Dermal/percutaneous absorption

E. The degree of occlusion (in fact, the tightness of the wrap over the test site) also alters percutaneous absorption and therefore irritation. One important quality control issue in the laboratory is achieving a reproducible degree of occlusion in dermal wrappings. 

Dermal exposure of rats and rabbits to endrin resulted in toxicity and death (Gaines 1960 Treon et al. 1955), indicating that percutaneous absorption of endrin occurs. It is likely that occupational poisonings reported by Hoogendam et al. (1962, 1965) also involved dermal absorption, but the extent and relative contribution of dermal exposure cannot be determined. Data describing the rate or extent of dermal absorption were not located. 

Hydrogen cyanide is moderately lipid-soluble, which, along with its small size, allows it to rapidly cross mucous membranes, to be taken up instantly after inhalation, and to penetrate the epidermis. In addition, some cyanide compounds, such as potassium cyanide, have a corrosive effect on the skin that can increase the rate of percutaneous absorption (NIOSH 1976). Information regarding dermal absorption in animals and evidence that cyanide can be absorbed through the skin of humans is provided in Sections 2.3.1.3 and 2.2.3, respectively. 

The stratum corneum consists of separated, nonviable, cornified, almost nonpermeable corneocytes embedded into a continuous lipid bilayer made of various classes of lipids, for example, ceramides, cholesterol, cholesterol esters, free fatty acids, and triglycerides [6], Structurally, this epidermis layer is best described by the so-called brick-and-mortar model [7], The stratum corneum is crucial for the barrier function of the skin, controlling percutaneous absorption of dermally applied substances and regulating fluid homeostasis. The thickness of the stratum corneum is usually 10-25 /an, with exceptions at the soles of the feet and the palms, and swells several-fold when hydrated. All components of the stratum corneum originate from the basal layer of the epidermis, the stratum germinativum. 

H. Raabe, R. Curren, S. Ward, and J. Harbell. Report from an in vitro dermal absorption assay workshop, 2005 In Vitro Percutaneous Absorption Expert Users Workshop, Gaithersburg, USA, 2005. 

Percutaneous absorption is another route of interest for the administration of peptides [158], with metabolism being a complicating factor [159]. Thus, [Leu5]enkephalin and Tyr-Pro-Leu-Gly-NH2 were rapidly degraded on the dermal side after penetration through rat skin preparations [160]. The use of inhibitors confirmed the involvement of serine proteases and metalloenzymes. 

Chloroform can also permeate the stratum comeum of rabbit skin (Torkelson et al. 1976) and mouse skin (Tsuruta 1975). Percutaneous absorption of chloroform across mouse skin was calculated to be approximately 38 pg/min/cm, indicating that the dermal absorption of chloroform occurs fairly rapidly in mice. No reliable studies report the percutaneous absorption of chloroform in humans however, a few clinical reports indicate that chloroform is used as a vehicle for drug delivery (King 1993). Islam et al. (1995) investigated the fate of topically applied chloroform in male hairless rats. For exposures under 4 minutes, chloroform-laden water was applied to shaved back skin for exposures of 4-30 minutes, rats were submerged in baths containing chloroform-laden water. Selected skin areas were tape-stripped a various number of times after various delay periods. It appeared that there was an incremental build-up of ehloroform in the skin over the first four minutes. When compared to uptake measured by bath concentration differences, approximately 88% of lost chloroform was not accounted for in the stratum comeum and was assumed to be systemically absorbed. 

Although dermal absorption of carbon tetrachloride is relatively modest compared to oral or inhalation, it would be helpful to quantify the rate and extent of percutaneous absorption of carbon tetrachloride from water. This information would be useful in determining the contribution of dermal exposure to the total dose received by persons using carbon tetrachloride-contaminated drinking water for bathing or showering, or to those who contact carbon tetrachloride-contaminated water near chemical waste sites. 

Toxicokinetic studies in humans have demonstrated that coumarin is rapidly absorbed from the gastrointestinal tract after oral administration and extensively metabolized by the liver in the first pass, with only 2-6% reaching the systemic circulation intact (Ritschel etal., 1977, 1979 Ritschel Hofimann, 1981).The elimination of coumarin from the systemic circulation is rapid, the half-lives following intravenous doses of 0.125, 0.2 and 0.25 mg/kg bw being 1.82, 1.46 and 1.49 h [109, 88 and 89 min], respectively (Ritschel et a/., 1976). Coumarin is also extensively absorbed after dermal application. In one study with human subjects, some 60% of a 2.0-mg dose applied for 6 h was absorbed (reviewed in Lake, 1999). The percutaneous absorption of coumarin has also been demonstrated in vitro with human skin (Beckley-Kartey et al, 1997 Yourick Bronaugh, 1997). 

In this section, we outline the applications of IR microscopic imaging to the molecular level determination of dermal and transdermal percutaneous absorption. The rationale for these experiments is that drugs often exhibit low penetration rates... 

