Cutaneous Exposure Research Articles

Cutaneous Exposure to Arsenicals Is Associated with Development of Constrictive Bronchiolitis in Mice.

Organoarsenicals, such as lewisite and related chloroarsine, diphenylchloroarsine (DPCA), are chemical warfare agents developed during World War I. Stockpiles in Eastern Europe remain a threat to humans. The well-documented effects of cutaneous exposure to these organoarsenicals include skin blisters, painful burns, and life-threatening conditions such as acute respiratory distress syndrome. In survivors, long-term effects such as the development of respiratory ailments are reported for the organoarsenical sulfur mustard; however, no long-term pulmonary effects are documented for lewisite and DPCA. No animal models exist to explore the relationship between skin exposure to vesicants and constrictive bronchiolitis. We developed and characterized a mouse model to study the long-term effects of cutaneous exposure on the lungs after exposure to a sublethal dose of organoarsenicals. We exposed mice to lewisite, DPCA, or a less toxic surrogate organoarsenic chemical, phenyl arsine oxide, on the skin. The surviving mice were followed for 20 weeks after skin exposure to arsenicals. Lung microcomputed tomography, lung function, and histology demonstrated increased airway resistance, increased thickness of the smooth muscle layer, increased collagen deposition in the subepithelium, and peribronchial lymphocyte infiltration in mice exposed to arsenical on skin.

Defining the temporal relationship between the skin microbiome, immune response and skin barrier function during flare and resolution of atopic dermatitis: protocol of a Danish intervention study

IntroductionLesional skin of atopic dermatitis (AD) is often colonised by Staphylococcus aureus and the bacterial abundance increases during a flare. However, the role of S. aureus and the skin microbiome...

Dysregulation of the mTOR pathway by mechlorethamine

Mechlorethamine (HN2) is a derivative of the chemical warfare agent sulfur mustard (SM) and cutaneous exposure to HN2 is associated with dermal-epidermal junction (DEJ) disruption (vesication). The primary purpose of the present study was to investigate the effect of HN2 on the mammalian target of rapamycin (mTOR) signaling pathway using an in vivo mouse ear vesicant model (MEVM). To this end, the ears of male C57BL/ 6 J mice were exposed to a single topical dose of HN2 (100 mM) or vehicle control (DMSO). Mice were then euthanized 30 min, 1 h or 24 h following exposure. Mouse ear skin exposed to HN2 and biopsied 24 h thereafter exhibited increased tissue expression of Raptor, an important member of the mTORC1 complex, relative to vehicle treated samples. HN2 reduced the downstream effectors phospho S6 (Ser 240/244) ribosomal protein and phospho 4E-BP1 (Thr 37/46) of the mTOR pathway in the epidermis at 30 min, 1 h and 24 h following HN2 exposure but not in the dermis. These results support the hypothesis that HN2-mediated cutaneous toxicity involves dysregulation of the mTOR signaling pathway in the epidermis.

Lipid transfer protein allergy and anaphylaxis in children

Lipid transfer protein (LTP) is a pan-allergen widely distributed in plants, including Rosaceae family fruits, non-Rosaceae family fruits (such as Vitaceae, Solanaceae and Oleaceae), tree nuts, legumes, vegetables, cereals, seeds and latex1. Food allergy (FA) to LTP is an IgE-mediated allergy with increasing incidence in children2. Studies from Spain report that LTP allergy explains 5% of cases of pediatric FA and that up to 26% of children with a history of reactions to vegetables/fruits are LTP sensitized2, which can develop through direct gastrointestinal, cutaneous or respiratory exposure to LTP2, with current evidence arguing against a primary pollen sensitization3.

