Permeation Of Chemicals Research Articles

An advanced in silico model of the oral mucosa reveals the impact of extracellular spaces on chemical permeation

Accurately predicting the permeation of chemicals through human epithelial tissues is crucial for pharmaceutical therapeutic design and toxicology. Current mathematical models of multi-layered stratified squamous epithelium such as those in the oral cavity use simplistic ‘bricks and mortar’ geometries that do not fully account for the complex cellular architecture that may affect chemical permeation in these tissues. Here we aimed to develop a new, advanced mechanistic mathematical model of the human epithelium that more accurately represents chemical tissue permeation. Using measurements of cell size and tortuosity from micrograph images of both human oral (buccal) and tissue-engineered buccal mucosa along with mechanistic mathematical modelling, we show that the convoluted geometry of the extracellular spaces within the epithelium significantly impacts chemical permeation. We next developed an advanced histologically and physiologically-relevant in silico model of buccal mucosal chemical permeation using partial differential equations, fitted to chemical permeation from in vitro assay data derived from tissue-engineered buccal mucosal models and chemicals with known physiochemical properties. Our novel in silico model can predict epithelial permeation kinetics for chemicals with different physicochemical properties in the absence or presence of permeability enhancers. This in vitro − in silico approach constitutes a step-change in the modelling of chemical tissue permeation and has the potential to expedite pharmaceutical innovation by improved and more rapid screening of chemical entities whilst reducing the need for in vivo animal experiments.

Simulating the Permeation of Toxic Chemicals through Barrier Materials.

Chemical warfare agents that are liquids with low vapor pressure pose a contact hazard to anyone who encounters them. Personal protective equipment (PPE) is utilized to ensure safe interaction with these agents. A commonly used method to characterize the permeability of PPE towards chemical weapons is to apply droplets of the liquid agent to the surface of the material and measure for chemical breakthrough. However, this method could produce errors in the estimated values of the transport properties. In this paper, we solved numerically the three-dimensional cylindrical Fick's second law of diffusion for a liquid permeating through a non-porous rubbery membrane to determine the time the permeating species will emerge on the other side of the polymer membrane. Simulations of different amounts of surface area coverage and the geometries of permeate on the membrane surface indicated that incomplete surface area coverage affects the estimation of the transport properties, making the experimentally determined transport properties unsuitable for predictive use. We simulated different permeation values to determine the factors that most influenced the estimation error and if the error was consistent over different permeate-membrane combinations. Finally, a method to correct the experimentally determined permeability is suggested.

A Mechanistic Study on the Fluidization and Enhancement Effects of Cineole Toward Stratum Corneum Intercellular Lamellar Lipids: A Liquid Crystalline Model Approach.

The stratum corneum (SC) serves as the primary barrier for permeation in human skin. Penetration enhancers, such as 1,8-cineole, are utilized to enhance the permeation of drugs. Cineole increases the permeation of chemicals through different mechanisms. However, its mechanism, particularly at high concentrations, has not been well-studied and is the subject of the present investigation. In continuation of our previous studies, the present investigation aims to elucidate the mechanism of action and concentration dependency of the effects of 1,8-cineole on the structure, diffusional properties, and partitioning behavior of the SC at high concentrations. This will be achieved through lamellar liquid crystalline models and ex-vivo skin studies. A lamellar liquid crystalline lipid matrix model in the presence (25 - 90%, w/w) and absence of cineole was prepared from SC lipids and characterized by X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and polarized light microscopy (PLM) studies. Release of the model lipophilic drug (diazepam) from cineole and cineole-treated matrices and the permeation of the drug from cineole and cineole-containing matrices (as a vehicle similar to the stratum corneum lipids) through excised rat skin were studied. Drug assay was performed by HPLC. The PLM, DSC, and X-ray studies showed that the model matrix had a lamellar gel-liquid crystalline structure, and cineole fluidized the structure concentration-dependently and created other mesomorphic textures, such as myelinic figures. Release experiments showed that diffusion coefficients remained almost constant at high cineole concentrations of 40-90%, suggesting similar fluidization states. Skin permeation studies indicated that the diffusion coefficient (estimated from lag-time) increased concentration-dependently and played a role in permeability coefficient (Kp) increments alongside the increased partitioning of the model drug into the skin. Data suggest that high concentrations of cineole at the skin surface might not provide enough cineole in the skin for full fluidization, despite the similarity of the vehicle to SC lipids and even at high concentrations. The enhancement effect of cineole is concentration-dependent and might reach maximum fluidization at certain concentrations, but this maximum might not be easily achievable when cineole is used in formulations as pure or in a vehicle.

