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Percutaneous AbsorptionPercutaneous Absorption Transdermal absorption/percutaneous

absorption Toxicants pass through the cell layers before

entering the small blood and lymph capillaries in the dermis

A complex event with many key factors relating to the physical, chemical, and biochemical constitution of the skin overlaid with the vast range of physicochemical behavior of the penetrant

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Pharmaceutical ResearchPharmaceutical Research

Local or systemic pharmacological response using dermally applied drugs

Current research is divided– restraint (slow release technology) and

– enhancement (occlusion, permeation enhancers)

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Occupational and Environmental Occupational and Environmental ExposuresExposures

Accidental or deliberate (chemical warfare)– commercial and home and garden pesticides

– polymer and paint chemicals

– detergents and cleaning chemicals

– a broad range of heavy industrial chemicals

– unscheduled exposures to environmental accidents and

– mishandling of toxic waste disposal

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Percutaneous AbsorptionPercutaneous Absorption Dermal absorption prevalent for any

compound, with the exemption of highly volatile chemicals

Research is directed towards understanding transdermal flux rates and the toxicological consequences of penetration

At the practical end, such data contribute to risk assessment

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Factors Affecting Percutaneous Absorption

Biological– skin age– skin condition– anatomical site– skin metabolism– circulatory effects

Physicochemical– hydration– drug-skin binding– temperature

Physical– drug concentration– surface area– exposure time– occlusion– vehicle

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Mechanisms of Percutaneous Absorption

Mechanisms by which chemicals cause visible effects on the skin differ from chemical to chemical– disruption of lipids and membranes

– protein denaturation

– keratolysis

– cytotoxicity

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Mechanisms of Percutaneous Absorption

The rate-determining barrier is Stratum Corneum (nonviable epidermis), which is densely packed keratinized cells (nuclei lost, biologically inactive)

SC contains 75-80% lipophilic materials– very little triglycerids (0%)

– cholesterol (27%)

– cholesterol esters (10%)

– various ceramides (41%; amides and/or esters of saturated and unsaturated fatty acids)

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The Steps Involved in Percutaneous Absorption

1. Partitioning2. Diffusion3. Partitioning4. Diffusion5. Capillary uptake

Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.

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The Putative Pathways of Penetration Across the Stratum Corneum

Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.

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Mechanisms of Percutaneous Absorption

Appendageal transport– a negligible contribution to the overall

percutaneous flux across human skin

– however, transport through the appendageal route has been shown to be significant during the initial (non-steady-state) period of percutaneous absorption

– remains controversial; question of the participation of the hair follicles in percutaneous absorption

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Mechanisms of Percutaneous Absorption

Permeation pathways– Polar (hydrophilic)

Path through corneocytes with their desmosomal connections

– Nonpolar (lipophilic) Agents dissolve in and diffuse through the lipid matrix

between the protein filaments Regional variations in skin permeability are

correlated with quantitative differences in lipid content rather than SC thickness or cell number

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Percutaneous Transport

Molecules traverse membranes either by– passive diffusion

solute flux is linearly dependent on the solute concentration gradient

– active transport typically involves a saturable mechanism

Percutaneous flux is directly proportional to the concentration gradient and, therefore, transport across the skin occurs primarily by passive diffusion

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Percutaneous Transport

At steady state, the flux due to passive diffusion may be described by Fick’s 1st law

J = kp a

J = flux of the permeant (moles/cm2s) kp = permeability coefficient of the permeant through the

membrane (cm/s) ∆a = activity gradient across the membrane (moles/cm3)

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Percutaneous Transport

kp is the inverse of the “resistance”, which the membrane offers to solute transport, and is defined by

kp = KD / h

K = membrane-aqueous phase partition coefficient of

the solute D = diffusion coefficient of the solute in the membrane

(cm2/s) h = diffusion path length through the membrane

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Percutaneous Transport

The flux rate is a rate process Rate = Driving Force / Resistance

Driving force for diffusion is the activity gradient (concentration gradient across the permeability barrier)

Molecular flux across the membrane can be determined by the solute’s size and lipophilicity if the driving force remains the same

Octanol/Water partition coefficient (Ko/w) has been chosen to be used as the index of lipophilicity

Example of Human Dermal Example of Human Dermal Exposure AssessmentExposure Assessment

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Tenax® tubes were used to measure evaporation

from arm

1.0 ml of jet fuel is applied at two sites

Surface area of exposure is 20 cm2

Exposure study was done inside a

fume-hood to prevent

inhalation exposure

Laboratory Human Volunteer StudyLaboratory Human Volunteer Study

Study PopulationStudy Population

5 male and 5 female adult volunteers Breathing-zone, dermal tape-strip, breath, urine,

and blood samples Exclusion criteria

– occupational exposure to PAH (e.g., auto mechanics)– cardiovascular disease– atopic dermatitis– smoking– use of prescription medication for illness– alcohol consumption during the study

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Fick’s Law of DiffusionFick’s Law of Diffusion

x0, C(x0)L1

L2 J = -D xC

x1, C(x1)

Permeability Coefficient Kp (cm/h)

