Molecular Diversity, 8: 331–342, 2004. KLUWER/ESCOM © 2004 Kluwer Academic Publishers. Printed in the Netherlands. 331 Full-length paper Structural invariants for the prediction of relative toxicities of polychloro dibenzo-p-dioxins and dibenzofurans J. M. Luco 1 , J. G´ alvez 2 , R. Garc´ ıa-Domenech 2∗ & J. V. de Juli´ an-Ortiz 3 1 Laboratorio de Alimentos, Facultad de Qu´ ımica, Bioqu´ ımica y Farmacia, Universidad Nacional de San Luis, Argentina; 2 Unidad de Investigaci´ on de Diseño de F´ armacos y Conectividad Molecular, Departamento de Qu´ ımica F´ ısica, Facultad de Farmacia, Universitat de Val` encia, Burjasot, Valencia, Spain; 3 Xarxa de Recerca de Malalties Tropicals, Facultat de Farm` acia, Universitat de Val` encia, Spain ( ∗ Author for correspondence, E-mail: ramon.garcia@uv.es) Received 26 November 2003; Accepted 12 January 2004 Key words: multiple linear regression, partial least squares, polychloro dibenzofurans, polychloro dibenzo-p-dioxins, topological indices Summary Multivariate models are reported that can predict the relative toxicity of compounds with severe environmental impact, namely polychloro dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs). Multiple linear regression analysis (MLR) and partial least square projections of latent variables (PLS) show the usefulness of graph-theoretical descriptors, mainly topological charge indices (TCIs), in these series. The general trends of the group are correctly reproduced and better results are presented than have previously been published. In general, the more toxic compounds exhibit more symmetric molecular structures. Introduction The prediction of toxicological properties is a topic of the utmost importance. No empirical toxicological data are available for most chemicals, mainly the new ones. In ad- dition, it is impractical to test all the elements in a set of congeneric compounds, for the identification of potentially harmful molecular structures. Some of the most toxic families of compounds, fre- quently found in the environment, are the polychloro dibenzo-p-dioxins (PCDDs) and polychloro dibenzofurans (PCDFs) [1] (Figure 1), the biological activity patterns of which are not fully understood. The best known com- pound of these series is 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and it has been identified in organisms from high trophic levels [2]. The exposure of animal cells to halogenated aromatic compounds promotes metabolizing activity. PCDDs and PCDFs induce the synthesis and activity of cytochrome P-450 and the associated monooxygenases such as eth- oxyresorufin O-deethylase (EROD) and aryl hydrocarbon hydroxylase (AHH). This results in a wide spectrum of toxic responses, including carcinogenicity, which has been established in animal experiments [2]. These polychlorodibenzo derivatives are assigned indi- vidual toxicity equivalence factor (TEF) values as defined by international convention [3]. Results of in vitro and in vivo Figure 1. Structure and numbering of PCDFs (upper) and PCDDs (lower). laboratory studies contribute to the assignment of a relative toxicity value. TEFs are estimates of the toxicity of dioxin- like compounds relative to the toxicity of TCDD, which is assigned a TEF of 1.0. All chlorinated dibenzodioxins