Perfluoroalkylated substances (PFAS) are persistent contaminants that are widely distributed in the global environment. Despite the fact that these chemicals have been manufactured and used for over 50 years, there has been little scientific and regulatory interest until very recently. An important research priority over the past decade has been to gain a better understanding of the mechanisms and pathways explaining the presence of these compounds in remote regions. One explanation is related to the use and release of volatile precursor compounds which undergo atmospheric transport and are also susceptible to degradation to PFAS through gas phase reactions with radical species. The main purpose of this doctoral thesis was to investigate an alternative explanation, namely the long-range transport (LRT) of PFAS themselves, which have been released into the environment in substantial quantities during manufacturing and product use. Papers I – III explore the LRT potential of perfluorocarboxylic acids and perfluorocarboxylates and demonstrate that both oceanic and atmospheric transport are efficient pathways of dispersion from source to remote regions of the Northern Hemisphere. Oceanic transport of perfluorooctane sulfonate (PFOS) was shown to be an important process in Paper IV as well. The role of precursor transport and degradation to PFOS was also examined in this paper. The most interesting aspect of the fate and transport of PFOS precursors is the rapid response in ambient concentrations exhibited by these compounds in the model simulations following production phase-out. Since precursor compounds are known to degrade to PFOS in vivo, the modeling results demonstrate that this exposure pathway is a plausible explanation for the declining trends in PFOS concentrations reported for marine mammals in some remote environments.

Abstract Persistent organic pollutants (POPs) are ubiquitous and bioaccumulative man-made chemicals, resistant to chemical, biological and photolytic degradation and widely distributed to sediments, wildlife, and human. Many of these chemicals have adverse effects on a variety of targets, including the endocrine system, organogenesis and reproduction. Due to these effects and wide distribution, many of them are either banned or strictly controlled. However, because of persistency, they continue to interact with organisms globally. Despite the existing knowledge of the adverse effects of POPs, the effects of many chemicals on bone tissue are still poorly known. In the present study, we investigated the adverse effects of three common POPs, including tributyltin (TBT), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and perfluorooctanoic acid (PFOA) on the skeletal system. In vitro models were used to study the effects of PFOA in mouse and in human, and the co-effects of TBT and TCDD on differentiating osteoblasts and osteoclasts of mice. An in vivo model for mice was used to study the developmental effects of maternal PFOA-exposure on pups among with morphometrical and biomechanical property analyses. Mass-spectrometry was used to study the presence of PFOA in bones both in mice and in human, the latter acquired from the bone bank held in the Oulu University Hospital, Finland. The bones were also analyzed with cone beam computer tomography and microcomputer tomography. The results show that PFOA exposure in utero and during lactation leads to the accumulation of PFOA in bone, traceable even 17 months after exposure. PFOA exposure decreased the mineral density of the tibias and increased the medullary area. Nearly all of the human samples contained PFAS, including PFOA. PFOA also disturbed the differentiation of osteoblasts and with lower doses, increased bone resorption of osteoclasts both in mouse and human, the phenomenon being slightly stronger in mice. Co-exposure to TBT and TCDD led to decreased differentiation of osteoblasts and osteoclast, and the co-effect was partially synergistic in osteoblasts. These results show disruption of bone development, bone cell differentiation, and PFAS accumulation in bone. Further studies are recommended to evaluate the co-effects of different POPs and the possible effects of long-term accumulation of POPs in bone and other tissues. / Tiivistelmä Pysyvät orgaaniset ympäristömyrkyt (POP-yhdisteet) ovat kemikaaleja, jotka ovat levinneet ihmisen toiminnan seurauksena laajalle ympäristöön, sen eliöihin ja ihmisiin. Monilla POP-yhdisteillä on haitallisia vaikutuksia esimerkiksi hormonaaliseen toimintaan, elinten muodostukseen ja hedelmällisyyteen. Toksisten vaikutusten ja niiden yleisyyden vuoksi monien POP-yhdisteiden käyttö on joko rajattua tai kielletty kokonaan. Laajan levinneisyytensä ja hitaan puoliintumisaikansa takia POP-yhdisteet ovat kuitenkin edelleen vuorovaikutuksessa ympäristön ja sen eliöiden kanssa. POP-yhdisteiden luustovaikutuksista tiedetään