Dermal absorption andtoxicological risk assessment: Pitfalls and Promises

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. I 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. I 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. I 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. I 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. I 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. I 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. </p

A TTC threshold for acute oral exposure to non-genotoxic substances

To derive an acute TTC threshold, the correlation between Allowable Daily Intakes (ADIs, chronic values) and Acute Reference Doses (ARfDs) of pesticides evaluated in the EU was investigated and their distributions were compared. The correlation between ARfDs and ADIs was significant (p ¼ 0.01), but weak (r2 ¼ 0.051). Consequently, using this approach to derive acute TTC values does not seem valid. Therefore, the distributions of ARfDs and ADIs were compared directly, in order to extrapolate from chronic to acute TTC values. This comparison made for the combined Cramer structural class II and III pesticides showed a ratio ARfD/ADI of approximately 3 at the fifth percentile of the distributions

Relative absorption and dermal loading of chemical substances: Consequences for risk assessment

Quantification of skin absorption is an essential step in reducing the uncertainty of dermal risk assessment. Data from literature indicate that the relative dermal absorption of substances is dependent on dermal loading. Therefore, an internal exposure calculated with absorption data determined at a dermal loading not comparable to the actual loading may lead to a wrong assessment of the actual health risk. To investigate the relationship between dermal loading and relative absorption in a quantitative manner, 138 dermal publicly available absorption experiments with 98 substances were evaluated (87 in vitro, 51 in vivo; molecular weight between 40 and 950, log P between -5 and 13), with dermal loading ranging mostly between 0.001 and 10 mg/cm2. In 87 experiments (63%) an inverse relationship was observed between relative dermal absorption and dermal loading, with an average decrease of factor 33 ± 69. Known skin irritating and volatile substances less frequently showed an inverse relationship between dermal loading and relative absorption. © 2009 Elsevier Inc. All rights reserved

Derivation of health effect factors for nanoparticles to be used in LCIA

In this paper, we discuss the derivation of respiratory health effect factors (HEFs) for use in Life Cycle Impact Assessment (LCIA) for five nanoparticles: nanosilver, nano TiO2, carbon black, high-aspect ratio, rigid MWCNT and flexible MWCNT. For this purpose, we applied the methodology of USEtox™, a consensus model to calculate human toxicity and ecotoxicity characterization factors. In view of the available data, the non-carcinogenic HEFs for carbon black and TiO2 can be attributed the recommended status. For MWCNT and nanosilver the non-carcinogenic HEFs should be awarded the indicative status due to the minimal effects observed in the animal studies. All carcinogenic HEFs are currently labelled as indicative since there is no consensus with respect to the human relevance of the overload mechanism of carcinogenicity observed in rats exposed to poorly soluble particles (carbon black, flexible MWCNT and TiO2), whereas for high-aspect ratio, rigid MWCNT, the extrapolation from asbestos carcinogenicity introduces uncertainty. For nanosilver no carcinogenic HEF could be derived. The present study clearly demonstrates the difficulties associated with the derivation of HEFs for the nanomaterials considered, in particular in the USEtox™ framework for comparative risk assessment, and makes recommendations to overcome them: • Nanoparticles for which a dose metric other than its mass is relevant for their toxicity require ‘normalisation’ to the mass metric. Adaptation of USEtox™ to accommodate other dose metrics than mass intake is therefore recommended.• Simplified estimates of deposited and retained dose are currently needed, ignoring particle size distribution dependency. Therefore, it is recommended to include kg deposited and kg retained as dose parameters for HEFs in USEtox™ and to link USEtox™ to the Multiple Path Particle Dosimetry model to convert kg intake to these dose parameters.• Establishment of the Point of Departure (PoD) for the derivation of the HEFs and the extrapolation factors to be used is recommended through consensus building. Although the ED50 is preferred as the PoD from the perspective of comparative risk assessment in LCA, for some nanoparticles, other PoDs could be considered when the dose-response data are limited.• Overall, the assessed nanoparticles are likely to be more toxic than most bulk chemicals regarding non-carcinogenic effects. However, the results of LCIA based on these HEFs must be interpreted with the necessary constraints and reservations due to the large uncertainty involved. © 201

Predicting blood:air partition coefficients using basic physicochemical properties

