Dermal absorption and toxicological risk assessment : pitfalls and promises
Buist, H. - \ 2016
Wageningen University. Promotor(en): Ruud Woutersen; Ivonne Rietjens, co-promotor(en): J.J.M. van de Sandt. - Wageningen : Wageningen University - ISBN 9789462577275 - 200
skin - absorption - permeability - in vitro - experiments - exposure assessment - risk assessment - toxicology - biocides - rodenticides - preservatives - disinfection - huid - absorptie - permeabiliteit - in vitro - experimenten - blootstellingsbepaling - risicoschatting - toxicologie - biociden - rodenticiden - conserveermiddelen - desinfectie
Absorption of toxic substances via the skin is an important phenomenon in the assessment of the risk of exposure to these substances. People are exposed to a variety of substances and products via the skin, either directly or indirectly, while at work, at home or in public space. Pesticides, organic solvents and metalworking fluids are seen to be important contributors to adverse health effects due to occupational exposure via the skin. In daily life, cosmetics, clothing and household products are the most relevant commodities with respect to exposure via the skin.
Given the importance of skin exposure in the assessment of the risk of toxic substances, the objective of this thesis was to further develop, evaluate and improve methods for including skin absorption data this assessment.
In this thesis, four factors influencing dermal absorption, namely dermal loading (chapters 3 and 6), irritative/corrosive potential (chapters 3 and 4), frequency of exposure (chapters 3, 4 and 5) and the vehicle used (chapter 5), were investigated in more detail. Furthermore, a model to extrapolate infinite dose absorption data to finite dose conditions, baptized Dermal Absorption Model for Extrapolation (DAME), was developed and tested.
n chapter 2 of this thesis, the relationship between relative dermal absorption and dermal loading was investigated. Hundred-and-thirty-eight dermal publicly available absorption experiments with 98 substances were evaluated. The results obtained revealed that dermal loading ranged mostly between 0.001 and 10 mg/cm2. In 87 experiments (63%), an inverse relationship was observed between relative dermal absorption and dermal loading. On average, relative absorption at high dermal loading was 33 times lower than at low dermal loading. Known skin irritating and volatile substances less frequently showed an inverse relationship between dermal loading and relative absorption. It was concluded that when using relative dermal absorption in regulatory risk assessment, its value should be determined at or extrapolated to dermal loadings relevant for the exposure conditions being evaluated.
n chapter 3 of this thesis, a literature search was presented with the aim to investigate whether neglecting the effects of repeated exposure may lead to an incorrect estimate of dermal absorption. The results demonstrated that the effect of repeated versus single exposure does not demonstrate a unique trend. Nevertheless, an increase in daily absorption was frequently observed upon repeated daily exposure. The little information available mostly concerned pharmaceuticals. However, consumers and workers may be repeatedly exposed to other types of chemicals, like disinfectants and cleaning products, which often contain biocidal active substances that may decrease the barrier function of the skin, especially after repeated exposure. These biocidal products, therefore, may present a safety risk that is not covered by the current risk assessment practice since absorption data are usually obtained by single exposure experiments. Consequently, it was decided to investigate the importance of this issue for biocide safety evaluation. As the literature search revealed that hardly any data on absorption upon repeated dermal exposure to biocides are available, it was concluded that data need to be generated by testing.
To cover the entire range of biocidal products in such testing, a representative series of biocidal substances should be tested, making in vitro testing of dermal absorption the preferred choice over in vivo testing. Based on an inventory made, it appeared that the 16 product types represented among the biocidal products authorised in the Netherlands could be clustered into 6 more or less homogeneous categories based on similarity in active substances. This result could facilitate experimental testing by providing a basis for selection of a limited number of representative compounds to be evaluated.
n chapter 4 of this thesis, the importance of the effect of repeated dermal exposure on skin permeability for biocide safety evaluation was investigated, using a selection of nine representative biocides from the inventory made in chapter 3. The in vitro dermal penetration of tritiated water and [14C]propoxur was chosen as a measure of the permeability and integrity of human abdominal skin after single and repeated exposure. The results indicated that single and repeated exposure to specific biocidal products (e.g. the quaternary ammonium chlorides DDAC and ADBAC) may significantly increase skin permeability, especially when the compounds are applied at high concentrations, while a substance like formaldehyde may reduce skin permeability under specific conditions.
