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Downloaded from orbit.dtu.dk on: Aug 20, 2022Systemic Absorption of Nanomaterials by Oral ExposurePart of the ”Better control of nano” initiative 2012-2015Binderup, Mona-Lise; Bredsdorff, Lea; Beltoft, Vibe Meister; Mortensen, Alicja; Löschner, Katrin;Löschner, Katrin; Larsen, Erik Huusfeldt; Eriksen, Folmer DamstedPublication date:2013Document VersionPublisher's PDF, also known as Version of recordLink back to DTU OrbitCitation (APA):Binderup, M-L., Bredsdorff, L., Beltoft, V. M., Mortensen, A., Löschner, K., Löschner, K., Larsen, E. H., &Eriksen, F. D. (2013). Systemic Absorption of Nanomaterials by Oral Exposure: Part of the ”Better control ofnano” initiative 2012-2015. Danish Environmental Protection 09/978-87-93026-51-3.pdfGeneral rightsCopyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyrightowners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. Users may download and print one copy of any publication from the public portal for the purpose of private study or research. You may not further distribute the material or use it for any profit-making activity or commercial gain You may freely distribute the URL identifying the publication in the public portalIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.
Systemic Absorptionof Nanomaterials byOral ExposurePart of the ”Better control of nano”initiative 2012-2015Environmental Project No. 1505, 2013
Title:Editing:Systemic Absorption of Nanomaterials by OralExposureDTU Food, National Food InstituteMona-Lise Binderup (project coordinator)Lea BredsdorffVibe Meister BeltoftAlicja MortensenKatrin LöschnerErik Huusfeldt LarsenFolmer D. EriksePublished by:The Danish Environmental Protection AgencyStrandgade 291401 Copenhagen KDenmarkwww.mst.dk/englishYear:ISBN no.2013978-87-93026-51-3Disclaimer:When the occasion arises, the Danish Environmental Protection Agency will publish reports and papers concerningresearch and development projects within the environmental sector, financed by study grants provided by the DanishEnvironmental Protection Agency. It should be noted that such publications do not necessarily reflect the position oropinion of the Danish Environmental Protection Agency.However, publication does indicate that, in the opinion of the Danish Environmental Protection Agency, the contentrepresents an important contribution to the debate surrounding Danish environmental policy.Sources must be acknowledged.2Systemic Absorption of Nanomaterials by Oral Exposure
ContentsForeword . 7Dansk resumé . 8Summary. 101.Introduction . 121.1 Danish initiative for “Better control of nano” . 121.2 Project outline .121.3 Background .121.4 Current understanding and models of systemic absorption of nanoparticles byoral exposure .141.5 Aim of the project . 152.Phase I: Establishing a database based on a survey of relevant literature . 162.1 Literature search .162.1.1Description of the search strategy .162.1.2Result of the search . 202.1.3Evaluation of the original papers using Klimisch criteria andnanomaterial characterisation . 212.2 Description of the database . 242.2.1Reference Manager database . 242.2.2Extraction of information into spreadsheet format. 242.3 Quality assurance of the search strategy. 273.Phase II: Review of current knowledge on absorption of differentnanomaterials after oral exposure . 283.1 Carbon nanotubes . 283.1.1Usage . 283.1.2In vivo studies . 283.1.3In vitro studies .313.1.4Synthetic set-ups . 323.1.5Conclusion on the studies concerning systemic absorption of CNTsfollowing oral exposure . 323.1.6Evaluation of factors influencing systemic absorption of CNTs followingoral exposure . 333.1.7Identification of gaps in current knowledge and future research needs inrelation to CNTs . 333.2 Cerium dioxide . 333.2.1Usage . 333.2.2In vivo studies . 343.2.3In vitro studies . 343.2.4Synthetic set-ups . 353.2.5Conclusion on the studies concerning systemic absorption of CeO2-NPsfollowing oral exposure . 353.2.6Evaluation of factors influencing systemic absorption of CeO2-NPsfollowing oral exposure . 35Systemic Absorption of Nanomaterials by Oral Exposure3
