Degradation Mechanism, Acute Toxicity And Carcinogenicity Of Organic Compounds Based On Density Functional Theory And QSAR Methods

With the development of the chemical industry, more and more new chemicals have been used in human life. According to the latest statistics of Chemical Abstracts Service (CAS), the total number of chemicals that have been found and synthesized has been more than 100 million. In the large number of chemicals, many ones are harmful to environment and human health. In order to protect human and environment, the basic method is obtaining information on their toxicity so as to regulate and use them in a reasonable way. However, according to the latest statistics, there are only 300,000 chemicals under regulatory state and the vast majority of chemicals have no toxicity information and there is a huge data gap. The traditional methods to obtain toxicity information are biological tests, but they are so time-consuming and costly that they can not meet the urgent need of testing so many chemicals, besides, they also conflict with "3R"principles for animal protection that are advocated by more and more people recent years.Thus, the QSAR (quantitative structure-activity relationship) method which is a fast and efficient computer simulation forecasting method has been accepted and used by more and more researchers.Sufficient experimental data is the basis of QSAR studies. Only on the basis, by combining computer and statistical methods, can a rational QSAR equation been built. And based on the equation, biochemistry, physical chemistry and other related knowledge were combined to find the relationships between the structures of molecular and their property and then to predict unknown property of the compound by known molecular structural features. Therefore, the object of QSAR studies should be variables with sufficient experimental data. In environment ecotoxicology field, some endpoints are commom and sufficient, such as acute toxicity, chronic toxicity, carcinogenicity, skin sensitivity and so on. In this study, the acute toxicity and carcinogenicity were studied by QSAR method.An important factor in a successful QSAR study is obtaining the accurate molecular structures and molecular descriptors, therefore reasonable geometry optimization of molecules was required. In this study, geometry optimization of all the molecular structures is based on density functional theory and at the level of MPWB1K/6-31+G(d,p). This method was tested through the study of OH-initiated degradation mechanism of methomyl in atmosphere. On this basis, the acute toxicity of organic compounds to aquatic organisms and carcinogenicity of organic compounds to rodents have been studied through QSAR methods. The main contents and results are as follows:(1) Study of OH-initiated Degradation Mechanism of Methomyl in Atmosphere based on Density Functional TheoryMethomyl is a carbamate pesticide and mainly been used as a broad-spectrum pesticide, however, it can also be toxic to animals and humans and therefore the study of the degradation mechanisms of methomyl is of important practical significance.In this study, the atmospheric degradation reactions of the two isomers of methomyl initiated by OH radical in the presence of O2, NO and H2O have been investigated. The reactants, intermediates and products were all optimized at the level of MPWBlK/6-31+G(d,p). Profiles of the potential energy surface were constructed and all possible channels involved in the reactions were discussed. Rate constants were calculated using canonical variational transition state theory (CVT) and small-curvature tunneling (SCT) over a suitable temperature range of 200-400 K based on the quantum chemical information.The study found that the reaction type of two isomers are the same, they can both initiated by OH radical through abstraction reactions or addition reactions. According to the ratio of rate constants for addition and abstraction reactions to the total rate constants of the two isomers, the variation trend with temperature of the two isomers is similar. The proportions of OH radical addition reaction and H atom abstraction reaction will changes as temperature varies. The ratio of addition reactions will raise evidently as the temperature rises, while the ratio of abstraction reactions will descend. At room temperature, abstraction reactions is more important to Z-methomyl. While for the E-methomyl, addition reactions is more important. Besides, atmospheric lifetime for the two isomers were calculated and there is no other reports been found so far.(2) QSAR Study of Carcinogenicity of Organic Compounds to Rodents based on Density Functional TheoryCancer is a major killer of human health and predictions for the carcinogenicity of chemicals are of great importance. In this article, predictive models for the carcinogenicity of organic compounds using QSAR methods for rats and mice were developed based on the data from CPDB. The models was developed based on the data of specific target site liver and classified according to sex of rats and mice. Meanwhile, models were also classified according to whether there is a ring in the molecular structure in order to reduce the diversity of molecular structure. Therefore, eight local models were developed in the final. Taking into account the complexity of carcinogenesis and in order to obtain as much information, Dragon descriptors were selected as the variables used to develop models. Models were developed by GA-MLR combining algorithm and fitting ability, robustness and predictive power of the models were assessed according to the OECD principles. The external predictive coefficients for validation sets of each model were in the range of 0.711-0.906, and for the whole data in each model were all greater than 0.8, which represents that all models have good predictivity. In order to study the mechanism of carcinogenesis, standardized regression coefficients were calculated for all predictor variables. In addition, the effect of animal sex on carcinogenesis was compared and a trend that female showed stronger tolerance for cancerogen than male in both species was appeared.(3) QSAR Study of Acute toxicity of Organic Compounds to Aquatic Organisms based on Density Functional TheoryIn this study, two typical aquatic organisms fathead minnow and daphnia magna were chosen as object of study. This two aquatic organisms are in different trophic levels. Based on molecular structures optimized by density functional theory methods, QSAR predictive models were developed and toxicity mechanism analysis were made.Acute fathead minnow toxicity is an important basis of hazard and risk assessment for compounds in the aquatic environment. In this paper, a large dataset consisting of 963 organic compounds with acute toxicity towards fathead minnow was studied with a QSAR approach. All molecular structures of compounds were optimized by the hybrid density functional theory method. Dragon molecular descriptors and logKow were selected to describe molecular information. Genetic algorithm and multiple linear regression analysis were combined to develop models. A global prediction model for compounds without known mode of action and two local models for organic compounds that exhibit narcosis toxicity and excess toxicity were developed, respectively. For all developed models, internal validations were performed by cross-validation and external validations were implemented by the setting of validation set. In addition, applicability domains of models were evaluated using a leverage method and outliers were listed and checked using toxicological knowledge.Daphnia magna belongs to the cosmopolite species because it distributed widely around the world. Besides, it is a standard toxicity test organism and therefore has sufficient experimental data. In this study,479 organic compounds with 48 hours acute toxicity data towards daphnia magna were collected from literature and other relevant experimental databases. Molecules were optimized at the MPWB1K/6-31+G(d,p) level, Dragon descriptors and logKow were selected to develop models. By using genetic algorithms and multiple linear regression, a general acute toxicity predictive model with 9 model variables were developed.In addition, according to Verhaar distinguish methods and toxicity ratio, compounds were classified by mode of action (MOA) and QSAR models were constructed subsequently, respectively. By QSAR models, toxicity mechanism of each MOA were discussed.Finally, the MOA of same chemical to fathead minnow and daphnia magna was compared. The study found that daphnia magna was more sensitive to toxicants than fathead minnow; and besides, aniline and phosphorothioate are more toxic to daphnia magna than fathead minnow.