n chapter 5 of this thesis, the in vitro dermal absorption kinetics of the quaternary ammonium compound didecyldimethylammonium chloride (DDAC) during single and repeated exposure was studied in more detail. In addition, the influence of biocidal formulations on the absorption of DDAC was investigated, because it was expected that formulation characteristics may be another factor influencing its dermal absorption. The analysis of biocidal products on the Dutch market, reported in chapter 3, indicated that DDAC is often used in combination with other active ingredients. DDAC was most frequently combined with formaldehyde, glutaraldehyde and/or alkyldimethylbenzylammonium chloride (ADBAC). Consequently, commercial formulations containing one or more of these additional active ingredients were selected, in addition to one formulation containing only DDAC as an active ingredient. The selected commercial formulations tended to reduce skin penetration of DDAC. This was most pronounced with the formulation containing the highest concentration of formaldehyde (196 mg/mL) and glutaraldehyde (106 mg/mL), which reduced the flux of DDAC across the skin by 95%. The reduction caused by the only tested formulation containing no other active ingredients than DDAC, and thus incorporating no aldehydes, was smallest, and did not reach statistical significance.
n chapter 6 of this thesis, a simple in silico model to predict finite dose dermal absorption from infinite dose data (kp and lag time) and the stratum corneum/water partition coefficient (KSC,W) was developed. This model was tentatively called Dermal Absorption Model for Extrapolation (DAME). As dermal exposure may occur under a large variety of conditions leading to quite different rates of absorption, such a predictive model using simple experimental or physicochemical inputs provides a cost-effective means to estimate dermal absorption under different conditions.
To evaluate the DAME, a series of in vitro dermal absorption experiments was performed under both infinite and finite dose conditions using a variety of different substances. The kp’s and lag times determined in the infinite dose experiments were entered into DAME to predict relative dermal absorption value under finite dose conditions. For six substances, the predicted relative dermal absorption under finite dose conditions was not statistically different from the measured value. For all other substances, measured absorption was overpredicted by DAME, but most of the overpredicted values were still lower than 100%, the European default absorption value for the tested compounds.
In conclusion, our finite dose prediction model (DAME) provides a useful and cost-effective estimate of in vitro dermal absorption, to be used in risk assessment for non-volatile substances dissolved in water at non-irritating concentrations.
n chapter 7 of this thesis, the results of the research reported in chapters 2 to 6 were put into perspective, the pitfalls and promises emanating from them discussed and general conclusions drawn. The possible influence of vehicles on absorption and the possible impact of irritative or corrosive vehicles or chemicals on the skin barrier have been demonstrated in this thesis. An in silico predictive model tentatively called DAME was developed, which enables the user to evaluate a variety of dermal exposure scenarios with limited experimental data (kp and lag time) and easy to obtain physicochemical properties (MW and log KOW). The predictions of our experiments reported in chapter 6 were compared to those of the Finite Dose Skin Permeation (FDSP) model published on the internet by the US Centers for Disease Control and Prevention (CDC). DAME outperformed FDSP (R2 of the correlation predicted/measured potential absorption 0.64 and 0.12, respectively). At present, the applicability domain of DAME is limited to non-volatile substances dissolved in aqueous solvents. However, in future the model will be adapted to include volatile substances as well.
Altogether, it is concluded that dermal exposure can be an important factor in risks posed by chemicals and should be taken into account in risk assessment. The methods to actually do this are still open for further improvement to better account for the various factors influencing skin penetration and to develop adequate combinations of in vitro and in silico models that can accurately predict human dermal absorption.
Preliminary UHPLC–PDA–ESI-MS screening of light-accelerated autoxidation products of the tetrapyrrole biliverdin
Weesepoel, Y.J.A. ; Gruppen, H. ; Vincken, J.P. - \ 2015
Food Chemistry 173 (2015). - ISSN 0308-8146 - p. 624 - 628.
spirulina-platensis - mass-spectrometry - c-phycocyanin - stability - preservatives - antioxidants - pigments
The application of phycobiliproteins, e.g. blue C-phycocyanin, as natural water-soluble food colourants is emerging. The chromophore of these proteins comprises a number of tetrapyrroles (or phycocyanobilins), which have an extensive conjugated system, vulnerable to autoxidation. To assess the autoxidation products, a simplified model system was used in which the free tetrapyrrole biliverdin, instead of phycobiliprotein, was subjected to light-accelerated autoxidation. Degradation products of biliverdin were subsequently annotated by reversed-phase ultra-high performance liquid chromatography with a photo diode array and positive mode in-line electrospray ionization mass spectrometry. To facilitate the analysis of degradation products, autoxidation of the three methine bridges in biliverdin was mimicked in silico. It was found that both the peripheral and central methine bridges of biliverdin were susceptible to light-accelerated autoxidation. Scission products tentatively annotated with MS2 and MS3 were propionic acid-containing pyrroles. From this, it can be speculated that tetrapyrroles attached to phycobiliproteins are susceptible to autoxidative degradation.
