Acute toxicity of binary mixtures: alternative methods, QSAR and mechanisms

Correspondence address: Assoc. Prof. Miloň Tichý, DSc. National Institute of Public Health Šrobárova 48, 100 42 Praha, Czech Republic, e-mail: [email protected] Committee accepted the program of chemical safety in October 2003 called REACH, meaning “Registration, Evaluation, Authorization of Chemicals”. The protection of health of nature, including human beings, against harmful effects of chemicals is a goal of these programs. The development and research on new chemicals can become, however, cheaper than their testing and registration. The aim of effort of the present is, thus, to develop and to use alternative methods of testing toxic and adverse effects of chemicals, which would be cheaper and more informative than traditional tests with experimental animals. Term “alternative tests” is used in toxicology to mark such tests, which can be used to substitute traditional tests with experimental animals and afford at least the same information, they are quicker, must be easy, cheaper, and giving information sufficient and comparable with information given by the traditional methods, or better. A joint term “integrated” means that more methods form a set of tests often quite different in their character (eg. biological, physicochemical and models). By this way we reach the situation when toxicity of chemical are found “without mice or rats” and to “chemistry without test-tubes” – to predictive toxicology. Terms “experimental toxicology” and methods/ models in silico, determination by calculation, may look as an absurd connection. Experimetnal toxicology uses experimental animals, tissues or organs, cells, in silico methods use calculators. On the contrary in fact, they have a common goal: Methods of both types belong to alternative methods for determination of hazard of chemicals, i.e. toxic and adverse effects of chemicals. QSAR (Quantitative Structure – Activity Relationships) models are the most known and the best developed among the alternative methods in silico. These models/mathematical equations become usable even for legislative usage substituting other methods. OECD committee for validation of QSAR models has formed a set of rules for buiding such acceptable QSAR models. QSAR is acronym for Quantitative Structure – Activity Relationships, for quantitative relationships between chemical structure and magnitude of biological effects of chemicals produced by chemical industry or in laboratories. Not of chemicals of natural origin when specific mechanisms of action participate. The QSAR models express a relationship between magnitude of biological effects (BA) and changes in a molecular a structure, eg. changes of substituents, in a series of chemicals (X) by a mathematical function (f). A series may be of homogeneous, a series of derivatives of benzene of the same basic structure, or of heterogeneous nature like miscellaneous chemicals of various structure: