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Session 4:
Dermal Bioavailability
Research Need for Dermal Absorption Methods of Chemically Contaminated Soils
Michael Dellarco, US
EPA,Washington DC
Effect
of Soil Loading and Soil Sequestration on Dermal
Bioavailability of Polynuclear Aromatic Hydrocarbons
Timothy A. Roy,
Petrotec Inc., Paulsboro, NJ
Comparison
of the Dermal Bioavailability of Polyaromatic Hydrocarbons
in Soil
Mohamed S.
Abdel-Rahman, University of Medicine and Dentistry of New
Jersey, Newark, NJ
Methodological Issues in Assessing Dermal Absorption of
Chemicals
Rosalind A. Schoof,
Gradient Corporation, Mercer Island, WA
Validation
for In Vitro Percutaneous Absorption of Chemicals from
Soil
Ronald C. Wester,
Univeristy of California, San Francisco, CA
Modeling
the Effects of PAH Sorption onto Soil on Estimates of
Dermal Bioavailability
Jo Anne Shatkin,
Menzie-Cura & Associates, Inc., Chelmsford, MA
Use of In Vivo and In Vitro Dermal Bioavailability
Research in the State of California to Establish Risk
Assessment Guidance for Regulatory Purposes
Stephen M. DiZio,
California Department of Toxic Substances Control,
Sacramento, CA
Research
Needs for Dermal Absorption Methods of Chemically
Contaminated Soils
Michael Dellarco, Dr. PH,
U.S. Environmental Protection Agency
Dermal contact with
chemically contaminated soil may be an important route of
exposure, especially in Superfund investigations and
pesticide reviews under the Food Quality and Protection
Act.. Soil can be contaminated directly as a result of
chemical applications and spills or indirectly as a result
of surface water runoff or erosion. Individuals may be
exposed by playing or working in contaminated dirt. To
improve dermal exposure assessments, information is needed
about the nature of activities where soil contact occurs
and about dermal absorption of chemicals in a soil matrix.
However, few such studies exist. EPA guidance recommends
experimentally derived values of percutaneous absorption
from soil for only nine chemicals. Investigations
sponsored by EPA in the1990s has led to the realization
that development of predictive models will require
additional research in several areas. Research is needed
to: estimate soil loading on skin, identify chemical and
physical properties of soil that affect chemical movement
from soil to skin and develop dermal absorption of test
methods. Additional work will be required to standardize
dermal absorption test procedures and validate their
applicability for chemicals of interest to the Agency and
the regulated community.
Effect
of Soil Loading and Soil Sequestration on Dermal
Bioavailability of Polynuclear Aromatic Compounds
Timothy A. Roy, Petrotec Inc.
Literature reports show that sorption of polynuclear
aromatic compounds (PAC) on soil can significantly impede
their penetration through skin. Studies conducted in our
laboratory with PAC-contaminated soils from industrial
sites show reductions in PAC dermal flux of 1-3 orders of
magnitude compared to neat PAC-containing contaminant.
Dermal flux values are used to calculate site-specific
dermally absorbed dose (DAD) values for estimating human
risk. Two criticisms of the in vitro procedure used
in previous studies are 1) the "infinite dose"
soil loading used (10 mg/cm2 ) is well above
what some consider the actual soil adherence factor (AF)
of 0.2 mg/cm2 and, 2) the procedure does not
account for the effect of contaminant aging or soil
sequestration phenomena. To address these concerns, in
vitro experiments were carried out using human skin
and PAC-spiked soil at 10, 5, 2.5 and 1 mg/cm2
to evaluate the effect of soil loading on dermal flux and
percent of dose absorbed (PADA). Dermal experiments were
conducted with freshly spiked (PAC) soil (day 1) and with
aliquots of the same soil following 45 and 110 days of
laboratory aging. Results from the soil loading study show
that flux is not affected by loading above "monolayer"
(~3 mg/cm2) coverage and that flux decreases in
proportion to soil loading below monolayer coverage.
