the dose increased. In another study the distribution pattern of the shorter homologue PFBS was compared to PFOS. 35S-PFBS was utilized and demonstrated a 5-40 fold lower tissue levels in comparison to PFOS. The pharmacokinetic parameters determined for PFHxS in mice, rats, and monkeys will provide valuable insight in establishing a proper risk assessment for this compound. The study confirms the common species differences in serum elimination half-life that are associated with PFASs. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 6: Manuscript.</p>

<div> <p>In recent years, the presence of per- and polyfluoroalkyl substances (PFAS) in aquatic systems has led to research on their fate, effects and treatability. PFAS have been found in various environmental matrices including wastewater effluents, surface, ground, and drinking water. Perfluoroalkyl acids (PFAAs) are the class of PFAS most commonly tested due to their ability to migrate rapidly through groundwater and include perfluoroalkyl sulfonic acids (PFSAs) and perfluoroalkyl carboxylic acids (PFCAs). Of the globally distributed and persistent PFAAs, PFSAs are the most resistant to biological and oxidative chemical attack. This doctoral study focused on a reductive treatment approach with zero valent metals/bimetals nanoparticles (NPs) synthesized onto a carbon material to reduce NP aggregation. Initial work focused on exploring reactivity of different combinations of nano (n) Ni, nFe⁰ and activated carbon (AC) at 22 ^oC to 60 ^oC for transforming perfluorooctanesulfonate (PFOS) from which nNiFe⁰-AC at 60 ^oC led to transformation of both linear (L-) and branched (Br-) PFOS isomers. The remaining research focused on work with nNiFe⁰-AC at 60 ^oC in batch reactors including optimizing nNiFe⁰-AC preparation, quantifying PFOS transformation kinetics and evaluating the effects of PFAA chain length (C4, C6 and C8) and polar head group (PFSA versus PFCA) as well a groundwater matrix on transformation magnitude. Optimization of analytical methods to provide multiple lines of evidence of transformation including fluoride, sulfite and organic product generation was an ongoing throughout the research.</p> <p>nNiFe⁰-AC prepared with a 3-h synthesis stirring time led to the highest PFOS transformation of 51.1 ± 2.1% with generation of ~ 1 mole of sulfite (measured as sulfate) and 12 moles of fluoride. Several poly/per-fluorinated intermediates with single and double bonds were identified using quadrupole time-of-flight mass spectrometry (QToF-MS) in negative electrospray ionization (ESI-) mode with MS/MS fragmentation confirmation as well as one and later two desulfonated products with QToF negative atmospheric pressure chemical ionization (APCI-). All organic transformation products were found in only particle extracts as well as most of the sulfite generated. PFOS transformation kinetics showed that generated fluoride concentrations increased for the first day whereas sulfate concentrations continued to increase during the 5-d reaction. The transformation products identified showed defluorination of single- and double-bond structures, formation of C8 to C4 PFCAs and paraffins from cleavage of the C-S bond.</p> <p>The length of the perfluoroalkyl chain affected the length of time to achieve peak removal, but overall magnitude of transformation when reactions appeared complete were similar for both PFSAs and PFCAs. Like PFOS, PFOA transformation maxed in 1 d whereas shorter chains required more time to reach their peak removal, which is hypothesized to be due to lower sorption of the shorter chain PFAAs to the reactive surfaces. Measured F mass balance was higher for PFOS and PFOA (>90% F) compared to shorter chain PFAAs (~50-70% F). The Perfluorohexanesulfonate (PFHxS) and perfluorobutanesulfonate (PFBS) degradation products include single bond polyfluoroalkyl sulfonates and shorter-chain perfluoroalkyl carboxylates. For example, PFHxS transformation resulted in perfluorohexane carboxylic acid (PFHxA) and perfluorobutane carboxylic acid (PFBA). PFCA transformation products included per- & polyfluoroalkyl carboxylates with single bonds and alcohols with single and double bonds. The effect of inorganic matrix on transformation with nNiFe⁰-AC at 60 ^oC was explored using a contaminated groundwater collected at a former fire-training area in Massachusetts. Transformation appeared ‘generally’ lower than in the single-solute clean water systems, which may have been due to the presence of PFAS precursors that degraded to PFAAs and competitive adsorption between anionic PFAAs and inorganic ions onto the NP surface.</p><p>The research presented here demonstrates that nNiFe⁰-AC at 60 ^oC can mineralize PFAAs even in a typical groundwater matrix. Additional lab and pilot scale studies are needed to clarify the mechanisms leading to transformation as well as why transformation reactions plateau prior to all the parent compounds being transformed. The latter may be due to a poisoning phenomenon that can occur in closed systems, which may not occur in a flowing system more characteristic of an environmental scenario, as well as surface area and reactive site constraints or particle passivation.</p></div>

