Humans percutaneous absorption studies

R. L. Bronaugh, R. E Stewart, and E. R. Congdon. Methods for in vitro percutaneous absorption studies. II. Animal models for human skin. Toxicol. Appl. Pharmacol. 62 481 188 (1982). 

Bronaugh, R. F., R. F. Stewart, and M. Simon. 1986. Methods for in vitro percutaneous absorption studies. VII Use of excised human skin./. Pharm. Sci. 75 1094-1097. 

Walker, M Dugard. P, H, and Scott, R. C. (1983). In vitro percutaneous absorption studies A comparison of human and laboratory species. Hum Toxicol. 2, 561-568. 

Reports have sporadically appeared in the literature on perfused pieces of animal and human skin used in various studies (Feldberg and Paton, 1951 Kjaersgaard, 1954 Hiemickel, 1985 Kietzmann etal., 1991) however, none have ever been optimized or validated for percutaneous absorption studies. In contrast, a human—rat sandwich skin flap on athymic rats has been employed to study dermal absorption of various compounds (Krueger etal., 1985 Wojciechowski etal., 1987 Silcox et al., 1990). The IPPSF is the focus of the present chapter. 

Advances of in vivo methods for dermal absorption studies have shown promising results. Microdialysis has bear ranployed successfully for measuring dermal penetration of a wide variety of compounds. This technique has been used extensively in topieal bioavaUabUity and bioequivalenee studies. The noninvasive techniques for percutaneous absorption studies such as tape-stripping, ATR-FTIR, and skin surface biopsies arc also becoming popular because these can be used safely in humans. Regulatory bodies rely on mass balance approaches because all of the topically... 

Bronaugh, R.L., Stewart, R.F., and Simon, M. (1986). Methods for in vitro percutaneous absorption studies VII use of excised human skin. Journal of Pharmaceutical Sciences, 75, 1094-1097. 

Percutaneous absorption studies utilizing rhesus monkeys have one Important single advantage. That is, their skin type and absorption characteristics seem to be similar to humans. This is of utmost concern since the purpose of this study is to simulate the human case. This is not a toxicology study, and it should not be the purpose of this study to estimate a worst case scenario as in a hazard identification study. Thus, in spite of the many shortcomings of the described procedures, monkey percutaneous absorption studies could play an important role in pesticide risk assessments. 

Percutaneous absorption studies with cypermethrin by Scott and Ramsay (1987) indicated that 1% of an in vivo dose to rats was absorbed after an 8-h exposure however, no absorption was detected in vitro using human and rat skin after 8 h. A Kp was not calculated from the information obtained in the in vivo study. 

Alcohol and alcohol ether sulfates have also been studied to determine their toxicity by percutaneous absorption in rats and guinea pigs [354-356]. Alcohol ether sulfates penetrate in the order of 1 ng/cm2/day and alcohol sulfates are less penetrant by a factor of 10. The surfactant absorbed was metabolized. Since it is known that human skin is less permeable than animal skin, only very small amounts of alcohol or alcohol ether sulfates can be absorbed even in the case of complete body exposure. 

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. 

Bronaugh RL, Maibach Fll. 1985. Percutaneous absorption of nitroaromatic compounds In vivo and in vitro studies in the human and monkey. J Invest Dermatol 84 180-183. 

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). 

Wester RC, Maibach Hl, Bucks DA, et al. 1990. Percutaneous absorption and skin decontamination of PCBs In vitro studies with human skin and in vivo studies in the Rhesus monkey. J Toxicol Environ Health 31 235-246. 

Percutaneous absorption of hydroquinone from an aqueous solution was studied in full-thickness rat skin in vitro-, the permeability constant was 2.3 x 10 cm/h, which was approximately two-fold faster than that of human skin (Barber et al., 1995). 

Barber ED, TeetselNM, Kolberg KF, et aL 1992. A comparative study of the rates of in vitro percutaneous absorption of eight chemicals using rat and human skin. Fund Appl Toxicol 19 493-497... 

The in vitro methods used to study the percutaneous absorption of drugs vary in the types of diffusion cells used, the skin sources used, and the techniques used to prepare skin for in vitro studies (1). We have attempted to improve the reproducibility and efficiency of measuring the in vitro flux rates of compounds through human skin when carrying out these experiments on a large number of diffusion cells. 

In vivo studies have been conducted in man and in several species to compare absorption fates of numerous compounds. Percutaneous absorption rates in the rat and rabbit were generally higher than in human while the skin permeability of monkeys and swine more closely resembles humans. Although these differences are not predicted by any single factor, such as epidermal thickness, they are not unexpected in light of differences in skin characteristics. There are interspecies differences in routes of excretion of some chemicals as well. This may be due in part to metabolism of the... 

The next level of in vitro systems employed is the use of isolated perfused skin flap preparations that are surgically prepared vascularized skin flaps harvested from pigs and then transferred to an isolated organ perfusion chamber. This model allows absorption to be assessed in skin that is viable and anatomically intact and that has a functional microcirculation. Studies conducted to assess the percutaneous absorption of drugs and pesticides in this model compared to humans show a high correlation. Validation of these in vitro methods is a prerequisite for regulatory acceptance. 

Dick, I.P., P.G. Blain and F.M. Williams (1997a). The percutaneous absorption and skin distribution of lindane in man. I. In vivo studies. Human Exp. Toxicol, 16, 645-651. 

There are many different animal models that have been used to assess the percutaneous absorption of toxic chemicals. There is little question that while in vivo human studies are best for predicting the absorption of percutaneous applied chemical warfare agents, ethics preclude conducting such studies. Rats have been widely used in the study of skin contamination, wounds, and healing and the efficacy of different decontamination modalities (Wester and Maibach, 2000 Shah et al, 1987 Baynes et al., 1997). 

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