Abstract for Poster 25

 

 

Dermal absorption in risk assessment: the use of relative absorption versus permeation coefficient (Kp)

H.E. Buist*¹, C. de Heer¹, J.G.M. Bessems¹, T. Bouwman¹, S. Chou², H.R. Pohl², J.J.M. van de Sandt^1
1TNO Quality of Life, Zeist, Netherlands
²ATSDR, Atlanta, United States

Introduction

Dermal absorption of chemicals is often expressed as percentage of the dose coming in contact with the skin. Until now, the k_p has not been incorporated in occupational risk assessment, but is sometimes used to estimate the severity of an acute exposure to a large amount of a chemical (e.g. incidents at work). With the implementation in Europe of REACH (Registration, Evaluation, Authorisation of CHemicals), QSARs will increasingly be used to estimate dermal absorption to meet the necessary improvement in the efficiency of the assessment of thousands of substances to be evaluated. The QSARs for dermal absorption that have been developed are all designed to predict k_p-values. This raises the question in which way and for which occupational settings the k_p-value will provide a meaningful estimate for dermal absorption.

Skin absorption, Flux and k_p; Theory and Definitions

Skin absorption is a passive, concentration-driven process that can be described by Fick’s law. For description of in vitro dermal absorption often a modification of this law is applied:

J_SS = k_p * C

 

J_SS  steady state flux (after an initial lag time)

k_p   permeation or permeability constant

C   concentration of penetrant in donor fluid (concentration in receptor fluid assumed nil)

 

Fick’s law only valid for:   

      1. Homogenous membranes

      2. Concentration gradient constant in time

      3. Diffusivity independent of concentration

 

k_p:                   Flux (mg/cm²/h) / concentration (mg/cm³) at infinite dose under ideal sink conditions (steady state)

Infinite dose:  Amount of test preparation applied to the skin that achieves and maintains a maximum flux (steady state flux) of the test substance

Finite dose:     Amount of test preparation applied to the skin that is insufficient to maintain a maximum flux of the test substance

Steady-state: The part of an absorption-time profile where the flux remains constant at infinite dose conditions

Practical considerations

Vehicles or substances may substantially influence absorption

Vehicles and substances may alter the barrier function of the skin, either increasing or decreasing its permeability. Furthermore, partitioning between vehicle and stratum corneum will vary with the nature of the vehicle.

 

An example from the TNO in vitro dermal absorption database. Dose solution: 128 mg/mL; 78 μL/cm² ; Dog skin in vitro ; relative absorption = % cumulative dose in receptor fluid at 24 h.

 

Steady state flux not always linear with concentration in entire concentration range

At higher concentrations ideal sink conditions may not prevail.

 

Example: Nicotine (Zorinet al., 1999)

 

Dose volume: 200 μL/cm², except for neat nicotine (liquid): 56 μL/cm²; Exposure time: 80 minutes

Present use of dermal absorption estimators in risk assessment and its advantages and disadvantages

 

Using k_p for finite dose dermal absorption estimates

k_p-values can be used to obtain a simple estimate of the maximum amount of absorption to be expected using the following formula:

A = k_p * C * t * SA

A =   amount absorbed (mg);

k_p =   permeability constant (cm h^-1);

C =   concentration (mg cm^-3);

t =   exposure time (h);

SA =   exposed skin area (cm²)

Calculation applied to in vitro data from the TNO- and EDETOX-databases, k_p-values estimated with Potts & Guy QSAR (Potts & Guy, 1992).

 

Developments in QSARs and models for skin absorption

Various QSARs predicting k_p and absorption models are currently being developed, in which lag time is taken into account and/or infinite dose to finite dose extrapolation is incorporated. At the moment these models are not considered sufficiently founded and validated against experimental data in order to replace experimental data for risk assessment purposes. Furthermore, they often require experimental absorption data on the substance to be evaluated to derive certain input parameters through fitting.

Conclusions

Use of modelled k_p-values (derived from QSARs) may lead to both overestimation and underestimation of dermal absorption.

Underestimation may occur when:

    - sink conditions are not ideal, e.g. when the compound accumulates in the dermis, leading to a reduced flux

    - presence of skin depot, which may become systemically available, is not taken into account

    - test compound or formulations decrease skin barrier function

    - absorption of compound in vehicle has a clearly higher skin penetration than neat compound (e.g. nicotine, 2-BE)

Overestimation may be due to:

    - Test compound or formulations increase skin barrier

    - Lag-time is significant compared to exposure time

When comparing relative dermal absorption data measured in vitro to calculations on the basis of modelled k_p-values, overestimations (of actual absorption) up to ca. 1000 times the measured values were observed and underestimations up to a factor 3.

Direct use of only k_p-values to calculate dermal absorption at finite doses does not seem sufficient to produce realistic results. Therefore, new approaches need to be developed to apply QSAR-derived data in the risk assessment of chemicals under finite conditions.

Recommendations

·        Develop generic models (preferably requiring little to no experimental data) to extrapolate k_p-values to finite doses

·        Investigate whether implicit and explicit assumptions for deriving k_p-values hold true for a (large) number of model compounds

·        In a later stage, develop QSARs for vehicles other than water (e.g. liquid formulations)

References

Potts & Guy (1992). Pharm. Res. 9:663-669.

Zorin et al.(1999). Annals of Occupational Hygiene 43 (6):405-413.

 

Content last modified: 12 July 2005