UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON. D.C, 20460
EPA-SAB-EHC-93-006
OFFICE OF THE ADMINISTRATOR
SCIENCE ADVISORY BOARD
February 15. 1993
Honorable Carol M. Browner
Administrator
U.S. Environmental Protection Agency
401 M Street, S.W.
Washington, D.C. 20460
Subject: Science Advisory Board's review of the Office of Research and
Development's draft report Dermal Exposure Assessment: Principles and
Applications (EPA/600/8-91/011B, January 1992)
Dear Ms, Browner:
Agency exposure assessors (particularly those dealing with contaminated waste
sites) face a difficult task In dealing with exposures via skin contact with toxicants in
air, water, and soil. To provide these assessors with an understanding of the princi-
ples of dermal exposure assessment and with the procedures for applying these
principles to human situations, the EPA's Office of Research and Development
developed the draft document referenced above, which summarized the current state
of knowledge on dermal exposure to air, water, and soil; presented methods and
models for estimating dermal absorption resulting from contact via these media;
summarized available chemical specific experimental data describing dermal absorp-
tion properties; and established procedures for evaluating experimental data for
* application to exposure assessments.
The Environmental Health Committee (EHC) was asked to assess the general
validity of the information in the document, and the way in which that information is
applied to dermal exposure assessment. Additionally, the Committee was asked to
consider more specific issues addressing (a) skin composition and dermal absorption
processes; (b) skin models for evaluation of dermal absorbed dose; and (c) the appli-
cability of measured absorption constants for chemicals in air, water, and soil.
Rteycbdffivqrcltbte
en ptrnf mm aoitaM

-------
The EHC met in Washington, DC on August 17-18, 1992 to carry out its review.
The Committee found the draft dermal exposure assessment document to be one of
the better documents it has reviewed, and commends the Agency on the document's
quality and general rigor. There are areas, however, in which improvements can still
be made.
There should be unequivocal guidance as to when to use experimental data,
rather than values estimated from models, and when there is a preference for using in
vitro, rather than in vivo data. The Committee finds that in vivo data are more
realistic, although they may be more difficult to derive and less likely to survive quality
assurance scrutiny. In general, more weight should be given to experimentally-derived
values than to those estimated from models. There are exceptions, however, and the
document's weight-of-evidence table (if it was revised to serve this purpose) couid be
a valuable aid in making the decision to accept or reject experimental values.
The Committee would like to see further examination of model performance
before the models are widely applied. Although the models appear to fit many com-
pounds well, there is an important subset of compounds where the fit is poor, howev-
er, and the report glosses over the differences between expected and estimated
values too readily. The document needs to clearly state the limitations of the models.
Additional data should be sought to both strengthen and expand the models. The
Committee also feels that it is important to have the model validation and estimation
efforts undergo a rigorous statistical analysis. Full validation of the model will require
also input of toxicologists with expertise in skin absorption and metabolism and
analytical chemists, in order to deal with the important issues of metabolic activa-
tion\detoxification by the skin itself.
Finally, although a model to estimate the dermally absorbed dose per-event is
s useful, it would be best if the model could use measured, rather than predicted,
dermal permeability values when possible. When measured data of good quality are
available, they should have precedence over model estimates.
2
*

-------
We appreciate the opportunity to review this document, and look forward to
your response to the issues we have raised.
Dr. Raymond C. Loehr, Chair
Science Advisory Board
Dr, Glry Carlson, Acting Chair
Environmental Health Committee
4
,3

-------
United States	Scfence Advisory	iFA-SAB-EHC.83.0Q6
Environmental	Boas! (A-101)	Februaiy 1993
Protection Agency
r/EPA AN SAB REPORT:
DERMAL EXPOSURE
ASSESSMENT
REVIEW OF THE OFFICE OF
RESEARCH AND
DEVELOPMENTS DRAFT
REPORT DERMAL EXPOSURE
ASSESSMENT: PRINCIPLES
AND APPLICATIONS
(EPA/600/8-91/011B, JANUARY
1992) BY THE
ENVIRONMENTAL HEALTH
COMMITTEE

-------
Distribution List
Administrator
Deputy Administrator
Assistant Administrators
Deputy Assistant Administrator for Research and Development
Deputy Assistant Administrator for Water
EPA Regional Administrators
EPA Laboratory Directors
EPA Headquarters Library
EPA Regional Libraries
EPA Laboratory Libraries
*
i
I
I

