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6
Testing and Evaluation
The testing and evaluation of equipment, methodologies, and toxico-
logical factors are critical for the development of CB defensive strategies.
Testing must be done on several different levels, ranging from rigorous
tests of components of protective equipment to assessments of current
doctrine and training by means of simulations and exercises (including
war games).
TOXICOLOGICAL TESTING
In keeping with the principles and spirit of the nonproliferation agree-
ments entered into by the United States, U.S. policy prohibits most tests
using real agents and studies with human volunteers (except with surro-
gate agents). Therefore, most human and animal studies are done with
simulants, which may not be adequate surrogates for potential threat
agents (Rhodes et al., 1998~. In fact, the airborne behavior of simulants
and real agents differ significantly, as do their dermal penetration and
metabolic effects. These differences make estimating absorbed doses and
toxic effects extremely difficult. Thus, based on simulant challenge data, it
is extremely difficult to determine whether specific pieces of equipment
meet requirements.
Although fewer studies have been done on dermal penetration than
on the inhalation or ingestion of agents, the current clothing R&D pro-
gram is predicated on the need to avoid a percutaneous challenge from
agents. Current efforts to develop a new protective ensemble (i.e., JSLIST)
and chemically protective undergarments are based on the principle of
138
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TESTING AND EVALUATION
139
preventing CB agents from contacting the skin. Although dermal contact
is an obvious danger for blister-type agents, such as nitrogen and sulfur
mustards, the percutaneous threat of other agents (e.g., G or V agents or
biological agents) has not been established. The available data on percuta-
neous absorption and the physiological effects of agents absorbed percu-
taneously are very limited.
For the most part, percutaneous threats from chemical agents have
been defined using data from animal studies. Percutaneous threats from
biological agents have been defined mostly anecdotally; however, there
are situations in which skin contact with biological agents has been shown
to have adverse effects (Johnson, 1990; LeDuc, 1989; Mikolich and Boyce,
1990~. Because the requirements for protection against percutaneous
threats are based on such sketchy data, the goals, requirements, and re-
sults of the R&D programs are necessarily based on uncertainties. Strate-
gies for rigorous testing of dermatological exposures will be necessary in
two important areas: (1) quantifying skin uptake and resultant toxicol-
ogy, and (2) determining the efficacy of skin decontamination.
Tests of percutaneous toxicology can be interpreted using well de-
fined models. DPK models are based on relationships among the amount
of agent presented to the skin surface, the amount of drug (or toxic chemi-
cal) absorbed into the body, and the rate of contamination. Dermato-
pharmacodynamic (DPD) models determine the CB effects of the absorbed
dose (Gupta et al., 1993; Marzulli and Maibach, 1991; Zhai and Maibach,
1996~. DPK models describe agent uptake as a function of dose and time;
while, DPD models are used to evaluate the relationship between the
concentration at the effecter or target site and the biologic effect. DPK
models may provide kinetic details and suggest mechanisms that could
supplement traditional clinical studies. Therefore, DPK models can be
used to evaluate both percutaneous absorption (Gupta et al., 1993; Shah et
al., 1991, 1993; Zhai and Maibach, 1996) and dermal decontamination
(Wester and Maibach, l999b).
Evaluation of Percutaneous Penetration
DPD models have been used to ascertain bioavailability from percu-
taneous exposure. Bioavailability can be defined as the rate and extent to
which the administered toxic agent is absorbed via the skin and becomes
available at the site of chemical action and/or reaches the general circula-
tion. Thus, the approach based on these models can be used to evaluate
the absorption and toxicity of agents during dermal exposures, the effec-
tiveness of decontamination, and the degree of protection provided by
protective treatments, such as applications of barrier creams.
DPD models can be used to estimate the movement of chemicals into
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40
STRATEGES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES
the first organ system (skin), and quantities can be determined indirectly
by noninvasive bioengineering techniques (e.g., calorimetry, transepidermal
water loss, laser doppler velocimetry, etc.) (Berardesca et al., 1995a, 1995b;
Elsner et al., 1994; Frosch et al., 1993a; McDougal, 1991, 1998; Wester and
Maibach, l999c; Wilhelm et al., 1997~.
