Diffusion and Partitioning in SC Membrane

Absorption and desorption rates have previously been measured according to diffusion models from a simple two-dimensional homogeneous SC to a brick-and-mortar model considering the lipoidal pathway [15, 18]. However, knowledge of the anatomical heterogeneity complexities of skin demands a more sophisticated model that further breaks down the diffusion and partitioning steps. With the addition of a homogenous epidermal/dermal compartment, the model membrane is represented as three phases, corneocytes, surrounding lipids, and the deep skin layer (DSL). Partition coefficients among these phases, thereby considering K_lip/don, K_DSL/lip, and K_SC/DSL in addition to simply K_SC/don, provide more accurate insight into the rate of transport of compounds through skin [11].

Water content has a significant effect on partitioning of substances. For example, flufenamic acid enters the DSL by both binding to proteins and by water of hydration, while caffeine only enters through solvation in water [11]. Thus, partitioning between phases is majorly dependent on the molecule’s lipophilicity and hydrophilicity.

In addition, partition and diffusion coefficients heterogeneity exist, as molecules penetrate deeper in the SC [33]. It is suggested that the diffusion gradient results from three distinct layers of the SC with distinct barrier properties. The upper layer allows passive movement of exogenous ions, the middle layer functions in skin hydration and as a selective barrier to specific ions such as K and Cr (VI), while the lower layer defends against different ions such as Cr (III) [16]. Nonetheless, constant coefficients may be used as good predictors of penetrant concentration – depth-profiles, indicating that diffusion and partitioning are coupled such that one may compensate for the other [24].

Attention has increasingly been put on slow desorption kinetics from keratin binding, believed a major drive for the SC reservoir, which results in prolonged existence in the body even after removal of the substance from the skin [29]. Slow desorption kinetics appear largely related to lipophilicity. Nonlipophilic molecules also accumulate in a reservoir, indicating additional factors involved in this retention [29].

In sum, much progress has been made to determine more accurate parameters that affect rates of diffusion and partitioning of molecules through the SC as well as properties driving formation of an SC reservoir, partly explaining difficulties in decontamination methods and predicting toxicant penetration behavior through SC.

Decontamination in Alternative In Vitro Models

An in vivo HS experiment is an ideal method to study chemical permeation through the skin for accurate risk assessment and decontamination analysis. However, this sometimes proves difficult due to financial, ethical, and safety considerations, as some chemicals are too toxic to be tested in vivo.

Alternative models using excised skins from humans and animals result in generally accepted good correlation with in vivo experiments and can help elucidate factors influencing dermal absorption, but an ideal model to confidently use vitro data as a predictive tool for in vivo behavior does not currently exist [17, 32]. Thus, there is continued exploration of different models that may give further insight into transfer of toxicants across the skin. The potential of using synthetic or natural membranes provides a novel approach toward decontamination studies. In addition, less expensive and more readily accessible models would be advantageous.

In vitro experiments regarding organophosphorus compounds (OPCs) provide insight into important considerations that affect dermal transfer. Frozen HS samples showed that chemical interactions between OPCs and the vehicle of application also affect absorption profiles; thus, the physicochemical properties, such as lipophilicity and vapor pressure, of the vehicle of application must be considered [23].

Recent use of synthetic membranes shed additional light on decontamination and diffusion kinetics of OPCs. Hydrophilic and lipophilic adsorptive powders are able to reduce toxicant transfers across the membrane [19]. Transfer of OPCs also exhibited first order processes, which agrees with in vitro HS experiments; however, synthetic membranes had a significantly less evident initial accumulation period of toxicant [19]. This accumulation period is an important phase of percutaneous absorption, as it reflects the reservoir effect.

Natural membranes such as peach skin, tomato, onion, egg, and cellophane have also been considered as possible alternatives to HS for in vitro studies. They have hydrophilic properties that allow small to middle size hydrophilic drugs to permeate and diffuse in a manner similar to human skin [2]. Extent of similarity for each membrane to HS depends on the specific drug tested, which ranged in lipophilicity and MW [2, 25]. Thus, the physicochemical nature of the drug and membrane are important considerations in understanding diffusion mechanism. These studies promote exploration of possible novel models to be used in chemical penetration experiments and to test decontamination methods.

