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 p.
skin - absorption - permeability - in vitro - experiments - exposure assessment - risk assessment - toxicology - biocides - rodenticides - preservatives - disinfection - huid - absorptie - permeabiliteit - 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.
Plants4Cosmetics : perspectives for plant ingredients in cosmetics
Boeriu, C.G. - \ 2015
Wageningen : Wageningen UR - Food & Biobased Research (Report / Wageningen UR Food & Biobased Research 1603) - 38 p.
cosmetics - plants - flavonoids - phenols - pigments - plant pigments - polysaccharides - geranium - hyacinthus - chrysanthemum - orchidaceae - skin - hair - oil plants - medicinal plants - natural products - biobased chemicals - biobased economy - cosmetica - planten - flavonoïden - fenolen - pigmenten - plantenpigmenten - polysacchariden - huid - haar - olieleverende planten - medicinale planten - natuurlijke producten - chemicaliën uit biologische grondstoffen
In opdracht van Bio Base Westland en de TKI Tuinbouw Koepel PPS Plantenstoffen, heeft Wageningen UR – Food & Biobased Research een exploratieve desktop studie uitgevoerd gericht op de identificatie van veelbelovende routes voor de valorisatie van plantinhoudstoffen - waaronder ook reststromen uit de tuinbouw - voor de cosmetische industrie. Een uitgebreide analyse van de beschikbare informatie werd uitgevoerd om de mogelijkheden voor de Nederlandse tuinbouwsector te bepalen. Er is gekeken naar marktkansen in de cosmetische industrie met inbegrip van natuurlijke en biologische ingrediënten.
Greep krijgen op krassen
Buisonjé, F.E. de; Veldkamp, T. - \ 2009
De Pluimveehouderij 2009 (2009)17. - ISSN 0166-8250 - p. 52 - 53.
pluimveehouderij - pluimvee - eenden - huid - poultry farming - poultry - ducks - skin
ASG heeft het huidkrassenprobleem met vleeseenden op drie manieren benaderd: enquete, klimaatmeting en weefselonderzoek. Uitsluitsel geeft het niet, wel zijn er aanwijzingen: via ventilatie valt veel te winnen
Oog voor welzijn, kijken naar veranderingen. Klauwen, gangen en huid in beeld
Heutinck, L.F.M. - \ 2007
V-focus 4 (2007). - ISSN 1574-1575 - p. 36 - 37.
melkveehouderij - dierenwelzijn - beoordeling - klauwen - huid - huidtests - voetziekten - onderzoeksinstituten - proefbedrijven - agrarische bedrijfsvoering - landbouwkundig onderzoek - dairy farming - animal welfare - assessment - claws - skin - skin tests - foot diseases - research institutes - pilot farms - farm management - agricultural research
Het High-techbedrijf heeft meerdere jaren een welzijnsscore op het melkvee uitgevoerd. Volgens een vast protocol bestond die score uit o.a. een beoordeling van de gangen van de koeien, de klauwen en huidbeschadigingen. De welzijnsscore is in 2001 voor het eerst uitgevoerd en herhaald in 2003, '04 en 06. De resultaten werden vergeleken met andere bedrijven, die dezelfde test deden
Koecomfort beoordelen is niet moeilijk
Smolders, E.A.A. ; Poelarends, J.J. - \ 2006
Veehouderij Techniek 9 (2006)5. - ISSN 1387-3105 - p. 14 - 15.
melkveehouderij - huisvesting van koeien - stallen - vloeren - ligboxen - gang - huid - huidletsels - dierenwelzijn - dierverzorging - dairy farming - cow housing - stalls - floors - cubicles - gait - skin - skin lesions - animal welfare - care of animals
Wanneer voelt een koe zich eigenlijk prettig in de stal? Het Praktijkonderzoek Veehouderij stelde er jaren geleden een maatstaf voor op, die het ook dit jaar weer toepaste op de bedrijven die deelnemen aan het Netwerk Maatwerk voor Koecomfort, waarbij de koe op haar lopen wordt beoordeeld en op huidbeschadigingen
Human skin emanations in the host-seeking behaviour of the malaria mosquito Anopheles gambiae
Braks, M. - \ 1999
Agricultural University. Promotor(en): Joop van Lenteren; Willem Takken. - S.l. : S.n. - ISBN 9789058081414 - 122
anopheles gambiae - culicidae - gedrag bij zoeken van een gastheer - zweet - huid - mens - host-seeking behaviour - sweat - skin - man
<p>Malaria is an infectious disease caused by a parasite ( <em>Plasmodium</em> spp.) that is transmitted between human individuals by mosquitoes, belonging to the order of insects, Diptera, family of Culicidae (mosquitoes) and genus of <em>Anopheles</em> (malaria mosquitoes). Mosquitoes feed on humans (and other animals) because they need blood for their reproduction. Like most other haematophagous insects, only the female mosquitoes bite and use the protein-rich blood meal for egg development. Whilst feeding on a person infected with malaria, the mosquito can be pick up the parasites from the blood stream. After a developmental period in the mosquito, the parasites can be transmitted to another person when the mosquito takes a next blood meal. Thus, malaria transmission depends largely on the characteristics of the mosquito population. Knowledge about the ecology, behaviour, infection level and size of the mosquito population is essential for the development, implementation and evaluation of control programs. Development of an adequate trapping device for monitoring the mosquito population is of high priority for ecological and epidemiological studies.</p><p>Malaria is one of the most important human parasitic infectious diseases and one third of the world population is under threat of the disease. Most victims are found in the sub-Saharan countries of Africa. The Afrotropical malaria mosquito, <em>Anopheles gambiae sensu stricto,</em> is the most important vector since it strongly prefers to feed on humans. Like most anopheline species, <em>An. gambiae s.s.