Delayed skin human studies

Evaluation must distinguish between primary irritation responses, which may disappear within a couple of days, and sensitization responses which may develop more slowly, persist longer, and are characterized by pruritis, erythema, edema, papules, vesicles, bullae, or a combination of these. Further identification of sensitization reactions may involve microscopic examination of skin biopsy samples. Some issues which may be encountered in human studies include reactions early in the induction phase which may be indicative of preexisting sensitization to the test material, or a delayed response at 192 h instead of at 48 or 96 h. Follow-up of subjects not completing the study may yield valuable information on the adverse effects of a preparation. 

Topical formulations are another special case. Over time, it has been shown that the minipig has a skin structure that is quite similar to humans, and that species is now used commonly as the nonrodent model. These types of formulations also require local irritation studies where guinea pigs are used to determine delayed contact sensitization. Selection of the animal species for the nonclinical program is often not straightforward. 

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. 

In hirman keratinocyte cultures, triethanolamine was categorized as a weak inducer of a delayed (> 4 h) stimulation of the release of key mediators (arachidonic acid, eicosanoids, interleukin-la) that are known to be indicative of hyperproliferative and inflammatory events in human skin (Miiller-Decker et al., 1994). In line with the in-vitro irritancy tests, triethanolamine was found to be a non-irritant in a clinical patch testing study of human skin in 20 male volunteers (Miiller-Decker et al., 1998). 

Levamisole was first synthesized for the treatment of parasitic infections. Later studies suggested that it increases the magnitude of delayed hypersensitivity or T cell-mediated immunity in humans. In immunodeficiency associated with Hodgkin s disease, levamisole has been noted to increase the number of T cells in vitro and to enhance skin test reactivity. Levamisole has also been widely tested in rheumatoid arthritis and found to have some efficacy. However, it has induced severe agranulocytosis (mainly in HLA-B27-positive patients), which required discontinuation of its use. The drug may also potentiate the action of fluorouracil (5-FU) in adjuvant therapy of colorectal cancer, and this combination has been approved for clinical use in the treatment of Dukes class C colorectal cancer after surgery. Its use in these cases reduces recurrences, and the mechanism... 

Probably the most widely reported information concerning petrolatum s effect on damaged skin was a 1992 article by Ghadially and coworkers.71 Newspapers across the United States reported the results of this study, which showed that, when applied to skin that had been damaged by acetone, petrolatum accelerated the recovery of the skin s normal barrier properties. It was noted that this is in contrast to materials that are highly impermeable to water vapor (such as polyethylene films) which hinder barrier repair. However, another publication has indicated that the repair of the permeability barrier in human skin is not delayed by occlusion.72... 

Information on toxic effects of acute-duration exposure to PCBs by routes other than oral are limited to LD50 values for dermal exposure (Fishbein 1974 Puhvel et al. 1982), but these data may not be reliable due to possible delayed lethality. PCBs are well absorbed after exposure by all routes, and distribution to and retention by adipose tissue has been observed in humans after inhalation, oral, and/or dermal exposure (Brown and Lawton 1984 Fait et al. 1989 Jensen 1987). Mobilization of PCBs from adipose tissue to target organs is likely to be similar regardless of the route of exposure. Additional acute dermal studies are relevant because the skin is a route of concern for exposure at or near hazardous waste sites, particularly due to possibilities for brief contact. Acute inhalation toxicity studies may be relevant due to the potential for inhalation exposure from electrical appliances in buildings and downwind from PCB disposal facilities and incinerators. 

Fig. 1 Methods to study delayed drug hypersensitivity reactions in humans, (a) T cells - mainly from the peripheral blood, but also from tissue sections (skin, kidney), proliferate when exposed to drugs in cell culture. The proliferating cells can be expanded and then cloned by limiting dilutions, and functional and phenotypic analysis performed to evaluate how drugs are stimulatory for T cells and which functions they perform, (b) Immunhistology of skin (and kidney) using antibodies to cell surface and cytokines, etc. the example shows that in a maculopapular exanthema both CD4+ and CD8+ T cells also express perforin...

A number of metal salts have been found to induce delayed hypersensitivity, mainly of the contact type, in humans or in laboratory animals. Sensitivity to ions of chromium, mercury, platinum, nickel, beryllium, and others seem well established and Table 2 shows some recent findings. The best studied metal sensitizers are the chromium salts, since chromium eczema due to cement is the most important occupational dermatosis (Polak et al. 1973). Hexavalent chromium, in the form of potassium dichromate, is a better sensitizer than trivalent chromium. This seems related to the much better skin penetrating capacity of the dichromate, since numerous studies have shown that trivalent chromium compounds as opposed to hexavalent salt are the actual sensitizers (Polak et al. 1973). The same authors conclude that chromium is probably a component of the determinants formed with autologous carriers and does not produce autoantigens without further participation of the metal ion. In particular, oxidation reactions as generators of determinants seem inoperative in chromium hypersensitivity, since other strong oxidizers like... 

Toxicity Ethylene oxide is a severe irritant to the eyes, skin, and respiratory tract and exhibits moderate acute toxicity by all routes of exposure. Symptoms of overexposure by inhalation may be delayed and can include nausea, vomiting, headache, drowsiness, and difficulty breathing. Ethylene oxide can cause serious bums to the skin, which may only appear after a delay of 1 to 5 hours. This substance may also be absorbed through the skin to cause the systemic effects listed above. Eye contact can result in severe bums. Ethylene oxide is not considered to have adequate warning properties. Ethylene oxide is listed by lARC in Group 2A ("probable human carcinogen") and is classified as a "select carcinogen" under the criteria of the OSHA Laboratory Standard. There is some evidence from animal studies that ethylene oxide may be a developmental and reproductive toxin in both males and females. Exposure to this substance may lead to sensitization. 

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