Dermal absorption in rats was found to be age-related. Banks et al. (1990) found that in Fischer 344 rats, the percutaneous absorption was decreased in middle-aged (36-week-old) and senescent (120-week-old) rats compared to that in young adults (10-week-old) 72 hours after application of a dose of 40 nmol (approximately 12.9 g) of 3H-labeled 2,3,7,8-TCDD. The authors suggested a decrease in blood flow through the skin between 3 and 4 months of age as a possible explanation for their findings. In a subsequent and similar study, the same group of investigators examined the dermal absorption of... 

Currently, for pesticide registration, there is an increasing consideration by regulatory jurisdictions of in vitro data as an alternative to in vivo dermal absorption data. At present, based on the OECD inventory and provided that levels of the pesticide remaining in the skin are included as absorbed, the results from in vitro methods seem to adequately reflect those from in vivo experiments, so supporting their use as a replacement test to measure percutaneous absorption (OECD, 2000 van de Sandt et al., 2004). This calculation, i.e. the inclusion of the amount... 

Tauber, U. and H. Matthes (1992). Percutaneous absorption of methylprednisolone aceponate after single and multiple dermal applications as ointment in male volunteers, Arzneim. Forsch., 42, 1122-1124. 

The vesicant properties of lewisite result from direct contact with the skin. Signs of dermal toxicity (pain, inflammation) may be experienced within a minute after exposure. Acute lethality is usually the result of pulmonary injury. Ocular exposure may result in corneal necrosis. Due to its lipophilicity, percutaneous absorption of lewisite is rapid and, at a sufficient exposure, may be associated with systemic toxicity characterized by pulmonary edema, diarrhea, agitation, weakness, hypothermia, and hypotension (lOM, 1993). The threshold for severe systemic toxicity in humans following dermal exposure to lewisite has been estimated at lOmg/kg (9.1-13.4 mg/kg) (Sollman, 1957). 

Siddiqui, O., Roberts, M. S., and Polack, A. E. Percutaneous absorption of steroids Relative contributions of epidermal penetration and dermal clearance. J. Pharmacokin. Biopharm. 17 405, 1989. 

Some fatty acids, especially unsaturated fatty acids, are well-known skin penetration enhancers. The addition of PC to dermal dosage forms has been reported to increase percutaneous absorption. Lipid disperse systems (LDSs) containing polar lipids, such as PC and glycosylceramide, are also useful for increasing the percutaneous permeation of drug through rat abdominal skin in both in vitro and in vivo systems. 

Lipid-soluble chemicals like organophosphate insecticides, tetraethyl lead, certain organic solvents, and certain dyes like aniline are relatively well absorbed through the skin. Percutaneous absorption is facilitated by increasing peripheral dermal blood... 

Different methods of human exposure assessment vary with respect to the input data or information required and the degree of uncertainty associated with resulting estimates. Eor example, the film-thickness approach to dermal exposure assessment is a screening-level methodology that assumes a uniform layer of material (e.g., a liquid consumer product) is on the skin, and that a portion of the material in this layer is absorbed, per the dermal absorption characteristics of the chemical. In contrast, dermal exposure assessment and percutaneous absorption methods can include metrics that account for time-dependent exposure and absorption processes. Eor example, in the case of secondary dermal contact with chemicals on surfaces (e.g., transfer of pesticide residues from... 

These linear kinetic models and diffusion models of skin absorption kinetics have a number of features in common they are subject to similar constraints and have a similar theoretical basis. The kinetic models, however, are more versatile and are potentially powerful predictive tools used to simulate various aspects of percutaneous absorption. Techniques for simulating multiple-dose behavior evaporation, cutaneous metabolism, microbial degradation, and other surface-loss processes dermal risk assessment transdermal drug delivery and vehicle effects have all been described. Recently, more sophisticated approaches involving physiologically relevant perfusion-limited models for simulating skin absorption pharmacokinetics have been described. These advanced models provide the conceptual framework from which experiments may be designed to simultaneously assess the role of the cutaneous vasculature and cutaneous metabolism in percutaneous absorption. 

Defining the amount of the topical dose applied that is available for absorption is particularly challenging when the compound under investigation is volatile or semivolatile as in the case of solvents and insect repellents. Following topical application, some of the applied dose will penetrate the skin and be absorbed. At the same time, some fraction will evaporate slowly from the surface of the skin and be lost, unavailable for percutaneous absorption. It has been demonstrated that the rate of evaporation, and consequently the relationship between evaporation and skin penetration, can influence the quantity of chemical absorbed dermally. The extent of evaporation from the skin surface is a function of the dose applied, airflow, and temperature at the skin surface. The extent to which these variables may be controlled or monitored can have a major impact on the results of in vivo skin absorption studies. Furthermore, consideration of the evaporative loss of the... 

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