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Appendix E Perculaneous Absorption Howard I. Maibach and Hongbo Zhai IN VITRO PASSIVE DIFFUSION Most in vitro techniques entail placing excised skin in a diffusion chamber, applying a chemical compound to its surface, and assaying the skin for the presence of the compound in the collection vessel on the other side. Excised human skin, animal skin, or artificial membranes can be used, and the skin may be intact or separated into epidermis and dermis (Wester and Maibach, 1993; Bronaugh, 1997; and Roberts et al., 1999~. In vitro systems can be used to test the percutaneous absorption of chemicals that are too toxic to test in humans. In viva, the penetrating compound may not pass completely through the dermis but may be removed by metabolic mechanisms, such as through capillaries, and enter the blood stream causing systemic effects. With in vitro systems, skin metabolism can be studied in viable skin with- out interference from systemic metabolic processes. Absorption measure- ments can be obtained more easily from diffusion cells than from analyses of biological specimens from clinical studies. In vitro techniques are easy to use, and the results can be obtained rapidly. A disadvantage, however, is that the collection bath is saline, thus compatible with hydrophilic but not hydrophobic compounds. 1The following material was prepared for the use of the principal investigators of this study. The opinions and conclusions herein are the authors' and not necessarily those of the National Research Council. 224
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APPENDIX E 225 COMPARTMENTAL MODELS Compartmental models are alternatives to diffusion models of percu- taneous absorption. Absorption of solute through the skin is generally assumed to follow first-order kinetics. Much of the data analyzed with compartmental models is characterized by "flip-flop" kinetics (i.e., the absorption half-time is much longer than the elimination half-time) (Rob- erts et al., 1999~. STRIPPING MODELS Stripping models can be used to determine the concentration of chemicals in the stratum corneum at the end of a short application period (e.g., 30 minutes). First, the chemical is applied to skin of animals or humans. After 30 minutes, the stratum corneum is removed by succes- sive applications of tape (Rougier et al., 1999; Surber et al., 1999~. By linear extrapolation, stripping models can predict the percutaneous ab- sorption of that chemical for longer periods. Rougier and coworkers (1986) established a linear relationship between the stratum corneum, reservoir content, and percutaneous absorption using the standard uri- nary excretion method (Feldmann and Maibach, 1967~. The major advan- tages of the stripping method are: (1) absorption can be determined inde- pendent of urinary (and fecal) excretion; and (2) nonradiolabeled percutaneous absorption can be determined because the stripped skin samples contain enough chemical for modern chemical assay methods (Wester and Maibach, 1999a). RADIOISOTOPIC TRACER METHODS Radiolabeled compounds are widely used as tracers in both in vitro and in viva studies. Many radiochemicals are commercially available; others may be synthesized to order. Radiochemicals are usually used to determine the amount of radioactivity in the "dermal"' compartment (receiver fluid) or in the skin compartment (epidermis, dermis). Radiochemicals are also used to determine percutaneous absorption in vivo by the indirect method of measuring radioactivity in excrete (urine and feces) after topical application. Plasma radioactivity can be measured and the percutaneous absorption determined by the ratio of the areas under the plasma concentration to time curves following topical and in- travenous administration (Wester and Maibach, 1999a). This method can detect low levels of chemical absorption.
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226 STRATEGIES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES ACCELERATOR MASS SPECTROMETER Accelerator mass spectrometry (AMS) uses mass selection and energy gain to separate the isotope of carbon (and other elements) so that ions of the radioisotope can be counted. Tissue samples can be analyzed to quan- tify radioisotopes regardless of their decay times (Keating et al., 1999~. AMS has distinct advantages over other methods of measuring percuta- neous penetration. First, its analytic sensitivity is a thousand times greater than liquid scintillation counting (LSC). Therefore, flux determinations can be made using test chemicals at low enough concentrations to con- duct human in viva studies. AMS can also be used with other methods to quantify chemical absorption on tape strips after in vivo human dermal exposure (Keating et al., 1999~. Gilman et al. (1998) used AMS to detect ~4C-labeled urinary metabo- lites of atrazine (a triazine herbicide) and compared the analytical perfor- mance of AMS with LSC. Human subjects were given a dermal dose of ~4C-labeled atrazine over a 24-hour period. Urine samples from the sub- jects were collected over a seven-day period. The concentrations of ~4C in the samples determined by AMS and LSC ranged from 1.8 fmol/mL to 4.3 pmol/mL. The data from these two methods have a correlation coeffi- cient of 0.998 for a linear plot of the entire sample set. AMS provides concentration (2.2 vs. 27 fmoI/mL) and mass (5.5 vs. 54,000 amol) detec- tion limits superior to those of LSC for these samples. The precision of the data provided by AMS for low-level samples is 1.7 percent; the day-to- day reproducibility of the AMS measurements is 3.9 percent. REAL-TIME IN VIVO BIOAVAILABILITY Wester and Maibach (1999a) used a real-time in vivo method to deter- mine the bioavailability of organic solvents following dermal exposure. Breath analysis was used to obtain real-time measurements of volatile organic compounds in expired air following exposure. Human volunteers and animals breathed fresh air via a breath inlet system for continuous real-time analysis of undiluted exhaled air. The air supply system was self-contained and separated from the exposure solvent-laden environ- ment. The system used an ion-trap mass spectrometer equipped with an atmospheric sampling glow discharge ionization source. The ion-trap mass spectrometer system was used to measure individual chemical com- ponents in the breath stream in the single-digit parts per billion detectable range for each of the compounds proposed for study, while maintaining linearity of response over a wide dynamic range.