Evolution of erythrocyte and urine lead concentrations after cutaneous exposure to mud packs embedded into micro-perforated polyethylene bags according to the protocol used in French medical spas

Lead (Pb) is an environmental pollutant which may cause harmful effects on human health. It may be present within the mud-packs deposed on patient'skin for treating some rheumatologic conditions. We aimed to evaluate the diffusion of Pb from therapeutic mud-packs toward the human body in order to exclude safety concerns.We quantified Pb using inductively-coupled plasma mass spectrometry in blood (erythrocytes) and urine (raw concentration and divided by creatinine concentration) of 35 young healthy volunteers before and after the 21-day pelotherapy procedure from French medical spas (i.e hot micro-perforated polyethylene bags embedded-mud packs soaked in mineral water and deposed during 10 min on five cutaneous sites, in 5-day sequences during 3 consecutive weeks). We did not evidence a significant increase in their erythrocyte (p: 0.89) or urine (p: 0.96) concentrations when comparing pre- and post-treatment samples by the bilateral apparied Student test. These levels were markedly inferior to the recommended cut-off in all our participants taking into account the exclusion of individuals with extreme urinary creatinine values. From our sample including individuals with an optimal transcutaneous diffusion capacity (young persons with low subcutaneous fat mass) we conclude that there is no risk of Pb overexposure in patients receiving this type of pelotherapy regimen.

Assessment of skin sensitization properties of few-layer graphene and graphene oxide through the Local Lymph Node Assay (OECD TG 442B)

Skin contact is one of the most common exposure routes to graphene-based materials (GBMs) during their small-scale and industrial production or their use in technological applications. Nevertheless, toxic effects in humans by cutaneous exposure to GBMs remain largely unexplored, despite skin contact to other related materials has been associated with adverse effects. Hence, this in vivo study was carried out to evaluate the cutaneous effects of two GBMs, focusing on skin sensitization as a possible adverse outcome.Skin sensitization by few-layer graphene (FLG) and graphene oxide (GO) was evaluated following the Organization for Economic Cooperation and Development (OECD) guideline 442B (Local Lymph Node Assay; LLNA) measuring the proliferation of auricular lymph node cells during the induction phase of skin sensitization. Groups of four female CBA/JN mice (8–12 weeks) were daily exposed to FLG or GO through the dorsal skin of each ear (0.4–40 mg/mL, equal to 0.01–1.00 mg/ear) for 3 consecutive days, and proliferation of auricular lymph node cells was evaluated 3 days after the last treatment. During this period, no clinical signs of toxicity and no alterations in body weight and food or water consumptions were observed. In addition, no ear erythema or edema were recorded as signs of irritation or inflammation. Bromo-deoxyuridine (BrdU) incorporation in proliferating lymphocytes from ear lymph nodes (stimulation indexes <1.6) and the histological analysis of ear tissues excluded sensitizing or irritant properties of these materials, while myeloperoxidase activity in ear biopsies confirmed no inflammatory cells infiltrate. On the whole, this study indicates the absence of sensitization and irritant potential of FLG and GO.

Subacute exposure to bisphenol F diglycidyl-ether induces chronic dermatitis characterized by psoriasis-like skin inflammation in mice.

Bisphenol F diglycidyl ether (BFDGE) is widely used in the synthesis process of plastic products. While exposure to bisphenol A diglycidyl ether (BADGE), which has a similar structure to BFDGE and which is used for the same purpose, has been reported to cause health risks, there is still little information on BFDGE. Because it is estimated that the industrial workers are exposed to large amounts of BFDGE, the health risks associated with BFDGE exposure need to be clarified. We investigated the toxicity of cutaneous exposure to BFDGE using an in vitro evaluation system and a mouse exposure model. The tumorigenic potential of BFDGE was confirmed by the Bhas 42 cell transformation assay, which showed that BFDGE has both promoter and initiator activity, in vitro. A single dermal application of BFDGE was associated with minor contact hypersensitivity symptoms. In contrast, repeated dermal exposure to BFDGE for 2 weeks induced persistent acute inflammation with features similar to inflammation in human psoriasis. This is the first report evaluating the toxicity of BFDGE in animals, and we showed that BFDGE carries a health risk of inducing skin dermatitis similar to that in human psoriasis in an exposure period-dependent manner.

