Human in vitro percutaneous absorption of bisphenol S: Assessment of the skin reservoir and occlusion effects.

Bisphenol S (BPS) was introduced in many industrial and commercial applications as a presumed safer alternative to bisphenol A. However, concerns have been raised surrounding skin absorption and potential persistence of BPS and its related toxic effects in humans. A previous study revealed the likelihood of a reservoir building up in exposed skin. Here, we studied the interactions of BPS solubilized in acetone, ultrapure water, or artificial sebum with freshly excised human skin samples. In vitro tests were performed in static Franz diffusion cells, to explore reservoir and occlusion effects, absorption and metabolism. Most BPS passed through the skin without metabolization - <10% was recovered as glucuronide or sulfate conjugates. Importantly, a substantial amount of BPS persisted in the skin, especially in the stratum corneum. This reservoir could lead to prolonged diffusion into the body after surface cleaning. Occlusion, that may occur with protective clothing, amplified BPS absorption up to six-fold. These findings have implications for occupational settings, highlighting the persistence of BPS contamination even after washing the skin's surface and the need to ensure protective equipment is correctly maintained and used.

An update of skin permeability data based on a systematic review of recent research.

The cutaneous absorption parameters of xenobiotics are crucial for the development of drugs and cosmetics, as well as for assessing environmental and occupational chemical risks. Despite the great variability in the design of experimental conditions due to uncertain international guidelines, datasets like HuskinDB have been created to report skin absorption endpoints. This review updates available skin permeability data by rigorously compiling research published between 2012 and 2021. Inclusion and exclusion criteria have been selected to build the most harmonized and reusable dataset possible. The Generative Topographic Mapping method was applied to the present dataset and compared to HuskinDB to monitor the progress in skin permeability research and locate chemotypes of particular concern. The open-source dataset (SkinPiX) includes steady-state flux, maximum flux, lag time and permeability coefficient results for the substances tested, as well as relevant information on experimental parameters that can impact the data. It can be used to extract subsets of data for comparisons and to build predictive models.

Occupational exposure assessment with solid substances: choosing a vehicle for in vitro percutaneous absorption experiments.

Percutaneous occupational exposure to industrial toxicants can be assessed in vitro on excised human or animal skins. Numerous factors can significantly influence skin permeation of chemicals and the flux determination. Among them, the vehicle used to solubilize the solid substances is a tricky key step. A "realistic surrogate" that closely matches the exposure scenario is recommended in first intention. When direct transposition of occupational exposure conditions to in vitro experiments is impossible, it is recommended that the vehicle used does not affect the skin barrier (in particular in terms of structural integrity, composition, or enzymatic activity). Indeed, any such effect could alter the percutaneous absorption of substances in a number of ways, as we will see. Potential effects are described for five monophasic vehicles, including the three most frequently used: water, ethanol, acetone; and two that are more rarely used, but are realistic: artificial sebum and artificial sweat. Finally, we discuss a number of criteria to be verified and the associated tests that should be performed when choosing the most appropriate vehicle, keeping in mind that, in the context of occupational exposure, the scientific quality of the percutaneous absorption data provided, and how they are interpreted, may have long-range consequences. From the narrative review presented, we also identify and discuss important factors to consider in future updates of the OECD guidelines for in vitro skin absorption experiments.

Human in vitro percutaneous absorption of bisphenol S and bisphenol A: A comparative study.

Bisphenol A (BPA) is widely used in industrial products. Due to the toxicity of this compound, and to comply with restrictions and regulations, manufacturers have progressively replaced it by substitutes. One of the main substitutes used is bisphenol S (BPS). Despite increasing use in many products, the effects of BPS on human health have been little investigated, and studies on percutaneous BPS absorption and particularly toxicokinetic data are lacking. However, the endocrine-disrupting activity of BPA and BPS appears comparable. Dermal contact is a significant source of occupational exposure and is the main route during handling of bisphenol-containing receipts by cashiers. Here, percutaneous BPS absorption was investigated and compared to that of BPA. Experiments were performed according to OECD guidelines. Test compounds dissolved in a vehicle - acetone, artificial sebum or water - were applied in vitro to fresh human skin samples in static Franz diffusion cells. Flux, cumulative absorbed dose and distribution of dose recovered were measured. BPA absorption was vehicle-dependent ranging from 3% with sebum to 41% with water. BPS absorption was much lower than BPA absorption whatever the vehicle tested (less than 1% of applied dose). However, depending on the vehicle 20% to 47% of the applied BPS dose remained in the skin, and was consequently potentially absorbable. Both BPA and BPS were mainly absorbed without biotransformation. Taken together, these results indicate that workers may be exposed to BPS through skin when handling products containing it. This exposure is of concern as its toxicity is currently incompletely understood.

Capacity of an in vitro rat skin model to predict human dermal absorption: Influences of aging and anatomical site.

In addition to inhalation, dermal absorption is a route of exposure to be considered when assessing occupational risks. To investigate dermal penetration of chemicals, human skin samples are regarded as the gold standard. As human samples can be difficult to obtain, many experiments are performed with rat skins, and the results extrapolated to describe human percutaneous absorption. Here, we examined the characteristics of rat skin samples and compared absorption to that measured with in vitro human skin. The thickness of the stratum corneum layer in rat skin samples was found to be uniform when samples were excised from the animals' backs once they were at least 7-weeks-old. Overall, dorsal skin samples from mature rats could be reliably used to measure the flux of hydrophilic liquid molecules, such as N-methyl-2-pyrrolidone, and N,N-dimethylformamide. In contrast, with a solid lipophilic substance, bisphenol A, dissolved in acetone, the flux obtained with rat skin samples was 3-fold higher than that measured with human skin. Consequently, it does not appear relevant to use rat skin in place of human skin to measure absorption of solid lipophilic substances.