A Mechanistic Study on the Fluidization and Enhancement Effects of Cineole Toward Stratum Corneum Intercellular Lamellar Lipids: A Liquid Crystalline Model Approach

Background: The stratum corneum (SC) serves as the primary barrier for permeation in human skin. Penetration enhancers, such as 1,8-cineole, are utilized to enhance the permeation of drugs. Cineole increases the permeation of chemicals through different mechanisms. However, its mechanism, particularly at high concentrations, has not been well-studied and is the subject of the present investigation. Objectives: In continuation of our previous studies, the present investigation aims to elucidate the mechanism of action and concentration dependency of the effects of 1,8-cineole on the structure, diffusional properties, and partitioning behavior of the SC at high concentrations. This will be achieved through lamellar liquid crystalline models and ex-vivo skin studies. Methods: A lamellar liquid crystalline lipid matrix model in the presence (25 - 90%, w/w) and absence of cineole was prepared from SC lipids and characterized by X-ray diffraction, differential scanning calorimetry (DSC), Thermogravimetric Analysis (TGA), and Polarized Light Microscopy (PLM) studies. The release of the model lipophilic drug (diazepam) from cineole and cineole-treated matrices and the permeation of the drug from cineole and cineole-containing matrices (as a vehicle similar to the stratum corneum lipids) through excised rat skin were studied. A drug assay was performed by HPLC. Results: The PLM, DSC, and X-ray studies showed that the model matrix had a lamellar gel-liquid crystalline structure, and cineole fluidized the structure concentration dependently and created other mesomorphic textures, such as myelinic figures. Release experiments showed that diffusion coefficients remained almost constant at high cineole concentrations of 40-90%, suggesting similar fluidization states. Skin permeation studies indicated that the diffusion coefficient (estimated from lag-time) increased concentration-dependently and played a role in permeability coefficient (Kp) increments alongside the increased partitioning of the model drug into the skin. Data suggest that high concentrations of cineole at the skin surface might not provide enough cineole in the skin for full fluidization, despite the similarity of the vehicle to SC lipids and even at high concentrations. Conclusions: The enhancement effect of cineole is concentration-dependent and might reach maximum fluidization at certain concentrations, but this maximum might not be easily achievable when cineole is used in formulations as pure or in a vehicle.

A comparative study of the in vitro permeation of 2-phenoxyethanol in the skin PAMPA model and mammalian skin

For permeation studies that use excised skin, experimental data may show variability associated with the use of biological tissues. As a consequence, achieving reproducible results and data interpretation may be challenging. The skin parallel artificial membrane permeability assay (skin PAMPA) model has been proposed as a high-throughput tool for predicting skin permeation of chemicals. A number of skin cleansing wipe formulations for the diaper area of infants contain 2-phenoxyethanol (PE) as a preservative and cetylpyridinium chloride (CPC) as a surfactant with antimicrobial activity. However, information regarding cutaneous absorption of PE and CPC in the scientific literatures is remarkably limited. The main aim of the present study was to assess the suitability of the skin PAMPA model for prediction of skin permeation of PE. A secondary aim was to investigate the influence of CPC on the dermal absorption of PE. PE (1 % w/w) was prepared in two vehicles, namely propylene glycol (PG) and water-PG (WP). Permeability of PE was investigated in vitro using the skin PAMPA membrane, porcine skin and human skin under finite dose conditions. The highest permeation of PE was observed for the water-PG preparation with 0.2 % w/w of CPC. This finding was consistently observed in the skin PAMPA model and in Franz cell studies using porcine skin and human skin. Permeation of CPC was not detected in the three permeation models. However, permeation of PE increased significantly (p < 0.05) in the presence of CPC compared with formulations without CPC. When comparing the skin PAMPA data and the mammalian skin data for the cumulative amount of PE permeated, the r2 values for PAMPA-porcine skin and PAMPA-human skin were 0.84 and 0.89, respectively. The findings in this study demonstrate the capability of the skin PAMPA model to differentiate between various doses and formulations and are encouraging for further applications of this model as a high throughput screening tool in topical formulation development.