Human exposures to Phytolacca americana in Kentucky

Phytolacca americana, known more commonly as “pokeweed”, is a large perennial plant found ubiquitously throughout the United States. Despite known toxicities, characterization of pokeweed exposure demographics, symptoms, treatments, and outcomes is currently limited. The objective of this study is to describe human pokeweed exposures, treatments, and outcomes, in the state of Kentucky, between 2000 and 2019. The National Poison Database System was queried for all Phytolacca americana exposures in the state of Kentucky between 2000 and 2019. After the removal of non-human cases, investigators independently reviewed data to ensure all coding was appropriate per the standards set forth by NPDS. The primary objective of this study was to describe pokeweed exposure demographics within the state of Kentucky during the previously established timeframe. Secondary objectives included characterizing pokeweed treatment trends and evaluating their affiliated medical outcomes. 1669 cases of human pokeweed exposure were reported. Patients were predominantly young in age, with a median age of 3 years reported. The majority of patients were male (54.9%), with unintentional exposures representing most exposure reasons (97.2%). Oral ingestion of plant material represented the bulk of the exposure route (98.3%), with pokeberries most often implicated in these cases (93.9%). Exposures were generally well tolerated. 239 total adverse events were noted during the timeframe. Abdominal pain, nausea, vomiting, and diarrhea were most common. Dermal exposures resulted in cutaneous edema, pain, and swelling. Treatments were mainly supportive, with no deaths reported during the study timeframe. In conclusion, Phytolacca americana is commonly encountered in the United States. In this observational study, patients most heavily implicated in pokeweed exposures are young males. Oral ingestion was most commonly reported, with berries most often implicated. Exposures are generally well tolerated, with gastrointestinal symptoms most frequently reported. Cutaneous exposures represent an underappreciated exposure route. Treatments are largely supportive in nature.

Validation of the food frequency questionnaire for the assessment of dietary vitamin D intake.

Vitamin D and its adequate status are related to many aspects of human health; therefore, an appropriate tool is needed for the valid assessment of vitamin D status. The main contributor to vitamin D status is endogenous synthesis after cutaneous exposure to ultraviolet B light (UVB), but in the absence of UVB radiation, vitamin D intake becomes an important source of vitamin D. Various tools are available for vitamin D intake assessments, with the Food Frequency Questionnaire (FFQ) being among the fastest, cheapest, and most convenient; however, until now, these tools have not been adapted for the Slovenia (SI). To enable valid vitamin D intake estimation, we developed a simple one-page semi-quantitative FFQ (sqFFQ/SI) and tested its validity using a 5-day dietary record (DR) as a reference method. The reproducibility was tested with the second sqFFQ/SI (sqFFQ/SI2) 6 weeks after the first (sqFFQ/SI1). The validity and reproducibility of this method were tested on 54 participants using Bland–Altman plots, Spearman’s correlation, and Kappa analyses of tertiles. The mean daily vitamin D intake was 3.50 ± 1.91 μg according to the 5-day DR, and 2.99 ± 1.35 and 3.31 ± 1.67 μg according to the sqFFQ/SI1 and repeated sqFFQ/SI (sqFFQ/SI2), respectively. When analyzing for validity, the sqFFQ/SI1 was found to be significantly correlated (p < 0.05) with the 5-day DR, with an acceptable correlation coefficient of 0.268 and a Bland–Altman index of 3.7%. For reproducibility, the correlation between the sqFFQ/SI1 and sqFFQ/SI2 was highly significant (p < 0.001), with a good correlation coefficient of 0.689 and a Bland–Altman index of 3.7%. Kappa analyses of tertiles showed a poor validity and acceptable reproducibility. Overall, we observed a higher reproducibility than validity. Validation and reproducibility analyses demonstrated that the proposed sqFFQ/SI is acceptable and is, therefore, an appropriate tool for the effective assessment of habitual vitamin D intake on an individual level. With this consideration, this tool will be used in further population studies to assess vitamin D intake and for the development of a screening tool for the assessment of the risk for vitamin D deficiency, which will be used as a foundation for evidence-based policy-making decisions.