3.2.7Identification of gaps in current knowledge and future research needs inrelation to CeO2-NPs . 353.3 Fullerenes . 353.3.1Usage . 353.3.2In vivo studies . 353.3.3In vitro studies . 363.3.4Synthetic set-ups . 363.3.5Conclusion on the studies concerning systemic absorption of fullerenesfollowing oral exposure . 363.3.6Evaluation of factors influencing systemic absorption of fullerenesfollowing oral exposure . 363.3.7Identification of gaps in current knowledge and future research needs inrelation to fullerenes. .373.4 Gold .373.4.1Usage .373.4.2In vivo studies .373.4.3In vitro studies . 383.4.4Synthetic set-ups . 383.4.5Conclusion on the studies concerning systemic absorption of Au-NPsfollowing oral exposure . 383.4.6Evaluation of factors influencing systemic absorption of Au-NPsfollowing oral exposure . 383.4.7Identification of gaps in current knowledge and future research needs inrelation to Au-NPs . 383.5 Iron oxide . 393.5.1Usage . 393.5.2In vivo studies . 393.5.3In vitro studies . 403.5.4Synthetic set-ups . 403.5.5Conclusion on the studies concerning systemic absorption of iron oxidefollowing oral exposure . 403.5.6Evaluation of factors influencing systemic absorption of iron oxidefollowing oral exposure . 403.5.7Identification of gaps in current knowledge and future research needs inrelation to iron oxide.413.6 Selenium .413.6.1Usage .413.6.2In vivo studies .413.6.3In vitro studies .413.6.4Synthetic set-ups .413.6.5Evaluation of factors influencing systemic absorption of Seleniumfollowing oral exposure .413.6.6Identification of gaps in current knowledge and future research needs inrelation to selenium . 423.7 Silicium dioxide . 423.7.1Usage . 423.7.2In vivo studies . 423.7.3In vitro studies . 433.7.4Synthetic set-ups . 433.7.5Conclusion on the studies concerning systemic absorption of SiO2-NPsfollowing oral exposure . 433.7.6Evaluation of factors influencing systemic absorption of SiO2-NPsfollowing oral exposure . 434Systemic Absorption of Nanomaterials by Oral Exposure
3.7.73.83.93.103.113.123.134.Identification of gaps in current knowledge and future research needs inrelation to SiO2-NPs . 44Silver . 443.8.1Usage . 443.8.2In vivo studies . 443.8.3In vitro studies . 463.8.4Synthetic set-ups . 473.8.5Conclusion on the studies concerning systemic absorption of Ag-NPsfollowing oral exposure . 483.8.6Identification of gaps in current knowledge and future research needs inrelation to Ag-NPs . 48Titanium dioxide . 493.9.1Usage . 493.9.2In vivo studies . 493.9.3In vitro studies . 523.9.4Synthetic set-ups . 533.9.5Conclusion on the studies concerning systemic absorption of titaniumdioxide following oral exposure. 533.9.6Evaluation of factors influencing systemic absorption of titanium dioxidefollowing oral exposure . 533.9.7Identification of gaps in current knowledge and future research needs inrelation to titanium dioxide . 54Zinc oxide . 543.10.1 Usage . 543.10.2 In vivo studies . 543.10.3 In vitro studies .573.10.4 Synthetic set-ups .573.10.5 Conclusion on the studies concerning systemic absorption of zinc oxidefollowing oral exposure .573.10.6 Evaluation of factors influencing systemic absorption of zinc oxidefollowing oral exposure . 583.10.7 Identification of gaps in current knowledge and future research needs inrelation to zinc oxide . 58Phase II.1 Evaluation of physical and chemical properties expected to influenceabsorption of nanomaterials . 58Phase II.2 Identification of most relevant test method(s) for systemic absorptionof nanomaterials following oral exposure. 60Phase II.3 Overall conclusion .61Phase III: Identification of knowledge gaps and research needs . 654.1 Recommendations on which nanomaterials could be candidates for futureexperimental testing . 66References . 67Appendix 1:Literature search . 72Appendix 2:Available hits based on “nano” and other search terms . 73Appendix 3:List of non-relevant “nano-terms” . 83Appendix 4:First screening for relevant original papers . 84Appendix 5:Second screening for relevant original papers . 87Systemic Absorption of Nanomaterials by Oral Exposure5