-------
ABSTRACT
The Environmental Health Committee (EHC) met in Washington, DC on August
17-18. 1992 to review the EPA draft report Dermal Exposure Assessment: Principles
and Applications (EPA/600/8-91 /011B, January 1992). The Committee addressed the
scientific support for document's general guidance on dermal exposure assessment and
considered specific issues relating to skin composition and dermal absorption pro-
cesses; skin models for evaluation of derma! absorbed dose; and the applicability of
measured absorption constants for chemicals in air, water, and soil.
The Committee commended the Agency on the document's quality and general
rigor, but also noted areas in which improvements were possible. The EHC recom-
mended that the document state more clearly when experimental data, rather than
values estimated from models, should be used for assessment, and stated its prefer-
ence for in vivo data, and for experimentally-derived data when availabfe.
The Committee would like to see further examination of model performance
before the models are widely applied. Although the models appear to fit many com-
pounds well, there is an important subset of compounds where the fit is poor, however.
The document needs to clearly state the limitations of the models. Additional data
should be sought to both expand and strengthen the models. The Committee also feels
that it is important to have the model validation and estimation efforts undergo a
rigorous statistical analysis. Full validation of the model will require also the input of
toxicologists with expertise in skin absorption and metabolism and analytical chemists,
in order to deal with the important issues of metabolic activation\detoxification by the
skin itself.
Finally, although a model to estimate the dermally absorbed dose per-event is
useful, it would be best if the model could use measured, rather than predicted, dermal
permeability values when possible. When measured absorption data of good quality
are available, they should have precedence over model estimates.
KEYWORDS: cutaneous exposure; dermal exposure; dermal absorption; dermal
# adsorption; dermal permeability; skin absorption; skin models.
i
*

-------
NOTICE
This report has been written as a part of the activities of the Science Advisory
Board, a public advisory group providing extramural scientific information and advice to
the Administrator and other officials of the Environmental Protection Agency. The
Board is structured to provide balanced, expert assessment of scientific matters related
to problems facing the Agency. This report has not been reviewed for approval by the
Agency and, hence, the contents of this report do not necessarily represent the views
and policies of the Environmental Protection Agency, nor of other agfencies in the
Executive Branch of the Federal government, nor does mention of trade names or
commercial products constitute a recommendation for use.

-------
U.S. ENVIRONMENTAL PROTECTION AGENCY
SCIENCE ADVISORY BOARD
ENVIRONMENTAL HEALTH COMMITTEE
Dermal Exposure Assessment Review
August 17-18, 1992
CHAIR f Acting?
Dr. Gary P. Carlson, School of Pharmacy, Purdue University, Bloomington, IN.
MEMBERS ANP CONSULTANTS
Dr. William B. Bunn, Mobil Oil Corporation, Princeton, NJ
Mr. Kurt Enslein, Health Design, Rochester, NY
Dr. David Gaylor, National Center for Toxicological Research, Jefferson, AR
Dr. Rogene F. Henderson, Inhalation Toxicology Research Institute, Albuquerque, NM
Dr. Nancy K. Kim, New York Department of Health, Albany, NY
Dr. Martha Radike, Dept. of Environmental Health, Univ. of Cincinnati, Cincinnati, OH
Dr. Marshall Steinberg, Health and Environment, Hercules Incorporated, Wilmington, DE
Dr. Bernard Weiss, Univ. of Rochester School of Medicine and Dentistry, Rochester, NY
Dr. Ronald Wyzga, Electric Power Research Institute, Palo Alto, CA
DESIGNATED FEDERAL OFFICIAL
Mr. Samuel Rondberg, Executive Secretary, Environmental Health Committee, Science
Advisory Board (A101F), U.S. Environmental Protection Agency, Washington, D.C. 20460 (202)
260-6552
STAFF SECRETARY
Ms. Mary L. Winston, Environmental Protection Agency, Science Advisory Board, A101-F),
»Washington, D.C. 20460 (202) 260-6552
ASSISTANT STAFF DIRECTOR
Mr, Robert Flaak, Science Advisory Board, U.S. Environmental Protection Agency
STAFF DIRECTOR
Dr. Donald G. Barnes, Science Advisory Board, U.S. Environmental Protection Agency
iit

-------
TABLE OF CONTENTS
1.	EXECUTIVE SUMMARY 								1
2.	INTRODUCTION			.....	3
2.1	Background								3
2.2	Charge 			3
3.	DETAILED FINDINGS 									6
3.1	Skirt Composition and Dermal Absorption Processes	i		6
3.2	Skin Models for Evaluation of the Dermal Absorbed Dose .		8
3.3	Applicability of Measured Absorption Constants 				11
4.	CONCLUSIONS		 								16
5.	REFERENCES						 .	18
*
iv