Further, the results show that PADA decreases
proportionately with increased soil loading above
monolayer and remains constant at sub-monolayer coverage.
Results from the soil sequestration study show a 50%
reduction in BaP dermal bioavailability following 110 days
of aging.
Comparison
of the Dermal Bioavailability of Polyaromatic Hydrocarbons
in Soil
Mohamed S. Abdel-Rahman, University of Medicine and
Dentistry of New Jersey/New Jersey Medical School
Gloria
A. Skowronski, University of Medicine and Dentistry of New
Jersey/New Jersey Medical School
Rita M. Turkall,
University of Medicine and Dentistry of New Jersey/New
Jersey Medical School and School of Health Related
Professions
Chemical bioavailability from soil and the associated
potential health risks will depend on a number of factors
including soil characteristics, chemical aging in soil,
and compound properties. This study compared the effects
of two soils (sandy and clay) and chemical time in soil on
the dermal bioavailability of naphthalene (NAP),
phenanthrene (PHEN), and benzo(a)pyrene (BaP). In vitro
flow-through diffusion cell methodology measured the
amount of radioactive chemical which penetrated dermatomed
male pig skin into receptor fluid and which became bound
to skin (total penetration). Because of the volatile
nature of NAP, the total penetration of pure NAP was only
7% of the initial dose. In contrast, the dermal
bioavailabilities of PHEN and BaP were 65 and 76%,
respectively. When the polyaromatic hydrocarbons (PAHs)
were added immediately to soil, the decrease in total
penetration for the chemicals in the clay soil (24 - 95%)
versus the pure compounds was greater than in the sandy
soil (0 - 89%). Furthermore, the order of the decrease in
total penetration for the PAHs recently added to each soil
was BaP> PHEN> NAP. However, after aging in soil for
3 months, the highest additional decrease in total
penetration was observed for NAP (96 and 75%,
respectively, for sandy and clay soils) followed by PHEN
(23, 6%) and BaP (6, 3%). The data indicate that for newly
contaminated soil, surface adsorption predominated in the
clay soil as the number of polyaromatic rings increased.
However, after aging in soil, partitioning into soil was
more important in the sandy soil as PAH size decreased.
(Supported through funding from the Hazardous Substance
Management Research Center and the New Jersey Commission
on Science and Technology).
Methodological
Issues in Assessing Dermal Absorption of Chemicals from
Soil
Rosalind A. Schoof, Ph.D.,
DABT, Gradient Corporation
Studies of dermal
absorption of organic chemicals from soil have generally
been limited to studies in which the chemicals are mixed
with the soils and tested soon after mixing. Studies using
aged soils that would be representative of actual
exposures to chemicals in contaminated soils are very
limited. The ability to accurately measure dermal
absorption of chemicals from aged soils is limited by a
number of methodological issues. One primary difficulty is
the need to devise sensitive analytical approaches that do
not rely on radiolabeled chemicals. Since dermal
absorption is often quite low for chemicals in soil,
analytical sensitivity is a primary consideration in study
design. For chemicals present as mixtures in soil, and for
chemicals extensively metabolized after absorption,
selection of analytes is also important. PCB mixtures will
be used to illustrate these concerns in study design.
Dermal absorption has been shown to decrease with
increasing chlorination of PCB congeners, and the
pharmacokinetics also vary with degree of chlorination.
The PCB congener metabolic profile may also be variable.
Other study design issues will also be reviewed, including
testing the particle size fraction of soil most likely to
adhere to skin, selecting an appropriate soil loading
rate, and using a representative exposure period. Some of
these issues apply primarily to the design of in vivo
studies, but others are important considerations for in
vitro studies as well. The implications of these study
design issues for the development of in vitro study
protocols and alternate approaches such as the use of
biomarkers to assess dermal absorption will be evaluated.
