Some propylene glycol ethers (PGEs) have been associated with reproductive toxicity. Ethoxypropanol (PGEE) and propoxypropanol (PGPE) are two common PGEs found in many commercial products. Although skin exposure is frequent when handling such products, no studies have investigated their skin absorption. Neat or aqueous concentrations of PGEs were applied with different concentrations on previously frozen human skin according to OECD guidelines. We also explored the use of frozen skin for skin irritation screening. Our results show that both PGEs readily permeate human skin (permeation coefficients: KpPGEE = 0.0005–0.002 cm/h; KpPGPE = 0.0002–0.002 cm/h; rates: JPGEE = 447.5–1075.2 µg/cm2/h; JPGPE = 193.9–826.1 µg/cm2/h; and time lag: 2–5 h). The permeability rate was four times greater for PGPE diluted in water compared to neat, and double for PGEE. Increasing the water content increased PGEE skin permeation but had no effect on PGPE. Cleaning products contain 1–5% PGEs, and water-based paints 10–50%, thus increasing the potential for skin uptake in consumers. Our skin irritation results were inconsistent, so we conclude that skin irritation cannot be assessed with previously frozen human skin. Future studies should assess the irritation using fresh skin and investigate the risk of health effects from PGEs exposures.

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Skin exposure to cleaning products in the general and occupational population are a public health concern. Among the most frequently identified amphiphilic organic solvents in cleaning products are propylene glycol monomethyl ether (PGME) and propylene glycol n-butyl ether (PGBE). Internal dose from skin exposure may be efficiently evaluated using in vitro flow-through diffusion cells with excised human skin. Our aim in this study was two-fold; 1) characterize the permeation rates (J), time lag (Tlag), and permeation coefficients (Kp) of PGME and PGBE in human ex-vivo skin permeation assays, and 2) determine a possible mixture effect on skin permeation characteristics when applied together. Our results showed a short Tlag for PGME and was reduced further depending on the amount of PGBE in the mixture (Tlag was reduced from 2 h to 1-1.7 h) for fresh skin. PGBE Tlag slightly increased when mixed with 50 % or more PGME. Permeation rate decreased to half for both PGME and PGBE in mixture at any concentration. This substantial permeation was greater with previously frozen skin. This mixture effect could favor permeation of other compounds through human skin.

Skin exposures are common during cleaning activities, and may contribute to the overall body burden. Cleaning products may contain irritants such as monoethanolamine (MEA) and diethanol amine (DEA). The significance of the skin exposure route is unknown, as no estimates for MEA skin permeation are available. We used in vitro flow-through diffusion cells with excised fresh human skin to measure skin permeation, and assessed skin damage with histological methods. MEA(aq) by itself (2%) or as a constituent in cleaning products (0.25% working solution) did not permeate after 1 h or 24 h of exposure. MEA(aq) (10%) did not permeate skin after 1 h but after 24 h with a delay (Tlag; 7 h) and a moderate permeation rate (J; 26.6 μg/cm2/h). MEA permeation rate was 20-fold greater (544 μg/cm2/h) and ¼ of the time lag (1.5 h) when applied as undiluted cleaning product (13% MEA) compared to 10% MEA(aq). DEA in cleaning products did not permeate skin after 24 h. MEA and DEA produced skin irritations at low concentrations (1% MEA) and severe skin irritations when tested as a constituent in cleaning products. Absorption increased from 0 to 3% after 24 h to 14–29% after 88 h of MEA exposure, and is likely explained by the increased damage of the skin barrier. Limitations of this study are the low number of skin donors (N = 5) available. Our results demonstrate that topically applied MEA permeates across human skin relatively slowly and not below 5% while relatively extensively as a constituent of a commercial cleaning product.