-------
1. EXECUTIVE SUMMARY
The Environmental Health Committee met in Washington, DC on August 17-18,
1992 to review the draft report Dermal Exposure Assessment: Principles and Applica-
tions (EPA/600/8-91/011B> January 1992), prepared by the Office of Health and
Environmental Assessment of EPA's Office of Research and Development, The
Committee was asked to address the scientific underpinnings of the general guidance
on dermal exposure assessment1 provided in the review document, as well as to
consider specific issues relating to (a) skin composition and dermal absorption pro-
cesses; (b) skin models for evaluation of dermal absorbed dose; and (c) the applicability
of measured absorption constants for chemicals in air, water, and soil.
The Committee found the draft dermal exposure assessment document to be
one of the better documents presented for review, and commends the Agency on the
document's quality and general rigor. There are areas, however, in which improve-
ments can still be made.
The document should state more clearly when experimental data, rather than
¦values estimated from models, should be used. It is also unclear whether there is
preference for in vitro or in vivo data. The Committee finds that in vivo data are more
realistic although they may be more difficult to derive and less likely to survive quality
assurance scrutiny. It is the opinion of the Committee that, in general, more weight
should be given to experimentally-derived values than to those estimated from models.
There are exceptions, however, and the document's weight-of-evidence table (if it was
revised to serve this purpose) could be a valuable aid in making the decision to accept
or reject experimental values .
The Committee would like to see further examination of model performance
' before the models are widely applied. Although the models appear to fit many com-
pounds well, there is an important subset of compounds where the fit is poor, however,
and the report glosses over the differences between expected and estimated values too
readily. The document needs to clearly state the limitations of the models. Additional
data should be sought to both expand and strengthen the models. The Committee also
* Th# term "Dermal Exposure* in used by EPA to describe any Contact with the skin by any medium containing
chemicals, and quantified as the amount on the skin and available for adsorption and possible absorption. Although the use of
"cutaneous exposure" and "dermal exposure" and/or "dermal absorption" might be somewhat more precise, this report follows
Agency practice in using the broader meaning.
1
%

-------
feels that it is important to have the model validation and estimation efforts undergo a
rigorous statistical analysis. Full validation of the model will require also the input of
toxicologists with expertise in skin absorption and metabolism and analytical chemists,
in order to deal with the important issues of metabolic activation\detoxification by the
skin itself.
Finally, although a model to estimate the dermally absorbed dose per-event is
¦ useful, it would be best if the model could use measured, rather than predicted, dermal
permeability values when possible. When measured data of good quality are available,
they should have precedence over model estimates.
2
¥

-------
2. INTRODUCTION
2.1	Background
EPA is faced with many situations in which humans are exposed to toxicants
through skin contact with air, water, or soil. Exposure assessors dealing with contami-
nated waste sites in particular face a difficult task in dealing with exposures through one
or all of media noted above. To provide these assessors with an understanding of the
principles of dermal exposure assessment and the procedures for applying these
principles to human situations, the EPA's Office of Research and Development develop-
ed a draft document {Dermal Exposure Assessment: Principles and Applications) which
summarized the current state of knowledge on dermal exposure to air, water, and soil;
presented methods and models for estimating dermal absorption resulting from contact
via these media; summarized available chemical specific experimental data describing
dermal absorption properties; and established procedures for evaluating experimental
data for application to exposure assessments.
2.2	Charge
The Environmental Health Committee was asked to assess the general validity of
the information in the review document, and the way in which that information is applied
to dermal exposure assessment Additionally, the Committee was asked to consider
the following more specific issues;
a) Skin composition vs. dermal absorption processes (Chapters 2,3}
In the draft document, the two layers of the skin which are considered to be the
main barriers to absorption are the stratum eomeum and the viable epidermis. The
"stratum corneum is composed of hydrophilic and lipophilic pathways. On the other
hand, the viable epidermis acts as if it was a thickened watery medium; Diffusion
through this living strata is thought to be roughly one-tenth as facile as in bulk water.
For lipophilic molecules, the stratum corneum could act as a reservoir, and therefore
the viable epidermis presents a hydrophilic barrier to these molecules. These assump-
tions provide the basis for the approaches presented in the document. The Committee
is asked to comment oh these assumptions.

-------
b) Skin model for evaluation of derma! absorbed dose (Chapters 4, 5, 6, 7)
The classical steady-state model based on Fick's first law was applied to
inorganics in water and all chemicals from air (Chapters 4, 5, 7). This model assumes
that the stratum comeum provides the limiting barrier to dermal absorption, and that
steady-state absorption is established at the onset of exposure and remains constant
during the entire exposure period (Chapter 4). For chemicals from soil, the mass
absorbed is a function of the soil concentration, the adherence factor, and the absorp-
tion fraction (Chapter 6, Equation 6.18), Please comment on these approaches. The
Committee is asked to comment on these assumptions.
For organics in water (Chapter 4, 5), the stratum corneum could act as a
reservoir, and the viable epidermis could act as the limiting barrier to absorption. A
two-compartment model was recommended (Cleek and Bunge, 1992) (Chapter 4,
Equations 4.35-4.48), which accounted for the contribution of these pathways in dermal
absorption of organic molecules as a function of the physicochemical properties of
these molecules (molecular weight and oil/water partition coefficient) and duration of
exposure (which measures the reservoir effect - lag time - of the stratum corneum). For
this model, estimation of the lag time is required. This lag time is defined in terms of
the diffusion coefficient and the thickness of the barrier membrane (Chapter 5, Equation
5.14). The latter can be estimated from experimental measurements, and the former
can be obtained from a correlation predicting permeability coefficients as a function of
molecular weight and oil/water partition coefficient (Chapter 5, Equations 5.11, 5.13).
This correlation is theoretically derived, and the coefficients of the dependent variables
are empirically determined from experimental data of permeability constants of organic
chemicals in water measured from in vitro absorption studies through human skin
(Chapter 5, Equation 5,11), Unlike the steady-state approach used for other situations,
experimental data for permeability coefficients of organics in water are not used directly
• in the estimation of the absorbed dose; instead new data on permeability coefficients
can be used to Improve upon the correlation. This approach provides a more conserva-
tive estimate of dermal absorption of organic chemicals than the steady-state assump-
tion, and accounts for the length of exposure as compared to the lag time of the
chemicals in the skin.
In light of the current information, is the steady-state assumption adequate for
inorganics in water and in air? Is the 2-compartment model appropriate for organics in