Validation
for In Vitro Percutaneous Absorption of Chemicals from
Soil
Ronald C. Wester,
Ph.D., University of California, San Francisco
The basic premise must be that the in vitro system is a
substitute for the in vivo situation; therefore,
limitations and validation are of paramount importance.
The in vitro system should be continuous flow diffusion
cells made of glass or other non-porous material with
temperature control. Dermatoned human skin is the only
logical choice for study. Skin viability can be monitored
during study. Preferred receptor fluid is MEM-BSS with 5%
gentamycin. End point assay should include residual soil,
skin surface wash, skin content and receptor fluid, all
totaled to an acceptable mass balance.
The soil should be characterized as to organic, clay
and moisture contents, and particle size. Soil volume has
been variable. In the in vivo situation, there is soil
turnover. For example, planting 100 tomato plants, there
will be ~ 1 mg/cm2 soil on the hand with the
first plant and still only ~ 1 mg/cm2 soil 4
hours later with plant #100. It is the chemical in the
soil that is of interest, not the amount of soil.
The major limitation of the in vitro system is
solubility of diffusing chemical in the receptor fluid
and, somewhat, in the skin. Human skin is lipophilic on
the surface but progresses to hydrophilic where absorption
occurs (blood microcirculation in upper dermis). Moderate
to high lipophilic chemicals exhibit low in vitro
absorption due to solubility limitations, giving false
negative results.
In vivo human percutaneous absorption for validation
should be done using a non-occlusive cover to contain the
soil against the skin, or with a portion of the body such
as the hand immersed in the soil. Bioavailability is
determined from body fluids and/or exhaled breath.
Modeling
the Effects of PAH Sorption onto Soil on Estimates of
Dermal Bioavailability
Jo Anne Shatkin, Sean Kent, Menzie-Cura &
Associates, Inc., Mandeera Wagle, Malcolm Pirnie, and
Charles A. Menzie, Menzie-Cura & Associates, Inc.
Measurements of contaminant bioavailability in soil
have identified conditions that affect the rate and extent
of chemical desorption. Factors including length aging of
contaminant in soil, organic carbon/organic matter
effects, and moisture content all affect the rate of
chemical desorption. This work explores the use of a
fugacity model to evaluate the potential effects of the
decreased bioavailability of soil bound contaminants on
their potential uptake via the dermal pathway. Studies of
desorption of polycyclic aromatic hydrocarbons (PAHs) from
soil indicates a two phase pattern. A fraction of the
compound is rapidly released from soil, and another
fraction is slowly released. A computer simulation model
to estimate the fraction of PAHs uptake by human skin
based on fugacity estimation was developed and used to
evaluate the potential impact of the two stage desorption
kinetics on overall dermal bioavailability of PAHs in
soil. Validation of the model against in vivo and in vitro
measurements of PAH uptake from soil indicates it is
potentially useful for considering soil types and
amendments that may decrease the biological availability
of PAHs in aged soils.
Use
of In Vivo and In Vitro Dermal Bioavailability Research in
the State of California to Establish Risk Assessment
Guidance for Regulatory Purposes
Stephen M. DiZio, Ph.D., California Department of Toxic
Substances Control
Guidance issued by the State of California (The
Preliminary Endangerment assessment Guidance Manual,
Department of Toxic Substances Control, 1994) states the
following: "Dermal absorption values from soil are
based on, in order of preference: In vivo, animal studies
on dermal absorption from soil; animal studies on dermal
absorption from an applicable cosolvent; in vitro: human
skin dermal absorption studies, in vitro, animal skin
absorption studies". The Department has funded and
utilized the results from both in vivo dermal absorption
studies in non-human primates as well as in vitro studies
using human skin, for DDT, benzo(a)pyrene,
pentachlorophenol, cadmium, and arsenic. Dermal absorption
fractions derived using these studies are used in risk
assessments supporting regulatory decisions in California.
Examples will be provided of regulatory decisions based in
part on oral and dermal bioavailability studies conducted
by the Department of Toxic Substances Control or the
regulated community.
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