Calcium, magnesium and aluminium ions as decontaminating agents against dermal fluoride absorption following hydrofluoric acid exposure.

The fluoride ions of the industrially largely irreplaceable, locally corrosive hydrofluoric acid (HF) can scavenge cations in biological tissues, which explains their high toxic potential, and also leads to local acidification through proton release. The influence of three complexing agents, calcium (Ca2+) gluconate (as 2.5% Ca2+gel and individually (2.84%) or commercially (10%) formulated Ca2+solution), magnesium (Mg2+) gluconate (2.84%) solution and aluminium (Al3+) solution (Hexafluorine®, pure and diluted) on the absorption of fluoride following HF exposure (1-3 min, 100 µl, 30%/0.64 cm2) through human skin was investigated in an ex-vivo diffusion cell model. Fluoride absorption was assessed over 6-24 h and analysed with a fluoride electrode. Decreasing the contamination time reduced the fluoride absorption distinctly which was further reduced by the application of fluoride-binding decontamination agents (Ca2+, Mg2+, Al3+) or water alone without being significantly different. Ca2+ appeared slightly more effective than Mg2+ in reducing fluoride absorption. Moreover, the addition of pH adjusting buffer promoted the decontamination efficacy. Fluoride-binding agents can facilitate the decontamination of dermal HF exposure. However, prompt decontamination appeared to be the key to successful limitation of fluoride absorption and pushes the choice of decontamination agent almost into the background.

Evaluation on the reliability of the permeability coefficient (Kp) to assess the percutaneous penetration property of chemicals on the basis of Flynn's dataset.

PURPOSE: The permeability coefficient (Kp) is often used for prediction of the dermal penetration of chemicals. Mathematical models have mostly been derived on Kp data basis. However, confusing Kp values are reported, questioning the general reliability of this parameter. In this study, we tested the plausibility of Kp values expressing the dermal penetration velocity (cm h-1) of chemicals on a larger dataset from literature. METHODS: Kp was applied for the calculation of the time for penetration through skin membranes of defined thickness (tCrossSkin). Kp values were obtained from Flynn's dataset (1990), containing data determined mostly under similar experimental conditions using diffusion cells. Further skin penetration parameters, e.g., times at which the chemicals were firstly measured in the receptor phase, lag times, steady-state times, and exposure duration, where available, were related to Kp values. The data congruence was tested comparing Kp values from Flynn's dataset with those reported in the EDETOX database. Variables, which could bias the results, such as different experimental protocols and research groups were also considered. RESULTS: Kp data for 94 chemicals matched the inclusion criteria were evaluated. According to the Kp values, 21 (22%) compounds would require longer than 100 h, and 20 (21%) further compounds longer than 10 h of exposure to penetrate skin membranes of ~ 0.01-2.5 mm thickness. Obviously, erroneous Kp were found in studies of almost all research groups in Flynn's database, indicating that neither the observer nor the experimental conditions alone biased the values. CONCLUSIONS: Our evaluation demonstrates high implausibility of Kp values to represent the dermal penetration velocity and supports general invalidity of the parameter for implementation in studies using skin membranes. The Kp should not be used to characterize the percutaneous penetration of chemicals or in risk assessment without verification.

Dermal penetration and resorption of beta-naphthylamine and N-phenyl-beta-naphthylamine from lubricants in an ex vivo human skin model.

Dermal Penetration of aromatic amines (AA's), often suspected or known to be carcinogenic, can play an important role in the overall human exposure. However, information on penetration of certain AA's is poor and inconsistent. Penetration of the former lubricant additive N-phenyl-beta-naphthylamine (PBNA) and its contaminant beta-naphthylamine (BNA) a known carcinogen was investigated and the influence of formulation and co-application characterized. Percutaneous penetration of BNA and PBNA through freshly excised human skin (n = 8; 48 h) was investigated using an ex vivo diffusion cell model. Both AA's were applied in a technical-conform lubricant or dissolved in hexane. The amount of BNA and PBNA applied to skin was 0.52 and 259 µg/0.64 cm2. The analytical determination of AA's was performed by GC-MS. Both, BNA and PBNA penetrated through human skin (38 vs. 5% of applied dose). In contrast to BNA, the percutaneous penetration of PBNA continued beyond the end of exposure. Co-exposure of both AA's increased the intradermal uptake of BNA and PBNA (p < 0.05). Exposure in lubricant showed the least overall penetration (2.9 and 1.9% of applied dose). The results clearly reveal that dermal penetration of both AA's depends strongly on the mode of application. Co-application and formulation alters the penetration of the AA's.

Dermal absorption and skin damage following hydrofluoric acid exposure in an ex vivo human skin model.

