According to the REACH chemicals legislation, formally adopted by the EU in 2006, Quantitative Structure–Activity Relationships (QSARs) can be used as alternatives to animal testing, which itself poses specific ethical and economical concerns. A critical assessment of the performance of the QSAR models is therefore the first step toward the reliable use of such computational techniques. This article reports the performance of the skin irritation module of three commercially-available software packages: DEREK, HAZARDEXPERT and TOPKAT. Their performances were tested on the basis of data published in the literature, for 116 chemicals. The results of this study show that only TOPKAT was able to predict the irritative potential for the majority of chemicals, whereas DEREK and HAZARDEXPERT could correctly identify only a few irritant substances.
CombesR., DandreaJ. & BallsM. (2006). A critical assessment of the European Commission's proposals for the risk assessment and registration of chemical substances in the European Union. ATLA34 Suppl. 1, 29–40.
DraizeJ.H., WoodardG. & CalveryH.O. (1944). Methods for the study of irritation and toxicity of substances applied topically to the skin and mucous membranes. The Journal of Pharmacology & Experimental Therapeutics82, 377–390.
6.
BallsM., BergN., BrunerL.H., CurrenR.D., de SilvaO., EarlL.K., EsdaileD.J., FentemJ.H., LiebschM., OhnoY., PrinsenM.K., SpielmannH. & WorthA. (1999). Eye irritation testing: the way forward. ATLA27, 53–57.
CroninM.T., JaworskaJ.S., WalkerJ.D., ComberM.H., WattsC.D. & WorthA.P. (2003). Use of QSARs in international decision-making frameworks to predict health effects of chemical substances. Environmental Health Perspectives111, 1391–1401.
9.
PappinenS., Pasonen-SeppanenS., SuhonenM., TammiR. & UrttiA. (2005). Rat epidermal keratinocyte organotypic culture (ROC) as a model for chemically induced skin irritation testing. Toxicology & Applied Pharmacology208, 233–241.
10.
TornierC., RosdyM. & MaibachH.I. (2006). In vitro skin irritation testing on reconstituted human epidermis: reproducibility for 50 chemicals tested with two protocols. Toxicology in Vitro20, 401–416.
11.
BagleyD.M., GardnerJ.R., HollandG., LewisR.W., RegnierJ.F., StringerD.A. & WalkerA.P. (1996). Skin irritation: reference chemicals data bank. Toxicology in Vitro10, 1–6.
12.
KodithalaK., HopfingerA.J., ThompsonE.D. & RobinsonM.K. (2002). Prediction of skin irritation from organic chemicals using membrane-interaction QSAR analysis. Toxicological Sciences66, 336–346.
13.
BasketterD.A., YorkM., McFaddenJ.P. & RobinsonM.K. (2004). Determination of skin irritation potential in the human 4-h patch test. Contact Dermatitis51, 1–4.
OECD (2002). Guidelines for the Testing of Chemicals. No 404: Acute Dermal Irritation/Corrosion, 13pp. Paris, France: Organisation for Economic Cooperation and Development (OECD).
RobinsonM.K., McFaddenJ.P. & BasketterD.A. (2001). Validity and ethics of the human 4-h patch test as an alternative method to assess acute skin irritation potential. Contact Dermatitis45, 1–12.
18.
SandersonD.M. & EarnshawC.G. (1991). Computer prediction of possible toxic action from chemical structure; the DEREK system. Human & Experimental Toxicology10, 261–273.
19.
RidingsJ.E., BarrattM.D., CaryR., EarnshawC.G., EggingtonC.E., EllisM.K., JudsonP.N., LangowskiJ.J., MarchantC.A., PayneM.P., WatsonW.P. & YihT.D. (1996). Computer prediction of possible toxic action from chemical structure: an update on the DEREK system. Toxicology106, 267–279.
20.
SmithingM.P. & DarvasF. (1992). HazardExpert: an expert system for predicting chemical toxicity. In Food Safety Assessment (ed. FinlayJ.W., RobinsonS.F. & ArmstrongD.J.), pp. 191–200. Washington, DC, USA: American Chemical Society.
21.
EnsleinK. (1988). An overview of structure–activity relationships as an alternative to testing in animals for carcinogenicity, mutagenicity, dermal and eye irritation, and acute oral toxicity. Toxicology & Industrial Health4, 479–498.
EnsleinK., BorgstedtH.H., BlakeB.W. & HartJ.B. (1987). Prediction of rabbit skin irritation severity by structure activity relationships. In Vitro Toxicology1, 129–147.
24.
DeardenJ.C., BarrattM.D., BenigniR., BristolD.W., CombesR.D., CroninM.T.D., JudsonP.N., PayneM.P., RichardA.M., TichýM., WorthA. & YourickJ.J. (1997). The development and validation of expert systems for predicting toxicity. ATLA25, 223–252.