Inflammation of Gill Epithelia in Fish Causes Increased Permeation of Petrogenic Polar Organic Chemicals via Disruption of Tight Junctions.

The epithelial cell layer that lines the gills of fish controls paracellular permeation of chemicals through tight junctions. The integrity of tight junctions can be affected by inflammation, which likely affects the bioavailability of chemicals. Here, the inflammation of the rainbow trout gill cell line RTgill-W1 was induced via exposure to bacterial lipopolysaccharides (LPS). Cells were then coexposed to extracts of oil sands process-affected water (OSPW), which contain complex mixtures of chemicals. After 24 h of exposure, cells exposed to LPS showed a reduction in transepithelial electrical resistance, an indicator of tight junction integrity. Quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis determined that abundances of transcripts of genes coding for tight junction proteins were significantly less in cells exposed to 20, 50, or 100 mg L-1 LPS. Chemical analysis revealed increased permeation of constituents of OSPW across epithelia at all studied LPS concentrations. These in vitro findings were confirmed in vivo in rainbow trout exposed to LPS and OSPW for 48 h, which resulted in greater accumulation of chemicals relative to that for fish exposed to OSPW alone. Our results demonstrated that inflammation and disruption of tight junctions could lead to greater uptake of potentially harmful chemicals from the environment, which has implications for mixture risk assessment.

Estimation of skin absorption of chemicals with Fick's diffusion model

The skin is not only the site of drug application, but also the site of exposure to various chemical substances. Prediction of skin permeability, body absorption, and local skin concentration of chemicals are very important to assure efficacy and safety. Most in silico models for skin permeation of chemical are based on the prediction of its permeability coefficient (P, unit cm/s), and a certain level of prediction accuracy has been obtained. On the other hand, the amount absorbed in the body of a chemical is calculated from the sum of the amount of skin permeation and the amount under the stratum corneum (viable epidermis and dermis). The amount of skin permeation can be calculated from the P value as mentioned above, however, the amount under the stratum corneum, which is related to the local skin safety of the chemical, cannot be predicted. This article describes the principles of permeation of chemicals across the skin, the relationship between skin permeability and concentration in the skin, and the method for calculating the chemical concentration under the stratum corneum using skin permeation parameters.

The Impact of Different Closures on the Flavor Composition of Wines during Bottle Aging.

Wine flavor undergoes major changes during bottle aging and can be influenced by the type of closure. The interaction between wine, the type of closure and the external environment has the potential to significantly influence the overall quality of bottled wines, especially when the storage period is relatively long (more than five years). Therefore, the choice of closure (cork, synthetic or screw cap) deserves special attention in order to establish the ideal sealing conditions for optimizing wine flavor attributes. The contribution of different closures to the quality of bottled wine is through mass transfer phenomena, including permeation, sorption (scalping) or desorption of chemicals between closure materials and wines. Thus, this article aims to review the impact of different closures on the flavor composition of wines during post-bottling conditions. The implications of closures on wine sensory properties are also discussed.

Relevance of desorption kinetics and permeability for in vitro-based predictions of hepatic clearance in fish.