Appendix 6:List of abstracts from second screening . 90Appendix 7:List of all references included in the Reference Managerdatabase . 92Figure 1:Key search terms used in step 1 . 16Figure 2:Overview of the literature search and validation strategy . 19Figure 3:Screenshot from Reference Manager database .20Table 1:Result of the final search with the number of papers for thedifferent type of nanomaterials sub-divided by "in vivo", "in vitro"and "synthetic" investigations . 21Table 2:Evaluation of in vivo studies . 22Table 3:Evaluation of in vitro studies . 23Figure 4:Example of allocation of Klimisch score and characterisation score. 24Table 4:Overview of identified physical and chemical properties withinfluence on absorption of the nanomaterial described in thisreport . .586Systemic Absorption of Nanomaterials by Oral Exposure
ForewordThe project “Systemic absorption of nanomaterials by oral exposure” was carried out during theperiod January to August 2013.This report and the accompanying database (see appendix 7) are intended to provide acomprehensive evaluation of the knowledge base regarding the systemic absorption ofnanomaterials by oral exposure based on the currently available scientific literature.These results regarding the oral exposure route for nanomaterials are part of the “Better control ofnano” initiative conducted by the Danish EPA with the aim of further clarifying possible risks toconsumers and the environment.The project was carried out by the National Food Institute, DTU.The project group consisted of the following members:Mona-Lise Binderup (project coordinator)Lea BredsdorffVibe Meister BeltoftAlicja MortensenKatrin LöschnerErik Huusfeldt LarsenFolmer D. EriksenChristina Ihlemann, Cand. Scient., Danish Environmental Protection AgencyGregory Moore, Cand. Scient., Ph.D., Danish Environmental Protection AgencyAnne Mette Boisen, Cand. Scient., Ph.D., Danish Environmental Protection AgencyMain authors:Mona-Lise Binderup and Erik Huusfeldt LarsenThe project was financed by the National Budget Agreement 2012 on Better Control ofNanomaterials and their Safety (“Bedre styr på nano”).Danish EPA, September 2013Systemic Absorption of Nanomaterials by Oral Exposure7
Dansk resuméI projektet "Systemisk absorption af nanomaterialer ved oral eksponering" er den udvalgtetilgængelige viden fra den videnskabelige litteratur om systemisk absorption af nanomaterialer efteroral eksponering vurderet. Projektet er en del af den danske Miljøstyrelses initiativ "Bedre kontrolaf nano", der skal præcisere den mulige risiko for forbrugerne og miljøet ved udsættelse fornanomaterialer.Det overordnede formål med projektet var at indsamle og vurdere eksisterende viden på området.De mere specifikke mål var:1.At udføre en omfattende litteratursøgning og vurdering af pålideligheden og relevansen afstudier med systemisk absorption af nanomaterialer ved oral eksponering (fase I).2.At evaluere de faktorer, der påvirker den systemiske absorption af nanomaterialer ved oraleksponering (fase II), herunder:3.a.En vurdering af de fysiske og kemiske egenskaber af nanomaterialer der erbeskrevet i litteraturen, og som forventes at påvirke den systemiske absorption afnanomaterialer efter oral eksponering.b.En vurdering af hvilke testmetode(r) der bedst simulerer systemisk absorption afnanomaterialer ved oral eksponering under hensyntagen til kompleksiteten affordøjelsessystemet og de faktorer, der kan have en indflydelse på den muligesystemiske absorption af nanomaterialer.At identificere manglende viden og forskningsbehov og anbefale, hvilke modeller ogmålemetoder der er mest velegnet til at simulere systemisk absorption af nanomaterialer vedoral eksponering hos mennesker. Endelig at anbefale relevante nanomaterialer som kandidatertil eksperimentel testning i fremtiden (fase III).En trinvis litteratursøgningsprofil blev anvendt til at identificere relevante videnskabeligedokumenter, som blev screenet for deres relevans med hensyn til absorption (og dermed potentiellesundhedsskadelige effekter på mennesker via oral eksponering (lægemidler undtaget). I alt 