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commercial and home and garden pesticides. polymer and paint chemicals ... Agents dissolve in and diffuse through the lipid matrix between the protein filaments ...

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Percutaneous absorption l.jpg
Percutaneous 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 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 Exposures

  • 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 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

  • Physical

    • drug concentration

    • surface area

    • exposure time

    • occlusion

    • vehicle

  • Biological

    • skin age

    • skin condition

    • anatomical site

    • skin metabolism

    • circulatory effects

  • Physicochemical

    • hydration

    • drug-skin binding

    • temperature


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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. Partitioning

2. Diffusion

3. Partitioning

4. Diffusion

5. 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 Corneum

  • 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 Corneum

  • 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 Corneum

  • 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 Corneum

  • 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 Corneum

  • 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 Corneum

  • 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



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Laboratory Human Volunteer Study Corneum

1.0 ml of jet fuel is applied at two sites

Exposure study was done inside a fume-hood to prevent inhalation exposure

Surface area of exposure is 20 cm2

Tenax® tubes were used to measure evaporation from arm


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Study Population Corneum

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

Fick’s Law of Diffusion

L1

x0, C(x0)

L2

J = -D

x1, C(x1)

Permeability Coefficient Kp (cm/h)



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Human Skin Permeability Coefficients (x 10 skin-5)

Rat Kp from McDougal et al. (2000)


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Estimation of the Internal Dose skin

hands ≈ 840 cm2

3 mg/ml

1 hr

M = Kp CJP-8 A  t

rat, pig, human

4 

Mrat = 1.29 mg

Mpig = 0.53 mg

Mhuman = 0.13 mg

10 

Rat Kp from McDougal et al. (2000)

Pig Kp from Muhammad et al. (2004)


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Dermatotoxicokinetic Models skin

A

B

C

D

surface

surface

surface

surface

k0

k0

k0

k0

stratum corneum

stratum corneum

skin

skin

k1

k1

k2

k1

k2

k1

viable epidermis

viable epidermis

blood

k3

blood

k3

k3

k2

k3

k2

k5

k4

blood

k4

blood

k4

storage

k6

k5

storage


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Which is the Optimal Model? skin

?

D

surface

k0

stratum corneum

k1

viable epidermis

k3

k2

blood

k4

k6

k5

storage

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


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U.S. Air Force Study skin

  • 85 fuel-cell maintenance workers from six Air Force bases

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

  • Work diaries

  • Questionnaires



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

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


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

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


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Occupational Exposure to JP-8 in the US Air Force skin

personal breathing zone

end-exhaled breath

Average concentration of naphthalene in air, skin, and breath

tape-strip

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.


Physiologically based toxicokinetic pbtk model for naphthalene l.jpg
Physiologically Based Toxicokinetic (PBTK ) Model for Naphthalene

DTK PBTK

  • CALIBRATION DATA

  • Volunteer study

  • USAF study

  • PARAMETER VALUES

  • PB = 54.7

  • PF = 40.4

  • PD = 12.7

  • Kps = 5.210-5 cm/h

  • Kpv = 2.0 cm/h

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


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Contribution of Dermal Exposure to Internal Dose Naphthalene

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


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Summary of Findings Naphthalene

  • 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


Summary l.jpg
Summary Naphthalene

Epidermal exposure

kuptake

stratum corneum

Kpv x Aexp / PD

viable epidermis

QE / PE

QE

QP / PB

QP

Inhalation exposure

blood

QL x EL

QF

QF / PF

storage

QO

QO / PO

other

IMPROVED EXPOSURE and RISK ASSESSMENT


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