Abstract for Poster 47

 

 

Evaluation and predictions of dermal absorption of toxic chemicals

F.M. Williams*¹, S. Cage², P. Carmichael³, J. Corish⁴, I. Dick⁵, D. Fitzpatrick⁶, D. Golden⁴, Y. Jakasa⁷, S. Kenyon³, S. Kezic⁷, G. Korinth⁸, J. Kruse⁷, F. Larese⁹, W Maas¹⁰,
J. Nielsen¹¹, J. O’Connor², J.P. Payan¹², P. Sartorelli¹³, K.H. Schaller⁸,
H. van der Sandt¹⁰, S. Soyei¹, M Venier⁹, S.C. Wilkinson^14
1University of Newcastle, Newcastle, UK
²Huntingdon Life Sciences, Eye, UK
³Imperial College, London, UK
⁴Trinity College, Dublin, Ireland
⁵Health and Safety laboratories, Sheffield, UK
⁶University of Cork, Cork, UK
⁷AMC, Amsterdam, The Netherlands
⁸University of Erlangen, Erlangen, Germany
⁹Univerisity or Trieste, Trieste, Italy
¹⁰TNO, Ziest, The Netherlands
¹¹University of Odense, Odense, Denmark
¹²INRS, Nancy, France
¹³University of Sienna, Sienna, Italy
¹⁴Health Protection Agency, Newcastle, UK kollas

This project aimed to standardise in vitro systems for predicting percutaneous penetration and to compare these to parallel in vivo studies. Also it aimed to use the in vitro system to generate occupationally relevant dermal absorption data acceptable for risk assessment and to evaluate predictive models of skin penetration of health related chemicals.

The robustness of the in vitro approach was determined using a protocol developed in line with OECD Guidelines, applying caffeine, testosterone, benzoic acid and 50% butoxyethanol/water to human and rat skin. Inter-laboratory variability was less than inter-skin variability. Several further studies defined the influence of factors such as skin thickness, vehicle, and receptor fluid on diffusion parameters for these marker chemicals.

Robust in vitro finite dose data was generated for chemicals at occupationally relevant exposures. Studies included the effect of sweat on absorption of metal, effect of water on butoxyethanol dermal absorption, effect of vehicle on caffeine and pesticide absorption, dermal absorption data for an extended series of glycol ethers, natural oils, pesticides and absorption and metabolism of aromatic amines.

Parallel studies of percutaneous penetration through skin in human volunteers and rodents confirmed the predictions of the in vitro systems.. These results added to  the data base of the OECD that confirmed the use of in vitro stems. Human volunteer studies also allowed comparison of biological monitoring and microdialysis endpoints for determining absorption. Infinite dose data was generated to extend the data bases gathered by Flynn or by Cronin as the basis of predictive models and to parallel this with absorption data at doses which were relevant to actual exposure. A databank of carefully evaluated literature data was produced and is available on the web http://edetox.ncl.ac.uk. These data and those generated during the project have been used in the QSAR (Quantitative Structure Activity Relationship) and predictive models. Comparisons of Kp derived from QSAR based on infinite doses of saturated aqueous solutions with in vitro determination of absorption for finite aqueous doses and doses in occupationally relevant vehicles indicated the limitations of using the QSAR approach for predicting absorption for risk assessment A mechanistically-based mathematical model was developed during the project and this was used to interpret some of the data measured. Generation of multiple point infinite and finite dose data enabled the time courses of various variables to be simulated. The development of new models and QSAR sets and their testing through application to data measured under actual exposure conditions has resulted in considerable progress towards the development of reliable predictive tools for the estimation of the extent of dermal penetration of a chemical.

Content last modified: 18 May 2005