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Percutaneous Absorption Transdermal absorptionpercutaneous ...

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 Transdermal absorptionpercutaneous ...

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  1. 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

  2. Pharmaceutical Research • Local or systemic pharmacological response using dermally applied drugs • Current research is divided • restraint (slow release technology) and • enhancement (occlusion, permeation enhancers)

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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)

  8. 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.

  9. The Putative Pathways of Penetration Across the Stratum Corneum Mukhtar, H., 1992. Pharmacology of the Skin. CRC Press, Inc., Boca Raton, FL.

  10. 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

  11. 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

  12. 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

  13. 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)

  14. 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

  15. 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

  16. Example of Human Dermal Exposure Assessment

  17. Laboratory Human Volunteer Study 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

  18. Study 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

  19. 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)

  20. Calculation of Kp

  21. Human Skin Permeability Coefficients (x 10-5) Rat Kp from McDougal et al. (2000)

  22. Estimation of the Internal Dose 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)

  23. Dermatotoxicokinetic Models 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

  24. Which is the Optimal Model? ? D surface k0 stratum corneum k1 viable epidermis k3 k2 blood k4 k6 k5 storage data ( ■ ), model A (-----), model B (------), model C ( ), model D ( )

  25. U.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

  26. Whole-body dermal exposure to naphthalene [ln(ng/m2)]

  27. Dermal exposure and urinary 1-naphthol level [ln(ng/l)] Chao et al. Environ Health Perspect 114:182-185, 2006

  28. Dermal exposure and urinary 2-naphthol level [ln(ng/l)] Chao et al. Environ Health Perspect 114:182-185, 2006.

  29. Occupational Exposure to JP-8 in the US Air Force 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.

  30. 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

  31. Contribution of Dermal Exposure to Internal Dose Kim et al. Environ Health Perspect 115:894-901, 2007

  32. Summary 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

  33. Summary 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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