The impact of desorption kinetics and permeation kinetics on in vitro-based predictions of in vivo hepatic blood clearances is investigated in the present study. Most commonly, possible limitations due to slow desorption of chemicals from albumin or slow permeation of chemicals through cellular membranes are not considered when in vivo clearances are predicted from in vitro biotransformation rate constants. To evaluate whether the most commonly used extrapolation models might thus overlook important kinetic limitations, we compare predictions of in vivo clearance that explicitly consider desorption and permeation kinetics with predictions of in vivo clearance that neglect these aspects. Our results show that strong limitations due to slow permeation kinetics are possible depending on the assumed permeability value. While permeability values estimated with a mechanistic approach are fast enough to avoid significant limitations, other experimentally derived permeability values lead to dramatically decreased in vivo clearance predictions. These latter values lead to unrealistically low in vivo biotransformation estimates. Furthermore, we also evaluated the implications of desorption kinetics using experimentally determined desorption rate constants. These evaluations show that slow desorption kinetics are unlikely to limit in vivo clearance.

Laponite-Incorporated UiO-66-NH2-Polyethylene Oxide Composite Membranes for Protection against Chemical Warfare Agent Simulants.

A strategy is developed to enhance the barrier protection of polyethylene oxide (PEO)-metal-organic framework (MOF) composite films against chemical warfare agent simulants. To achieve enhanced protection, an impermeable high-aspect-ratio filler in the form of Laponite RD (LRD) clay platelets was incorporated into a composite PEO film containing MOF UiO-66-NH2. The inclusion of the platelets aids in mitigating permeation of inert hydrocarbons (octane) and toxic chemicals (2-chloroethyl ethyl sulfide, 2-CEES) of dimensions/chemistry similar to prominent vesicant threats while still maintaining high water vapor transport rates (WVTR). By utilizing small-angle neutron scattering, small-angle X-ray scattering, and wide-angle X-ray scattering, the LRD platelet alignment of the films was determined, and the structure of the films was correlated with performance as a barrier material. Performance of the membranes against toxic chemical threats was assessed using permeation testing of octane and 2-CEES, a common simulant for the vesicant mustard gas, and breathability of the membranes was assessed using WVTR measurements. To assess their robustness, chemical exposure (in situ diffuse reflectance infrared Fourier transform spectroscopy) and mechanical (tensile strength) measurements were also performed. It was demonstrated that the barrier performance of the film upon inclusion of the LRD platelets exceeds that of other MOF-polymer composites found in the literature and that this approach establishes a new path for improving permselective materials for chemical protection applications.

Glove permeation of chemicals: The state of the art of current practice—Part 2. Research emphases on high boiling point compounds and simulating the donned glove environment

This second part of the review of the 21st century literature on glove permeation is divided into the following major themes; permeation data and mathematical models, exposure/risk assessment, and manufacturer data. The major issues in the literature were the demonstrations that increasing temperature and applying forces increased permeation; and that glove manufacturer data were sometimes not reproducible. Double gloving of disposable gloves was found to be effective in resisting chemical permeation for short periods of time. Harmonization of standards and commercial glove classifications were called for at conditions that were closer to the temperature and applied forces actually present in the workplace, including whole glove testing and quantitative rather than just qualitative criteria. More research was recommended in each section and subsection with particular emphasis on defining the efficiency of solid phase collection devices, and more data in areas like exposure to cosmetics, household products, liquid foods, drinks, and cleaning liquids. More research in exposure assessment for permeated chemicals with sensors on the inner glove surface and on the skin was called for. Finally, it was decided that the state of the art of current practice was in a situation that needed the permeation standards, research, and the permeation charts of glove manufacturers to be at conditions that better reflected those encountered by workers with donned gloves.

Glove permeation of chemicals: The state of the art of current practice, Part 1: Basics and the permeation standards

Skin exposure to chemicals in the workplace environment is a major concern, the hands being the major exposure sites. Employers purchase gloves that have permeation data generated from permeation “standards” of the American Society for Testing and Materials International (ASTM International), European Committee for Standardization (EN), and the International Organization for Standardization (ISO) that test pieces of glove material and allow a user-defined temperature. The relevant standards based on continuous contact are ASTM F739, ASTM D6978, EN 374, EN 16523, and ISO 6529. The aim was to analyze the current state of the scientific literature on glove permeation in the 21st century up to December 2018. The introduction sets out the background, objectives and rationale of the review and its methodology followed by presentation of basic glove chemical resistance terms and Fick’s first law of diffusion, the details of the major permeation standards, their comparison, their critique, their research gaps; the scientific literature on whole glove permeation, and final conclusions. The major recommendation was to harmonize all the permeation standards and perform them at realistic work conditions, especially temperature. The whole glove system would be most useful for testing the thinnest gloves.