</em> is nocturnal and its host-seeking behaviour is mainly odour-mediated. Consequently, odour-baited traps are considered as possible monitoring devices. However, despite the important role of this mosquito in malaria transmission, knowledge regarding host odour components (or kairomones) that bring about the attraction to humans is limited. For the development of odour-baited traps, attractive host odours need to be identified. In this thesis a behavioural ecological investigation to the source, identification and production of kairomones for <em>An. gambiae</em> (henceforth simply termed 'malaria mosquitoes') is described.</p><H3>Source of kairomones for malaria mosquitoes</H3><p>Since the beginning of the century it has been recognised that malaria mosquitoes utilise host odours in their host-seeking behaviour. The source of these olfactory stimuli is expired air, the skin or both. Carbon dioxide present in expired air is an important kairomone for many haematophagous insects. For this reason carbon dioxide is often used in odour-baited traps. From field research (Chapter 2) we learnt that malaria mosquitoes can find their host in the absence of breath, and, thus, the presence of carbon dioxide is not compulsory for finding a host. This suggests that volatiles from the skin of the host also play a role in the attraction of malaria mosquitoes. The addition of skin volatiles to a carbon dioxide baited trap will probably bring about higher trap catches. Moreover, for logistic reasons, an odour-baited trap without presence of carbon dioxide is preferable. Carbon dioxide is highly volatile and can be delivered only by gas cylinders or dry ice (= frozen carbon dioxide), which is impractical in the African field situation. The composition of body odour is complex: more than 300 components have been identified. However, a synthetic blend of the complete human odour has not yet been synthesised. For this reason, the identification of some important components that attract malaria mosquitoes was initiated. A prerequisite for the identification was the entrapment of natural skin emanations separate from the skin. Sweat appeared to be an attractive complex olfactory stimulus since it is not artificial but rather true to nature (Chapter 4 and 5) in the bioassays in the laboratory and it forms the 'heart' of the thesis.</p><H3>The identification of kairomones for malaria mosquitoes</H3><p>Sweat was collected from the foreheads of a number of volunteers, who performed exercises on a hometrainer in a warm and humid room. The behavioural response of the malaria mosquitoes to this fresh sweat was rather variable; they were attracted to some fresh sweat samples (Chapter 8 and 9) but not to others (Chapter 5 and 7). However, the response of the mosquitoes to sweat that had been incubated for two days at body temperature was stable, and all incubated sweat samples were attractive to the mosquitoes. It appeared that the incubation released volatile components that were attractive to mosquitoes. Sweat is basically a watery solution of lactic acid, urea and ammonia. After incubation the lactic acid and urea concentration had decreased and the ammonia concentration showed a distinct increase (Chapter 8 and 9). For this reason ammonia was tested in the bioassay. For the first time, malaria mosquitoes were attracted to a single component other than carbon dioxide, namely ammonia. Lactic acid is an essential kairomone for another mosquito species, the yellow fever mosquito <em>Aedes aegypti</em> . However, the selective removal of lactic acid from the sweat did not affect the reaction of malaria mosquitoes. Therefore, we conclude that lactic acid is not an essential component of attractive odour blends for malaria mosquitoes. Urea was not tested, as it is not volatile. The fact that attraction was sometimes found to the fresh sweat with a rather low concentration of ammonia indicates that components other than ammonia also play a role in the host-seeking behaviour of malaria mosquitoes. The identity of these components needs further exploration.</p><H3>The production of kairomones for malaria mosquitoes</H3><p>The skin of humans (and other animals) forms a good habitat for some microorganisms (bacteria and fungi), together called the skin microflora. During the collection of sweat samples, microorganisms are taken up with the sweat. An exponential growth of microorganisms in the sweat samples is found during incubation (Chapter 4, 6 and 7). Sweat constituents are broken down into more volatile components by the growing microorganismal population and this appears to bring about the enhancement of the attractiveness of sweat to malaria mosquitoes (Chapter 9). Such processes also probably play a role in the production of kairomones on the skin. However, this needs further exploration.</p><H3>Conclusions</H3><p>Kairomones for malaria mosquitoes originate from the human skin, in addition to carbon dioxide from exhaled air. Microorganisms of the skin flora play an important role in the production of kairomones for malaria mosquitoes <em>An. gambiae s.s..</em> Ammonia is one of the components responsible for the attraction of malaria mosquitoes to sweat.</p>