The following 10 factors should be included in rigorous evaluations
of percutaneous absorption (Wester and Maibach, 1983~:
· vehicle release
· absorption kinetics
· excretion kinetics
· cellular and tissue distribution
· substantivity
· wash and rub resistance
· volatility
· binding
· anatomical pathways
· cutaneous metabolism
For more detailed scientific information on these 10 factors, see Appendix E.
Vehicle Release
Percutaneous absorption of a drug from a vehicle (i.e., mechanism of
transport) depends on the partition of the chemical between the vehicle
and the skin and the solubility of the drug in the vehicle (e.g., isopropyl
alcohol, dimethyl sulfoxide). Solubility, concentration, and pH of the drug
can influence interactions among the vehicle, the active chemical, and the
skin. Vehicles sometimes contain agents, such as urea, that can enhance
percutaneous absorption. In some cases, the vehicle itself may enhance
absorption or change skin integrity. An occlusive vehicle, for example,
could alter skin hydration.
Absorption Kinetics
Absorption kinetics vary according to a number of factors: (1) skin
application site, (2) individual variations, (3) skin condition, (4) occlu-
sion, (5) chemical concentration and surface area, and (6) number of
applications. Percutaneous absorption in humans and animals varies
with the anatomical site to which the compound is applied. Even if appli-
cation conditions remain the same (e.g., application site, compound,
concentration, dose, vehicle), absorption can vary by several-fold be-
cause of individual variations.
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TESTING AND EVALUATION
141
Any change in skin condition, especially changes in the barrier func-
tion of the stratum corneum, whether natural or inflicted, may alter per-
cutaneous absorption. Skin condition also changes with age; the stratum
corneum of preterm infants is not fully developed and, therefore, is more
permeable than in a fully developed infant. Damage, disease, and occlu-
sion (overhydration) may also increase absorption levels. Percutaneous
absorption is often increased when the application site is occluded. Chemi-
cal concentration and surface area are also critical parameters in deter-
mining the amount of absorption. As the concentration of the applied
dose increases, the total amount absorbed increases. As the surface area of
the applied dose increases, the total amount of absorption also increases.
If any topically administered compound is applied more than once a
day, the topical exposure may be chronic. Absorption from one applica-
tion of a high concentration may be greater than the same concentration
applied in equally divided doses. The mechanisms controlling this are not
yet understood.
Excretion Kinetics
A potentially toxic chemical will be more or less damaging depend-
ing on the rate of excretion or retention in the body. For instance, al-
though lindane and hexachlorophene are not well absorbed, their poten-
tial for toxicity is enhanced by their slow excretion and storage in lipid
compartments. In general, water-soluble compounds are rapidly excreted
and are generally less toxic.
Cellular and Tissue Distribution
The concentration of chemical in the skin is usually highest near the
surface and lowest in the dermis. Differences in percutaneous absorption
depend not only on the thickness, surface area, and number of cell layers
in the stratum corneum, but also on lipid composition and concentration
distribution of the chemical in the skin layers.
Substantivity
Substantivity is a measure of the portion of the applied dose that
binds to the skin surface and may eventually be lost by skin exfoliation.
When radioisotopes are used, substantivity can be monitored by surface
counting; otherwise, skin stripping cellophane tape can be used.
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142
Wash and Rub Resistance
STRATEGES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES
A compound applied to skin surface can be partially removed by
washing or rubbing. Mechanical stress on the skin, such as friction from
clothing, may alter both the distribution of the applied dose and percuta-
neous absorption.
Volatility
Volatility refers to the partition of a chemical between its vehicle on
the skin surface and the surrounding air (an important factor for mos-
quito repellents). Accurate determinations of percutaneous absorption in
vitro or in vivo with animal and human models require simulations of air
flow with volatile chemicals.
Binding
Chemicals may bind to the stratum corneum (i.e., substantivity) or to
other tissue compartments (e.g., viable epidermis, dermis, fat, or append-
ages). The rate and extent of binding have only been documented for a
few compounds, but the methodology appears to be adequate. Toxic
agents presumably bind to several tissue compartments. Chemical defen-
sive agents might saturate binding sites to decrease the toxicity of the
attacking agent.