Nove norme i izbor odijela za zaštitu od kemijskih i bioloških opasnosti

SUMMARY: Selection of chemical protective clothing in industry is based on the known hazards. Firefighters and other intervention personnel face danger from many different hazardous chemicals which are usually not known in advance. On the whole, firefighters select the highest possible protection level offered by gastight suits. Their choice are frequently still reusable garments, although limited and single use garments, beside lower price, offer a number of important advantages in terms of weight, volume, chemical resistance, ease of maintenance, and comfort. New European norms do not divide chemical protective garments into reusable and limited use any more, which is in concert with the progress achieved in material technology. The issue of total lifecycle cost has become the decisive factor in the selection process. Following correct selection based on risk assessment is the maintenance specified in manufacturers’ recommendations, which is a critical factor in garment functionality. Modelling toxicity for new materials gives the opportunity for more precise risk assessment regarding permeation of dangerous chemicals and removes certain deficiencies in European norms. Some of most important parameters which must be analysed and compared during selection process are presented in the paper.

Sympathetic neural hyperalgesia edema syndrome as a cause of autoimmune hearing loss

To describe another previous unreported manifestation of the sympathetic neural hyperalgesia edema syndrome - autoimmune hearing loss. Dextroamphetamine sulfate 30 mg extended release capsules was given to a woman to try to help her conceive since, with her pelvic pain, chronic fatigue syndrome, and diarrhea, it was thought that an inflammatory condition related to permeation of unwanted chemicals into endometrial tissue related to the sympathetic neural hyperalgesia edema syndrome could be inhibiting her failure from conceiving despite three cycles of embryo transfer. Not only did the symptoms mentioned above disappear, but she also noted marked improvement of hearing loss that had been present for several years. The improvement in hearing was documented by audiology tests and had not responded to many months of 15 mg/day prednisone. Autoimmune hearing loss (diagnosis established by her ear nose and throat specialist) should be added to the long list of manifestation of the sympathetic neural hyperalgesia edema syndrome.

Development of a new test cell to measure cumulative permeation of water-insoluble pesticides with low vapor pressure through protective clothing and glove materials.

A collaborative approach, involving resources and expertise from several countries, was used to develop a test cell to measure cumulative permeation by a solid-state collection technique. The new technique was developed to measure the permeation of pesticide active ingredients and other chemicals with low vapor pressure that would otherwise be difficult to test via standard techniques. The development process is described and the results from the final chosen test method are reported. Inter-laboratory studies were conducted to further refine the new method and determine repeatability and reliability. The revised test method has been approved as a new ISO/EN standard to measure permeation of chemicals with low vapor pressure and/or solubility in water.

Contribution of the Hair Follicular Pathway to Total Skin Permeation of Topically Applied and Exposed Chemicals.

Generally, the blood and skin concentration profiles and steady-state skin concentration of topically applied or exposed chemicals can be calculated from the in vitro skin permeation profile. However, these calculation methods are particularly applicable to chemicals for which the main pathway is via the stratum corneum. If the contribution of hair follicles to the total skin permeation of chemicals can be obtained in detail, their blood and skin concentrations can be more precisely predicted. In the present study, the contribution of the hair follicle pathway to the skin permeation of topically applied or exposed chemicals was calculated from the difference between their permeability coefficients through skin with and without hair follicle plugging, using an in vitro skin permeation experiment. The obtained results reveal that the contribution of the hair follicle pathway can be predicted by using the chemicals’ lipophilicity. For hydrophilic chemicals (logarithm of n-octanol/water partition coefficient (log Ko/w) < 0), a greater reduction of permeation due to hair follicle plugging was observed than for lipophilic chemicals (log Ko/w ≥ 0). In addition, the ratio of this reduction was decreased with an increase in log Ko/w. This consideration of the hair follicle pathway would be helpful to investigate the efficacy and safety of chemicals after topical application or exposure to them because skin permeation and disposition should vary among skins in different body sites due to differences in the density of hair follicles.