64videnskabelige artikler blev udvalgt til nærmere vurdering af disses videnskabelige kvalitet baseretpå de såkaldte Klimisch kriterier (om udførelsen af toksikologiske/biologiske eksperimenter), ogdetaljerne i karakteriseringen af nanopartiklerne blev noteret. Det endelige antal på 47 artikler meden Klimisch score på 1 eller 2 (nogle få artikler med en score på 3, blev også udvalgt baseret på enekspert vurdering) blev udvalgt til yderligere vurdering. De typer af nanopartikler, der indgik i denvalgte litteratur omfattede: kulstofnanorør, cerium dioxid, fullerener, guld, jernoxid, selen, siliciumdioxid, sølv, titandioxid og zinkoxid.Evalueringen af fysiske og kemiske egenskaber, der forventes at påvirke absorptionen afnanopartikler viste, at få af disse parametre var undersøgt eller dokumenteret. For noglenanomaterialer kunne en evaluering af de faktorer, der påvirker deres systemiske absorption efteroral eksponering ikke gives på grund af manglende data. Dette gælder for kulstofnanorør, ceriumdioxid, fullerener, silicium dioxid og selen. Det blev påvist, at tarmens optagelse af jernoxid, guld ogsølvnanopartikler var højere for de mindre partikelstørrelser end for de større partikler.8Systemic Absorption of Nanomaterials by Oral Exposure
Indflydelsen på absorptionshastigheden af polymerbelægninger på sølv nanopartikler blevundersøgt, men ingen klar tendens blev observeret. Opløseligheden af sølv og zinkoxidnanopartikler viste sig at være en uventet faktor i studiet af absorptionen på grund af de opløste,ioniske former af disse partikeltyper. For titandioxid nanopartikler var der ingen klare oplysningerom forholdet mellem størrelse og absorption, men der var tegn på, at agglomereringen af anatasekrystalformen kunne forklare den lave absorption heraf og dermed indirekte forklare, hvorforkrystalformen rutil blev bedre absorberet end anataseformen.De metoder, der var mest lovende til vurdering af systemisk absorption af nanomaterialer blevevalueret. Metoder baseret på in vitro test eksisterer og er i øjeblikket under udvikling. Der erimidlertid behov for yderligere forfining før disse metoder kan anvendes til vurdering af absorptionaf nanopartikler efter oral eksponering. Den mest lovende modeltype bør omfatte et syntetisksystem under brug af fysiologisk relevante betingelser (enzymer, pH, salte og temperatur) aleneeller bør anvendes i kombination med en in vitro absorptionsmodel baseret på f.eks. humanttarmepitel eller Caco-2celler. Sølv og siliciumdioxid nanopartikler er blevet testet under sådannesyntetiske betingelser, og tilstedeværelsen af nanopartikulært materiale i kunstige tarmsaft udeneller med tilstedeværelsen af en fødevare matrix blev demonstreret. En in vitro-model baseret påhumant follikelstimulerende epithel blev udviklet, men der var en tendens til at overvurderetransporten af nanopartikler over denne cellebarriere. Dette viste, at resultaterne fra in vitromodeller på absorption af nanopartikler bør fortolkes med forsigtighed.Det sidste kapitel i rapporten er afsat til identifikation af huller i vores viden og til anbefalingervedrørende fremtidig testning af nanomaterialer. Generelt er meget få robuste og validerede in vivoabsorptionsstudier blevet identificeret. Den kombinerede Klimisch og nanomaterialekarakteriseringsscore tyder på, at især fremskridtet i arbejdet med karakterisering af nanopartiklerer begrænset. Dette er sandsynligvis forbundet med tekniske og videnskabelige udfordringerforbundet med påvisning af nanopartikler i biologiske matricer. Detaljerede undersøgelser afindflydelsen af fysisk-kemiske egenskaber på absorption er nødvendige, og kunne i første omgangudføres in vitro for at spare tid samt minimere anvendelsen af forsøgsdyr. Når flere data er blevettilgængelige, kan det blive muligt at overføre viden eller at udvikle "in situ" modeller for absorptionaf "næsten ens" nanomaterialer.Analytiske metoder til karakterisering af nanomaterialer er under intens udvikling og omfatter vådkemiske teknikker, der ofte er baseret på atomspektroskopi og på billeddiagnostiske metoder, f.ekselektronmikroskopi. Der er behov