Permeability coefficient, dermal

The occurrence of coma, death, and systemic effects in two humans dermally exposed to cresols (Cason 1959 Green 1975) indicates that these compounds can be absorbed through the skin. No studies were located that sought to quantify the rate or extent of absorption in intact humans. An in vitro study of the permeability of human skin to cresols found that these substances had permeability coefficients greater than that for phenol, which is known to be readily absorbed across the skin in humans (Roberts et al. 1977). 

Percutaneous penetration of 7V-nitrosodiethanolamine was measured using cryo-preserved human trunk skin and three vehicle formulations (isopropyl myristate, sunscreen cream or a 10% shampoo) containing 7V-nitroso[ C]diethanolamine. The absorption rate of a low dermal dose (10 ixg/cm ) of 7V-nitrosodiethanolamine was a linear function of the concentration (0.06, 0.2 or 0.6 Xg/ xL) applied to the skin. The peak rates for the isopropyl m uistate and shampoo vehicles were seen within five hours and for the sunscreen somewhat later. Total 48-h absorption ranged from 35 to 65% of the dose and was formulation-dependent (isopropyl m uistate > shampoo > sunscreen). A total absorption of 4-6 x JcaE was estimated to equate to an applied N-nitrosodiethanolamine dose of 10 x%lcaE. When applied as a large infinite dose (0.5 mg/cm ), total 7V-nitrosodiethanolamine absorption (4-35% of the applied dose) followed a different rank order (shampoo > isopropyl m uistate > sunscreen), probably due to the barrier-damaging properties of the vehicles. The permeability coefficient for isopropyl myristate was 3.5 X 10 cm/h (Franz etal., 1993). 

Dermal permeability coefficient and the dermally absorbed dose per event. 

In the consideration of therapeutic activity following dermal application, emphasis is placed on quantifying the extent of absorption of a drug through the skin or some relevant pharmacodynamic response. The amount absorbed (Q) may be expressed in terms of the area of application and the exposure time (T). The amount absorbed will be determined by the permeability coefficient of the drug, the diffusional lag time across the barrier (lag) and the concentration of the drug in the vehicle ... 

It is evident, therefore, that a number of principles apply in dermal absorption. These include the fact that the amount of a drug absorbed will depend on the area of application, the concentration applied, the duration of application and the permeability coefficient, which, as shown above, is defined by the physicochemical properties of the solute and the vehicle. 

As mention previously, dermal absorption of contaminants in water can be significant. The permeability of the skin to a chemical is influenced by an agent s molecular weight, electrostatic charge, hydrophobicity, and solubility in aqueous and lipid media. Chemicals that can penetrate the skin easily, are generally nonio-nized, lipid soluble, low molecular weight substances. Chemical-specific permeability coefficients should be used to estimate dermal absorption of a chemical from water. 

One expert system for the prediction of skin permeability is available. This is the Dermal Permeability Coefficient Program (DERMWIN). This program is freely available from the U.S. Environmental Protection Agency through the EPISuite software and can be downloaded from http //www.epa.gov/oppt/expo-sure/docs/episuite.htm. DERMWIN estimates the dermal permeability coefficient and the dermally absorbed dose per event (DA it) organic compounds. As explained in the section Quantitative Structure-Activity Relationships, and is... 

The challenge in determining the dermal absorption values most relevant to factor into a risk assessment process for environmental contaminants is to define the most relevant parameter (i.e., flux, permeability coefficient, percentage absorption, or total systemic load). For example, when using in vitro techniques to determine potential dermal absorption of a contaminant in water (in which it will probably be present at low concentrations), the most common model would use an infinite dose aqueous application. This will allow the determination of flux and the calculation of a permeability coefficient. However, from such an experiment, the percentage absorption value will be practically meaningless. The total systemic load will be dependent on many other factors, such as concentration and solubility of contaminant within the medium, pH of the medium (and thus the degree of ionization of the contaminant). 

The updated guidance document (EPA, 2001) includes refinements to the above equation to accoimt for the potential bioavailability of contaminants in the stratum comeum when exposure has ended and variable exposure times. Furthermore, the newer document discusses, in depth, the use of mathematical predictions of the permeability coeffident in dermal risk assessment. It is important to appreciate that the permeability coefficient should be determined experimentally using, ideally, a donor phase that mimics as closely as possible the existing environmental conditions. The use of permeability coeffidents predicted from theoretically derived equations adds a further imcertainty to the overall risk calculation. Although it has been suggested that the dermal permeability estimates are the most uncertain of the parameters in the dermal dose computation (EPA, 1992), it could be argued, given the refinement of in vitro techniques and the correlation between in vitro and in vivo measurements of human skin (Franz, 1978 Wester et al., 1992 van de Sandt et al., 2000 Cnubben et al., 2002 Zobrist et al., 2003 Colombo et al., 2003), that these measurements are the least assumptive and the most accurate of all the parameters used. 