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APPENDIX E 227 OCCLUSION Occlusion is covering the applied dose, either intentionally (e.g., ban- daging) or unintentionally (e.g., putting on clothing) after applying a topical agent. A vehicle such as an ointment can also have occlusive prop- erties. Occlusion results in a combination of many physical factors that affect the skin and the applied compound by enhancing hydration and sometimes increasing skin temperature. Occlusion also prevents the acci- dental wiping or evaporation of the applied compound, in essence ensur- ing a higher applied dose. Occlusion increases flux and is synergistic with skin damage (Wester and Maibach, 1983~. Occlusion is a practical clinical method of enhancing percutaneous absorption, which suggests that its use in chemical defense should be studied further. The relationship between occlusion and rate of penetration depends on the solubility of the penetrant. Furthermore, the extent of penetration may depend on the method of occlusion (Bucks and Maibach, 1999~. REGIONAL VARIATION Feldmann and Maibach (1967) systematically investigated regional variations in percutaneous absorption and found that the absorption of hydrocortisone differed at different anatomical sites. The scrotum was the highest absorbing skin site and the sole of the foot the lowest. Other studies have also focused on the influence of anatomical site on the ab- sorption of various drugs and chemicals in humans and in animals (Wester and Maibach, l999b). For example, scopolamine transdermal sys- tems are placed in the postauricular area because an effective amount of the drug is absorbed at this site. Mathematical models are used to estimate human health hazards of environmental contaminants even though data may be available for only one anatomic site. With toxicants on the exposed areas of the skin (head, face, and neck), flux will be greater than on glabrous skin. Estimates of skin absorption rates are integral to estimates of potential hazards (Wester and Maibach, l999b). ANIMAL VERSUS HUMAN STUDIES Human skin is unique, and the structural differences in various ani- mal species may or may not affect the penetrability of a specific com- pound. Numerous in viva and in vitro studies have been conducted com- paring percutaneous absorption in animal and human skin. In general,
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228 STRATEGIES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES the skin of monkeys (rhesus and squirrel) and weanling pig most re- sembles human skin. The skin of rats and rabbits is more permeable than human skin. Animals can be used to generate kinetic data; but no one animal skin can simulate the percutaneous penetration in humans for all compounds. Therefore, the best estimates of human percutaneous absorption are based on in vivo experiments on humans (Zhai and Maibach, 1996~. IN VITRO VERSUS IN VIVO STUDIES Methods of in vitro percutaneous absorption are widely used to mea- sure the absorption of topically applied compounds. A major advantage of in vitro systems is that they can be used to test compounds that are too toxic to test in humans. Metabolism can be measured if viable skin is obtained and the viability is maintained in the diffusion cells (Wester et al., 1998~. Skin metabolism can be studied in viable skin without interfer- ence from systemic metabolic processes (Bronaugh et al., 1999~. Finally, absorption measurements can be made more easily from diffusion cells than from analyses of biological specimens from clinical studies. In vitro methods are simple, rapid, and safe and are recommended as a first step in defining percutaneous absorption. The major disadvantages of in vitro tests are: (1) excised (and usually stored) skin may not retain full enzymatic activity; (2) drug metabolism probably does not affect the amount of compound entering the stratum corneum, but it may affect the metabolic profile emerging from the skin; (3) the collection bath is saline, which is compatible with hydrophilic compounds but not with hydro- phobic compounds; and (4) in viva, the penetrating compound does not pass completely through the dermis but is removed by dermal capillaries (Wester and Maibach, 1983~. Because of notable differences between in vivo and in vitro skin, the in vitro method alone is not always a reliable or accurate predictor of in vivo percutaneous absorption. References Bronaugh, R. L. 1997. Methods for In Vitro Percutaneous Absorption. Pp. 7-14 in Dermatotoxicology Methods: The Laboratory Worker's Vade Mecum. Washington, D.C.: Taylor and Francis. Bronaugh, R., H. Hood, M. Kraeling, and J. Yourick. 1999. Determination of Percutaneous Absorption by In Vitro Techniques. Pp. 229-233 in Percutaneous Absorption, 3rd ea., R.L. Bronaugh and H.I. Maibach, eds. New York: Marcel Dekker, Inc. Bucks, D., and H.I. Maibach. 1999. Occlusion Does Not Uniformly Enhance Penetration In Vivo. Pp. 81-105 in Percutaneous Absorption, 3rd ea., R.L. Bronaugh and H.I. Maibach, eds. New York: Marcel Dekker, Inc.