Anatomic Pathways
Penetration occurs throughout the stratum corneum. Empirically, it is
known that hairy areas (terminal or vellus hairs) are more permeable than
glabrous sites (e.g., the retroauricular area, face, scalp, and axilla are more
permeable than the forearm). Understanding the mechanisms controlling
these differences might provide insights for chemical defense.
Cutaneous Metabolism
The skin is an extremely active metabolic organ that contains numer-
ous chemical-metabolizing enzymes. Metabolism of a chemical in skin
may alter the pharmacological and/or toxicological effect on the system.
When studying the availability of topically administered drugs or envi-
ronmental contaminants, one must consider the metabolizing ability of
the skin, which may affect the bioavailability of the drug during the first
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TESTING AND EVALUATION
143
passage through the skin. For example, hydrocortisone can be metabo-
lized to cortisone and dihydrodiols can be metabolized to expoxide dials,
which are more potent carcinogens than the original chemicals.
Evaluation of Barrier Creams
Recently, DPD models and noninvasive bioengineering techniques
have been adapted to quantify the efficacy of protective or decontaminat-
ing barrier creams. These tests provide accurate, reproducible, and objec-
tive observations that can reveal subtle differences before visual clinical
signs (e.g., blisters) appear (Berardesca et al., 1995a, 1995b; Elsner et al.,
1994; Frosch et al., 1993a; Wilhelm et al., 1997~. These tests are considered
to be more humane than traditional tests because, by the time a blister
develops after vesicant exposure, critical biological events have occurred.
Data on the efficacy of barrier creams from recent experiments are sum-
marized in Table 6-1. The in viva and in vitro methods used to evaluate
barrier creams are provided in Appendix C.
TEST EQUIPMENT
Because the United States has moved to a joint service environment
and adheres to the CWC and the BWC, testing has become a complicated
issue in two respects. First, simulant agents that mimic the chemical and
physical properties of real agents must be used. Second, responsibilities
must be distributed across services. For example, the Marine Corps is
responsible for testing ISLIST but does not "own" the expertise for per-
forming these tests; the toxicological expertise resides in the Army at
SBCCOM Soldier Systems Center. The U.S. Army Chemical School (now
relocated to Ft. Leonard Wood) has the capability to conduct exercises
using real chemical agents, but such experiments are limited to training
exercises. Army facilities cannot be used for testing components of PPE or
ensembles, per se (DoD, 1999~.
PPE components and ensembles have been tested by contract person-
nel at Dugway Proving Ground in Utah using simulants. The Dugway
facilities have excellent capabilities (1) for testing with CB simulants, such
as methyl salycilate (MES), which is environmentally benign and rela-
tively nontoxic; (2) for large-scale field testing of the integrity, degree of
protection, and decontamination of PPE; and (3) for modeling exercises
using various exposure scenarios. Unfortunately, although the capability
for performing quantitative tests is available, no mechanism has been
established for coordinating the toxicological, human factors, and expo-
sure assessments of the studies.
The lack of coordination becomes apparent in a review of the studies
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STRATEGIES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES
TABLE 6-1 Efficacy of Barrier Creams
Models
In Vivo
Animals or Irritants Barrier
In Vitro Human or Allergens Cream
Guinea pigs
G. .
umea pigs
Humans with a history of
allergic reactions to test
allergens
Humans who had positive
patch tests to toxicodendron
extract
n-Hexane, trichloroethylene,
and toluene
cutting oil
epoxy resin, glyceryl
monothioglycolate, frullania, and
tansy
toxicodendron extract
3 waterer
2 barrier
1 barrier
various ~
preparati
Guinea pigs and humans sodium lauryl sulfate, sodium several b,
hydroxide, toluene, and lactic acid
Human skin dyes (eosin, methylviolet, oil red 0) 16 barrie
Machinists Castrol oil 1 barrier
Humans with a history of urushiol
allergic reaction to poison
ivy/oak
Nickel-sensitive patients nickel disc
quaterni
bentonit
ethylenes
acetate (]
Humans dyes (methylene blue and oil red 0) 3 barrier
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TESTING AND EVALUATION
145
Barrier
Cream Efficacy References
ne, 3 water-miscible creams Had limited Mahmoud and Lachapelle, 1985
protective effects.
2 barrier creams Exacerbated the Goh, 1991a, l991b
irritation.
