The aim of this article is to show the main aspects of quantitative structure activity relationship (QSAR) modeling for regulatory purposes. We try to answer the question; what makes QSAR models suitable for regulatory uses. The article focuses on directions in QSAR modeling in European Union (EU) and Russia. Difficulties in validation models have been discussed.
ABSTRACT:Using an oxenoid model, we investigated dependences of carcinogenic potency of the benzenes C 6 H 5 -X on a nature of substituents X. According to the model, a P450 enzyme breaks a dioxygen molecule and generates the oxens, which readily react with substrates. We suggest that a stability of the intermediate OC 6 H 6 -X with tetrahedrally coordinated C atom relative to the molecule C 6 H 5 -X determines a rate of substrate biotransformation. Using MO LCAO MNDO approach, we calculated the total energies of molecules C 6 H 6 -X and arene oxides OC 6 H 6 -X. A difference ⌬E min of these values determines activation energy of oxidation reaction. The compounds with the low ⌬E min values are noncarcinogenic. Benzene derivatives with high ⌬E min values belong to carcinogenic compounds series. The carcinogenicity of amino-and nitro-substituted benzenes is also determined by N-oxidation of amino and reduction of the nitro group. As the phenylhydroxylamines XC 6 H 4 NHOH and nitrenium ions XC 6 H 4 NH ϩ are the common metabolites of the nitro-and amino-substituted benzenes and nitrenium ions XC 6 H 4 NH ϩ are the ultimate carcinogens, we use the differences ⌬E N ϭ E(XC 6 H 4 NH ϩ ) Ϫ E(XC 6 H 4 NHOH) as the second parameter characterizing the carcinogenic activity of amino-and nitro-substituted benzenes.
Currently in the world there is no universal scientifically based criteria system aimed at assessing the dangers of waste. There are two waste classification systems adopted in Russia: SP 2.1.7.1386-03 on the degree of the impact on the environment and human health wastes are divided into 4 hazard classes; Criteria of the Ministry of Natural Resources and Environment (MNRE) of the Russian Federation on the degree of the negative impact of wastes on the environment are divided into 5 classes of danger. In the Russian practice in all areas of toxicology and health care, in justifying the MAC in the fishery waters 4 classes of dangerous substances are used. The least dangerous substances are referred to class 4 of danger, “a little dangerous.” Any chemical substance under certain conditions can have adverse effects on human health and nature. Introduction of hazard class V in Criteria MPR is contrary to the generally accepted concepts and practice of evaluation of substances. Examples of differences in the contents of two documents are given, indicating the intention of the authors of MPR Criteria to reduce the requirements for waste treatment conditions. The MNRE Criteria miss the very concept and method of the evaluation of substances that have carcinogenic properties. The SP 2.1.7.1386-03 in case of the presence in waste of substances with proven carcinogenicity for humans, assigns to the waste component the highest value of the danger index, other indices may not be considered. This approach is not proposed in MNRE Criteria. They completely ignore results of basic research, which showed the lack of the regular toxicity relationship for bioassays and mammals. MNRE criteria cannot be regarded as the only document on the determination of the waste hazard class. It is necessary to create a universal document to determine the hazard class of waste in production and consumption, ensuring safe conditions of human life and protection of the natural environment.
Cyclohexene exhibits no mutagenic effect in the Ames test. Products of its transformation (chlorination) produced a mutagenic effect in the Ames test on TA 100 strain without metabolic activation and in the micronucleus test on epithelial cells from mouse urinary bladder and colon. These findings are consistent with epidemiological data on higher incidence of urinary bladder and rectal cancers in subjects consuming chlorinated drinking water from surface water reservoirs.
The literature review has shown the problem of endocrine disrupting chemicals (EDC) to be associated with their wide distribution in the environment, the abundance, and variety of the chemical structure. Three leading mechanisms of EDCs action are identified as follows: imitation of the naturally occurring hormones action, blocking of receptors within the target cells of hormones, the impact of their kinetics in the body. Epidemiological studies indicate an increase in diseases caused by a disorder of the hormonal system. They are associated with the effect of EDCs. Substances that are completely dissimilar in chemical structure can cause the same effects. According to WHO [6], it is impossible, based on the chemical structure, to determine whether a substance is a disruptor of the endocrine system. However, some structural features determine the estrogenic, thyreogenic and glucocorticoid activity of chemicals. Hence, the need to differentiate the specific (primary) effect of a chemical substance on the endocrine system and the indirect (secondary) effect on it via other mechanisms comes to the fore. In own research, specific mechanisms were shown to be determined in the experiment when studying the complexity of effects, taking into account the processes of adaptation and decompensation, and identifying the effects manifested with the lowest doses. One of the methodological approaches can be the developed “structure-biotransformation-activity” prediction system aimed at revealing the primary types of effects: using quantum-chemical calculations and the plausible reasoning class (called the JSM-reasoning in honour of John Stuart Mill) logico-combinatorial method, it was possible to identify structural fragments of substances responsible for the manifestation of carcinogenic, allergenic effects, methemoglobin formation, etc. The results of clinical studies show the use of pharmacological drugs as models for in vivo study of the effects of EDC to allow not only studying atypical mechanisms of the impact of EDCs from the point of view of molecular genetics but also to predict the individual susceptibility to them taking into account polymorphism of candidate genes. The EDCs problem poses the need for a complex of interdisciplinary research, including three main relationships: exposure assessment-biomonitoring data-the prevalence of endocrine-dependent diseases, taking into account the qualitative and quantitative contribution of individual endocrine disrupters to the development of an ecologically dependent endocrine pathology using molecular genetic methods.
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