The wide industrial use of hydrofluoric acid (HF) poses a high risk for accidental dermal exposure. Despite local and systemic hazards associated with HF, information on percutaneous penetration and tissue damage is rare. In the present ex vivo study, the dermal absorption of HF (detected in terms of fluoride ions) was quantified and the skin damaging potential as a function of concentration and exposure duration was assessed. Percutaneous penetration of HF (c=5, 30, and 50%) at 3 exposure durations (3, 5, and 10 min) was investigated in a static diffusion cell model using freshly excised human skin. Alterations of skin were histologically evaluated. HF rapidly penetrated through skin under formation of a considerable intradermal reservoir (∼ 13-67% of total absorbed fluoride). Histologically, epidermal alterations were detected already after exposure to 5% HF for 3 min. The degree of skin damage increased with rising concentration and exposure duration leading to coagulation necrosis. For HF concentrations of ≥ 30%, skin damage progressed into deeper skin layers. Topically applied HF concentration was the principal parameter determining HF induced skin effects. The intradermal HF retention capacity associated with progression and prolongation of HF induced skin effects must be considered in the review of skin decontamination procedures.

Influence of artificial sebum on the dermal absorption of chemicals in excised human skin: A proof-of-concept study.

In an initial diffusion cell study, the influence of artificial sebum on dermal penetration and intradermal reservoir of ethanol and toluene was investigated in comparison with the effects of a skin cream (o/w- and w/o-emulsion) and untreated (control) skin. Human skin was exposed to neat ethanol and toluene for 4h, respectively. During the experiments, the penetration of the compounds was assessed in the receptor fluid. The amounts of the test compounds in the skin were determined at the end of exposure. In the control experiments, 42% of the total resorbed ethanol amounts were found in the intradermal reservoir after 4h, whereas 82% of the toluene amounts were found in the skin compartments. The treatment with artificial sebum showed no significant differences in dermal absorption of both test compounds compared to control skin. In contrast, the treatment with skin cream increased the percutaneous penetration (p<0.001) and the intradermal reservoir of ethanol ~2-fold but not of toluene. In all exposure scenarios, a relevant intradermal reservoir was formed. The results indicate that sebum does not influence the percutaneous penetration and the intradermal reservoir of epidermally applied chemicals, whereas the application of skin creams may increase the dermal penetration of the compounds.

Evaluation of the effect of skin cleaning procedures on the dermal absorption of chemicals.

To reduce the internal exposure, skin decontamination is the most important measure after dermal contact to chemicals. However, no harmonized skin cleaning procedure for experimental ex vivo studies is published. In our study, the impact of two skin cleaning techniques on dermal penetration kinetics and intradermal deposition of 1,4-dioxane, 5% hydrofluoric acid (HF, detected in terms of fluoride ions), and anisole was evaluated to develop a reliable ex vivo skin cleaning method using the diffusion cell technique. After exposure (duration: 3 min (HF); 1h (1,4-dioxane and anisole)) of excised human skin (n=6-8) decontamination was performed by (I) water-soaked cotton swabs or (II) direct application of water on the exposure area. The effect of skin cleaning was investigated by analysing the concentration time course of chemicals in the receptor fluid of diffusion cells and by determining the deposition in skin. Both skin cleaning procedures reduced the amount of fluoride in the skin compartments (p<0.05) and the receptor fluid (p<0.1). However, the effect of cleaning on the dermal absorption of the organic test compounds was not significant. The results demonstrate the suitability of the applied ex vivo protocol for investigating the effectiveness of skin cleaning measures following dermal exposure. In addition, data reveal that the determination of test compounds in both, skin compartments as well as receptor fluid as equivalent for the systemic uptake needs to be considered in studies assessing the effectiveness of skin decontamination procedures.

Studies on percutaneous penetration of chemicals - Impact of storage conditions for excised human skin.

According to international guidelines skin penetration experiments can be carried out using freshly excised or frozen stored skin. However, this recommendation refers to data obtained in experiments with human cadaver skin. In our study, the percutaneous penetration of the occupationally relevant chemicals anisole, cyclohexanone and 1,4-dioxane was investigated for freshly excised as well as for 4 and 30 days at -20°C stored human skin using the diffusion cell technique. As indicator for the impairment of skin barrier by freezing cholesterol dissolution was determined in the solvents in exposure chambers of diffusion cells. Considering the percutaneously penetrated amounts, the following ranking was determined: 1,4-dioxane>anisole>cyclohexanone (decline to a factor of 5.9). The differences of fluxes between freshly excised and frozen stored skin (4 and 30 days) were not significant (p>0.05). Cholesterol dissolved from the skin indicates no significant differences between freshly excised and frozen stored skin. This study shows that freezing of human skin for up to 30 days does not alter the skin barrier function and the permeability of chemicals.