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OCR for page 224
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.:
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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.
OCR for page 229
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.
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R.C. Wester, X. Hui, and H.I. Maibach. 1998. Analytical performance of accelerator
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Representative terms from entire chapter:
accelerator mass
