A Mini Review of Mammalian Toxicity (Q)SAR Models

This paper is based on an in-depth review performed by the European Chemicals Bureau of the European Commission's Joint Research Centre in support of the development of technical guidance for the implementation of the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation, and is one of a series of minireviews in this journal. Compared with the QSAR modelling of ecotoxicity, the modelling of mammalian toxicity is more complicated. This is reflected by the relatively small number of QSAR studies on mammalian toxicity published in the literature. The main problem is related to wide variations in the accuracy of the in vivo data, in the organisms used, and also in the complexity and poor understanding of the mechanisms involved, especially for long-term effects. Nevertheless, the efforts already made to develop QSAR models for mammalian toxicity demonstrate the usefulness of the approach not only for predictive purposes but also for a better understanding of the multiple mechanisms involved in the toxicity. However, there is a need to better characterise existing models in accordance with the OECD QSAR validation principles, to develop new models, and to investigate the applicabilities of individual models in the regulatory context, such as for the purposes of the REACH legislation.

[1]  J.-M. Richard,et al.  Analyse QSAR de la toxicité d'une série pyridinique apparentée à la toxine fongique orellanine : comparaison des résultats obtenus à l'aide de paramètres physico-chimiques, stériques et quantiques , 1990 .

[2]  J. K. Seydel,et al.  QSAR and strategies in the design of bioactive compounds , 1985 .

[3]  Werner Klein,et al.  Prediction of Mammalian Toxicity by Quantitative Structure Activity Relationships: Aliphatic Amines and Anilines , 1991 .

[4]  Thomas B. Gaines,et al.  The acute toxicity of pesticides to rats , 1960 .

[5]  Andrew P Worth,et al.  Quantitative structure-activity-activity and quantitative structure-activity investigations of human and rodent toxicity. , 2006, Chemosphere.

[6]  J. Devillers.  Prediction of mammalian toxicity of organophosphorus pesticides from QSTR modeling , 2004, SAR and QSAR in environmental research.

[7]  N. Kruhlak,et al.  Estimating the safe starting dose in phase I clinical trials and no observed effect level based on QSAR modeling of the human maximum recommended daily dose. , 2004, Regulatory toxicology and pharmacology : RTP.

[8]  R L Lipnick.  Correlative and mechanistic QSAR models in toxicology. , 1999, SAR and QSAR in environmental research.

[9]  J V de Julián-Ortiz,et al.  Predictability and prediction of lowest observed adverse effect levels in a structurally heterogeneous set of chemicals , 2005, SAR and QSAR in environmental research.

[10]  L A Knauf,et al.  Assessment of effect levels of chemicals from quantitative structure-activity relationship (QSAR) models. I. Chronic lowest-observed-adverse-effect level (LOAEL). , 1995, Toxicology letters.

[11]  Nigel Greene,et al.  Computer systems for the prediction of toxicity: an update. , 2002, Advanced drug delivery reviews.

[12]  Andrew P. Worth,et al.  Review of Quantitative Structure - Activity Relationships for Acute Mammalian Toxicity , 2006 .

[13]  M T D Cronin,et al.  The importance of hydrophobicity and electrophilicity descriptors in mechanistically-based QSARs for toxicological endpoints , 2002, SAR and QSAR in environmental research.

[14]  N. Kruhlak,et al.  Assessment of the health effects of chemicals in humans: I. QSAR estimation of the maximum recommended therapeutic dose (MRTD) and no effect level (NOEL) of organic chemicals based on clinical trial data. , 2004, Current drug discovery technologies.

[15]  Robert M. Bruce,et al.  Assessment of the Oral Rat Chronic Lowest Observed Adverse Effect Level Model in TOPKAT, a QSAR Software Package for Toxicity Prediction , 2004, J. Chem. Inf. Model..

[16]  T W Schultz,et al.  Health-effects related structure-toxicity relationships: a paradigm for the first decade of the new millennium. , 2000, The Science of the total environment.

[17]  Andrew P Worth,et al.  Quantitative structure‐activity relationships for human health effects: Commonalities with other endpoints , 2003, Environmental toxicology and chemistry.

[18]  E Frantík,et al.  Relative acute neurotoxicity of solvents: isoeffective air concentrations of 48 compounds evaluated in rats and mice. , 1994, Environmental research.

[19]  Klaus L.E. Kaiser,et al.  Interspecies toxicity correlations of rat, mouse and Photobacterium phosphoreum , 1994 .

[20]  John D. Walker,et al.  Application of QSARs: Correlation of Acute Toxicity in the Rat Following Oral or Inhalation Exposure , 2004 .

[21]  Paolo Mazzatorta,et al.  Integrated Computational Methods for Prediction of the Lowest Observable Adverse Effect Level of Food‐Borne Molecules , 2007 .

[22]  T B Gaines,et al.  Acute toxicity of pesticides. , 1969, Toxicology and applied pharmacology.

[23]  Mark T. D. Cronin,et al.  QSAR in Toxicology. 2. Prediction of Acute Mammalian Toxicity and Interspecies Correlations , 1995 .

[24]  R. García-Domenech,et al.  True prediction of lowest observed adverse effect levels , 2006, Molecular Diversity.

[25]  C L Alden,et al.  Survey of the QSAR and in vitro approaches for developing non-animal methods to supersede the in vivo LD50 test. , 1990, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[26]  M. Cronin,et al.  Quantitative structure-Activity relationship (QSAR) analysis of the acute sublethal neurotoxicity of solvents. , 1996, Toxicology in vitro : an international journal published in association with BIBRA.

[27]  R A Ford,et al.  Correlation of structural class with no-observed-effect levels: a proposal for establishing a threshold of concern. , 1996, Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.

[28]  T B Gaines,et al.  Acute toxicity of pesticides in adult and weanling rats. , 1986, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[29]  J. Hermens,et al.  Classifying environmental pollutants , 1992 .

[30]  E Walum,et al.  Acute oral toxicity. , 1998, Environmental health perspectives.

[31]  J L Benoit-Guyod,et al.  A quantitative structure-activity relationship study on substituted pyridines as a contribution to the knowledge of the toxic effects of orellanine, a toxin from the mushroom Cortinarius orellanus. , 1985, Toxicon : official journal of the International Society on Toxinology.

[32]  K. Kaiser,et al.  Correlations of Vibrio fischeri bacteria test data with bioassay data for other organisms. , 1998, Environmental health perspectives.

[33]  M. Pavan,et al.  The role of the European Chemicals Bureau in promoting the regulatory use of (Q)SAR methods , 2007, SAR and QSAR in environmental research.

[34]  F. Lu,et al.  Basic Toxicology: Fundamentals, Target Organs, and Risk Assessment, 3rd ed. , 1996 .