Ekwall, B., C. Clemedson, F. Bartle, M.C. Calleja, J. Castell, C. Chesne, R. Clothier, R. Curren, P. Dierichx, E. McFarlane-Abdulla, M. Ferro, G Fiskesjo, L. Garza-Ocanas, M.J. Gomez-Lechon, M. Gulden, B. Isomaa, J. Janus, G. Kerszman, U. Kristen, M. Kunimoto, S. Karenlampt, K. Lavrijsen, L. Lewan, T. Ohno, G. Persoone, R. Roguet, L. Romert, T. Sayer, H. Seibert, R. Shrivastava, K. Stadtlander, A. Stammati, N. Tanaka, D. Triglia, M. Valentino, E. Walum, X Wang, F. Zucco, J.D. Harvell, and H. Maibach. Comparison Between Human Skin Irritancy and In Vitro Cytotoxicity From 77 Systems for the First 12 MEIC Chemicals. In Vitro Toxicol. 1994. 7(2): 156.

aspirin - 00050-78-2; 1,1,1-trichloroethane - 00071-55-6; phenol - 00108-95-2; ferrous sulfate - 07720-78-7; digoxin - 20830-75-5; methyl alcohol - 00067-56-1; ethyl alcohol - 00064-17-5; isopropyl alcohol - 00067-63-0; acetaminophen - 00103-90-2; diazepam - 00439-14-5; amitriptyline - 00050-48-6; ethylene glycol - 00107-21-1

To evaluate the relevance for human skin irritancy of in vitro cytotoxicity, the first 12 chemicals in the MEIC program (Multicenter Evaluation of In Vitro Cytotoxicity Tests, organized by the Scand. Soc.Of Cell Toxicology) have been tested for their cutaneous irritancy in man. Results were compared with cytotoxicity of the same substances (aspirin, 1,1,1-trichloroethane, phenol, ferrous sulfate, digoxin, the methyl, ethyl and isopropyl alcohols, acetaminophen, diazepam, amitriptyline and ethylene glycol) in 77 varied in vitro cytotoxicity tests. Dose-response (24 hr/5 day accumulated) skin irritancy (17 ul Finn chambers, visual 0-4 scale) was measured i.e. the concentrations resulting in a mean score of 0.5 of the panel (median minimal skin irritancy conc. = MSIC50), 24 h, for the 12 chemicals (log M) were: -0.92, 1.0, 0.027, >0.64, >-1.9,>1.4,>1.2,>1.1,>-1.3,>-0.85, >0,56, and >1.2. Five day accumulative toxicity was similar. The 77 cytotoxicity tests gave roughly similar results among themselves, irrespective of cell type and toxicity criterion. Representative are average IC50 (median inhibitory conc.) values for the 12 human cell line systems with incub. time 24 h (log M): 2.3, -1.8, -2.2, -2.5, -5.8, 0.04, -0.27, -.98, -2.0, -3.9, -4.2, and -0.39. Thus IC50 was 1.5-3 orders of magnitude lower than MSIC50 for the first three, irritating chemicals and 1-5 orders of magnitude lower than the highest tested non-irritant conc. for remaining chemicals. In conclusion, cytotoxic concentrations did not predict measured MSIC50 well. Overprediction probably was due to 1. A comparatively low sensitivity of the human assay (17 ul dosage). 2. The conc. below the keratin barrier is lower than the tested conc., and 3. This low conc. may for most chemicals be rapidly cleared by the circulation. Hence, the (in vitro) cytotoxic concentration/exposure time was not reached in the skin for most chemicals. To predict skin irritancy, supplementary kinetic data/tests will therefore be quite necessary.