Road construction workers are simultaneously exposed to two carcinogens; solar ultraviolet (UV-S) radiation and polycyclic aromatic hydrocarbons (PAHs) in bitumen emissions. The combined exposure may lead to photogenotoxicity and enhanced PAH skin permeation rates. Skin permeation rates (J) for selected PAHs in a mixture (PAH-mix) or in bitumen fume condensate (BFC) with and without UV-S co-exposures were measured with in vitro flow-through diffusion cells mounted with human viable skin and results compared. Possible biomarkers were explored. Js were greater with UV-S for naphthalene, anthracene, and pyrene in BFC (0.08-0.1 ng/cm(2)/h) compared to without (0.02-0.26 ng/cm(2)/h). This was true for anthracene, pyrene, and chrysene in the PAH-mix. Naphthalene and benzo(a)pyrene (BaP) in the PAH-mix had greater Js without (0.97-13.01 ng/cm(2)/h) compared to with UV-S (0.40-6.35 ng/cm(2)/h). Time until permeation (Tiags) in the PAH-mix were generally shorter compared to the BFC, and they ranged from 1 to 13 h. The vehicle matrix could potentially be the reason for this discrepancy as BFC contains additional not identified substances. Qualitative interpretation of p53 suggested a dose-response with UV-S, and somewhat with the co-exposures. MMP1, p65 and cKIT were not exploitable. Although not statistically different, PAHs permeate human viable skin faster with simultaneous exposures to UV.

Background. Polysensitization, defined as being allergic to three or more haptens from the European baseline series, is considered to reflect increased susceptibility to developing a contact allergy, and is likely to be associated with an impaired quality of life. Objectives. To evaluate the prevalences of polysensitization across Europe and to analyse factors associated with polysensitization. Methods. Patch test data collected by the European Surveillance System on Contact Allergies (ESSCA; www.essca-dc.org) in consecutively patch tested patients from January 2009 to December 2014, comprising 11 countries and 57 departments, were retrospectively analysed. Results. A total of 86 416 patients were available for analysis, showing a standardized prevalence of polysensitization of 7.02%, ranging from 12.7% (Austria) to 4.6% (Italy). Allergen pairs with the strongest association are reported for the total population, for South Europe, and for North/Central Europe. Overall, polysensitized patients showed a higher percentage of extreme (+++) positive patch test reactions than oligosensitized patients. Female sex, occupational dermatitis and age > 40 years were risk factors for polysensitization. Conclusions. The varying prevalences of polysensitization across Europe most likely reflect differences in patient characteristics and referral patterns between departments. Knownrisk factors for polysensitization are confirmed in a European dermatitis population.

Methylchloroisothiazolinone (MCI) and methylisothiazolinone (MI) are biocides used in many types of products such as cosmetics, paints, and cleaning agents. Skin contact is often encountered when using these products. Although MCI and MI are strong allergens and cause skin irritation, no scientific skin permeation study has been reported except for some unpublished data. Therefore, this study assessed the permeation of MCI and MI both separately and as a mixture through freshly dermatomed human skin (800 µm) in a flow-through diffusion cell system. Different concentrations of aqueous standards (1.5/1, 70/50, 150/35, and 750/175 µg/mL of MCI/MI) and various commercial products were assessed after 15–20 h of exposure. In parallel, the dose-dependent irritant effects of MCI/MI and MI were estimated by histology following 6- or 24-h exposure. Overall results show that MI in formulations or in aqueous standard solutions quickly permeated the skin with time lags less than 15 min while MCI was much slower (>3.5 h). MCI in formulations had permeation rates up to five times greater than that for MI in the same product, and in two tested creams were not found to permeate skin. Some signs of irritation were observed by histology; especially at the highest MCI/MI concentrations (750/250 µg/mL) in aqueous solutions. This confirms that MCI reacts readily with skin and may induce local irritation. The MCI and MI permeations are also greatly influenced by the topical vehicle. It is, therefore, more relevant to test exposures to formulations than aqueous standard solutions.

•This new in vitro allows us to assess in a valuable way skin irritation.•Although using fresh skin, we had no false positive and no false negative results.•Samples exposed to irritants showed alteration of epidermis with suffering cells.•With the new added substances to this work, there is now a qualitative available “irritation scale”.•We obtained 100% accuracy with the HPT model; 80% with the RHE models and 60% with the Draize test for 4 tested substances.