-------
water, arid is it necessary to extend this model to organics in air? Should we attempt to
develop a comparable model for soil absorption?
c) Applicability of measured absorption constants
For all chemicals In water (Chapter 5), a scoring system (Chapter 5, Table 5-1)
was developed to assess the applicability of the experimental data to actual exposure
scenarios. For inorganics in water, based on the observation that no measured
permeability coefficient exceeds 10'3 cm/hr (Chapter 5, Table 5-3), a conservative
default value of 10'3 cm/hr was adopted for all inorganics in water for which no experi-
mental data exist (from the expert panel in the April, 1991 EPA Peer Review Work-
shop). For organics, a correlation was used to predict permeability coefficient as a
function of molecular weight and log (Chapter 5, Equation 5,8). Please comment
on the scoring system for the experimental data, and the choice of the default value for
inorganics as well as the correlation for organics.
For all chemicals in air (Chapter 7), some experimental data are available, and a
regression equation is presented which correlates the permeability coefficient to fat/air
partition coefficients for organic molecules from data in rats (Chapter 7, Equation 7,2),
How much more work should be put in this area?
For all chemicals in soil (Chapter 6), useful experimental data of absorption con-
stants exist for only three chemicals (Chapter 6, Table 6-3). Several approaches are
discussed for estimating the values for other chemicals, but no recommendation was
selected. Please evaluate these approaches in terms of their potential usefulness in
addressing actual exposure scenarios, and if possible rank them on their order of
priority for further development. Since the absorption fraction is actually dependent on
the applied dose as well as exposure time, there has also been discussion about
"developing a permeability coefficient-based model to evaluate the absorbed dose.
Please comment on this possibility and on the pros and cons of the various approach-
es.
§

-------
3. DETAILED FINDINGS
3.1 Skin Composition and Dermal Absorption Processes
Certain specific assumptions about the skin's functioning as a barrier between
the environment and the body's internal biochemistry provide the basis for the ap-
proaches presented in the draft document under review. The two layers of the skin {the
stratum corneum and the viable epidermis) are considered to be the main barriers to.
absorption. It is posited that the stratum comeum provides hydrophilic and lipophilic
pathways, but the viable epidermis acts as if it was a thickened watery medium, with
diffusion through this living strata estimated to be roughly one-tenth as facile as in bulk
water. For lipophilic molecules* the stratum corneum could act as a reservoir, and
therefore the viable epidermis would present a hydrophilic barrier to these molecules.
The validity of this assumption is the first issue presented in the Charge to the Commit-
tee.
*
The Committee agrees that the stratum corneum provides both hydrophilic and
lipophilic pathways for entry of toxicants into the viable epidermis. The stratum
corneum is an effective barrier for large polar compounds but is an ineffective barrier for
non-polar compounds which are metabolized in the avascular viable epidermis.
Polycyclic aromatic hydrocarbons (PAHs) and N-heterocyelic hydrocarbons are exam-
ples of such compounds, and it is well established that there is aryl hydrocarbon
hydroxylase (AHH) activity in the viable epidermis. If the viable epidermis has the
necessary P-450 enzymes to oxidize non-polar compounds to more polar.metabolites,
the absorption from the stratum corneum will be increased. When a one-^mole dose of
dibenz (c,g) carbazole (DBC) was applied to the shaved skin of female ICR Mice, 97%
entered the systemic circulation in 12 hours (John Meier, unpublished data). The
metabolites and the parent compound both appear in the blood stream. For com-
pounds metabolized in the skin, the Committee therefore suggests that the viable
epidermis does not necessarily present a hydrophilic barrier. This finding is really part
of a larger concern of the Committee on the importance of considering metabolic activa-
tion\detoxification by the skin itself.
There are many confounding factors which complicate attempts to assess the
skin's functioning as semi-permeable barrier. Research has shown that:

-------
a.	an increase in temperature, in vitro, increased uptake and decreased
evaporation - high humidity increased the penetration of water soluble
compounds but had no effect on lipophilic compounds (Hawkins and
Reifenrath, 1984)
b.	at a pH of 5.4 the uptake of zinc oxide (in vitro) was about 21 times
greater than at pH 7.4 (Agren, 1990)
c.	some studies use solvents (hexane in this case) which only extract the
parent compound from tissues - the metabolites and conjugated moieties
also represent the parent compound crossing the epidermis (Shu et al.,
1988)
d.	lipophilic compounds are stored in fatty tissues, thus affecting measured
blood levels
e.	increased activity such as exercise/work will Increase blood flow and
increase absorption of toxicants - most of the in vivo data are from studies
performed on animals in the resting state (restricted movement, occluded,
anesthetized).
For the reasons listed above, validation of the model will require a joint effort,
and the Committee recommends that toxicologists with expertise in skin absorption and
metabolism and an analytical chemist select the studies.
The lack of data regarding how the model will handle mixtures is an important
omission. The Committee realizes, however, that the EPA is aware of, and attempting
to deal with, the thorny issue of exposure to complex mixtures in a much broader
context. Revisions of the draft document should include a statement that the model
does not deal with the absorption of complex mixtures. Such a caveat will have to
suffice until such time as the state-of-the-art advances. The Committee also noted, in
passing, that the document does not deal explicitly with the immunological functions of
the skin.

-------
3.2 Skirt Models for Evaluation of the Derma! Absorbed Dose
The approach proposed by EPA is based on a classical steady-state model
which assumes that the stratum comeum provides the limiting barrier to dermal
absorption, and that steady-state absorption is established at the onset of exposure and
remains constant during the entire exposure period. For soil-borne chemicals, the
mass absorbed is assumed to be a function of the agent's concentration, the adherence
factor, and the absorption fraction. For agents in water, a two-step model is proposed
(see discussion below).
There are two major issues to be addressed, in addition to providing guidance for
the calculation of dermal exposure. First, the document should clearly identify the data
gaps and types of data needed to confirm and refine the equations. Second, although
the exposure determination process, the document should encourage development of
indicated data for the purpose of improving the model.
In each analysis It should be acknowledged that the ultimate objective is not only
a simple model but a model that accurately predicts human exposures. Therefore
efforts to assure that in vitro/in vivo correlations are strong for the environmental
contaminants in the instant exposure scenario are of paramount importance.
In recognition of the limited human data available on only a relatively small
number of environmental agents, the exposure evaluation must recognize and utilize
well conducted studies of the compounds of specific interest, in preference to model-
derived calculations. If data are not available in the literature or are not generated by
the potentially regulated industry, then the model must be invoked, using 100%
absorption as a default position. Although the complexities of these studies (particularly
human in vivo studies) are numerous, they should provide a more accurate exposure
~ assessment and will simultaneously generate data for refinement of the current model
(which is based primarily on in vitro data) by expansion by the number of in vitro tests
and utilization of in vivo test systems.
With regard to the utilization of the two step model and its possible extension
beyond the organics in water exposure route, there are both theoretical and practical
considerations. First, efforts should be made to confirm the applicability of the model to
the data available.
I

-------
Examining the data provided in Table 5.4 of the draft document, a simple
cross-tabulation of log Kow (partition coefficient between octanol and water) values vs.
molecular weight (MW) shows that two chemicals, i.e., digitoxin and sucrose, are dear
outliers, and should not be used in the predictive model, as they would unduly influence
the characteristics of the model, and give a false impression of the range of its applica-
bility. It is not clear as to why these two very different substances are outliers, and a
further examination of the data might be of value in furthering out understanding of the
underlying processes involved.
The regression equation estimating Kp (the permeability coefficient), recalculated
on the basis of the remaining 91 chemicals, is:
log Kp = -2.75 + 0.776 log - 0.00677 MW
The resulting adjusted R2 (coefficient of determination, a measure of the percent
of total variance accounted for by the predictive estimators) for this equation is 0.67,
i.e., not materially different from that of equation 5.8.
The contribution of each of the variables to the R2 is about equal. A plot of the
residuals shows that there is considerable correlation between the residuals and log Kp.
This indicates that there is at least one missing explanatory variable which, if it (they)
was (were) included in the equation, would materially improve the explanatory power,
and therefore predictive power, of the equation. This is another way of saying that the
fact that the R2 is not nearer unity is not only due to the noise in the data but to a
clearly identifiable extent, the incompleteness of the model.
Three other compounds appear to be outliers; ethyl benzene, styrene and
toluene. However, their removal from the equation does not significantly affect its
^ performance.
An examination of the correlation between log and MW (after removing the
outlier compounds sucrose and digitoxin discussed earlier) shows it to be 0.44. While it
is not possible (within the scope of this review) to precisely define the extent to which
this correlation limits the applicability of the equation, at the very least it can only be
used within the boundaries of a polygon with the following (log K^,, MW) limits; (-1.4,
30), (1.8, 520), (5.3, 480), (3.5, 100). All other regions of the space are forbidden. For
example, it would not be allowable to apply the equation to a compound for which log
9

