In light of growing use of engineered nanomaterials (ENM) in a wide variety of applications, it has become evident that research on their safety must also be conducted. This thesis aimed at uncovering the possible toxicity of two commonly used nanomaterials, titanium dioxide (TiO2) and carbon nanotubes (CNT), especially in the occupational context. This work focused on the direct effects of repeated nanoparticle exposure on the development of lung inflammation in vivo. Whether exposure to nanoparticles modulates development of allergic asthma was also investigated.
When looking at the direct effects following TiO2 or CNT exposure, it can be concluded that they reside on the opposite sides of the spectrum. In general TiO2 nanoparticles do not pose alarming risks to pulmonary health. In this thesis they only caused mild or moderate inflammatory effects, which were characterized by activated macrophages and following neutrophilia. Out of the two different CNT studied in this thesis, one was rather harmless (tCNT) and another with potentially very toxic effects (rCNT). The granulomas, AHR, eosinophilia, mucus producing cells, Charcot-Leyden-like crystals and inflammatory mediators seen in four weeks after a single aspiration exposure exceeded the effects seen with crocidolite asbestos. Inhalation exposure to rCNT revealed a novel allergic-like inflammation mediated by the innate immunity. It seems that rigid fibre-like CNT pose a special threat to pulmonary health and may eventually cause serious fibrosis and impairment of the lungs.
When asthmatic mice were exposed to TiO2, the discoveries were rather surprising. It seemed that exposure to certain nanosized and fine TiO2 caused modulation in the allergic inflammation, resulting in local and systemic reduction of several features of experimental asthma. In contrast with e.g.
severe effects of particulate air pollution (Gavett et al. 2001, Pandya et al.
2002) on allergic asthma, a similar suppressive phenomenon has been seen with e.g. oak dust (Määttä et al. 2007) and microbe exposure (Whitehead et al. 2014). It would be interesting to pursue this lead and to find out more about
the mechanisms behind this suppression. The results could open new doors in understanding mechanisms of human allergic asthma.
Considering human exposure to nanosized TiO2 in general, it could be concluded that exposure to large enough quantities of TiO2 to cause serious harm is somewhat unlikely. However considering the very wide use of TiO2 it is crucial to design products and manufacturing processes in ways that do not allow TiO2 to accumulate in humans or the environment. In the case of CNT, significant release and following exposure from consumer products is unlikely, if one excludes manufacturing and processing, tires, recycling and their potential use in textiles. Even in the above mentioned scenarios, the exposure levels will be low (Guseva Canu et al. 2016). Special attention should still be paid to new MWCNT that are designed, produced and used in application. Without thorough toxicity evaluation (e.g. LOAEL, follow-up studies) they should always be treated as potentially hazardous materials.
As both studied materials, TiO2 and MWCNT, are already being introduced into novel areas e.g. in diagnostics, pharmacology and therapeutics, it is good to also keep in mind the numerous advantages of these materials. For example, TiO2 has demonstrated potential as a cancer drug due to its photocatalytic killing effect (Sha et al. 2013). CNT on the other hand, can be used to deliver drugs to specific sites in the organism due to the fact that they are hollow and with functionalization easily targeted to specific sites (Amenta et al. 2015).
This exciting development should still always proceed hand-in-hand with toxicological testing.
Due to the rapidly growing numbers of different ENM, vivid toxicity testing cannot be performed on all new materials. Standard in vitro tests to assess basic ENM toxicity will hopefully become available in the near future and they will most likely be enough for pre-evaluated low risk ENM. For example thorough characterisation can give vital clues about the possible toxicity of ENM. The situation at the moment calls for actual exposure studies to be conducted to provide solid evidence of possible exposure scenarios. However,
the analytical methods available have great problems monitoring exposure in real-world conditions (Guseva Canu et al. 2016, Liou et al. 2015).
The main contributions of this thesis could be summarized as providing information on a potential inhibitory mechanism of allergic asthma, helping to unveil mechanisms of a new Th2 type eosinophilic airway inflammation and providing new information on diverse abilities of different ENM to impact the immune system. This information can be further utilized in hazard assessment.
7 ACKOWLEDGEMENTS
This work was carried out in the Finnish Institute of Occupational Health (FIOH), Unit of System Toxicology (former Unit of Excellence for Immunotoxicology) where Director General Harri Vainio (retired) is acknowledged for ensuring such excellent research facilities. The financ ia l support for this study was provided by the Finnish Work Environment Fund, Academy of Finland and the European Union.