<p>  </p> <p>Perfluoroalkyl substances (PFAS) are synthetic chemicals that are composed of fluorinated aliphatic chains and are widely used in industrial and consumer products. These chemicals are very stable and persist in the environment. Due to concerns linked with longer chain PFAS, shorter chain chemicals are being used as replacements. There are limited human health data regarding the shorter chain chemicals. In addition, these alternatives are persistent in the environment similar to the longer chain PFAS. The main objective of this dissertation was to assess developmental toxicity of the shorter chain PFAS or shorter chain PFAS with chemical modifications represented by perfluorobutanoic acid (PFBA, C4), perfluorohexanoic acid (PFHxA, C6), perfluorobutane sulfonate (PFBS, C4), and perfluoro-2-proxypropanoic acid (GenX, C6). Overall, the results showed that chain length and functional group are determinants of toxicity of PFAS. All tested PFAS induced one or more developmental adverse outcome, but the effects of each chemical are unique, warranting further studies to address the toxicity of the replacement PFAS. </p>

Les composés perfluorés (PFC) de formule chimique générale CF3-(CF2)n-SO3- ( sulfonates) ou CF3-(CF2)n-1-CO2- (acides) sont des polluants organiques émergents, dont la persistance, la bioaccumulation et la toxicité sont maintenant considérées préoccupantes au plan sanitaire et environnemental. L'objectif de notre recherche a été de mettre en évidence les effets cancérogènes in vitro et le mécanisme d'action impliqué lors de l'exposition pendant 7 jours de cellules embryonnaires de hamster Syrien (SHE) aux principaux représentants perfluorés, le sulfonate de perfluorooctane (PFOS), le perfluorooctanoate (PFOA), et à leur substitut, le sulfonate de perfluorobutane (PFBS). Le test de transformation cellulaire dans sa version standard ou selon un protocole de type initiation-promotion a permis de détecter les substances cancérogènes de profil initiateur ou promoteur de tumeur. La génotoxicité des PFCs a été explorée par le test Comet en conditions alcalines. PFOS a présenté un profil cancérogène non génotoxique de type initiateur aux concentrations de 0,37 et 3,7 µM (p<=0,01), coïncidant avec les concentrations sériques des travailleurs exposés au PFOS. L'activation des gènes PPARs a été observée après 7 jours d'exposition au PFOS, avec une induction plus importante et plus précoce (dès 24 heures d'exposition) du gène ppar-bêta/gamma aux concentrations transformantes (p<=0,05). PFOA appliqué seul n'induit pas la transformation néoplasique des cellules SHE. Par contre, il induit la transformation des cellules présensibilisées par un initiateur. Il agit selon un profil cancérogène non génotoxique de type promoteur de tumeur aux concentrations de 3,7 x 10-4 à 37 µM. Ces concentrations coïncident avec les concentrations sériques mesurées dans les populations professionnellement et non professionnellement exposées. PFBS ne s'est révélé ni initiateur, ni promoteur de tumeur. La mise en cause de ces PFCs dans l'augmentation des cancers de la vessie (pour le PFOS) et celui de la prostate (pour le PFOA) chez les travailleurs exposés ne peut être exclue / Perfluorinated compounds (PFCs) is a collective name for fluorinated surfactants and polymers with the general structure CF3-(CF2)n-SO3- (sulfonates) or CF3-(CF2)n-1-CO2- .(acids). This group is characterized by a high persistence, bioaccumulation and long term toxicity which are rising environmental and public health concerns. In the present work, we analyzed the in vitro carcinogenic potential of the two major PFCs, perfluorooctane sulfonate (PFOS), and perfluorooctanoic acid (PFOA), and their substitute, perfluorobutane sulfonate (PFBS). Cell transformation assays were carried out on Syrian hamster embryo (SHE) cells in a 7 day-treatment using the standard and the initiation-promotion protocols. Genotoxicity was tested using the comet assay. PFOS was not genotoxic on SHE cells, but it induced cell transformation at non cytotoxic concentrations 0,37 and 3,7 µM (p<=0,01). These concentrations coincided with serum PFOS concentrations measured in occupationally exposed workers. An increased expression of PPARs was registered after 7 days. The ppar-beta/gamma mRNA appeared to increase rapidly (24 hours after PFOS treatment) at concentrations closely related to cell transformation (p<=0,05). PFOA was inactive alone, but induced cell transformation of SHE cells pre-initiated with benzo(a)pyrene (BaP). Therefore PFOA was shown to act as a tumor promoter and a non genotoxic carcinogen at a large range of concentrations (3,7 x 10-4 à 37 µM). This range of concentrations covered seric concentrations in non-occupationally exposed and occupationally exposed populations. PFBS was negative alone and on BaP-pretreated SHE cells. For this reason, its use as a substitute for PFOS appears to be justified. To conclude, the cell transforming potenty of PFOS and PFOA denotes in vitro carcinogenic potential. Consequently, the hypothesis of their implication in human cancer recorded in occupationally exposed populations cannot be ruled out