-------
Kow = -1.0 and MW - 300. There is little point in determining the exact limits at this
time,2 as the equation needs to be refined through the inclusion of additional parame-
ters, as discussed below, before that endeavor is worthwhile.
It is difficult, however, to make serious suggestions as to what the additional
parameters may be without knowing a great deal more about the sources of the data in
Fiynn's 1990 collection. Perhaps indicator variables identifying the sources and/or
types of data could be considered. Because of the substantial residual correlation it is
more likely that one or more additional physicochemical parameters) may be indicated.
One may want to consider aspect ratio, i.e., some function of area and volume in place
of molecular weight. In the absence of a mechanism-derived parameter one could also
consider molecular connectivity or kappa indices. The Committee is reasonably confi-
dent that some parameter can be found to improve the fit of the equation.
Quite separately from the equation itself, one wonders whether there are not
more data in the literature than the 97 data points in the Flynn paper. The Committee
recommends strongly that, before any predictive equation is published, the literature be
thoroughly searched to identify any further experimental K,, values. Even an additional
20 data points would be worthwhile, particularly if some of the additional points provide
data outside of the polygon specified above.
The Committee is also concerned that the physio-chemical model does not take
into account metals or ionic compounds, substances of obvious concern In environmen-
tal toxicology .
As noted above, a special consideration is that the bioavailability of the com-
pound from the soil should be verified and quantified before the dose to the skin is
estimated. The section on vapor/skin exposure and the models to be used in that
situation offer a similar issue in that there may be no environmental exposure situation
(excluding occupational where respiratory protection may be used and other principles
and documentation may apply) where the vapor/skin exposure route would be determi-
native for exposure/risk assessment or would be a major contributor to risk assessment.
If not, then it may not be necessary to calculate exposure and a default or afe minimis
assumption may be used rather than attempting to define exposure from limited data.
2The procedure for determining exact limit# to described in Mandal, 1985.
10

-------
(Further detail will be provided in the sections on the specific areas of water, soil, and
vapor exposures.)
There are several additional issues which indirectly impact the questions posed
and the document. In addition to the previously discussed issues the text (perhaps in a
concluding section) should clarify the logic for using different models in different (e.g.,
water, soil) exposure situations, since the draft is to be a guidance document. Also, the
issue of different exposure assessments for children should be discussed, as weil as
situations in which the skin may not be intact.
The Committee recommends an opening summary or introduction clearly stating
the limitations of the data and consequent restriction of the utilization of the models to
be proposed. This revision would make the document easier to read. As the document
is now organized, the reader becomes aware of the limitations only after wading
through a great deal of complex material. In addition in the initial section and in the
document the preference for measured data should be stated. More recognition should
be given to human exposure as the ultimate target and the in vitro/in vivo correlations
that lead to that result.
Given these additions and revisions, including the caveats about limitations of
the model, the Committee believes the document to be informative and useful. It is
appropriate to use the non-steady state, two step model for organics in water and to
use the steady state models for soil and vapor. When better data are available the two
step model may then be appropriate for all chemical exposure assessments.
3.3 Applicability of Measured Absorption Constants
Chapter 6 of the dermal exposure assessment guide discusses several ap-
proaches for estimating absorption values for soil-borne chemicals, but no recommen-
dation is offered. The Committee was asked to evaluate these approaches re their
potential usefulness in addressing actual exposure scenarios.
Exposure to contaminants via exposure to soil presents a much more complex
evaluation problem than the other two exposure vehicles considered. As noted earlier
in this report, not only would mixtures present a more difficult problem, but the matrix
itseif is certain to present the dominant variable. This is certainly proving to be the
case when considering the absorption of TCDD (tetracholorodibenznyl-p-dioxin) and lead.
11