edelleen vähän. Tässä väitöskirjassa tutkittiin kolmen yleisen POP-yhdisteen, tributyylitinan (TBT), 2,3,7,8-tetraklooridibentso-p-dioksiinin (TCDD) ja perfluoro-oktaanihapon (PFOA), vaikutuksia luustoon. PFOA:n vaikutuksia hiiren ja ihmisen luustoon sekä TBT:n ja TCDD:n yhteisvaikutuksia hiiren erilaistuvien osteoblastien ja osteoklastien suhteen selvitettiin in vitro -malleilla. In vivo -mallilla tutkittiin hiiriemon PFOA-altistuksen vaikutusta syntyvien poikasten luuston kehitykseen ja remodelaatioon analysoimalla poikkileikekuvia sekä luiden biomekaanisia ominaisuuksia. Lisäksi luiden PFOA-pitoisuudet mitattiin massaspektrometrilla. Tutkimusta laajennettiin ihmiseen analysoimalla Oulun yliopistollisen sairaalan luupankkinäytteitä. Ihmisnäytteet analysoitiin myös kartiokeila-TT:n ja mikro-TT:n avulla. Tulosten mukaan PFOA kertyy luuhun; hiiriltä voitiin mitata PFOA-pitoisuuksia jopa 17 kuukautta altistumisen jälkeen. Lisäksi PFOA-altistus pienensi luun mineraalitiheyttä ja kasvatti luuydinontelon tilavuutta. Lähes kaikki ihmisluunäytteet sisälsivät PFOA:ta ja muita PFAS-yhdisteitä. Solukokeiden perusteella PFOA-altistus häiritsee osteoblastien erilaistumista ja pienillä pitoisuuksilla lisää osteoklastien luunhajotusta sekä hiirellä että ihmisellä. TBT:n ja TCDD:n yhteisaltistus vaikuttaa puolestaan vähentävän sekä osteoblastien että osteoklastien erilaistumista ja toimintaa; osteoblastien osalta yhteisvaikutus oli osaksi synergistinen. Väitöskirja antaa lisätietoa POP-yhdisteiden vaikutuksista luun kehitykseen ja luusolujen erilaistumiseen sekä PFAS-yhdisteiden kertymisestä luuhun. Väitöksessä myös suositellaan lisätutkimuksia yhdisteiden yhteisvaikutuksista sekä pitkän aikavälin ympäristökemikaalikertymän vaikutuksista luussa ja muissa kudoksissa.

Perfluoroalkylated substencies are priority organics polutants. They are evolved to the environment from many sources. We classify them as new xenobiotics which are present in the environment. There will be described their chemical, physical and environmental properties in theoretical part and there will be described the analytical chemistry of these substancies in varios types of environmental samples. There will be developed metod for their identification and quantification. For this assignment will be use especially chromathografic methods. There will be developed standard operation procedure. The procedure will be verify on real environmental samples.

Les estuaires sont des écosystèmes aquatiques particulièrement soumis au changement global et notamment à la pollution par de nombreux xénobiotiques pouvant présenter un risque écotoxicologique et sanitaire. En toxicologie environnementale et en évaluation des risques la bioaccumulation est un processus fondamental car elle contrôle les doses internes de toxiques potentiels. Or les flux de contamination et de décontamination des organismes dépendent de processus internes (e.g. nutrition, croissance) eux-mêmes dépendant des conditions environnementales (e.g. température, nourriture) qui peuvent être affectées par le changement global.Dans ce contexte, cette thèse se propose de décrire, dans un cadre de modélisation mécaniste, les processus de bioaccumulation de deux familles de polluants organiques persistants (POP) halogénés potentiellement toxiques et bioaccumulables, aux propriétés physico-chimiques contrastées : les polychlorobiphényles (PCB, composés historiques fortement lipophiles) et les substances perfluorées (PFAS, composés émergents amphiphiles). Ce travail se focalise sur l’estuaire de la Gironde dont la fonction de nourricerie est fondamentale pour de nombreuses espèces de poissons marins dont la sole commune (Solea solea), souvent utilisée comme indicatrice de la qualité des nourriceries côtières et estuariennes.Pour permettre de tenir compte des fluctuations des conditions environnementales sur la bioaccumulation, dans la première partie de ce travail, j’ai développé un modèle de toxicocinétique(TK) couplé avec un modèle mécaniste bioénergétique basé sur la théorie DEB (Dynamic Energy Budget). Ce modèle DEB a été paramétré pour la sole commune et calibré pour chaque sexe (package DEB tool). Il permet de prédire les principales évolutions des fonctions physiologiques d’intérêt en bioaccumulation (ingestion, croissance, reproduction...), tout au long du cycle de vie d’un individu, en fonction de conditions environnementales dynamiques. Le modèle TK développé a été complexifié par l’ajout d’un flux d’élimination de contaminants, non considéré dans les précédents modèles DEB-TK.La calibration des paramètres toxicocinétiques (TK) du modèle, pour 4 congénères de PCB, est basée sur une méthode innovante de prise en compte de la variabilité individuelle d’ingestion, appliquée à une expérimentation de contamination de juvéniles de sole via leur nourriture. Ce travail a montré que même en tenant compte de l’ingestion