Dermal permeability

McKone (1993) demonstrated that chloroform in shower water had an average effective dermal permeability between 0.16 and 0.42 cm/hour for a 10-minute shower. The model predicted that the ratio of chloroform dermally absorbed in the shower (relative to chloroform-contaminated water concentration) ranged between 0.25 and 0.66 mg per mg/L. In addition, the McKone model demonstrated that chloroform metabolism by the liver was not linear across all dermal/inhalation exposure concentrations and became nonlinear at higher (60-100 mg/L) dose concentrations. 

Abraham et al. (1999) generated a QSAR equation for the permeation of 47 aqueous solutes across human skin. This demonstrated that dermal permeability increased with increasing molar refraction and McGowan volume and decreased as hydrogen bond acidity, basicity, and dipolar-ity/polarizability increased. 

Dermal permeability coefficient and the dermally absorbed dose per event. 

In the assessment of the uptake of a chemical after dermal exposure, for instance, the dermal permeability of the skin is often estimated using the Potts-Guy quantitative structure-activity relationship (Guy Potts, 1992), which was derived from an experimental data set of in vitro measured steady-state skin permeations (Wilschut et al., 1995). Uncertainty in the use of a value for the skin permeation obtained this way comes from questions of how well a regression model based on Kow and molecular weight predicts the skin permeability of a chemical that was not in the original data set, and how representative the steady-state permeability measured in vitro is for a (possibly) non-steady-state permeability in vivo (see also IPCS, 2006b). 

Probabilistic risk assessment methods are used to incorporate uncertainty and variability into both aggregate and cumulative risk assessments. Herein, uncertainty refers to lack of knowledge or the limitations in the current state of knowledge. For example, the dermal permeability of a pesticide may not be known with certainty. Variability, on the other hand, refers to a value that differs from one individual to another individual in a population or from one instance to another. For example, the number of apphcations of a residential pesticide in a year may vary from one individual to another. Probabilistic methods use probability distributions to incorporate uncertainty and variability into both aggregate and cumulative risk assessments. 

Figure 24.2 QSAR plots showing effects of including a mixture factor (MF) [Refractive Index] on prediction of dermal permeability when dosed in complex chemical mixtures. (Top plate) No MF included n = 288, R2 = 0.57, Q2 = 0.56, s = 0.55, F = 77. (Bottom plate) MF included n = 288, R2 = 0.80, Q2 = 0.79, s = 0.37, F = 192.

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 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. 

Service men and women working on the flight line in the U.S. Air Force were exposed daily to the military jet fuel JP-8. My recently concluded studies with Riviere et al. (2002) demonstrated that JP-8 significantly increased permethrin absorption in skin by twofold and skin penetration by threefold. This dermal enhancer effect of JP-8 is not surprising as these jet fuels contain aliphatic and aromatic components as well as performance additives that by themselves or as a mixture can alter dermal permeability. In separate studies, JP-8 fuel additives were... 

Exercise also increases skin circulation and perspiration, which both enhance dermal penetration of compounds into the body. Furthermore, skin lesions, such as wounds and dermatitis, can increase the permeability of the skin to chemicals. Also, exposure of the skin to solvents and removal of skin fat increase dermal penetration of a number of compounds. Compounds penetrate the skin more readily in places where the skin is thin, like the face, hands and scrotum. Increased dermal blood flow due to exercise facilitates the penetration of the skin by chemicals. 

Absorption across biological membranes is often necessary for a chemical to manifest toxicity. In many cases several membranes need to be crossed and the structure of both the chemical and the membrane need to be evaluated in the process. The major routes of absorption are ingestion, inhalation, dermal and, in the case of exposures in aquatic systems, gills. Factors that influence absorption have been reviewed recently. Methods to assess absorption include in vivo, in vitro, various cellular cultures as well as modelling approaches. Solubility and permeability are barriers to absorption and guidelines have been developed to estimate the likelihood of candidate molecules being absorbed after oral administration. ... 

