Abstract for Plenary Talk 2.2

 

 

Method Development and Modeling to Characterize Penetration, Absorption, Dose and Local Effects Resulting from Dermal Exposures

R. Guy, University of Bath, Bath, UK

Toxicity, whether local or systemic, following dermal exposure to chemicals in the workplace or the environment, is the result of the inherent activity of the substance contacting the skin and its ability to penetrate and/or permeate the barrier. Evaluating the percutaneous absorption of all potential skin contaminants is clearly impractical, and this has led to the development of predictive models – both theoretical and experimental – for the estimation of topical exposure. These developments are important per se, and are necessary to improve upon the typically conservative estimates of risk following dermal exposure in current use.

From a theoretical standpoint, the permeation of chemicals through human skin can be adequately described in most cases by a model based upon transport through the extracellular lipid domains of the stratum corneum (SC), skin’s outermost and least permeable layer. Extension of a simple solubility-diffusion model of membrane transport has produced an explicit relationship for a drug's permeability coefficient (K p) through the SC, from an aqueous solution, in terms of its molecular size and octanol-water partition coefficient (P) [1, 2]. However, the use of P pre-supposes an unsubstantiated similarity between the properties of octanol and those of the SC lipids. The analysis has therefore been developed to express molecular partitioning into the SC by a transfer free energy model which depends upon the solute's ability to donate and/or accept a hydrogen bond, and upon its molecular size [3]. As expected, K p has been deduced to be inversely dependent upon the molecule's hydrogen bonding ability. The dependence of K p upon molecular size is more complicated: while increasing size leads to lower diffusivity (and hence, a smaller K p), larger molecules have more opportunity for hydrophobic interactions with SC lipids, thereby favoring partitioning and increasing K p. Despite the mechanistic insight afforded by these interpretations, additional effort is required (a) to correctly deal with the penetration/absorption of very lipophilic compounds [4], and (b) to effectively model chemical uptake from non-aqueous “vehicles” (including particulates, such as soil).

Experimentally, a new, so-called 'dermatopharmacokinetic' (DPK) approach to assess the topical bioavailability of chemicals contacting the skin has been described (and has attracted, in particular, the attention of the U.S. Food & Drug Administration [5]). The method proposes to use tape-strip sampling of skin's outermost layer, the stratum corneum, as a surrogate for the determination of chemical levels at the target site in the skin (similar to the way in which blood levels are used for systemically-active substances). The technique has the advantage of being simply performed either in vivo in man [6-8], or ex vivo using porcine ear skin (a well-accepted model for the human barrier). While the concept has merit, implementation of the approach demands that: (1) DPK be validated as a tool with which to determine the availability of a percutaneously absorbed chemical to its site of action within the skin, and (2) the DPK protocol be sufficiently robust for the reliable evaluation and comparison of topical chemical bioavailability from different “vehicles”. To achieve these broad objectives, tape-stripping experiments are integrated with mathematical models of dermal absorption: (1) to quantify uncertainties in the DPK method, (2) to evaluate how modifications of the DPK method improve the quality of the information derived, and finally (3) to assess the suitability and limitations of the DPK method for evaluating the rate and extent of chemical delivery following diverse exposure scenarios [e.g., 9].

References

1. Potts, R.O. and Guy, R.H. (1992). Predicting Skin Permeability. Pharm. Res. 9, 663-669.

2. Guy, R.H. and Potts, R.O. (1993). Penetration of Industrial Chemicals Across the Skin. Amer. J. Ind. Med. 23, 711-719.

3. Potts, R.O. and Guy, R.H. (1995). Predicting Skin Permeability: II. The Effects of Molecular Size and Hydrogen Bond Activity. Pharm. Res.12, 1628-1633.

4. Cleek, R.L. and Bunge, A.L. (1993). A new method for estimating dermal absorption from chemical exposure. 1. General approach. Pharm Res, 10:497-506.

5. FDA (1998). Guidance for Industry: topical dermatological drug product NDAs and ANDAs-in vivo bioavilability, bioequivalence, in vitro release, and associated studies. Draft Guidance, June 1998, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER).

6. Alberti, I. , Kalia, Y., Naik, A., Bonny, J.-D. and Guy, R.H. (2001). In vivo assessment of enhanced topical delivery of terbinafine to human stratum corneum. J Controlled Release, 71:319-327.

7. Alberti, I. , Kalia, Y.N., Naik, A., Bonny, J.D. and Guy, R.H. (2001). Assessment and prediction of the cutaneous bioavailability of topical terbinafine in vivo. Pharm Res, 18:1472-1475.

8. Alberti, I. , Kalia, Y.N., Naik, A., Bonny, J.-D. and Guy, R.H. (2001). Effect of ethanol and isopropyl myristate on the availability of topical terbinafine in human stratum corneum, in vivo. Int J Pharm, 219:11-19.

9. Modeling Dermal Absorption from Soils and Powders Using Stratum Corneum Tape-Stripping In Vivo.  A.L. Bunge, G.D. Touraille, J.-P. Marty, and R.H. Guy, Chapter in Dermal Absorption Models in Toxicology and Pharmacology. Edited by J.E. Riviere, CRC Press, Boca Raton , FL , 2005 (in press).

Acknowledgements: This research has been supported by the US Food & Drug Administration and by Leo Pharmaceutical Products, Inc., Denmark . Collaboration with Professors Annette Bunge and Jonathan Hadgraft has been particularly fruitful, and the input of Christophe Herkenne, Ingo Alberti, Yogeshvar Kalia and Aarti Naik indispensable.

 

Content last modified: 3 April 2005

 

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