de chaque poisson, l’assimilation efficace de contaminant était très variable et corrélée aux taux de lipides des individus. Dans une seconde partie, ce modèle a été appliqué aux conditions in situ de l’estuaire de la Gironde. Il a permis de mettre en évidence la forte influence de la composition du régime alimentaire sur la variabilité de l’âge à la maturité sexuelle et de la contamination des soles pour les deux familles de contaminant étudiées. La confrontation des prédictions du modèle aux mesures de contaminants dans les juvéniles de sole de l’estuaire a permis de calibrer les paramètres TK du composé majeur de chaque famille dans l’environnement (CB153 et PFOS). Cette calibration a conduit à deux constats dans le cadre de l’évaluation du risque : (1) un manque de connaissances pour extrapoler les calibrations de paramètres TK en conditions contrôlées vers les conditions naturelles ; (2) la différence d’erreur d’évaluation du risque liée à l’utilisation des mêmes paramètres TK «les plus pessimistes » quels que soient les composés. Enfin, des scenarios prospectifs simples ont été développés pour illustrer ces résultats et les possibles applications du modèle développé.In fine, ces prédictions de la contamination, de la croissance et du développement des soles pourront être reliées, lors de travaux ultérieurs, à des effets potentiels sur les fonctions physiologiques de la sole (modèles DEBtox), et aux conséquences sur la dynamique des populations de soles (e.g.modèles matriciels de population). / Estuarine ecosystems are particularly impacted by global change and, specifically, bychemical pollution from numerous xenobiotics that may be associated to ecotoxicological and health risks. In environmental toxicology and risk assessment, bioaccumulation is a fundamental process as it controls the internal doses of potential toxicants in organisms. However, the contamination and decontamination flows depend on internal processes thatare themselves dependent on environmental conditions (e.g. temperature, food) and thus on the other variables of global change.In this context, this manuscript aims at describing, within a mechanistic modelling framework, the bioaccumulation processes of two families of potentially toxic and bioaccumulable halogenated persistent organic pollutants (POPs) with contrasting physicochemical properties: the polychlorinated biphenyls (PCBs, highly lipophilic historical compounds) and the perfluorinated substances (PFAS, amphiphilic emerging compounds).This work focuses on the Gironde estuary whose nursery function is fundamental for many species of marine fish including the common sole (Solea solea), often used as an indicator of the quality of coastal and estuarine bursary grounds. In order to account for the influence of environmental conditions on bioaccumulation, the first part of this work consisted in developing a toxicokinetic model (TK) coupled with a mechanistic bioenergetic model based on the theory DEB (Dynamic Energy Budget). This DEBmodel has been parameterized for common sole and calibrated for each sex (packageDEBtool). It allows predicting the main evolution of the physiological functions of interest forbioaccumulation (ingestion, growth, reproduction...) throughout the life cycle of an individualaccounting for dynamic environmental conditions. The developed TK model was first calibrated for some PCBs, under controlled conditions, using an innovative method to take into account individual ingestion variability. This work showed that even if the individual ingestion of each fish is accounted for, the effective assimilation of contaminant is very variable and correlated with the lipid levels of the individuals. The application of the model tothe in situ conditions of the Gironde estuary led to identify that, whatever the contaminant family, the composition of the soles diet had a strong influence on the variability of soles contamination and age at sexual maturity. The comparison of model predictions with measurements made in juveniles of the estuary allowed calibrating the TK parameters values for the major compound of each family in the environment (CB153 and PFOS). This calibration led to two observations in the context of a risk assessment: (1) a lack of knowledge to extrapolate calibrations of TK parameters under controlled conditions to natural conditions;(2) the difference in risk assessment error related to the use of the same "worst case" TK parameters regardless of the compounds. Lastly, simple prospective scenarios have beendeveloped to illustrate these results and the possible applications of the model developed.Ultimately, these predictions of soles contamination, growth and development may be related in future work to potential effects on the physiological functions of sole (DEBtox models), and to consequences on soles population dynamics (e.g. matrix population models).