Research studies investigating exposure to JP-8 via oral administration offers an alternative examination of the systemic effects of JP-8 on immune function. Admittedly, this does not ideally mimic occupational exposures, but it does eliminate technical limitations associated with inhalation and dermal penetration of JP-8. It has been suggested that the only route available that can assess the whole mixture (JP-8 in its entirety), without fractionation due to volatilization of components, is the oral route [1] as select components of JP-8 may have increased permeability during dermal exposure, other specific components may be enriched following inhalation exposures[71]. 

Under normal conditions, the transcellular route is not considered as the preferred way of dermal invasion, the reason being the very low permeability through the corneocytes and the obligation to partition several times from the more hydrophilic corneocytes into the lipid intercellular layers in the stratum corneum and vice versa. The transcellular pathway can gain in importance when a penetration enhancer is used, for example, urea, which increases the permeability of the corneocytes by altering the keratin structure. 

Comparative studies on the bioavailability of three different tretinoin gel formulations showed that the dimensions of the sampling area may play a critical role in determining the extent of dermal drug uptake [33, 34], If, by lateral spreading, a substance is distributed over an area sufficiently larger than the sampling area, significant proportions of compound will not be recovered and hence permeability will be underestimated. 

The technique consists of a microdialysis probe, a thin hollow tube made of a semi-permeable membrane usually around 200-500 /xm in diameter, which is implanted into the skin and perfused with a receiver solution that recovers the unbound permeant from the local area. In principle, the driving force of dialysis is the concentration gradient existing between two compartments separated by a semi-permeable membrane. For skin under in vivo conditions, these compartments represent the dermal or subcutaneous extracellular fluid (depending on the probe position) and an artificial physiological solution inside the probe [36-38],... 

Potentially, individuals with low activities of the enzymes phenol sulfotransferase and glucuronyl-transferase may be more susceptible to phenol toxicity. Persons with ulcerative colitis may have an impaired capacity to sulfate phenol (Ramakrishna et al. 1991), which may increase the amount of unchanged phenol that is absorbed following oral exposure. Neonates may also be more susceptible to toxicity from dermally-applied phenol because of increased skin permeability and proportionately greater surface area. A study in which 10-day-old rats were more sensitive to lethality following oral exposure to phenol than 5-week-old or adult rats (Deichmann and Witherup 1944) further suggests that the young may be more sensitive to phenol. (For a more detailed discussion please see Section 2.6.) Because phenol is a vesicant, individuals with sensitive skin or pulmonary incapacity may be more sensitive to phenol. Individuals with kidney or liver diseases that impair metabolism or excretion of phenol and phenol metabolites may be more susceptible to phenol. 

Hexanone has also been shown to potentiate the neurotoxic effects of some compounds. In hens, dermal or inhalation exposure to 2-hexanone in combination with dermal application of the pesticide O-ethyl-O-4-nitrophenyl phenylphosphonothioate (EPN) has resulted in earlier onset and far more severe clinical and histological manifestations of neurotoxic effects than with either chemical exposure alone (Abou-Donia et al. 1985a, 1985b). The authors speculated that this potentiation effect may have been due to induction of hepatic microsomal cytochrome P-450 by EPN, leading to increased metabolism of 2-hexanone to its neurotoxic metabolite, 2,5-hexanedione. An alternate explanation is that local trauma to the nervous tissue produced by 2-hexanone and EPN might increase vascular permeability and thus increase the entry of these compounds and their metabolites from circulation. 

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 penetration of/V-nitroso[ C]diethanolamine (4 xg/cm ) in vivo was investigated by applying skin lotion and acetone to 3-15 cm of the skin of monkeys (the abdomen) and pigs (the back) for a 24-h contact time. The skin penetration capacity was greater in monkeys (23% in skin lotion, 34% in acetone) than in pigs (4% in skin lotion, 11.5% in acetone) and the permeability was greater from acetone than skin lotion (Marzulli et al., 1981). 

When studying dermal absorption using animals, a species with an absorption comparable to that of humans must be used. For example, rat and rabbit skin are more permeable than human while that of cats, dogs, and mice are less permeable. Guinea pigs, pigs and monkeys have dermal characteristics similar to those of humans. 

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