Quantitative Property Property Relationships (QPPRs) for human and rat blood:air partition coefficients (PBAs) have been derived, based on vapour pressure (Log(VP)), the octanol:water partition coefficient (Log(K_OW)) and molecular weight (MW), using partial least squares multilinear modelling. These parameters are all included in the standard data to be submitted under REACH. The chemical dataset consisted of volatile organic chemicals, principally aliphatic hydrocarbons, benzene derivatives with one aromatic ring, and ethers, with and without halogen atoms. Other chemicals represented were cyclic hydrocarbons and carbonic acid esters. Separate rat and human models were derived, as well as mixed ones. Log(VP) and Log(K_OW) contributed most to the prediction of Log(PBA) in the three-parameter model, while the contribution of MW was relatively small. Still, the three-parameter model differed significantly from the two-parameter model and performed better. Its performance was comparable to that of models published in public literature, which are based on more complex molecular parameters or on measured olive:oil air and saline/water:air partition coefficients. Since, based on the available data for humans, rats, mice, dogs and rabbits, existence of interspecies differences of PBAs cannot be clearly excluded, the use of separate models for each species is advisable. Concluding, the three-parameter human model Log(PBA) = 6.96 – 1.04 Log(VP) – 0.533 Log(K_OW) – 0.00495 MW and the three-parameter rat model 6.16 – 0.888 Log(VP) – 0.521 Log(K_OW) – 0.00201 MW provide robust and reliable models for predicting PBA values of volatile organic chemicals using commonly available chemical properties of molecules. © 2011 Elsevier Inc. All rights reserved

Derivation of the minimal magnitude of the Critical Effect Size for continuous toxicological parameters from within-animal variation in control group data

Assuming that temporal fluctuations in physiological parameters (e.g. haematology, biochemistry) in individual healthy non-exposed animals are non-adverse, the minimal magnitude of the Critical Effect Size (CES) for a number of continuous parameters of toxicity studies was derived. A total of 36 studies (19 pharmaceutical preclinical studies in dogs and 17 chemical risk assessment studies in rats) were analysed to determine within-animal variation in their control groups. Minimal CES-values were derived for each group of studies, differentiating where necessary between strains and sexes, using the 2.5 percentile (lower limit) and/or 97.5 percentile (upper limit) of the distribution of the within-animal variation around the mean of each parameter. We concluded that minimal CES-values for continuous clinical chemistry and haematology parameters should be established separately per species, strain, sex and study duration investigated. Grouping of minimal CES-values, leading to more or less "general" values, seems possible for those parameters that are subject to tight homeostatic control and consequently show little within-animal variation. Nearly a quarter of the proposed CES-values is ≤5%, nearly a quarter range from 6% to 10%, a quarter is 15% or 20%, and nearly 30% of the proposed values is ≥20% of the mean of the control animals. © 2009 Elsevier Inc. All rights reserved

New in vitro dermal absorption database and the prediction of dermal absorption under finite conditions for risk assessment purposes.

Contains fulltext : 89678.pdf (publisher's version ) (Closed access)Most QSARs for dermal absorption predict the permeability coefficient, K(p), of a molecule, which is valid for infinite dose conditions. In practice, dermal exposure mostly occurs under finite dose conditions. Therefore, a simple model to predict finite dose dermal absorption from infinite dose data (K(p) and lag time) and the stratum corneum/water partition coefficient (K(SC,W)) was developed. To test the model, a series of in vitro dermal absorption experiments was performed under both infinite and finite dose conditions using acetic acid, benzoic acid, bis(2-ethylhexyl)phthalate, butoxyethanol, cortisone, decanol, diazinone, 2,4-dichlorophenol, ethacrynic acid, linolenic acid, octylparaben, oleic acid, propylparaben, salicylic acid and testosterone. For six substances, the predicted relative dermal absorption was not statistically different from the measured value. For all other substances, measured absorption was overpredicted by the model, but most of the overpredictions were still below the European default absorption value. In conclusion, our finite dose prediction model provides a useful and cost-effective estimate of dermal absorption, to be used in risk assessment for non-volatile substances dissolved in water at non-irritating concentrations

NanoData Landscape Compilation. Photonics

Photonics emerged in the 1960s and 1970s from work on semiconductor light emitters, lasers and optical fibres. Nanoscale effects impact on photonics, e.g. in the surface quality of waveguides and optical fibres. The focus here remains as closely as possible on photonics as it relates to nanotechnology, e.g. where nanotechnology enhances photonics and vice versa. Photonics more widely is also described and referenced