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APPENDIX E 229 Feldmann, R.J., and H.I. Maibach. 1967. Regional variation in percutaneous penetration of 14C cortisol in man. Journal of Investigative Dermatology 48~2~: 181-183. Gilman, S.D., S.J. Gee, B.D. Hammock, J.S. Vogel, K. Haack, B.A. Buchholz, S.P. Freeman, R.C. Wester, X. Hui, and H.I. Maibach. 1998. Analytical performance of accelerator mass spectrometry and liquid scintillation counting for detection of 14C-labeled atrazine metabolites in human urine. Analytical Chemistry 70~16~: 3463-3469. Keating, G.A., K.T. Bogen, and J.S. Vogel. 1999. Measurement of short-term dermal uptake in vitro using accelerator mass spectrometry. Pp. 475-486 in Percutaneous Absorption, 3rd ea., R.L. Bronaugh and H.I. Maibach, eds. New York: Marcel Dekker, Inc. Roberts, M.S., Y.G. Anissimov, and R.A. Gonsalvez. 1999. Mathematical models in percuta- neous absorption. Pp. 3-55 in Percutaneous Absorption, 3rd ea., R.L. Bronaugh and H.I. Maibach, eds. New York: Marcel Dekker, Inc. Rougier, A., D. Dupuis, C. Lotte, R.C. Wester, and H.I. Maibach. 1986. Regional variation in percutaneous absorption in man: measurement by the stripping method. Archives of Dermatology Research 278: 465-469. Rougier, A., D. Dupuis, C. Lotte, and H.I. Maibach. 1999. Stripping method for measuring percutaneous absorption in vivo. Pp. 375-394 in Percutaneous Absorption, 3rd ea., R.L. Bronaugh and H.I. Maibach, eds. New York: Marcel Dekker, Inc. Surber, C., F.P. Schwarb, and E.W. Smith. 1999. Tape-stripping technique. Pp. 395-409 in Percutaneous Absorption, 3rd ea., R.L. Bronaugh and H.I. Maibach, eds. New York: Marcel Dekker, Inc. Wester, R.C., and H.I. Maibach. 1983. Cutaneous pharmacokinetics: ten steps to percutane- ous absorption. Drug Metabolism Review 14: 169-205. Wester, R.C., and H.I. Maibach. 1993. Topical Drug Delivery: Percutaneous Absorption. Pp. 3-15 in Topical Drug Bioavailability, Bioequivalence, and Penetration, V.P. Shah, and H.I. Maibach, eds. New York: Plenum Press. Wester, R.C., J. Christoffel, T. Hartway, N. Poblete, H.I. Maibach, and J. Forsell. 1998. Hu- man cadaver skin viability for in vitro percutaneous absorption: storage and detrimen- tal effects of heat-separation and freezing. Pharmacology Research 15~1~: 82-84. Wester, R.C., and H.I. Maibach. 1999a. In Vivo Methods for Percutaneous Absorption Mea- surements. Pp. 215-227 in Percutaneous Absorption, 3rd ea., R.L. Bronaugh and H.I. Maibach, eds. New York: Marcel Dekker, Inc. Wester, R.C., and H.I. Maibach. l999b. Regional Variation in Percutaneous Absorption. Pp. 107-116 in Percutaneous Absorption, 3rd ea., R.L. Bronaugh and H.I. Maibach, eds. New York: Marcel Dekker, Inc. Zhai, H., and H.I. Maibach. 1996. Pp. 193-205 in Prevention of Contact Dermatitis, Current Problems in Dermatology, P. Elsner, J.M Lachapelle, J. E. Wahlberg, and H.I. Maibach, eds. New York: Karger.
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