1 barrier cream Minimized the McClain and Storrs, 1992
via, and development of
allergic contact
dermatitis.
various barrier Most provided Grevelink et al., 1992
preparations good protective
effects.
lium several barrier creams Some suppressed Frosch et al., 1993b, 1993c, 1993d;
actic acid irritation, some Frosch and Kurte, 1994
failed, and some
caused severe
irritation.
oil red 0) 16 barrier creams Various protection Treffel et al., 1994
effects.
1 barrier cream and Had no significant Gob and Gan, 1994
1 afterwork emollient effect against
dermatitis from
cutting fluid.
quaternium-18
bentonite (Q18B) lotion
ethylenediamine-tetra
acetate (EDTA) gels
Significantly reduced Marks et al., 1995
reactions.
Significantly reduced Fullerton and Menne, 1995
the amount of nickel
in the epidermis in
vitro, and significantly
reduced positive
. . .
reactions in Salvo.
Oil red 0) 3 barrier creams Two creams were Zhai and Maibach, 1996
effective, one
increased the
cumulative amount
of dye.
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146
STRATEGES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES
TABLE 6-1 Efficacy of Barrier Creams (continued)
Models
In Vivo
Animals or Irritants Barrier
In Vitro Human or Allergens Cream
Humans water 2 barrier
a moistu
Humans 10% sodium lauryl sulfate, 4 barrier
1% NaOH, 30% lactic acid, and white pe
undiluted toluene
Humans toluene several b
Humans toluene and NaOH several b
Guinea pigs sulphur mustard povidon~
ointment
Humans self-application of barrier cream oil-in-we
Human skin [35S]-SLS 3 quaterr
(Q18B), ~
Humans sodium lauryl sulfate, ammonium several p
hydroxide (NH4OH), urea, Rhus
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TESTING AND EVALUATION
147
Barrier
Cream
Efficacy
References
2 barrier creams and
a moisturizer
,
1, and
cream
monium
i, Rhus
4 barrier creams and
white petrolatum
several barrier creams
several barrier creams
povidone iodine (PI)
ointment
oil-in-water emulsion
Various protection
effects.
Had different
protective effects
but all products
were very effective
against SLS.
Olivarius et al., 1996
SchlAter-Wigger and Elsner, 1996
All markedly reduced Grunewald et al., 1996
the effect of repetitive
toluene contact.
None prevented the
skin erythema
induced by toluene.
One barrier cream,
as well as petrolatum
and a fatty cream,
protected the skin
significantly against
NaOH.
Showed powerful
protective effect.
Self-application was
incomplete.
3 quaternium-18, bentonite Protection effects
(Q18B), gels were 88%, 81%, and
65%, respectively.
several Protestants
Treffel and Gabard, 1996
Wormser et al., 1997
Wigger-Alberti et al., 1997
Zhai et al., 1999
Most suppressed the Zhai et al., 1998
SLS irritation and
Rhus allergic
reaction, but did
not suppress
NH4OH and urea
irritation.
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STRATEGES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES
referred to as the Man-in-Simulant Test (MIST) Program. Despite its short-
comings (described below), MIST is an extremely valuable program that
has the potential to test complete and partial PPE ensembles under con-
trolled field conditions. A series of tests in which individuals were ex-
posed to MES at a steady-state concentration of 100 mg/m3 for a period of
two hours provided a useful "reality check" (NRC, 1997b). As is often
necessary in field-testing situations, however, compromises had to be
made. In the MIST ensemble testing, the PPE components were worn and
compared with standard issue uniforms. As the test progressed, some of
the PPE were damaged. Of these, some were repaired and reworn, while
others were worn without repair. Although this is probably what would
happen in real-world use, the initial protocol was degraded, thus com-
promising the use of the data to predict what would happen if PPE were
used in a contaminated environment during an actual field deployment.
Another problem with the MIST study was that the comparability of
MES to H or V agents was not taken fully into account. Thus, the MIST
review committee judged that the MIST data might be used qualitatively
to rank some types of PPE, but that the data could not be used to make
quantitative assessments because the information obtained using the pas-
sive dosimeters (i.e., samplers) could not be correlated to the amount of H
or V agents that contacted the skin.
