In-vitro mutagenicity assays have traditionally been used for first line identification of potential genotoxic hazard, purporting to chemical carcinogenesis and heritable genetic damage. The recent advances m combinatorial chemistry and high throughput screening technologies have led to a massive explosion in numbers of possible therapeutic candidates being produced at the early stages of drug discovery. This rapid increase in the number of chemicals to be classified results in a greater need for to acquire alternative methods for the prediction of toxicity. Quantitative StructureActivity Relationships (QSAR) can till this need for early hazard identifications by elucidating the physicochemical basis of biological activity. The assumption with predictive QSARs for toxicity is that "biological activity may be described as a function of chemical constitution". This thesis focuses on the Ames mutagenicity assay data for two compound sets; one of 90 compounds, with limited structural flexibility, comprising a range of chemical classes (non-congeneric series), the second, a set of 30 flavonoid compounds. Three physicochemical descriptor sets were generated: EV A, a theoretical molecular descriptor based on the normal co-ordinate modes of vibration; WHIM, derived from weighting functions applied to the 3D-structural molecular co-ordinates; and TSAR, a series of hydrophobic, electronic and steric parameters traditionally associated with the production of biological QSARs. Various "unsupervised" data pre-treatment methods were adopted, to reduce the level of degeneracy within the individual descriptor sets, prior to the calculation of stepwise linear discriminant classification functions. Good predictive models for Ames mutagenicity, as determined by leave-one-out (jackknife) cross-validation, were obtained with each of the three physicochemical descriptor sets. An increase in the predictive ability was observed following the combination of variables from the individual descriptor sets, inferring that some unique information associated with mutagenic activity is contained within each descriptor set. The predictive stability of the models produced was assessed via independent compound predictions, with a poor overall success rate determined. This failure in external prediction was investigated and fundamental differences in physicochemical data space occupancy revealed. Conclusions on training set composition and general model applicability are made with consideration to individual model physicochemical data space coverage.

Electromagnetic fields (EMFs) have been associated with increased incidences of cancer as suggested by epidemiological studies. The in vitro sister chromatid exchange (SCE) technique, radiation-induced micronucleus assay (MN assay), COMET assay, and fluorescence in situ hybridization (FISH) were used in the present study to test the carcinogenic potentiality of extremely low frequency (ELF) EMFs on human peripheral blood lymphocytes. All experiments were performed single blind and used lymphocytes taken from 6 age-matched donors. The SCE experiments were conducted twice: round 1 (R1) and round 2 (R2), in order to determine whether or not the results obtained could be duplicated. Detailed analysis of the SCE results showed that there was a significant increase in the number of SCEs/cell in the grouped experimental conditions compared to the controls in both rounds. Similarly, in the MN assay, a significant increase of mean number of micronucleated CB cells/100 CB cells (Ma) and mean number of micronuclei/100 CB cells (Mb) was observed in the grouped experimental conditions compared to the controls. Moreover, the highest SCE frequency in R1 was 10.03 for a square continuous field, and the SCE frequency of 10.39 for a square continuous field in R2 (albeit a different strength) was the second highest in this latter round. But in the MN assay a square pulsed field with increasing EMF strength showed the greatest effect on the DNA repair system. The COMET assay also showed that both a l m T square field (continuous or pulsed) resulted in significant fragmentation of the DNA. On the other hand, a FISH analysis failed to show any translocations. In the field of EMF research, perhaps the most outstanding question that remains to be answered with certainty is how weak EMFs exert their effects at the molecular level. Various mechanisms are reviewed and evaluated in this thesis. From the results of the research performed in the current study which concentrated on testing and discovering genetic effects, a model is postulated that weak EMFs stimulate the production of free radicals which result in genetic damage. Further extensive research should be conducted to test this hypothesis.

No / In recent years, two techniques for detecting genetic damage in the whole genome have gained importance: the alkaline comet assay, to detect DNA damage such as strand breaks and alkali-labile sites, and a multicolour FISH method, spectral karyotyping (SKY), to identify chromosomal aberrations simultaneously in all metaphase chromosomes. In the present study, the induction of DNA damage in human sperm and lymphocytes in vitro has been studied employing an anticancer drug, doxorubicin (DX). An increase in DNA damage was observed with the comet assay as the median per cent head DNA of sperm significantly decreased from 82.07 and 85.14% in the untreated control groups to 63.48 and 72.52% at doses of 0.8 µM DX. At 1.6 µM the percentage declined to 60.96% (the corresponding tail moment increased from 4.42 to 12.19). In stimulated lymphocytes, a significant increase was observed in tail moment, from 0.72 and 0.53 in controls to 15.17 and 12.10 at 0.2 µM DX, continuing at the same level to a final concentration of 1.6 µM. Structural aberrations found in the parallel SKY study in stimulated lymphocytes at 0.2 µM DX consisted of 14% chromatid-type and 2% chromosome-type aberrations; none were found in controls. The SKY results correlate very well with the findings of the comet assay in lymphocytes where DNA damage was observed at similar doses. This study is the first reporting use of the comet assay and SKY analysis in parallel after chemical treatment. The potential of the two techniques together is evident, as they represent a set of assays feasible for evaluating damage in human somatic and germ cells after chemical treatment (i) by direct observation of two different end-points, detecting general DNA damage and chromosomal aberrations and (ii) by extrapolation from lymphocytes to sperm, which provides a `parallelogram¿ approach in human cells.

The choosen ethical problems connected with genetical malformations of fetus are very often discussed nowadays. This discussion is somehow connected with development of modern technologies in prenatal diagnostics. Is it ethically correct to admit termination of pregnancy if the fetus is genetically impaired. My diploma work deals with the views of parents whose children were born with malformations and also students of ZSF JCU. The main target of my work is to analyse views on prenatally diagnosed malformations of chosen group of respondents The theoretical part of ma work deals with the beginning of human life and prenatal malformations. I have noticed chosen ethical problems which are connected with prenatal malformations, prenatal diagnostics, termination of pregnancy and integration of disabled people in the society. The legal document are also mentioned. The practical part of my work deals with views of parents whose children were born with malformations and students of ZSF JCU. I apply the method of analytic research. The questionnaire survey is used. As respondent are chosen parents of disabled children and students of ZSF JCU because they can work with handicapped clients. Finally the statements are assessed and compared.