Allergy Diagnostics 2021

Allergic diseases are among the most common diseases worldwide. For appropriate management knowledge of the allergy trigger is crucial. The clinical picture of allergic diseases is diverse and correct diagnosis is often a challenge. The allergist needs to distinguish intolerances from allergies and infectious diseases from non-infectious triggers. Test results have to be interpreted accordingly to differentiate sensitizations from allergies. In this review current state of the art diagnostic measures to diagnose type I and type IV allergies are described and discussed.Immediate type allergies such as allergic rhinoconjunctivitis, asthma and anaphylaxis are mediated by allergen-specific IgE antibodies detectable both in serum and tissue. Typical triggers are pollen, mites, animal epithelia, food, insect toxins and pharmaceuticals. In everyday practice, diagnostics are based on three complementary pillars: the allergy-specific anamnesis as a prerequisite of correct interpretation of subsequent diagnostic tests like skin testing and serological immunoglobulin detection. These can be supplemented as required and available by provocation tests to prove clinical reactivity and cellular assays to demonstrate the cellular immune response.Type IV allergic reactions are mediated by T cells causing contact allergy with a local eczematous reaction with a latency of several hours to days. Some 3,500 triggers, often from occupational environment, are known; e. g., nickel, chromium, cobalt, fragrances, rubber, plastics, preservatives, dyes, neomycin, benzocaine, sulfonamides, quinidine, wool wax, perubalsam, eye therapeutics, light filter substances, disinfectants, pesticides, technical oils or plants. Diagnosis of contact allergy combines the history of cutaneous exposure with associated symptoms and patch testing, with detection of a late phase clinical reaction after 6 to 48, up to a maximum of 96 hours after antigen contact.

LB1034 Chromatin remodeling by warfare arsenicals in porcine skin

Accidental or deliberate exposure to highly toxic chemical warfare agents and many industrial chemicals pose significant threat to environment and human health. Skin exposure to arsenical vesicants, developed as chemical weapons in World War I/II, causes painful inflammation and skin wounds. The lack of human relevant animal models has been a key impediment for defining the underlying mechanism/s of these devastating chemicals. The Gottingen minipig skin closely resembles to human skin and we demonstrate that cutaneous exposure to molar equivalent doses of lewisite or structurally related arsenicals [diphenylchlorarsine (DPCA), diphenylcyanoarsine (DPCYA), diethylchlorarsine (DECA)] leads to skin inflammation and wound that progresses in dose- and time-dependent manner.

Sodium Hypochlorite and its Environmental Impacts; Time to Switch for Herbal Alternatives

Sanitizers are anti-microbial products in the form of spray, lotions, and creams. Sodium hypochlorite now plays an essential role in preserving hand cleanliness by denaturing microbial proteins by lysing the cell. These Sanitizers have also been used in medical, dental, and surgical treatments. If consumed, or through cutaneous or ocular exposure, sodium hypochlorite can be hazardous. When combined with acid it forms chlorine gas and when combined with basic solutions, chloramine is formed, both of which contribute to harmful consequences and it is an incredibly powerful oxidant. Furthermore, chlorination of drinking water with sodium hypochlorite oxidase organic pollutants, resulting in trihalomethanes, which are hazardous. It is critical for health care practitioners, particularly physicians, to understand the ways in which NaOCl can cause toxicity. The study of natural cures used to treat human sickness over millennia has laid the foundation for pharmaceutical development. The adaptation of alternative hand sanitizer formulations based on natural and herbal resources is one reasonable solution to address this toxicity problem. More extensive screens of indigenous plants with elevated flavonoids levels for antibacterial activities and the development of ecofriendly and efficient hand sanitizers should be conducted as contrast to artificial formulations.

Assessment of dermal absorption of beryllium and copper contained in temple tips of eyeglasses

Dermal exposure to hazardous substances such as chemicals, toxics, metallic items and other contaminants may present substantial danger for health. Beryllium (Be) is a hazardous metal, especially when inhaled and/or in direct contact with the skin, associated with chronic beryllium disease (CBD) and Be sensitization (BeS). The objective of this study was to investigate the percutaneous penetration of beryllium and copper contained in metallic items as eyeglass temple tips (specifically BrushCAST® Copper Beryllium Casting Alloys containing Be 0.35 < 2.85%; Cu 95.3–98.7%), using Franz diffusion cells. This work demonstrated that the total skin absorption of Cu was higher (8.86%) compared to Be (4.89%), which was expected based on the high percentage of Cu contained in the eyeglass temple tips. However, Be accumulated significantly in the epidermis and dermis (up to 0.461 µg/cm2) and, to a lesser extent, in the stratum corneum (up to 0.130 µg/cm2) with a flux of permeation of 3.52 ± 4.5 µg/cm2/hour and lag time of 2.3 ± 1.3 h, after cutaneous exposure of temple tip into 1.0 mL artificial sweat for 24 h. Our study highlights the importance of avoiding the use of Be alloys in items following long-term skin contact.