Challenges to Mass Decontamination Methods

Optimal decontamination procedures are a necessary precaution to any toxic exposure. Use of water and/or detergents are generally considered safe and historically used for mass decontamination for their ease of use and low cost, although risk assessment remains ongoing as progressive insights are made [21].

Passive diffusion is involved in the transfer of toxicants across skin. Compounds prefer to remain in their own physicochemical environment unless there is an external driving force to push compounds into a new environment. Analyzing the solubility within the layers of the skin helps explain diffusion behavior of different substances through the donor fluid to the skin compartment to the receptor fluid. Since the skin compartment is more lipophilic than the donor fluid, diffusion is slower for hydrophilic compounds, so wash off after 6 hours more effectively reduces skin deposition of hydrophilic compounds compared to lipophilic compounds [26]. Moreover, receptor fluid is more hydrophilic than the skin compartment; thus, there is preference for the formation of a skin reservoir for lipophilic compounds [26]. With this understanding, immediate action to reduce the concentration of any substance in the donor fluid will subsequently reduce the amount available in the reservoir and the risk of later entry into the systemic circulation.

Use of water and/or detergents pose risk for a wash in effect, in which percutaneous absorption is enhanced after decontamination attempts with skin washing [22]. Increased skin hydration and the surfactant effect are two of a variety of explanations for the wash in effect [22]. Wet swine skin resulted in an increased amount of permeated paraoxon (pox) compared to dry skin, warm, or cold skin [20]. Moreover, decontamination through showering with the detergent Argos (solution containing, e.g., sodium alkylethersulphate, sodium alkylbenzensulphonate, and cocamide DEA) or FloraFree (mainly consisting of surfactants, e.g., potassium tallate and potassium cocoate) added to the water, regardless the use of physical removals, increased pox permeation [20].

Risks of detergents themselves remain under investigation. Detergents can remove skin lipids, disrupt epidermal barrier function, and are considered permeation enhancers [27, 30]. Furthermore, detergents can include anionic, cationic, nonionic, or zwitterionic surfactants, but a majority are anionic surfactants such as sodium lauryl sulfate (SLS) [4]. Repeated exposure to alkaline agents, including SLS, impairs skin barrier function and reduces natural moisturizing factors (NMF), which are necessary to regulate water balance in the SC [1]. Thus, anionic detergents threaten SC membrane integrity and may enhance risk of irritant contact dermatitis [1].

However, detergents Argos (containing, e.g., sodium alkylethersulphate, sodium alkylbenzesulphonate, and cocamide DEA) and triton X (polyethylene glycol p-(1,1,3,3-etramethylbuyl)-phenyl ether), themselves, did not permeate the skin either as a 5% water solution or as a concentrate [21]. Permeation rate of the detergent althosan MB 50% (50% benzalkonium chloride) as a concentrate, not a 5% water solution, was detectable, although not at an acutely toxic level [21]. Thus, more data are needed to elucidate the toxicity of detergent based mass decontamination.

Disinfectant Wipes to Measure Dermal Absorption

Skin wipes are a useful tool to measure toxicant levels on the skin surface, which provide insight into the potential harm humans are exposed to. For example, lead is a ubiquitous toxic element known to cause development health problems. Surface wipes of floor dust showed lead contamination levels that significantly correlated with blood lead levels in children [10]. Thus, improved measures to decontaminate households from lead-filled dust are necessary.

In addition, concerns of phthalates in indoor dust in China also led to investigation. Phthalates commonly used in many commercial products can cause adverse health effects such as asthma and neurodevelopment problems [12, 34]. Skin wipe samples showed detectable levels of di(isobutyl) phthalate (DiBP), di(n-butyl) phthalate (DnBP), and di(20ethylhexl phthalate (DEHP) in multiple regions of the body [9]. Dermal absorption estimations of these phthalates from the measured skin surface levels represented a significant percent of total phthalate uptake, thereby indicating a need to limit dermal exposure to phthalates [9]. However, due to the complexities of HS, accurate predictions of dermal absorption rates from skin surface concentrations remain difficult. Thus, skin wipes have helped to shed light on the need to limit dermal exposure to phthalates, but a quantified contribution assessment of dermal absorption to total phthalate uptake requires further investigation.