BackgroundPrurigo nodularis (PN), or nodular prurigo, is a chronic, debilitating, inflammatory skin disease. It can be very difficult to manage, and represents a challenge for the physician. Methotrexate (MTX) is a safe folic acid antagonist widely used in the management of inflammatory skin diseases such as psoriasis. Weekly administration of 7.5-20mg methotrexate (low-dose methotrexate, LD-MTX) represents an attractive treatment option, and could therefore find a place in the management of PN.AimTo evaluate the efficacy of LD-MTX as a treatment option for PN.MethodsThirteen patients who had failed to respond to conventional therapies such as topical steroids, phototherapy and antipruritic agents were treated with LD-MTX. The mean age of the patients was 75.83. Objective symptoms (Prurigo Nodularis Area and Severity Index; PNASI) and subjective symptoms (Pruritus Numeric Rating Scale; PNRS) were recorded. Treatment consisted of one subcutaneous injection of MTX 7.5-20mg once weekly for a minimum of 6months. Adjuvant application of emollients and topical steroids was maintained where needed.ResultsThere was remission or marked improvement (decrease in both PNRS or PNASI of >75%) in 10 cases, a trend to improvement in 2 cases and relapse in 1 case after treatment discontinuation.ConclusionsLD-MTX may allow improvement of PN in some patients, with long-lasting remission.

Skin exposures to chemicals may lead, through percutaneous permeation, to a significant increase in systemic circulation. Skin is the primary route of entry during some occupational activities, especially in agriculture. To reduce skin exposures, the use of personal protective equipment (PPE) is recommended. PPE efficiency is characterized as the time until products permeate through material (lag time, Tlag). Both skin and PPE permeations are assessed using similar in vitro methods; the diffusion cell system. Flow-through diffusion cells were used in this study to assess the permeation of two herbicides, bentazon and isoproturon, as well as four related commercial formulations (Basagran®, Basamais®, Arelon® and Matara®). Permeation was measured through fresh excised human skin, protective clothing suits (suits) (Microchem® 3000, AgriSafe Pro®, Proshield® and Microgard® 2000 Plus Green), and a combination of skin and suits. Both herbicides, tested by itself or as an active ingredient in formulations, permeated readily through human skin and tested suits (Tlag < 2 h). High permeation coefficients were obtained regardless of formulations or tested membranes, except for Microchem® 3000. Short Tlag, were observed even when skin was covered with suits, except for Microchem® 3000. Kp values tended to decrease when suits covered the skin (except when Arelon® was applied to skin covered with AgriSafe Pro and Microgard® 2000), suggesting that Tlag alone is insufficient in characterizing suits. To better estimate human skin permeations, in vitro experiments should not only use human skin but also consider the intended use of the suit, i.e., the active ingredient concentrations and type of formulations, which significantly affect skin permeation.

Large or giant cellular blue nevi are usually congenital and represent a challenge for the physician. Close anatomic structures may be altered by the size of the moles. In this article, we report the case of an uncommon large, agminated, cellular blue nevus of the 'plaque type' in a 42-year-old female. Due to the risks of malignant melanoma development on a large or giant blue nevus, we highlight the importance of proper histopathological diagnosis. Furthermore, because of the possibility that the nevus may invade the bone and cerebral tissues, we discuss the indication of a radiological diagnosis. The accurate correlation to clinical and histopathological findings and appropriate multidisciplinary management can save the lives of patients. (C) 2013 S. Karger AG, Basel