Development of BRD4 inhibitors as anti-inflammatory agents and antidotes for arsenicals

Arsenicals belong to the class of chemical warfare agents known as vesicants, which are highly reactive, toxic and cause robust inflammatory response. Cutaneous exposure to arsenicals causes a wide range of systemic organ damage, beginning with cutaneous injuries, and later manifest multi-organ damage and death. Thus, the development of suitable antidotes that can effectively block injury following exposure to these agents is of great importance. Bromodomain 4 (BRD4), a member of the bromodomain and extra terminal domain (BET) family, plays crucial role in regulating transcription of inflammatory, proliferation and cell cycle genes. In this context, the development of potent small molecule inhibitors of BRD4 could serve as potential antidotes for arsenicals. Herein, we describe the synthesis and biological evaluation of a series of compounds.

Saponins of Korean Red Ginseng May Protect Human Skin from Adipokine-Associated Inflammation and Pigmentation Resulting from Particulate Matter Exposure.

Background: Exposure to airborne particulate matter (PM) is an ever-increasing concern worldwide. Strategies to counter the detrimental effects that follow cutaneous exposure to PM, such as induction of pigmentation, inflammation, and alterations in adipokine profile, need to be investigated further. Korean red ginseng (KRG) extracts and individual ingredients have been demonstrated to play an effective role in suppression of ROS, inflammation, and resultant skin aging. In addition, recent investigations revealed that Rg3 and Rf saponins work as antimelanogenic agents. In this study, we investigated whether saponins of KRG can protect against or reverse the PM-induced detrimental effects. Methods: The biological effects of PM and saponins were evaluated both in vitro and ex vivo. Cell viability and intracellular ROS levels were determined in normal human epidermal melanocytes (NHMs), human epidermal keratinocytes (NHKs), and their cocultures. Experiments to demonstrate the protective properties of saponins against consequences of exposure to PM were performed. Melanin assay, quantitative real-time PCR, and Western blotting were carried out to determine the effects on melanogenesis and the implicated molecular signaling pathways. Results: Exposure to PM resulted in decreased keratinocyte viability, which was coupled with augmented oxidative stress. These changes were attenuated by treatment with saponins. PM exposure resulted in increased expression of leptin, which was reduced by saponins. Moreover, PM exposure led to increased melanin production in a coculture model, which was mitigated by treatment with saponins. Treatment with saponins resulted in a decrease in matrix metalloproteinase (MMP) levels after exposure to PM. Conclusion: Saponins of KRG can protect the skin from the harmful effects of PM exposure by reducing levels of ROS, leptin, inflammatory cytokines, and melanin.

Type I Interferons Enhance the Repair of Ultraviolet Radiation-Induced DNA Damage and Regulate Cutaneous Immune Suppression.

Type I interferons (IFNs) are important enhancers of immune responses which are downregulated in human cancers, including skin cancer. Solar ultraviolet (UV) B radiation is a proven environmental carcinogen, and its exposure contributes to the high prevalence of skin cancer. The carcinogenic effects of UV light can be attributed to the formation of cyclobutane pyrimidine dimers (CPD) and errors in the repair and replication of DNA. Treatment with a single dose of UVB (100 mJ/cm2) upregulated IFNα and IFNβ in the skin of C57BL/6 mice. IFNα and IFNβ were predominantly produced by CD11b+ cells. In mice lacking the type I IFN receptor 1 (IFNAR1), the repair of CPD following cutaneous exposure to a single dose of UVB (100 mJ/cm2) was decreased. UVB induced the expression of the DNA repair gene xeroderma pigmentosum A (XPA) in wild-type (WT) mice. In contrast, such treatment in IFNAR1 (IFNAR1-/-) mice downregulated XPA. A local UVB regimen consisting of UVB radiation (150 mJ/cm2) for 4 days followed by sensitization with hapten 2,4, dinitrofluorobenzene (DNFB) resulted in significant suppression of immune responses in both WT and IFNAR1-/- mice. However, there were significantly higher CD4+CD25+Foxp3+ regulatory T-cells in the draining lymph nodes of IFNAR1-/- mice in comparison to WT mice. Overall, our studies reveal a previously unknown action of type I IFNs in the repair of photodamage and the prevention of UVB-induced immune suppression.

