In vivo skin absorption

In vivo skin absorption studies for risk assessment purposes are most often performed on laboratory rats. While the USEPA (1998) states that the rat is the only acceptable species, the OECD (2004b) mentions that also other animal species can be used when they have been proven to have more similar skin absorption rates to human. An advantage of the rat is that this is the species used in most toxicological and kinetic studies. On the other hand, it is known that data from rat studies generally overestimate human skin absorption (ECETOC, 1993 van de Sandt et al, 2000). As indicated before, and to the best of our knowledge, no extensive validation of the rat in vivo study has been performed in which reproducibility and the relationship to human skin absorption have been established. 

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... 

Chilcott RP, Dalton CH, Hill I et al. (2005b). In vivo skin absorption and distribution of the nerve agent VX (0-ethyl-5 -[2(diisopropylamino)ethyl] methylphosphonothioate) in the domestic white pig. Human Exp Toxicol, 24, 347-352. 

Loss of radioactive material from the skin surface has been used to estimate in vivo percutaneous absorption. The difference in applied dose and residue on the skin is assumed to be absorbed. The characteristics of the radioisotope, penetrant, and vehicle may limit the usefulness of this procedure. Volatile materials may leave the surface without penetrating, and it is difficult to recover all material from the skin surface. In addition, skin may retain a reservoir of the penetrant that has not entered the circulation. 

Several in vivo and in vitro studies conclusively demonstrate that benzene can be absorbed through human skin (Blank and McAuliffe 1985 Franz 1984 Susten et al. 1985 Tsuruta 1989). In general, skin absorption is considered a minor source of concern in the occupational environment as it occurs at a much lower rate and extent compared with benzene absorption through the respiratory system (OSHA 1989). However, benzene absorption through the skin as a result of benzene contamination in rubber solvents is a major route of exposure in tire building operations (Susten et al. 1985). Benzene is an irritant to the skin and, by defatting the keratin layer, may cause erythema, vesiculation, and dry and scaly dermatitis... 

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... 

If appropriate dermal penetration data are available for rats in vivo and for rat and human skin in vitro, the in vivo dermal absorption in rats may be adjnsted in light of the relative absorption throngh rat and human skin in vitro. The latter adjustment may be carried out because the permeability of human skin is often lower than that of animal skin (McDougal et al., 1990 Sato et al., 1991 Barber et al., 1992 Howes et al., 1996). A generally applicable correction factor for extrapolation to man can, however, not be derived, because the extent of overestimation appears to be agent- and animal-specific (Bronaugh and Maibach, 1987 ECETOC, 1993). 

Development of guidance on the interpretation of residues remaining on the washed skin in in vivo dermal absorption studies. 

Gorsline, J. Okerholm, R.A. Rolf, C.N. Moos, C.D. Hwang, S.S. Comparison of plasma nicotine concentrations after application of nicoderm (nicotine transdermal system) to different skin sites. J. Clin. Pharmacol. 1992,32, 576-581. Wester, R.C. Maibach, H.I. Bucks, D.A.W. In vivo percutaneous absorption of paraquat from hand, leg and forearm of humans. J. Toxicol. Environ. Health 1984, 14, 759-762. Taskovich, L. Shaw, J.E. Regional differences in the morphology of human skin correlation with variations in drug permeability. J. Invest. Dermatol. 1978, 70, 111. Roberts, M.S. Eavretto, W.A. Meyer, A. Reckmann, M. Wongseelashote, T. Topical bioavailability of methyl sahcy-late. Aust. N.Z. J. Med. 1982, 12, 303-305. 

When a topically applied compound induces a biological response following skin absorption, the quantitation of that response may provide a basis for assessing skin absorption. Indeed, such physiological or pharmacological responses have been employed as endpoints in assessing skin absorption in vivo, and perhaps the most successful example is the vasoconstrictor response to topical corticosteroids. However, while these pharmacodynamic endpoints may be very sensitive and selective for defined classes of compounds, it should be noted that the parameter measured is the product of both the quantity and the potency of the compound under investigation and may not necessarily reflect the extent of skin absorption, cutaneous metabolism, or disposition. 

There are few published data on the percutaneous absorption of sunscreens through human skin (239,242-248). Most of the information came from in vitro penetration studies or by estimation from the amount recovered in the stratum corneum after tape stripping. The rationale for using the latter method (often referred to as the "reservoir technique") is based on the finding by Treffel and Gabard (248)that a linear relationship exists between the drug concentration in the stratum corneum and its in vivo percutaneous absorption. 

Wilhelm K, Surber C, and Maibach HI. Effect of Sodium Lauryl Sulfate-Induced Skin Irritation on In Vivo Percutaneous Absorption of Four Drugs. J Invest Dermatol 1991 97 927-932. 

In a related study. Wester et al. (1990,1993) assessed the in vivo percutaneous absorption of PCBs in adult female Rhesus monkeys. " C-Labeled Aroclor 1242 and 1254 were separately administered iv and topically to Rhesus monkeys and urinary and fecal excretion of radioactivity was measured for the next 30 days. Following iv administration, the 30-day cumulative excretion was 55% of the administered dose (39% urine, 16% feces) for Aroclor 1242 and 27% (7% urine, 20% feces) for Aroclor 1254. The percentage of the dose absorbed following topical administration to abdominal skin (after light clipping of hair) was estimated from the ratio of the total urinary and fecal excretion following topical and iv administration. Topical administration of Aroclor 1242 in soil, mineral oil, tiichlorobenzene, or acetone resulted in 14, 20, 18, and 21% absorption of the administered dose, respectively. In contrast to the above in vitro results with human skin, the vehicle had little effect on the systemic absorption of the PCBs applied to the skin of monkeys. This may be due to the uncertain viability of the human skin used in the in vitro studies and the fact that the in vitro study primarily assessed retention of PCBs in human skin and could not estimate systemic absorption. 

Percutaneous absorption in the IPPSF was correlated (r 0.8) to in vivo human absorption for live diverse compounds (Wester et al., 1998). The IPPSF estimate for absorption used was the amount absorbed into the perfusate plus the amounts penetrated into the skin. Comparative absorption values (% dose, mean + SD) were as follows ... 

Silcox, G.D., Parry, G.E., Bunge, A.L., Pershing, L.K., and Pershing, D.W., 1990, Percutaneous absorption of benzoic acid across human skin. II. Prediction of an in vivo, skin-flap system using in vitro parameters, Pharm. Res., 7 352-358. 

Wester, R.C., Hui, X., Hartway, T, Maibach, H.I., Bell, K, Schell, M.J., Northington, D.J., Strong, R, and Culver, B.D. (1998). In vivo percutaneous absorption of boric acid, borax, and disodium octaborate tetrahydrate in humans compared to in vitro absorption in human skin from infinite and finite doses. Toxicological Sciences, 45, 42-51. 

Chatterjee, D.J., Li, W.Y., and Koda, R.T. (1997). Effect of vehicles and penetration enhancers on the in vitro and in vivo percutaneous absorption of methotrexate and edatrexate through hairless mouse skin, Pharm. Res., 14 1058-1065. 

Bress, W. C., In Vitro and In Vivo Percutaneous Absorption of Organoleads, Lead Salts, and Inorganic Lead in Guinea Pig and Human Autopsy Skin, DIss. St. John s Univ., Jamaica, N.Y., 1984 C.A. 101 [1984] No. 105414. 

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