Figure 15.1 is similar to a comparable figure for the human skin database (see Figure 2 in Vecchia and Bunge, 2002b), suggesting that the underlying mechanism of dermal absorption is similar for both spedes. Several spedfic comparisons with the human permeability coefficients are noteworthy ... 

Figure 15.1 to Figure 15.6 bear many similarities to comparable plots of human skin permeability coefficient data (Vecchia and Bunge, 2002b). It is not surprising that skin from different terrestrial species has similar characteristics of dermal penetration. Several mechanistic trends are consistently observed and also make good chemical sense ... 

Dermal absorption in different animal species has many qualitative similarities to dermal absorption in humans that can be observed through examination of permeability coefficients. However, for the purpose of estimating dermal absorption in humans, the large numbers of permeability coefficient values determined in animal skins are of limited use until quantitative relationships to human skin are established. Based on the data collected so far, we have developed regression equations of permeability coefficients as functions of log and MW for several animal species (hairless mouse, hairless rat, rat, and snake). The regression equation from hairless mouse skin is similar to an equation of the same form for human skin. On average, hairless mouse skin is 3.1 times more permeable than human skin this ratio appears to be independent of but may increase weakly for higher MW compounds. 

The panel of authors who wrote the interim report on dermal absorption (U.S. Environmental Protection Agency, 1992) reviewed several earher experimental studies comparing permeability coefficients of human and animal skin, especially the review by Bronaugh et al. (1982), which was discussed separately in this appendix. No new data were presented in this report. The opinion of this panel was that the numerical differences between human skin and animal skin permeability coefficients vary with the test compound. Thus, they concluded that it was not possible to find a constant factor for adjusting the permeabihty coefficient from a specified animal to reliably represent the permeabihty coefficient for human skin. Major conclusions of this report were that animal skins are generally more permeable than human skin, and that dermal absorption data from animals could be used as a conservative estimate of absorption in humans. 

Vecchia BE, Bunge A. Animal models a comparison of permeability coefficients for excised skin from humans and animals. In Riviere JE, editor. Dermal absorption models in toxicology and pharmacology. Boca Raton CRC Press 2006. p. 305-33. 

In an in vitro experiment using Fischer 344 rat skin, the partition coefficient for skin air was determined for benzene at 203 ppm (Mattie et al. 1994). The partition coefficient of a chemical in skin is an indicator of the capacity of the skin for the chemical, and may reflect the rate at which a chemical is absorbed through the skin and enters the circulation. Results indicated a partition coefficient of 35, with an equilibration time of 4 hours. This value more closely correlates with the permeability constant of 1.5 derived by McDougal et al. (1990), than does the commonly used octanol/water partition coefficient of 134.9, as derived by Leo et al. (1971). The skin air partition coefficient is necessary for developing the dermal compartment of a PBPK model. 

The dermal penetration coefficient Kp in this simplest case depends on both the partitioning of the chemical from its vehicle (usually water) into the stratum corneum, and its diffusion through the stratum corneum. Both of these quantities can be estimated from a chemical s properties or structure. Partitioning from water into the stratum corneum can be estimated from a chemical s octanol-water partition coefficient, Kow Diffusion through the stratum corneum is dependent on the molecular volume of the chemical, which is in turn a function of its molecular weight (MW). Perhaps the most widely used expression of the dependence of stratum corneum permeability on readily available physicochemical properties is the Potts-Guy equation ... 

While the infinite dose technique has been invaluable in the determination of important skin permeability parameters such as dermal penetration coefficients and in the development of transdermal drug delivery concepts, to mimic in vivo conditions, the so-called finite dose technique was developed. This is essentially a modification of the traditional steady-state method. The important difference is that the skin preparation is supported over the receptor so that the epidermal surface is exposed in a manner that mimics the real-life exposure scenario, and the compound of interest is applied to the surface of the skin in a manner also similar to exposure in vivo. Although the results of such studies may give valuable information about the absorption of materials under specific exposure conditions, they are generally not amenable to extrapolation to other exposures since no invariant skin properties such as penetration coefficients can be readily calculated. 

MNA) in PSFT models, for which permeability was less than predicted from log soMix> effect that carried into the IPPSF, suggesting a potential interaction with epidermal cells or dermal components, the only consistent factors different between isolated stratum comeum and SMFT compared to PSFT and IPPSF models. This interaction was also seen with other compounds. For PCP, stratum comeum partitioning appears to be the dominant factor. These findings support the hypothesis that a mixture component effect (such as SLS) in a specific solvent system will reduce permeability across penetrants (independent of the compound s specific QSPR relation to log K, ) and can be estimated by partition coefficients in simpler system. 

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