Development of Milk Allergy Models in Mice Induced by Epicutaneous Exposure

Cow's milk allergy is one of the most common and life-long allergies. Therefore, it is highly important in the field to develop a robust and reproducible model and to dissect the immunologic mechanisms involved in development and clinical manifestation of the disease. Milk proteins are largely divided into two classes; caseins and whey proteins. The goal of this project was to develop milk allergy models in mice via cutaneous exposure and compare the effects of these two proteins.

Atopic Dermatitis and Food Allergy: Best Practices and Knowledge Gaps—A Work Group Report from the AAAAI Allergic Skin Diseases Committee and Leadership Institute Project

Allergists are often asked to evaluate children with atopic dermatitis (AD) for allergen triggers to disease. Testing, particularly for food triggers, often leads to elimination diets in an effort to improve AD control. However, the dual exposure hypothesis suggests that oral tolerance to food antigens is promoted through high-dose oral exposure, where sensitization occurs through lower dose cutaneous exposure. This suggests that strict elimination diets may pose some risks in children with AD. In addition, emerging evidence suggests an important role of skin inflammation in further allergic disease and the importance of dietary exposure to maintain oral tolerance. This work group report reviews current guidelines-based management for children with moderate-to-severe AD, the evidence for current recommendations for the evaluation and management of these children, provides a nuanced examination of these studies, and addresses current knowledge gaps in the care of these children.

Deferoxamine Treatment Improves Antioxidant Cosmeceutical Formulation Protection against Cutaneous Diesel Engine Exhaust Exposure.

Skin is one of the main targets of the outdoor stressors. Considering that pollution levels are rising progressively, it is not surprising that several cutaneous conditions have been associated with its exposure. Among the pollutants, diesel engine exhaust (DEE) represents one of the most toxic, as it is composed of a mixture of many different noxious chemicals generated during the compression cycle, for ignition rather than an electrical spark as in gasoline engines. The toxic chemicals of most concern in DEE, besides the oxides of nitrogen, sulfur dioxide and various hydrocarbons, are metals that can induce oxidative stress and inflammation. The present study aimed to evaluate the effects of topical application, singularly or in combination, of the iron-chelator deferoxamine and a commercially available formulation, CE Ferulic, in up to 4-day DEE-exposed skin. DEE induced a significant increase in the oxidative marker 4-hydroxy-nonenal (4HNE) and matrix-metallopeptidase-9 (MMP-9), the loss of cutaneous-barrier-associated proteins (filaggrin and involucrin) and a decrease in collagen-1, while the formulations prevented the cutaneous damage in an additive manner. In conclusion, this study suggests that iron plays a key role in DEE-induced skin damage and its chelation could be an adjuvant strategy to reinforce antioxidant topical formulations.

Chemical quality assessment and health risk of heavy metals in groundwater sources around Saravan landfill, the northernmost province of Iran

ABSTRACT The penetration of landfill leachate into the subsoil contaminates soil and groundwater and has a negative effect on health. Therefore, the present study was conducted to investigate the quality and health risk of groundwater around Saravan landfill in Guilan province. To determine the effects of landfill on groundwater, leachate and water sampling of 5 wells around Landfill were performed according to standard procedures. The sampling was repeated 2 times and the samples were run through 0.45 Wattman filters to measure heavy metals. Then physico-chemical parameters were analysed and the results were compared with WHO standard and Environmental Protection Organization of Iran. Finally, the water quality index and potential health risks in children and adults were calculated. The results showed that the high pH of the leachate indicates the long life of the landfill. The concentrations of chromium, lead and manganese were higher than the allowed amount. The results of non-carcinogenic cumulative risk assessment in children and adults were 4.77 and 2.48 and the result of carcinogenic cumulative risk assessment in children and adults were 11 × 10 −3 and 23 × 10 −3, respectively Also, the health risk index of heavy metals for lead and manganese in gastrointestinal and cutaneous exposure in children was more than 1, respectively. Water quality index of 68.935 was obtained which was lower than recommended. According to the findings, the waste burial in Saravan landfill has led to a decrease in the quality of adjacent groundwater. The results of heavy metal concentrations and their health risk assessment showed the potential for pathogenic risk to the health of groundwater consumers in the study area. Therefore, due to the proximity of water wells to Saravan landfills and possible changes in the concentration of heavy metals, continuous monitoring is necessary.