Development and Evaluation of an In Silico Dermal Absorption Model Relevant for Children

The higher skin surface area to body weight ratio in children and the prematurity of skin in neonates may lead to higher chemical exposure as compared to adults. The objectives of this study were: (i) to provide a comprehensive review of the age-dependent anatomical and physiological changes in pediatric skin, and (ii) to construct and evaluate an age-dependent pediatric dermal absorption model. A comprehensive review was conducted to gather data quantifying the differences in the anatomy and physiology of child and adult skin. Maturation functions were developed for model parameters that were found to be age-dependent. A pediatric dermal absorption model was constructed by updating a MoBi implementation of the Dancik et al. 2013 skin permeation model with these maturation functions. Using a workflow for adult-to-child model extrapolation, the predictive performance of the model was evaluated by comparing its predicted rates of flux of diamorphine, phenobarbital and buprenorphine against experimental observations using neonatal skin. For diamorphine and phenobarbital, the model provided reasonable predictions. The ratios of predicted:observed flux in neonates for diamorphine ranged from 0.55 to 1.40. For phenobarbital, the ratios ranged from 0.93 to 1.26. For buprenorphine, the model showed acceptable predictive performance. Overall, the physiologically based pediatric dermal absorption model demonstrated satisfactory prediction accuracy. The prediction of dermal absorption in neonates using a model-based approach will be useful for both drug development and human health risk assessment.

Effects of Artificial Sweat Formulation and Extraction Temperature on Estimation of the Dermal Bioaccessibility of Potentially Toxic Elements in a Contaminated Soil from an E-Waste Recycling Site

Informal recycling of electronic waste leads to soil contamination that can impact human health. To accurately assess exposure to potentially toxic elements (PTE) in soil it is necessary to consider their bioavailability through ingestion, inhalation and dermal contact. However, bioaccessibility tests that estimate dermal absorption following adhesion of contaminated soil particles to skin are not well established. In this study the concentrations of As, Cd, Cr, Cu, Fe, Mn, Ni, Pb and Zn were estimated in the <45 µm particle size fraction of a bulk composite soil from an e-waste recycling site using five different artificial sweat formulations. Extractions were performed at temperatures ranging from 17 to 47 °C to investigate the effect of ambient temperature on bioaccessibility. Results obtained using the different artificial sweats were not consistent with one another. In particular, the NIHS 96-10 formulation solubilized larger amounts of analytes (ranging from 6.3 times the next most effective extractant for Cu to 1700 times the next most effective for Pb). There was a general increase in release of PTE with increasing temperature, except for As. Although trends varied between analytes and formulations, this highlights the need to consider ambient temperature when estimating dermal bioaccessibility of PTE in soil.

New Strategies for Improving Budesonide Skin Retention

The aim of this work was to evaluate the ex vivo effect of the combination of two strategies, complexation with cyclodextrin, and poloxamer hydrogels, for improving water solubility in the dermal absorption of budesonide. Two hydrogels containing 20% poloxamer 407, alone or in combination with poloxamer 403, were prepared. Each formulation was loaded with 0.05% budesonide, using either pure budesonide or its inclusion complex with hydroxypropyl-β-cyclodextrin, and applied in finite dose conditions on porcine skin. The obtained results showed that for all formulations, budesonide accumulated preferentially in the epidermis compared to the dermis. The quantity of budesonide recovered in the receptor compartment was, in all cases, lower than the LOQ of the analytical method, suggesting the absence of possible systemic absorption. The use of a binary poloxamer mixture reduced skin retention, in line with the lower release from the vehicle. When the hydrogels were formulated with the inclusion complex, an increase in budesonide skin retention was observed with both hydrogels. Poloxamer hydrogel proved to be a suitable vehicle for cutaneous administration of budesonide.