I am grateful to my supervisor, Harri Alenius, for taking me into this wonderful group of people and for opening the door to the amazing world of nanoparticles. You have shown me true dedication towards science and always been most kind towards me. It never felt embarrassing to ask even the most stupid questions in your presence. You were always most eager to hear the latest results from our experiments and many moments of happiness and delight were shared, as were some more gloomy ones. Thank you for sharing this adventure with me! I especially thank you for being so encouraging and understanding about my own expanding family.
I am deeply grateful to Lea Pylkkänen for being my backbone all these years.
I can’t thank you enough for all the encouraging talks we have had, both professional and otherwise. You were always there when I had no one else to turn to. Early on, you taught me how to brush off disappointments and failures and quickly move on or to try again. Being a person of big feelings, this has undoubtedly saved me from a lot of misery during these years. Special thanks for all the dog talk and company during long days in the dark cellar.
My most sincere thanks also belong to my pre-reviewers Marjut Roponen and Juha Pekkanen for all your valuable comments and suggestions for improving the final version of this thesis. Ewen MacDonald is acknowledged for the language revision of this thesis completed on a catamaran from Split to Hvar.
I want to thank all my co-authors of the original publications. This thesis has really been a triumph of multidisciplinary science. I wish to thank you all for sharing your expertise and interesting discussions we have had trying to make some sense out of a nano-world. I want to thank Marit Ilves for being a wonder woman in the lab and elsewhere. I don’t know if my thesis would have ever been finished if it wasn’t for all your hard work. Joonas Koivisto is thanked for making possible all of the inhalation exposures and for helping me with the physics parts. My warm thanks also go to Henrik Wolff for all the fun and amazing moments we shared around the microscope.
I give my warmest thanks to all the members of our former group, Unit of System Toxicology and Unit of Excellence for Immunotoxicology, with whom I have had the pleasure of working with. Marina Leino and Marja-Leena Majuri are thanked for teaching me all the necessary lab and other skills to actually perform the research. Heli Nykäsenoja is thanked for beginning this journey with me. Minna Anthoni, Päivi Kankkunen and Elina Välimäki are thanked for sharing the room and pieces of your life with me. Terhi Savinko, Sari Lehtimäki, Maili Lehto, Nanna Fyhrquist, Piia Karisola, Rita Helldan, Päivi Alander and Santtu Hirvikorpi are thanked for sharing in on all things murine. Sari Tillander, Sauli Savukoski, Tuula Stjernvall and Esa Vanhala are acknowledged for help with technical and analytical things. Johanna Kerminen and Jukka Sund, I thank you for your friendship. Niina Ahonen, Dario Greco, Vittorio Fortino, Pia Kinaret, Juha Määttä, Sampsa Matikaine n, Joe Ndika, Jaana Palomäki, Alina Poltajainen, Anne Puustinen, Annina Rostila, Kristiina Rydman, Sara Sajaniemi, Ossian Saris, Helene Stockmann-Juvala, Sandra Söderholm, Laura Teirilä, Ville Veckman, Johanna Vendelin, Sara Vilske and Anna-Mari Walta were also part of this very special group of people, among which help was always given however big or small the question or problem was. Thank you all for creating the most pleasant place to work!
I also want to extend my thanks to everyone at the Nanosafety Centre and especially to the members of our very own Nanoclub. Amazing scientific things were discussed in the Nanoclub. I want to thank Hanna Lindberg for
sharing the ups and downs of research and motherhood with me. Thank you for your friendship. Kati Hannukainen and Miia Antikainen, what can I say about you two - you bring laughter with you wherever you are. I also salute Kai Savolainen, Mr. Nano, for traveling the world for us and always making us PhD students feel like amazingly talented scientist.
Many hugs to all my dearest friends: Satu, Anne and Johanna. We have been through so many things together and hopefully it’s just the beginning! I run out of big words with you, äiti and iskä. All I can say is thank you. Thank you for all your endless love and support. The same goes for you, my lovely sisters, Anniina and Katriina. You are the best. And Kasperi, Dixie and Penni, one should never forget the dogs. They are important.
Last, but most certainly not the least, I wish to thank my dear husband Walter and the centers-of-my-universe Saima and Hilda. Walter, you have made me so happy over the years I cannot thank you enough. Thank you for all your support and taking such good care of me. Saima and Hilda, you are by far the most amazing things in my life and I love you endlessly. Thank you Lord, for all the blessings in my life.
Helsinki, May 2016
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