-------
Especially for soil, simple in vitro models seem rather remote from exposure
assessment aims. Fick's law, often used to introduce dermal toxicology, represents an
approximation to an approximation to an approximation. As embodied in equation 6.2
and following, it does not seem to be very useful as a guide. A defect, not due to the
document but to the way research is typically conducted, is that only pieces of such
models are investigated. For clarity in the document, incidentally, the components of
equation 6.2 {and others) should be more clearly described.
Perhaps the most important lack in this section is the kind of information
indicating how soil matrix influences exposure. It would appear that the assumption
was made that all materials found in the environment in soil or other media were readily
available for skin penetration. Studies performed on materials of concern, such as
dioxin and lead, indicate that there are significant differences in bioavailability de-
pending upon soil types. In addition to these studies, there are vast amounts of data
on human exposure and subsequent absorption available from industrial and military
sources, a supposition supported by comments at the Committee's meeting. For
example, controlled studies with pesticides have been conducted on humans. These .
pesticides (malathion, lindane, and a carbamate (Abate)) were mixed with pyrax
powder.3 Cholinesterase levels in the blood were measured, and with the exception of
one of the materials, there were no indications of skin penetration even when the
materials were applied over a 28-day period (Steinberg et al,, 1971, 1972). While these
studies lack the elegance of studies being conducted twenty years later, had the two
ounces of 1-2% pesticide powder applied to the total body surface and to the clothing of
the individuals, penetrated the skin as described by the model, there would most
certainly been a decrease in blood cholinesterase. Although the Committee realizes
that such matrix effects complicate the model considerably, they are important from the
standpoint of "real-life exposure" situations.
The Committee recommends that the Office of Research and Development's
' Exposure Assessment Group explore the availability of such data, some of which
apparently are available in the open literature, and some of which are available in EPA
files without conflicting with proprietary interests. Risk management initiatives will be
based on dermal availability if this is a critical mode of exposure.
'Pyrax is a clay used for several purposes including the production of powders.
12

-------
For chemicals in air (Chapter 7), some experimental data are available, and 3
regression equation is presented which correlates the permeability coefficient to fat/air
partition coefficients for organic molecules from data in rats (Equation 7,2). The Agency
is seeking guidance on how much more work should be committed to this area.
In general, this chapter is clearly written although some of the introductory
material is redundant with that in earlier chapters. It provides valuable equations for the
person who is working in the field and needs to calculate vapor pressure or to convert
ppm to mg/m3. The decision tree shown in Figure 7-1 is particularly useful.
The heart of the chapter is the regression equation for predicting the dermal
permeability coefficient of chemical vapors based on a model developed by McDougal
et al. (1990). Such models can be quite useful in predicting the activities of chemicals
in the absence of experimental knowledge on a particular compound. However, the
limitations of the model must be recognized and discussed more explicitly.
The only limits to the model discussed in Chapter 7 are that compounds with
unknown permeability coefficients must have fat/air partition coefficients within the
range of the compounds from which the model was derived. Obviously, such a model
is also limited, by the number and type of vapors used to derive the model. Only eight
vapors were studied. As with chemicals in other physical states, discussed elsewhere,
one would expect that factors other than the fat/air partition coefficient would influence
permeability, such as metabolism of the compound or the ability of the vapor to damage
the skin barrier, particularly those chemicals which may remove lipid. Such limitations
should be discussed. In answer to the question posed in the charge, additional work
should be done to determine if the model is valid for a more extensive list of vapors and
to determine what properties of chemicals influence the fit to the model. It is important
to know not only what chemicals do not fit the model but why they don't fit so that the
# model can evolve and be improved. In fad, the simple correlation presented looks so
useful, it is imperative to determine whether the correlation is that simple or is a result
of the particular data set used. Chemicals that are known to be metabolized in the skin
and chemicals that damage the skin should be included in the studies.
The Committee also believes that additional data are available dealing with
absorbed doses of gases and vapors, A great many studies have been done in
humans by the military. While some of the data are not readily available, other results
13
*

-------
do appear in the published literature. Such data, while perhaps limited in the number of
chemicals examined, could be very useful in testing the validity of the model.
Chapter 7 also extends discussions of dermal exposure of vapors into the risk
assessment process. In the Committee's view, this seems out of line with the scope of
the rest of the document and is not necessary.
An example using n-hexane vapor in a risk characterization is given. The
maximum achievable concentration is calculated based on the vapor pressure of
n-hexane. This is a* valuable calculation for eliminating any compounds that have vapor
pressures too low to present any hazard from vapor absorption. However, in the
example given, the authors appear to use this calculation of maximum achievable
concentration as an example of a vapor exposure to n-hexane, 6 hr/day for 5
days/week. It would be hard to imagine when a person might be exposed to such a
high vapor concentration of hexane (610 g/m3) and if they were, they would not last 6
hours before death due to central nervous system effects. This example needs to be
rewritten using a reasonable, environmentally relevant, vapor concentration for n-hex-
ane.
Four different values for the dermal permeability coefficient of benzene are given
in Chapter 7 (all within an order of magnitude). Some discussion of the possible
reasons for the variability should be given. The user of the document will need
guidance for choosing among them. For risk assessments, such a range of values is
not so bad and perhaps that should be stated.
The document proposes (page 7-26), that the irritant properties of a chemical
toward the skin can be estimated from the irritant properties of the same chemicals
toward the respiratory tract. The Committee recommends caution in making such
(estimations, because the properties of the epithelium lining the respiratory tract are
quite different from the skin. Respiratory tract irritants should be considered as possible
skin irritants, but the concentration causing the irritancy is likely to be quite different for
the two sites.
The document also states ( page 7-4) that the partition coefficient between the
skin and blood is the "best" partition coefficient parameter. It is not at all clear what the
authors mean by "best." Both the partition coefficient between the air and the skin and

-------
the partition coefficient between the skin and the blood are important for consideration
of potential exposure. The Committee recommends deletion of the sentence.