Feed additives : annual report 2012 of the National Reference Laboratory
Driessen, J.J.M. ; Beek, W.M.J. ; Zuidema, T. ; Jong, J. de - \ 2013
Wageningen : RIKILT Wageningen UR (Report / RIKILT Wageningen UR 2013.008) - 15
voedertoevoegingen - toevoegingen - conserveermiddelen - versterkers (enhancers) - voer - mycotoxinen - feed additives - additives - preservatives - enhancers - feeds - mycotoxins
This report of the Dutch National Reference Laboratory (NRL) for feed additives (RIKILT Wageningen UR) descreibes the activities employed in 2012. The main tasks of the NRL are: providing assistance to the European Union Reference Laboratory (EURL) on their request, as well as providing advice and support to the competent authority, which is the Dutch Ministry of Economic Affairs - Department 'Plantaardige Agroketens en Voedselkwaliteit'.
Proceedings of the 2nd international symposium on natural preservatives in food, feed, and cosmetics : Amsterdam, the Netherlands, June 7-8, 2006
Havkin-Frenkel, D. ; Dudai, N. ; Mheen, H.J.C.J. van der - \ 2008
Leuven : International Society for Horticultural Science (Acta horticulturae 778) - ISBN 9789066057302 - 110
conserveermiddelen - voedselconserveermiddelen - voer - cosmetica - natuurlijke producten - medicinale planten - antioxidanten - etherische oliën - aromatische gewassen - preservatives - food preservatives - feeds - cosmetics - natural products - medicinal plants - antioxidants - essential oils - aromatic plants
|Nieuwe conserveringstechnieken op punt van doorbreken
Groote, Y. de; Bartels, P.V. - \ 2004
ZuivelZicht 96 (2004)3. - ISSN 0165-8573 - p. 21 - 23.
conservering - conserveermiddelen - voedselbewaring - houdbaarheid (kwaliteit) - bewaartijd - voedingsmiddelen - technologie - technieken - conservation - preservatives - food preservation - keeping quality - storage life - foods - technology - techniques
Nieuwe technologieën voor het langer houdbaar maken van voedsel staan op het punt om door te breken in de zuivelindustrie. Vooral het gebruik van hoge druk en pulserende elektrische velden zijn veelbelovend voor niche producten, meent dr. Paul Bartels.
Top, J.L. ; Ketelaars, N.J.J.P. ; Hulzebos, J.L. - \ 2004
Voedingsmiddelentechnologie 37 (2004)4. - ISSN 0042-7934 - p. 27 - 27.
conserveermiddelen - voedselconserveermiddelen - voedselindustrie - eigenschappen - databanken - voedingsstoffendatabanken - informatiesystemen - internet - preservatives - food preservatives - food industry - properties - databases - nutrient databanks - information systems - internet
Antimicrobials Online is een Engelstalige database die wetenschappelijke informatie over natuurlijke conserveermiddelen via internet beschikbaar stelt aan de levensmiddelenindustrie. Het project is uitgevoerd door Wageningen UR-Agrotechnology & Food Innovations. Er volgt uitbreiding met traditionele voedingsmiddelen
|Pathogenen beheersen de kunst van het veranderen
Aantrekker, E.D. den; Janssen, A.G.W. - \ 1999
Voedingsmiddelentechnologie 32 (1999). - ISSN 0042-7934 - p. 44 - 46.