How to estimate permeation of JP-8 How to estimate permeation of JP-8 components across the skincomponents across the skin

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0

1000

2000

3000

4000

5000

0 60 120 180 240

Time (min)

Cu

mu

lati

ve m

ass

per

are

a (n

g/c

m2)

naphthalene 1-methyl naphthalene 2-methyl naphthalene

decane undecane dodecane

Calculation of KCalculation of Kpp

Kp J

C

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Human Skin Permeability Coefficients (x 10Human Skin Permeability Coefficients (x 10-5-5))

Subject naphthalene 1-methyl naphthalene 2-methyl naphthalene decane undecane dodecane

1 16.0 1.3 5.3 0.85 0.021 0.13

2 3.4 2.8 3.1 0.86 0.036 0.15

3 3.2 3.1 3.0 0.76 0.023 0.30

4 3.7 2.7 3.2 1.2 0.025 0.20

5 5.4 2.8 2.9 0.33 0.067 0.13

6 5.7 3.3 3.0 0.80 0.048 0.15

7 4.1 3.1 3.0 0.71 0.033 0.15

8 4.1 2.9 3.1 0.56 0.041 0.13

9 3.3 3.1 3.0 0.22 0.076 0.11

10 4.2 3.5 2.8 0.20 0.083 0.12

mean 5.3 2.9 3.2 0.65 0.045 0.16

SD 3.8 0.59 0.74 0.33 0.023 0.56

minimum 3.2 1.3 2.8 0.20 0.021 0.11

maximum 16.0 3.5 5.3 1.2 0.083 0.30

rat Kp 51.0 16.0 16.0 5.5 2.5 1.4

Rat Kp from McDougal et al. (2000)

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Rat Kp from McDougal et al. (2000)

Pig Kp from Muhammad et al. (2004)

M = Kp CJP-8 A t

Mrat = 1.29 mg Mpig = 0.53 mg Mhuman = 0.13 mg

10

4

1 hr

hands ≈ 840 cm23 mg/ml

rat, pig, human

Estimation of the Internal DoseEstimation of the Internal Dose

A B

surface

skin

blood

k0

k1

k3

k2

C

surface

skin

blood

k0

k1

k3

k2

k4k5

storage

surface

viable epidermis

blood

k0

k2

k4

k3

stratum corneum

k1

surface

viable epidermis

blood

k0

k2

k4

k3

k5k6

storage

stratum corneum

k1

D

Dermatotoxicokinetic ModelsDermatotoxicokinetic Models

naphthalene

0

0.5

1

1.5

0 60 120 180 240 300

Time (min)

Con

cent

rati

on (

ng/m

l)

decane

0

2

4

6

0 60 120 180 240 300

Time (min)

Con

cent

rati

on (

ng/m

l)

1-methyl naphthalene

0

0.5

1

1.5

0 60 120 180 240 300

Time (min)

Con

cent

rati

on (

ng/m

l)

undecane

0

2

4

6

0 60 120 180 240 300

Time (min)

Con

cent

rati

on (

ng/m

l)

2-methyl naphthalene

0

0.5

1

1.5

0 60 120 180 240 300

Time (min)

Con

cent

rati

on (

ng/m

l)

dodecane

0

2

4

6

0 60 120 180 240 300

Time (min)

Con

cent

rati

on (

ng/m

l)

surface

viable epidermis

blood

k0

k2

k4

k3

k5k6

storage

stratum corneum

k1

D

?

data ( ■ ), model A (-----), model B (------), model C ( ), model D ( )

Which is the Optimal Model?Which is the Optimal Model?

U.S. Air Force StudyU.S. Air Force Study 85 fuel-cell

maintenance workers from six Air Force bases

Breathing-zone, dermal tape-strip, breath, and urine samples

Work diaries Questionnaires

Exposure Group

Job Title n Min Max Mean ± SD

All All 124 4.61 15.4 7.61 ± 2.27

Higha All 85 4.61 15.4 8.34 ± 2.23

(1) Entrant, Attendant, Runnerb 50 5.08 13.2 8.45 ± 2.01

(2) Entrant, Attendantb 22 5.08 15.4 8.31 ± 2.45

(3) Entrant, Runner 4 4.61 10.9 7.48 ± 2.99

(4) Entrantc 8 4.94 13.0 8.14 ± 2.96

Medium All 19 5.01 9.49 6.18 ± 1.35

(5) Attendant, Runner 10 5.08 8.39 6.39 ± 1.23

(6) Attendant 9 5.01 9.49 5.95 ± 1.52

Low (7) Other Field Workers 20 5.07 10.9 5.84 ± 1.34

a Significantly different from the medium- and low-exposure group (for both P < 0.0001). b Significantly different from the job titles 5, 6, and 7 (for all P < 0.0148). c Significantly different from the job titles 6 (P < 0.0286) and 7 (P < 0.0078). Chao et al. Ann Occup Hyg 49(7):639-645, 2005

Whole-body dermal exposure to naphthalene [ln(ng/mWhole-body dermal exposure to naphthalene [ln(ng/m22)])]

R2 PredictorParameterEstimate

Standard Error

P-ValueRelative

Contribution (%)

0.27(n = 83)