for yderligere udvikling af følsomme og pålidelige metoder tilpåvisning og karakterisering in situ og til kvantificering af masse og partikelantal især ifødevarer/foder og i væv/celler indsamlet fra in vivo eller in vitro modeller. Fra sådanneundersøgelser, er det vigtigt at indsamle oplysninger om, hvorvidt stofferne optages som partikler,ioner eller en kombination af begge. I projekter, hvor forskerne har adgang til en moderne"analytisk værktøjskasse", kan den selektive påvisning af ioner vs partikler af et givet nanomaterialeopnås på en række måder. I almindelighed kan metoder, som bygger på kombinationen af enseparationsteknik og en selektiv detektor (ICP-MS) være en måde at opnå mere relevantekarakteriseringsoplysninger i fremtidige projekter.Baseret på den nærværende vurdering af nanomaterialer, er materialer med et højt oralteksponeringsniveau de mest relevante kandidater til fremtidige projekter vedrørende systemiskabsorption af nanomaterialer efter oral eksponering. Disse materialer omfatter sølv, siliciumdioxid(E 551), titandioxid (E 171) og zinkoxid.Systemic Absorption of Nanomaterials by Oral Exposure9
SummaryIn the project “Systemic absorption of nanomaterials by oral exposure” the available knowledgeselected from the scientific literature on systemic absorption of nanomaterials following oralexposure is evaluated. The project is part of the “Better control of nano” initiative by the DanishEPA aiming at clarifying possible risks to consumers and the environment upon exposure tonanomaterials.The overall aim of the project was to gather and evaluate existing knowledge in the area. Morespecifically the objectives were:1.To perform an extensive literature search and assessment of the reliability and relevance ofstudies involving systemic absorption of nanomaterials by oral exposure (Phase I).2.To evaluate the factors influencing systemic absorption of nanomaterials by oral exposure(Phase II) including:3.a.An evaluation of the physical and chemical properties of nanomaterials described inthe literature, which are expected to affect the systemic absorption of nanomaterialsfollowing oral exposure.b.An evaluation of which test method(s) would most closely simulate systemicabsorption of nanomaterials by oral exposure taking into account the complexity ofthe digestive system and the factors that may have an influence on the possiblesystemic absorption of nano
opinion of the Danish Environmental Protection Agency. However, publication does indicate that, in the opinion of the Danish Environmental Protection Agency, the content represents an important contribution to the debate surrounding Danish environmental policy. Sources must be acknowledged. 2 Systemic Absorption of Nanomaterials by Oral Exposure
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ion coefficient. The average absorption coefficient is defined as the ratio between the total absorption in the hall to the total surface area of the hall. 2 Measurement of sound absorption coefficient. Let us consider a smaple fo. r which the absorption coefficient (a. m) is to be measured.
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absorption in an appropriate setting (Bronkhorst,2016). As Glicksohn and Berkovich Ohana(2011, p. 54) have suggested, “the higher the absorption score, the more entranced the individual will be, circumstances permitting.” Absorption is typically assessed using Tellegen’s Absorption Scale (TAS; Tellegen
particles in size between 1 to 100nm is known as nano science and nano technology. b) Classification of nanomaterials on the basis of dimensions On the basis of reduction in size of materials in different dimensions, nanomaterials are classified into three groups. S. No. Reduction in size i
nanomaterials differ remarkably from bulk materials. This difference can be mainly attributed to the quantum confinement effects, unique surface phenomena, and efficient energy and charge transfer over nanoscale distances within nanomaterials. The origin of the color difference in the cup is attributed to the
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