voedselmicrobiologie - micro-organismen - pathogenen - kiemgetal - antibiotica - immunologie - antigenen - antilichamen - antiseptica - reticulo-endotheliaal systeem - antimicrobe-eigenschappen - biotechnologie - genetica - recombinant dna - voedselbewaring - conserveermiddelen - programmaeffectiviteit - detectie - technieken - monitoring - voedselveiligheid - conferenties - food microbiology - microorganisms - pathogens - bacterial count - antibiotics - immunology - antigens - antibodies - antiseptics - reticuloendothelial system - antimicrobial properties - biotechnology - genetics - food preservation - preservatives - program effectiveness - detection - techniques - food safety - conferences
De proceedings van dit congres zijn verkrijgbaar bij TNO Voeding te Zeist. Info: 030-6944144
Clean up procedure (GPC) voor de GC bepaling van de antioxidanten BHA, BHT en TBHQ in botervet
Slangen, J. ; Traag, W. ; Kamp, H. van der; Hollman, P. - \ 1987
Wageningen : RIKILT (Rapport / RIKILT 87.64) - 6
boterolie - conserveermiddelen - besmetting - achteruitgang (deterioration) - voedseladditieven - butylhydroxyanisol - butylhydroxytolueen - gaschromatografie - butter oil - preservatives - contamination - deterioration - food additives - butylated hydroxyanisole - butylated hydroxytoluene - gas chromatography
Voor het opstellen van een normvoorschrift voor de bepaling van de antioxydanten BHA, BHT en TBHQ in botervet worden door werkgroep E43 van de "International Dairy Federation" methoden geëvalueerd. Uitgangspunt voor deze norm is de gaschromatografische bepaling beschreven in ISO 6463-1982. De wens bestaat echter om gebruik te maken van capillaire gaschromatografie, dit in afwijking van ISO 6463.
Bezoek aan Frankrijk t.b.v. chemische controle van champignonconserven op toevoegingen, 5 t/m 8 juli 1987
Elenbaas, H.L. ; Venema, D.P. ; Herstel, H. - \ 1987
Wageningen : RIKILT (Rapport / RIKILT 87.55) - 8
voedselbewaring - inblikken - ingeblikte producten - agaricus - paddestoelen - conserveermiddelen - food preservation - canning - canned products - agaricus - mushrooms - preservatives
De Franse, interprofessionele associatie van champignonproducenten (ANICC), vertegenwoordigd door de heer F. Falconnet, heeft het RIKILT de gelegenheid gegeven om twee instituten in Frankrijk te bezoeken om te zien hoe waterbindende stoffen, i.h.b. ovalbumine (kippeei-eiwit) , in verduurzaamde champignons kunnen worden bepaald.
Ontwikkeling methode voor de kwantitatieve bepaling van benzoëzuur en sorbinezuur in (vlees)salades
Oostrom, J.J. van; Struijs, T.B.D. van der; Ruig, W.G. de - \ 1982
Wageningen : RIKILT (Verslag / RIKILT 82.27) - 3
emulsies - conserveermiddelen - voedselconserveermiddelen - analytische methoden - benzoëzuur - sorbinezuur - vloeistofchromatografie met omgekeerde fase - emulsions - preservatives - food preservatives - analytical methods - benzoic acid - sorbic acid - reverse phase liquid chromatography
Ontwikkeling van een analysemethode voor de kwantitatieve bepaling van conserveermiddelen in sterk emulsievormende produkten. Er wordt een methode beschreven voor de bepaling van benzoëzuur en sorbinezuur in sterk emulsievormende produkten, bestaande uit een voorbewerking m.b.v. Extrelut kolommen van de Fa. Merck, gevolgd door hogedrukvloeistofchromatografische scheiding m.b.v. een reversed phase systeem.
Orienterend onderzoek naar de kwaliteit van champignonconserven
Worp, H.H.M. van de; Herstel, H. - \ 1981
Wageningen : RIKILT (Verslag / RIKILT 81.79) - 8
voedselbewaring - inblikken - conserveerkwaliteit - agaricus - paddestoelen - conserveermiddelen - kwaliteit voor voedselverwerking - houdbaarheid (kwaliteit) - kwaliteitsnormen - food preservation - canning - canning quality - agaricus - mushrooms - preservatives - food processing quality - keeping quality - quality standards
Oriënterend onderzoek naar de kwaliteit van champignonconserven in verband met het in werking treden, per 1 januari 1982, van Verordening PGF 1981 Verduurzaamde Groenten. Vijf monsters champignonconserven werden onderzocht op etikettering, bijzondere kwaliteitsvoorschriften, de toevoegingen keukenzout, zwaveldioxyde en mononatriumglutaminaat, sensorische eigenschappen, zware metalen en bestrijdingsmiddelen.
|Het scald-onderzoek 1957-1958: Dimethyldifenylureum-proeven met vier scald-gevoelige rassen
Staden, O.L. ; Laar, J. van - \ 1960
Wageningen : Instituut voor Bewaring en Verwerking van Tuinbouwproducten (Rapport / Instituut voor Bewaring en Verwerking van Tuinbouwproducten no. 1102) - 7
appels - schilsterfte - opslagkwaliteit - conserveermiddelen - apples - scald - storage quality - preservatives