Interceptln(breathing-zone naphthalene)Smoking (0 = no, 1 = yes)

3.480.500.28

1.320.100.16

0.0101<0.00010.0808

88.211.8

0.318(n = 72) Intercept

ln(end-exhaled breath naphthalene)Smoking (0 = no, 1 = yes)

6.140.430.36

0.750.080.17

<0.0001<0.00010.0399

87.212.8

Dermal exposure and urinary 1-naphthol level [ln(ng/l)]Dermal exposure and urinary 1-naphthol level [ln(ng/l)]

Chao et al. Environ Health Perspect 114:182-185, 2006

R2 PredictorParameterEstimate

StandardError

P-ValueRelative

Contribution (%)

0.26(n = 83)

Interceptln(breathing-zone naphthalene)ln(dermal naphthalene)Smoking (0 = no, 1 = yes)

5.110.330.110.34

1.530.130.040.18

0.00130.01140.01190.0603

51.135.813.1

0.31(n = 72)

Interceptln(end-exhaled breath naphthalene)ln(dermal naphthalene)Smoking (0 = no, 1 = yes)

6.800.300.100.45

0.870.120.050.19

<0.00010.01280.07090.0238

52.932.314.8

Chao et al. Environ Health Perspect 114:182-185, 2006.

Dermal exposure and urinary 2-naphthol level [ln(ng/l)]Dermal exposure and urinary 2-naphthol level [ln(ng/l)]

tape-strip

personal breathing zoneend-exhaled

breath

Exposure Category

Media Low Medium High

Air (µg/m3) 1.9 29.8 867

Skin (ng/m2) 344 483 4188

Breath (µg/m3) 0.7 0.9 1.8

Average concentration of naphthalene in air, skin, and breath

Egeghy, P. P., Hauf-Cabalo, L., Gibson, R., and Rappaport, S. M. (2003). Benzene and naphthalene in air and breath as indicators of exposure to jet fuel. Occup. Environ. Med. 60, 969-76.

Chao, Y. C., Kupper, L. L., Serdar, B., Egeghy, P. P., Rappaport, S. M., and Nylander-French, L. A. (2006). Dermal Exposure to Jet Fuel JP-8 Significantly Contributes to the Production of Urinary Naphthols in Fuel-Cell Maintenance Workers. Environ Health Perspect. 114, 182-5.

Occupational Exposure to JP-8 in the US Air Occupational Exposure to JP-8 in the US Air ForceForce

Physiologically Based Toxicokinetic (PBTK ) Model for NaphthalenePhysiologically Based Toxicokinetic (PBTK ) Model for Naphthalene

fat

dermal exposure

Kpv x Aexp / PD

QF QF / PF

QO QO / PO

QEQE / PE

inhalationexposure

QL x EL

QP / PB

Kuptake

other

QP

blood

viable epidermis

stratum corneum

storage

dermal exposure

k1

k5 k6

k2 k3

k4

k0

blood

viable epidermis

stratum corneum

A BDTK PBTK

PARAMETER VALUES

• PB = 54.7• PF = 40.4• PD = 12.7• Kps = 5.210-5 cm/h• Kpv = 2.0 cm/h

CALIBRATION DATA

• Volunteer study• USAF study

Kps Kuptake DERMDOSE

Aexp CJP 8

Kim et al. Environ Health Perspect 115:894-901, 2007

Percentile Breath (µg/m3)

AUCex (µgįmin/m3)

INHAL1adj (µg/m3)

INHAL1pred (µg/m3)

Ratio (%)

10% 1.7 1.7 7.4 0.1 1

50% 4.7 41.7 18.8 0.7 4

90% 29.4 521 103 11.7 11

AUCex Area under the breath concentration-time plot for dermal exposures only.

INHAL1adj The adjusted value of the estimated air concentration of naphthalene during work (INHAL1est); a better estimate for the inhalation exposure of fuel-cell maintenance personnel who wore respirators during work inside fuel tanks.

INHAL1pred Determined by varying the air concentration of naphthalene to obtain the same value of AUCex.

Contribution of Dermal Exposure to Internal DoseContribution of Dermal Exposure to Internal Dose

Kim et al. Environ Health Perspect 115:894-901, 2007

Summary of FindingsSummary of Findings In vivo studies may be used to make reasonable predictions

of dermal absorption and penetration of JP-8 components in humans

Human permeability coefficients are 10-fold lower than estimates made in vivo; however, there is a wide range of Kp values among study volunteers

A two-compartment model of the skin best describes the toxicokinetic behavior of dermal exposure to aromatic and aliphatic components of JP-8

Dermal exposure to JP-8 contributes significantly to urinary 2-naphthol but not to 1-naphthol levels among the fuel-cell maintenance workers

Dermal exposures may contribute up to 35% of the internal dose of naphthalene

SummarySummary

IMPROVED EXPOSURE and RISK ASSESSMENT

viable epidermis

blood QL x EL

Kpv x Aexp / PD

Epidermal exposure

kuptake

stratum corneum

QE / PE QE

QF / PFstorage

QF

other

Inhalation exposure

QP

QP / PB

QO QO / PO

33