Phthalates are suspected to be endocrine disruptors. Di(2-ethylhexyl) phthalate (DEHP) is assumed to have low dermal absorption; however, previous in vitro skin permeation studies have shown large permeation differences. Our aims were to determine DEHP permeation parameters and assess extent of skin DEHP metabolism among workers highly exposed to these lipophilic, low volatile substances. Surgically removed skin from patients undergoing abdominoplasty was immediately dermatomed (800 μm) and mounted on flow-through diffusion cells (1.77 cm(2)) operating at 32°C with cell culture media (aqueous solution) as the reservoir liquid. The cells were dosed either with neat DEHP or emulsified in aqueous solution (166 μg/ml). Samples were analysed by HPLC-MS/MS. DEHP permeated human viable skin only as the metabolite MEHP (100%) after 8h of exposure. Human skin was able to further oxidize MEHP to 5-oxo-MEHP. Neat DEHP applied to the skin hardly permeated skin while the aqueous solution readily permeated skin measured in both cases as concentration of MEHP in the receptor liquid. DEHP pass through human skin, detected as MEHP only when emulsified in aqueous solution, and to a far lesser degree when applied neat to the skin. Using results from older in vitro skin permeation studies with non-viable skin may underestimate skin exposures. Our results are in overall agreement with newer phthalate skin permeation studies.

A 77-year-old man with a 5-year history of mycosis fungoides (MF) who had received several lines of therapy, including intravenous courses of Methotrexate (MTX) for the past 2 years, went on to develop several ulcerated cutaneous nodules on the left leg. Biopsy revealed diffuse sheets of EBV-positive large B cells (CD20+ CD30 ± IgM Lambda), with an angiocentric distribution and a monoclonal IGH gene rearrangement. Although the pathological features were diagnostic for an EBV-positive diffuse large B-cell lymphoma (DLBCL), several possibilities could be considered for assignment to a specific entity: EBV-positive DLBCL of the elderly, methotrexate-induced lymphoproliferative disorder (LPD), lymphomatoid granulomatosis, or the more recently described EBV-positive mucocutaneous ulcer. The development of EBV+ lymphoproliferations has been reported in two other patients with MF under MTX, and occurred as skin lesions of the leg in one of these and in the current case, which may question the relatedness to primary cutaneous DLCBL, leg-type.

Sarcoidosis is a systemic granulomatous disorder of unknown origin commonly affecting the lung, the lymphoid system and the skin. We report here two cases of cutaneous sarcoidosis in two former intravenous drug users following interferon (IFN)-α and ribavirin therapy for chronic hepatitis C. Both patients developed skin sarcoidosis along venous drainage lines of both forearms, coinciding with the areas of prior drug injections. The unique distribution of the skin lesions suggests that tissue damage induced by repeated percutaneous drug injections represents a trigger for the local skin manifestation of sarcoidosis. Interestingly, skin damage was recently found to induce the local expression IFN-α, a well-known trigger of sarcoidosis in predisposed individuals. Here we review the literature on sarcoidosis elicited in the context of IFN-α therapy and propose a new link between the endogenous expression of IFN-α and the induction of disease manifestations in injured skin.

We describe a patient with interstitial granuloma annulare associated with subcutaneous injection therapy (SIT) for desensitization to a type I allergy. Asymptomatic, erythematous, violaceous annular patches were located at the injection sites on both her arms. Medical history revealed perennial rhinoconjonctivitis treated with SIT (Phostal Stallergen® cat 100% and D. pteronyssinus/D.farinae 50%:50%).

Birt-Hogg-Dube Syndrome (BHD) is a rare condition, transmitted as an autosomal-dominant trait. The etiology is due to a mutation in the BHD gene, which encodes folliculin (FLCN), located on chromosome 17p. The skin changes observed are benign skin tumors consisting of hamartomas of the hair follicle with dermal changes. Patients with BHD have an increased risk of spontaneous pneumothorax due to rupture of lung cysts and an increased risk of kidney tumors. We report 3 new cases of BHD and discuss their clinical features, histopathological findings, and molecular diagnostics. We highlight the importance of genetic analysis to confirm the diagnosis because of the clinical pitfalls involved in establishing a diagnosis. Finally, we discuss the histopathological features in BHD and tuberous sclerosis complex and focus on their overlapping criterias. A correct diagnosis is essential as it can be life saving for patients.