Based on the assumption that MES was a reasonable surrogate for H
agents, the test data showed the following results:
· Under the most favorable conditions (PPE in excellent condition),
the complete ensemble provided protection against a challenge of
< 3,000 mg-min/m3.
· Damage to the ensemble during use degraded performance to a
challenge capability of < 500 mg-min/m3.
· Ensembles that were damaged, repaired, or reworn provided pro-
tection against a challenge of < 500 mg-min/m3.
· The areas of greatest vulnerability in an intact PPE are seals and
closures.
· The passive dosimeters used to test other components of the pro-
tective equipment did not function reliably in the mask.
Because of problems in the experimental design, the data on protec-
tion afforded by PPE ensembles could only be used in a qualitative way.
Nevertheless, they can still be very useful. For example, the data showed
that, within the limits of statistical error, the BDO did not afford signifi-
cantly greater protection than chemical protective undergarments. This
apparent anomaly is attributable to the large differences among ensemble
components.
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TESTING AND EVALUATION
149
The MIST study might be considered a pilot study for more definitive
future studies. The data from the MIST study could be used to design a
stronger statistical study based on the basic science aspects of using
simulants, such as MES, to determine whether or not PPE ensembles
provide adequate protection against challenges with CB agents (or suitable
simulants). To facilitate the selection of suppliers of materials, closures,
and other parts of the PPE ensemble, the tests should be designed to
compare the performance of various ensembles (or components). At a
minimum, better methods for validating the use of simulants will be nec-
essary so that results can be used quantitatively. This may require better
coordination among groups at SBCCOM and Dugway Proving Ground.
Current mask filters are extremely efficient and afford adequate pro-
tection under expected challenge conditions. The point of failure in respi-
ratory protection is the mask seal, not the filter cartridge. The MIST Pro-
gram did not test masks because the passive monitors used to detect MES
and the mask systems were incompatible. This problem has not yet been
resolved.
PREDICTIVE MODELS AND SIMULATIONS
Modeling and simulation are often used in place of prototyping to
predict the operational characteristics of protective systems. Current mod-
els, however, may not be robust or reliable enough to use for making
crucial decisions. A major problem is the lack of basic science informa-
tion, such as the persistence of agents in various environments and under
various conditions, rates of deposition, uptake and metabolism in living
human skin, and rates of penetration under realistic conditions.
EXERCISES AND SYSTEMS EVALUATIONS
Various types of exercises are used to evaluate the ability of deployed
and deploying forces to operate in a CB environment. Computer exercises
and war games can be used to predict the likely behavior and effects of
operating in a CB environment. The accuracy of the predictions depends
on the quality of the data used in the computer model parameter esti-
mates. Computerized war games and scenarios, such as CB2010 (a simu-
lation of the effects of a "low-tech" CB attack on a U.S. force during
deployment from a base in CONUS in the year 2010) predicted that a CB
attack would significantly impact force projection capabilities, especially
the speed of deployment and the effectiveness of forces. A subsequent,
more realistic war game with a similar scenario was "played" during a
deployment exercise at Pope Air Force Base and Fort Bragg. The actual
effects of spraying a simulated thickened mustard on mission-critical
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50
STRATEGES TO PROTECT THE HEALTH OF DEPLOYED U.S. FORCES
equipment and service areas from a crop-duster-type aircraft demon-
strated that the computer simulation might have been optimistic. The
impacts were more protracted and additional problems were identified.
FINDINGS AND RECOMMENDATIONS
Finding. Testing of dermatological threat agents has not been consistent.
The available data are not sufficiently precise to make an accurate evalu-
ation of potential percutaneous threats from agents other than blister
agents or irritants.
Recommendation. Tests of dermatological threat agents should be con-
ducted to establish the level of protection necessary to provide adequate
margins of safety and to establish quantitative criteria for evaluating the
performance of protective equipment, such as gloves, undergarments,
and overgarments.
Finding. Mask testing under the MIST program was unreliable because
the passive dosimeters did not function satisfactorily.
Recommendation. Active samplers or improved passive samplers for
mask testing using simulants should be developed and made available
for tests of the joint service lightweight integrated suit technology (ISLIST)
ensemble.
Representative terms from entire chapter:
percutaneous absorption