Maintenance of Low-Pressure Carburising Furnaces: A Source of PAH Exposure.

OBJECTIVES: Low-pressure carburising is a new technology used to harden steel; the process has been shown to be a source of considerable polycyclic aromatic hydrocarbons (PAH) pollution. Some PAH are carcinogenic, and activities such as furnace maintenance may thus represent a risk to workers. Occupational exposure during these operations should therefore be assessed. METHODS: In this study, the PAH-related carcinogenic risk associated with furnace maintenance was assessed by monitoring atmospheric levels of benzo[a]pyrene (BaP), a representative marker, alongside urinary levels of 3-hydroxybenzo[a]pyrene (3-OHBaP), one of its metabolites. PAH exposure levels were monitored during seven sampling campaigns in four different factories specialized in heat-treatment of mechanical workpieces for the automotive and helicopter industries. Two types of furnace were studied, and 37 individuals were monitored. RESULTS: Values up to 20-fold the French regulatory value of 150 ng/m3 for atmospheric BaP, and, for urinary 3-OHBaP values up to 40-fold the French biological limit value (BLV) of 0.35 nmol/mol of creatinine were detected. Very high concentrations of BaP, close to or even exceeding those found in coal-tar pitch (up to about 20 g/kg), were measured in residues (tars, dusts) deposited inside the furnace. Even when adequate and suitable personal protective equipment was used, urinary 3-OHBaP values often exceeded the BLV. We hypothesize that this exposure is linked to insidious and fortuitous dermal contamination through contact with factory equipment and staining.

The occupational exposure of dermatology nurses to polycyclic aromatic hydrocarbons - evaluating the effectiveness of better skin protection.

OBJECTIVES: We studied the uptake of polycyclic aromatic hydrocarbons (PAH) in nurses who apply ointments containing coal tar to patients and investigated the effectiveness of skin protection methods. METHODS: We determined gas-phase PAH on XAD-2 and particle-associated PAH on filters. We also used pads to determine PAH on the skin. Pyrene and benzo(a)pyrene were analyzed by gas chromatography/mass spectrometry and gas chromatography/tandem mass spectrometry; their respective urinary metabolites 1-hydroxypyrene and 3-hydroxybenzo(a)pyrene were analyzed using high performance liquid chromatography with fluorescence detection. RESULTS: We ruled out the inhalation of airborne pyrene and benzo(a)pyrene as the sources of PAH exposure. However, substantial amounts of pyrene and benzo(a)pyrene were observed on the hands of the nurses (median 33.0 and 16.4 ng/cm (2), respectively). Excretion of urinary 1-hydroxypyrene indicated an increased uptake of pyrene in 8 out of 12 nurses. We asked 35 nurses to perform a treatment with gloves followed by a second treatment without gloves. The use of gloves changed the excretion of 1-hydroxypyrene by -0.58 mumol (range -5.1-1.0 mumol), corresponding to a median reduction of 51.5% (P<0.001). Based on this finding, a new protocol was adopted, involving the permanent use of vinyl gloves and Tyvek sleeves. The effectiveness of this protocol was tested against pre-existing work practices and showed a 97% reduction in skin contamination with pyrene and benzo(a)pyrene, and a lowering in urinary excretion of 1-hydroxypyrene of 57%. CONCLUSION: Protecting the skin more stringently reduced pyrene and benzo(a)pyrene contamination of the hands, and lowered urinary excretion of 1-hydroxypyrene.

Genotoxic effects of bitumen fumes in Big Blue transgenic rat lung.

Road paving workers are exposed to bitumen fumes (CAS No. 8052-42-4), a complex mixture of volatile compounds and particles containing carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons. However, epidemiological and experimental animal studies failed to draw unambiguous conclusions concerning their toxicity. In order to gain better insights on their genotoxic potential, we used an experimental design able to generate bitumen fumes at road paving temperature (temperature: 170 degrees C, total particulate matter: 100mg/m3) and perform a nose-only exposure of Big Blue transgenic rodents 6h/day for five consecutive days. The mutagenic properties of bitumen fumes were determined by analyzing the mutation frequency and spectrum of the neutral reporter gene cII inserted into the rodent genome. We previously observed in mouse lung, that bitumen fumes did not induce an increase of cII mutants, a modification of the mutation spectrum, nor the formation of DNA adducts. Since DNA adducts were found in the lungs of rats exposed to asphalt fumes in similar conditions, we decided to carry out an analogous experiment with Big Blue rats. A DNA adduct was detected 3 and 30 days after the end of treatment suggesting that these genetic alterations were quite steady. Thirty days after exposure, the cII mutant frequency was similar in control and exposed rats. In addition, a slight but not significant modification of the mutation spectrum associated with an increase of G:C to T:A and A:T to C:G transversions was noticeable in the treated animals. Then, these data failed to demonstrate a pulmonary mutagenic potential for bitumen fumes generated at road paving temperature in our experimental conditions despite the presence of a DNA adduct. These results may provide information concerning the pulmonary mechanism of action of this aerosol and may contribute to the occupational health hazard assessment.