-------
4. CONCLUSIONS
The Committee commends the Agency {and the staff Involved) on the quality and
general rigor of the draft dermal exposure assessment document; it is our consensus
that this is one of the better documents presented for our review. This praise not
withstanding, the Committee has identified areas in which improvements can still be
made.
The document does not clearly state when experimental data are to be used and
when values estimated from models are to be used. A decision tree flow chart or some
other tool might be helpful in articulating guidance here. In general, more weight should
be given to experimentally-derived values than to those estimated from models. There
are exceptions, however, and here the weight-of-evidence table could be used in the
decision to accept or reject experimental values. The current weight-of-evidence criteria
are not sufficient and need to be revised for this purpose. Data quality is an important
issue here, and it is not covered comprehensively in the current scoring system. Some
of the second order criteria (e.g., number of animals, chemical concentrations) might be
as important as the first order criteria for this purpose. The document is unclear
whether there is preference for in vitro or in vivo data; superficially the current scoring
system provides no guidance, and the text appears to prefer in vivo data. Some verbal
comments of EPA participants at the review seemed to suggest that in vitro data are
preferred; the Committee finds that in vivo data are more realistic although they may be
more difficult to derive and less likely to survive quality assurance scrutiny.
The Committee would like to see further examination of model performance
before the models are widely applied. The models appear to fit many compounds well;
however, as indicated in detail above, there is an important subset of compounds where
the fit is poor. More discussion and analysis of the types of compounds where the fit is
• poor are needed. The current report glosses over the differences between expected
and estimated values too readily, and it was not comforting to hear at the meeting that
some of the predictions were poor because they were compared with in vivo rather than
in vitro data. Good quality data of the former type are of greater concern, and if the
models predict the latter rather than the former, the models must undergo further
development The Committee also feels that it is important to have the model valida-
tion and estimation efforts undergo a rigorous statistical analysis. Full validation of the
model will require also the input of toxicologists with expertise in skin absorption and

-------
metabolism and analytical chemists, in order to deal with the important issues of
metabolic activation\detoxification by the skin itself.
It clearly is useful to have a model to estimate the dermally absorbed dose per
event. The same model concerns addressed above are also relevant here. In addition,
the availability of a model that could use measured, rather than predicted, dermal
permeability values would be very useful. When measured data of good quality are
available, they should have precedence over model estimates.
17

-------
5. REFERENCES
Agren, M.S., 1990. Percutaneous absorption of zinc from zinc oxide applied topically to
intact skin in man. Dermatologica, 180(1):36-39.
Cleek, R,L. and A.L. Bunge. (1992) A new method for estimating dermal absorption
from chemical exposures. Submitted.
EPA (U.S. EPA) 1991. Peer Review Workshop, Herndon VA. Unpublished notes.
Flynn, G.L. 1990. Physicochemlcal determinants of skin absorption. In: Gerity, T.R.;
Henry, C.J. eds. Principles of route-to-route extrapolation for risk assessment
Amsterdam: Elsevier Science Publishing Co. Inc:93-127.
Hawkins, G.S. and W.G. Reifenrath. 1984. Development of an in vitro model for deter-
mining the fate of chemicals applied to the skin. Fundam. Appl. Toxicol., Apr. 4
(2, pi 2):S133-S144.
McDougal, J.N., Jepson, G.W., Cieweil, H.J., Gargas, M.L. and M.E. Anderson. 1990,
Dermal absorption of organic chemical vapors in rats and humans. Fundam,
Appl. Toxicol. 14:229-308.
Mandel, J. 1985. The regression analysis of collinear data. Journal of Research of the
National Bureau of Standards. 90:465-478.
Meier, J, unpublished dissertation research at the University of Cincinnati, cited by M.
Radike.
Shu, H., Teitelbaum, P., Webb, A.S., Marple. L„ et al. 1988, Bioavailability of soil-
bound TCDD; dermal availability in the rat. Fundam Appl. Toxicol., Feb.
10(2):336-343.
Steinberg, M., Cole, M., Miller, T.A., and R.A. Goclke, 1971. Toxicological and entomo-
* logical field evaluation of Mobam and Abate powders used as body louse toxi-
cants. J. Med. Entomol. 2(1):73-77.
Steinberg, M., Cole, M.M., Evans, E.S., Whitlaw, J.T., and J.J. Yoon, 1971. Toxicologi-
cal and entomological field evaluation of the effects of Mobam powder against
body lice (Anoplura: Pediculidae). J. Med. Entomol. (1):68-72.
16

-------
I

-------