Effect of Esters on the Permeation of Chemicals with Different Polarities through Synthetic Artificial Membranes Using a High-Throughput Diffusion Cell Array.

This study investigated the effects of 25 kinds of esters that are used in cosmetics on the permeation of four model compounds with different polarities (caffeine [CF], aminopyrine [AMP], benzoic acid [BA], and flurbiprofen [FP]). The amount of each model compound that permeated through two types of artificial membrane (silicone and Strat-M®) was measured and correlated with the physicochemical properties of the esters, including their solubility, viscosity, wettability, surface tension, and uptake. The amount of each model compound that permeated through the silicone membrane was not significantly correlated with the solubility of the esters but was significantly correlated with all other measured physical properties of the esters. Similar correlations were observed for the amounts of AMP, BA, and FP that passed through the Strat-M® membrane. However, the amount of CF that permeated through the Strat-M® membrane also correlated with the solubility of the esters. There was a highly significant correlation between the amount permeating through the silicone and Strat-M® membranes because the model compounds had high lipophilicity. These findings demonstrated that to control the permeation of various chemicals through artificial membranes, it is important to consider the uptake of the esters and that the solubility of the esters is also an important consideration when using a more complex membrane.

Predicting skin permeation rate from nuclear magnetic resonance spectra

A predictive method is reported for estimating skin permeation of organic chemicals exclusively from NMR spectroscopic data and molecular weight, which does not require knowledge of chemical structure.

Effect of Frozen Human Epidermis Storage Duration and Cryoprotectant on Barrier Function Using Two Model Compounds

Skin is commonly stored frozen and then thawed prior to use for in vitro permeation experiments. Does frozen storage of skin alter its barrier property? Numerous studies have found contradictory answers to this question. In this study, the steady-state flux and lag time of diethyl phthalate (DEP) were measured for fresh human skin and skin frozen at -85°C for 1, 2, 3, 6, 9, 12, and 18 months with 10% glycerol as a cryoprotective agent. No significant differences in steady-state flux were found between fresh and previously frozen samples (p = 0.6). For lag time, a significant (p = 0.002) difference was found among all groups, but comparisons with fresh skin were not significant. Does glycerol have a cryoprotective effect? The steady-state flux and lag time of DEP and caffeine were measured through human skin stored at -85°C for up to 12 months with and without 10% glycerol. No significant differences in steady-state flux or lag time were found between samples stored with or without glycerol for either DEP or caffeine (p ≥ 0.17). These findings support the use of frozen skin to measure the passive permeation of chemicals in studies unconcerned with viability and metabolism. Published by S. Karger AG, Basel.

Differential Cerebrovascular Toxicity of Various Tobacco Products: A Regulatory Perspective.

Blood-Brain Barrier (BBB) is a dynamic anatomical interface that separates brain parenchyma from blood circulation and is principally constituted by the cerebral microcapillary endothelial cells [1,2]. BBB is composed of distinct structural and functional organization through the presence of inter-endothelial tight junction complexes, abundant expression of nutrient and efflux transporters including metabolically active sites. While the TJ complexes tightly seal the paracellular gaps and contribute to high resistance of BBB [3], the presence of specific nutrient transporters and receptor systems selectively regulate the delivery of metabolic substrates, nutrients and macromolecules to the brain. In addition, efflux transporters belonging to the ABC superfamily prevent the brain permeation of blood-borne neurotoxic chemicals including xenobiotics and eliminates the accumulation of toxic metabolites within the brain parenchyma [1]. Taken together, the BBB serves as a physiological, transport and metabolic barrier that critically regulates ion, molecular and cellular flux into the brain, thus maintaining the CNS microenvironment for optimal neuronal function [2]. Importantly, impairment of BBB integrity by various exogenous or endogenous pathological stimuli involving increased load of oxidative/inflammatory stress in the neurovascular unit, is a potential mechanism underlying the pathogenesis of a host of neurologic and degenerative disorders [3,4].