Organophosphate Esters in Children and Adolescents in Liuzhou City, China: Concentrations, Exposure Assessment and Predictors

Dermal contact with dust is commonly considered an important pathway of exposure to organophosphate esters (OPEs), but the importance of OPE uptake from diet is unclear. Herein, we used hand wipes to estimate OPE exposure from indoor dust and examined whether urinary OPE metabolite concentrations were influenced by sociodemographic characteristics, OPE amount in hand wipes, and dietary factors. OPEs were measured in urine and hand wipes from 6–18-year old children and adolescents (n=929) in Liuzhou, China. Sociodemographic and dietary factors were obtained from questionnaire. Six OPE metabolites were detected in >70% of the urine samples, and seven OPEs were detected in >50% of the hand wipes. Estimated daily intakes (EDIs) were calculated using urinary OPE metabolites to investigate the total daily intake of OPEs, in which 0.36–10.1% of the total intake was attributed to the exposure from dermal absorption. In multivariate linear regression models, sex, age, and maternal education were significant predictors of urinary OPE metabolite concentrations. Urinary diphenyl phosphate (DPHP) is positively associated with its parent compounds 2-ethylhexyl-diphenyl phosphate (EHDPP) and triphenyl phosphate (TPHP) in hand wipes. High versus low vegetable intake was associated with a 23.7% higher DPHP (95% confidence interval (CI): 0.51%, 52.1%). Barreled water drinking was associated with a 30.4% (95% CI: 11.8%, 52.0%) increase in bis(1-chloro-2-propyl) 1-hydroxy-2-propyl phosphate (BCIPHIPP) compared to tap water drinking. Our results suggested the widespread exposure to OPEs in children and adolescents. In additional to dermal absorption, dietary intake may be an important exposure source of certain OPEs.

Occurrence of Disinfection By-Products in Swimming Pools in the Area of Thessaloniki, Northern Greece. Assessment of Multi-Pathway Exposure and Risk

This study investigated the occurrence of disinfection by-products (DBPs) (trihalomethanes (THMs), haloacetic acids (HAAs), halonitriles (HANs), halonitromethane (TCNM) and haloketones (HKs)) in different type of swimming pools in the area of Thessaloniki, northern Greece by employing the EPA methods 551.1 and 552.3. Moreover, general water quality parameters (pH, residual chlorine, dissolved organic carbon, UV254 absorption, total nitrogen, alkalinity and conductivity) were also measured. The concentrations of DBPs showed great variability among swimming pools as well as within the same pool between sampling campaigns. HAAs exhibited the highest concentrations followed by THMs, HANs, TCNM and HKs. Exposure doses for four age groups (3–<6 y, 6–<11 y, 11–<16 y and adults) were calculated. Route-specific exposures varied among DBPs groups. Inhalation was the dominant exposure route to THMs and TCNM (up to 92–95%). Ingestion and dermal absorption were the main exposure routes to HAAs (40–82% and 18–59%, respectively), depending on the age of swimmers. HANs contributed up to 75% to the calculated cytotoxicity of pool water. Hazard indices for different exposure routes were <1, suggesting non-carcinogenic risk. Inhalation posed the higher carcinogenic risk for THMs, whereas risk via oral and dermal routes was low. Ingestion and dermal contact posed the higher risk for HAAs. Risk management strategies that minimise DBPs exposure without compromising disinfection efficiency in swimming pools are necessary.

Localized alopecia and suppression of hypothalamic-pituitary-adrenal (HPA) axis in dogs following treatment with difluprednate 0.05% ophthalmic emulsion (Durezol®)

