Ann. occup. Hyg., Vol. 47, No. 2, pp. 167-168, 2003
© 2003 British Occupational Hygiene Society
Published by Oxford University Press
Letters to the Editor |
Reply
1 University of Aberdeen; 2 Institute of Occupational Medicine, UK; 3 TNO Chemie, The Netherlands
Received 2 October 2002;
We have read with interest the comments made by Professors Kissel and Bunge concerning research to estimate the skin permeability coefficient, Kp (Sartorelli et al., 1998), which we have used to estimate solvent dermal uptake among spray painters (Semple et al., 2001).
The primary aim of our paper was to identify and model the factors influencing the deposition of paint onto the skin and clothing of a worker carrying out paint-spraying activities, and we note that this aspect of the work is unaffected by the comments of Kissel and Bunge. However, our work also modelled the mass of solvent that would pass through the skin and contribute to systemic load. To achieve this we used the regression equation derived by Sartorelli and colleagues linking permeation with various physico-chemical parameters of liquids.
Kissel and Bunge provide a detailed criticism of the methods used by Sartorelli in calculating Kp and his resultant regression equation. We accept their argument that the calculation of Kp from skin surface loading (mass per unit area), as performed by Sartorelli and colleagues, rather than concentration (mass per unit volume) produces a Kp with units different from those shown in the paper, and we acknowledge that our use of the Sartorelli et al. regression equation led to an error in our model predictions. It should, however, be noted that we did not use Sartorelli’s equation without first checking that the flux estimates it produced for xylene were in broad agreement with other published experimental results. Using the equation, the steady-state rate of flux was predicted to be 2.1 mg/cm2/h and this is broadly in line with data from Dutkiewicz and Tyras (1968), who experimentally derived the flux of pure xylene through the human forearm to be in the range of 4.5–9.6 mg/cm2/h. More recent experimental work by Kezic et al. (2001) indicates dermal flux of neat solvent to be 0.3 mg/cm2/h, placing the flux estimate we used between two experimentally derived results. We therefore believe that the flux we chose to use was not unrealistic.
We have reanalysed the data presented by Sartorelli et al. using the calculated flux through the test skin rather than the quoted permeability coefficient in an attempt to compare their database with other published information. Linear regression produced a highly significant association (adjusted R2 = 0.92) between the flux and water solubility along with the natural logarithm of the octanol–water partition coefficient. This association was dependent on an outlier (dimethoate) and excluding this point resulted in a non-significant regression. The regression equation including the outlier data is shown below.
J = 1.41 + 0.059 [water] – 0.012 ln Kow (1)
where J is the flux measured in nmol/cm2/h, [water] is the solubility of the compound in water in g/l, and Kow is the octanol–water partition coefficient
The predicted flux for xylene using this equation (6 x 10–5 mg/cm2/h) is very much lower than the value we used in our paper, i.e. 2.1 mg/cm2/h. We have also compared the magnitude of the flux through the test skin with data from in vivo and in vitro assessments of uptake flux. The flux data quoted from the in vivo experiments of Kezic et al. (2001), for a range of solvents with similar octanol–water partition coefficients and slightly higher water solubility, were ~104 times the levels predicted by the above equation. In vitro data quoted by the WHO Environmental Health Criteria for xylene (WHO, 1997) suggest the dermal flux is ~0.15 mg/cm2/h, ~2000 times higher than predicted. In vitro experiments by Wilkinson and Williams (2001) also indicate that neat m-xylene flux was 0.026 mg/cm2/h, some 400 times greater than predicted from Sartorelli’s data. We are not certain why there are such large differences between these data but feel that this is an issue that merits further investigation. Some of the apparent underestimate of flux in Sartorelli’s data may be as a result of incomplete coverage of the skin in the original experimental work as suggested by Kissel and Bunge. There are also likely to be influences from the vehicle used and the effect of occlusion/evaporation in these experiments.
We realize that the use of regression equations derived from a limited range of in vitro tests is not ideal for commercial products. For example, there are complications for paint estimation since as a drop of paint that deposits in the skin contamination layer begins to dry, the outer surface becomes progressively covered by a film of paint solids, occluding the wet paint and undoubtedly increasing the uptake through the skin initially, then preventing or reducing uptake thereafter. Similarly, the presence of a solvent in a complex mixture will affect the rate of permeation through the skin in a way that the simple experimental data does not properly reflect. However, to focus on the complications is to miss the real point: occupational hygienists urgently need practical and useful tools to help understand dermal exposure.
There is a need for a standardized and validated in vitro method for estimating skin permeation that is relevant to real-life occupational exposure and uptake scenarios. The effects of vehicle, occlusion, applied volume and concentration should be examined as part of this process and we are encouraged by recent and planned work as part of the EDETOX project presented by Professors Sartorelli and Williams at the recent NIOSH conference ‘Occupational and Environmental Exposure of Skin to Chemicals: Science and Policy’. However, it is important that the data from these experiments are presented in a way that can be reliably used by occupational hygienists and others to estimate human dermal uptake.
REFERENCES
Dutkiewicz T, Tyras H. (1968) Skin absorption of toluene, styrene and xylene by man. Br J Ind Med; 25: 243.
Kezic S, Monster A, van de Gevel I, Kruse J, Opdam J, Verberk M. (2001) Dermal absorption of neat liquid solvents on brief exposures in volunteers. Am Ind Hyg Assoc J; 62: 12–18.
Sartorelli P, Aprea C, Cenni A et al. (1998) Prediction of percutaneous absorption from physiochemical data: a model based on data of in-vitro experiments. Ann Occup Hyg; 42: 267–76.
Semple S, Brouwer D, Dick F, Cherrie JW. (2001) A dermal model for spray painters. Part II: Estimating the deposition and uptake of solvents. Ann Occup Hyg; 45: 25–33.
WHO. (1997) Xylenes. Environmental Health Criteria 190. Geneva: World Health Organization.
Wilkinson S, Williams F. (2001) In vitro dermal absorption of liquids. Contract Research Report 350/2001. UK: HSE Books.
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  P. SARTORELLI Reply Ann. Hyg., March 1, 2003; 47(2): 168 - 172. [Full Text] [PDF]
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