Background Despite the common use of topical ophthalmic corticosteroids in dogs, detailed reports on systemic and dermatologic adverse effects are limited. Results Nine purpose-bred research Beagles were treated with difluprednate 0.05% ophthalmic emulsion in one or both eyes 2–3 times daily. Some difluprednate treated dogs developed mild to severe alopecia of the periocular region, face, and distal pinna (5/9). The median duration of treatment prior to onset of dermatologic signs for difluprednate treated dogs was 550 days (453–1160 days). Diagnostic testing included complete blood count (CBC) and serum biochemistry, adrenocorticotropic hormone (ACTH) stimulation testing combined with endogenous ACTH measurement, and skin biopsy. The CBC and chemistry were within normal limits for all dogs. There were varying degrees of suppression of the hypothalamic-pituitary-adrenocortical (HPA) axis with difluprednate treatment. Dogs with the most profound alopecic changes had less pronounced HPA axis suppression compared to dogs with no integumentary changes. Skin biopsies demonstrated follicular atrophy and follicular keratosis. When topical difluprednate was reduced to unilateral therapy, the hair regrew on the untreated side of the face. In addition to the affected research dogs, a 7-year old female spayed Chihuahua that was being treated as a clinical patient with long-term difluprednate 0.05% ophthalmic emulsion developed generalized hypotrichosis on the head and body and a potbellied appearance. ACTH stimulation testing revealed suppression of the HPA axis with a mild increase in serum alkaline phosphatase (ALP) activity and a urine specific gravity of 1.016. The combination of clinical signs and laboratory abnormalities was supportive of iatrogenic hyperadrenocorticism. Conclusions In dogs long-term use of difluprednate ophthalmic emulsion results in HPA axis suppression and in some cases iatrogenic hyperadrenocorticism. A novel pattern of localized alopecia is suspected to be related to dermal absorption and local action due to superior potency and penetration compared to other commonly utilized ophthalmic corticosteroids.

Epigenetic Mechanisms of Endocrine-Disrupting Chemicals in Obesity

The incidence of obesity has dramatically increased over the last decades. Recently, there has been a growing interest in the possible association between the pandemics of obesity and some endocrine-disrupting chemicals (EDCs), termed “obesogens”. These are a heterogeneous group of exogenous compounds that can interfere in the endocrine regulation of energy metabolism and adipose tissue structure. Oral intake, inhalation, and dermal absorption represent the major sources of human exposure to these EDCs. Recently, epigenetic changes such as the methylation of cytosine residues on DNA, post-translational modification of histones, and microRNA expression have been considered to act as an intermediary between deleterious effects of EDCs and obesity development in susceptible individuals. Specifically, EDCs exposure during early-life development can detrimentally affect individuals via inducing epigenetic modifications that can permanently change the epigenome in the germline, enabling changes to be transmitted to the next generations and predisposing them to a multitude of diseases. The purpose of this review is to analyze the epigenetic alterations putatively induced by chemical exposures and their ability to interfere with the control of energy metabolism and adipose tissue regulation, resulting in imbalances in the control of body weight, which can lead to obesity.

Hygienic assessment of the skin-resorptive effect of xenobiotics (literature review)

The basis of safety for working with chemicals, including pesticides, is to minimize contact with them and prevent them from entering the body by inhalation and dermal route, sometimes in actual production conditions, the skin pathway can be more dangerous. The most studied inhalation route of harmful substances entering the body of a working person is confirmed by an extensive evidence base, the presence of regulatory and methodological documents, experimentally established and approved MPC in the air of the occupational area for 2484 substances, and 601 substances included in SanPiN 1.2.3685-211. The maximum permissible levels (MPL) on the skin are presented for only 26 substances in the same document. Identification and evaluation of the skin-resorptive effect of xenobiotics have methodological features due to the properties of the skin, which performs a barrier-protective function, and the physico-chemical, toxic properties of substances. The main stages of development in the domestic hygienic science and practice of research on the study and assessment of the skin-resorptive effect of xenobiotics in industrial contact with them are presented. The continuity of research on the study and evaluation of the skin-resorptive impact of chemicals used in various industries and agriculture is shown, making it possible to develop methodological approaches to the identification and risk assessment of dermal absorption of xenobiotics, including pesticides, within the organisms of workers. Evaluating the risk of skin contamination is the main argument for the development of measures for the primary prevention of skin resorptive action. Establishing the priority of the dermal route of toxicant intake is an evidence-based justification for making decisions about the possibility of using, for example, pesticides on the territory of the Russian Federation. The literature review is based on open sources hosted on virtual database platforms: Scopus, Web of Science, MedLine, Global Health, e-LIBRARY, Electronic Fund of Legal and Regulatory Documents, etc.